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Bibliography on: Invasive Ductal Carcinoma (causes)

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 30 Mar 2020 at 01:38 Created: 

Invasive Ductal Carcinoma (causes)

Invasive ductal carcinoma (IDC), also known as infiltrating ductal carcinoma, is cancer that began growing in a milk duct and has invaded the fibrous or fatty tissue of the breast outside of the duct. IDC is the most common form of breast cancer, representing 80 percent of all breast cancer diagnoses.

The causes of invasive ductal carcinoma have not been conclusively established. Researchers have determined that cancer can form when the cells in a milk-producing duct undergo changes that cause them to grow uncontrollably, divide very rapidly or remain viable longer than they should. The result is an accumulation of excess cells that can form a mass, or tumor, and potentially spread to nearby lymph nodes and distant areas of the body. The underlying reason for those cellular changes, however, remains unclear.

By evaluating the results of extensive studies, scientists have identified certain hormonal, environmental and lifestyle factors that are believed to influence a person's breast cancer risk, such as smoking, poor nutrition and prior radiation therapy administered to the chest area. Even so, it's important to keep in mind that some individuals who have no risk factors develop cancer, while others with one or more risk factors do not. Most likely, the precise cause is a complex interaction of many factors.

In rare cases, the causes of invasive ductal carcinoma have been traced to inherited attributes, such as mutations of the: (a) Breast cancer gene 1 (BRCA1), a tumor suppressor gene, (b) Breast cancer gene 2 (BRCA2), a tumor suppressor gene, or (c) ErbB2 gene, which produces the HER2 protein that promotes cellular proliferation.

Created with PubMed® Query: ("invasive ductal carcinoma" OR IDC) and (cause OR caused OR etiology) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2020-03-26
CmpDate: 2020-03-26

Wang YF, J Han (2019)

OTOR in breast carcinoma as a potent prognostic predictor correlates with cell proliferation, migration, and invasiveness.

Biochemistry and cell biology = Biochimie et biologie cellulaire, 97(6):750-757.

Otoraplin (OTOR), recognized as an important cochlear gene, has a predicted secretory signal peptide sequence and harbors a high degree of cross-species conservation. However, its role in tumor progression is relatively unclear, especially in breast carcinoma (BC). This study investigated the clinicopathological significance of OTOR in breast infiltrating ductal carcinoma (IDC) with high metastasis to uncover its biological function in BC. OTOR was highly overexpressed in BC tissues and cells compared with normal samples. OTOR overexpression was associated with certain clinicopathological characteristics and poorer prognosis (overall survival; OS) of patients with breast IDC. As determined using CCK-8, colony formation, wound-healing, and Transwell assays, silencing OTOR using siRNA impeded BC-cell proliferation, migration, and invasiveness, which may have resulted from inactivating the mitogen-activated protein kinase - extracellular-signal-regulated kinase pathway. These results indicate that OTOR plays a crucial role in the progression of and prognosis for BC, which could help to identify future therapeutic targets for treating BC patients.

RevDate: 2020-03-19

Lee RA, Vo DT, Zurko JC, et al (2020)

Infectious Diseases Consultation Is Associated With Decreased Mortality in Enterococcal Bloodstream Infections.

Open forum infectious diseases, 7(3):ofaa064 pii:ofaa064.

Background: Enterococcus species frequently cause health care-associated bacteremia, with high attributable mortality. The benefit of consultation with infectious disease (ID) specialists has been previously illustrated with Staphylococcus aureus bacteremia. Whether ID consultation (IDC) improves mortality in enterococcal bacteremia is unknown.

Methods: This is a retrospective cohort single-center study from January 1, 2015, to June 30, 2016, that included all patients >18 years of age admitted with a first episode of Enterococcus bacteremia. Patients were excluded if death or transfer to palliative care occurred within 2 days of positive blood culture.

Results: Two hundred five patients were included in the study, of whom 64% received IDC. Participants who received IDC were more likely to undergo repeat cultures to ensure clearance (99% vs 74%; P < .001), echocardiography (79% vs 45%; P < .001), surgical intervention (20% vs 7%; P = 0.01), and have appropriate antibiotic duration (90% vs 46%; P < .001). Thirty-day mortality was significantly higher in the no-IDC group (27 % vs 12 %; P < .007). In multivariate analysis, 30-day in-hospital mortality was associated with both E. faecium bacteremia (adjusted odds ratio [aOR], 2.39; 95% confidence interval [CI], 1.09-5.23) and IDC (aOR, 0.35; 95% CI, 0.16-0.76).

Conclusions: Patients who received IDC for Enterococcus bacteremia had significantly lower 30-day mortality. Further prospective studies are necessary to determine if these outcomes can be validated in other institutions for patients who receive IDC with Enterococcus bacteremia.

RevDate: 2020-03-18
CmpDate: 2020-03-18

Zhou J, Tan H, Bai Y, et al (2019)

Evaluating the HER-2 status of breast cancer using mammography radiomics features.

European journal of radiology, 121:108718.

PURPOSE: The aim of our study was to evaluate the HER-2 status in breast cancer patients using mammography (MG) radiomics features.

METHODS: A total of 306 Chinese female patients with invasive ductal carcinoma of no special type (IDC-NST) enrolled from January 2013 to July 2018 were divided into a training set (n = 244) and a testing set (n = 62). One hundred and eighty-six radiomics features were extracted from digital MG images based on the training set. The least absolute shrinkage and selection operator (LASSO) method was used to select the optimal predictive features for HER-2 status from the training set. Both support vector machine (SVM) and logistic regression models were employed based on the selected features. The area under the receiver operating characteristic (ROC) curves (AUCs) of the training set and testing set were used to evaluate the predictive performance of the models.

RESULTS: Compared with the SVM model, the performance of the logistic regression model using a combination of cranial caudal (CC) and mediolateral oblique (MLO) MG views was optimal. In the training set, the sensitivity, specificity, accuracy and area under the curve (AUC) values of the logistic regression model for evaluating HER-2 status based on quantitative radiomics features were 87.29%, 58.73%, 80.00% and 0.846 (95% confidence interval (CI), 0.800-0.887), respectively, and in the testing set, the values were 73.91%, 68.75%, 77.00% and 0.787 (95% CI, 0.673-0.885), respectively.

CONCLUSIONS: Radiomics features could be an efficient tool for the preoperative evaluation of HER-2 status in patients with breast cancer.

RevDate: 2020-03-17

Arispe Angulo KR, Jawa Z, Visotcky A, et al (2019)

A high mitotic score in breast cancer after neoadjuvant chemotherapy is predictive of outcome and associated with a distinct morphology.

Histopathology [Epub ahead of print].

AIMS: Neoadjuvant chemotherapy (NAC) is frequently used for the treatment of breast cancer. We sought to analyse the clinical, morphological and immunohistochemical features of tumours from patients who did not achieve pathological complete response following NAC.

METHODS AND RESULTS: We identified stage I-III post-NAC breast cancers from surgical resections (2000-2016) with evaluable residual invasive carcinoma [ypT1a(m) or greater and ≥15% tumour cellularity]. One hundred and forty-three tumours from 142 patients were included. On univariable analysis, a high (score 3) post-NAC mitotic score (as compared with 1 or 2) was significantly associated with invasive ductal carcinoma (IDC) subtype (P = 0.023), high grade, pushing borders with zones of necrosis, hormone receptor and triple-negative status, lack of hormonal therapy, higher cellularity (P < 0.001), and a higher percentage of tumour-infiltrating lymphocytes (P = 0.016). Multivariable analysis showed a high post-NAC mitotic score to be significantly associated with recurrence, distant metastasis, and shortened survival (hazard ratios of 5.73, 4.49, and 3.68, respectively). High post-NAC mitotic score tumours (n = 32) were IDC and had a high Ki67 proliferation index (median, 55%). Of these, 24 (75%) had pushing borders with zones of necrosis; 19 (79.2%) of these had necrosis on preoperative imaging, and 24 (75%), 15 (46.9%) and four (12.5%) lacked androgen receptor, GATA-3 and cytokeratin 18 expression, respectively.

CONCLUSIONS: High post-NAC mitotic score breast cancers cause high morbidity and mortality, frequently have pushing borders and zones of necrosis, and may show loss of common 'breast cancer markers'. Our findings support that necrosis in pretreatment studies and post-NAC mitotic score should be routinely reported, as they offer significant additional prognostic information to guide management.

RevDate: 2020-03-13
CmpDate: 2020-03-13

Roth JD, Pariser JJ, Stoffel JT, et al (2019)

Patient subjective assessment of urinary tract infection frequency and severity is associated with bladder management method in spinal cord injury.

Spinal cord, 57(8):700-707.

STUDY DESIGN: The Neurogenic Bladder Research Group (NBRG) registry is a multicenter prospective observational study. This manuscript is retrospective based on a cross-sectional survey.

OBJECTIVES: To assess patient subjective assessment of urinary tract infection (UTI) frequency and severity are associated with the degree of use of catheters or incontinence products.

SETTING: Multiple hospitals across the United States.

METHODS: Eligibility included: age > 18 years and acquired SCI. Over 1.5 years, 1479 eligible participants were enrolled. We excluded those with surgical reconstruction or diversion of the bladder. In total, 1282 participants were grouped by bladder management: (1) indwelling catheter (IDC), (2) clean intermittent catheterization (CIC), (3) external devices (pads/condom), and (4) volitional voiding (Void). UTI frequency was classified as 0, 1-3, 4-6, or > 6 over the prior year. UTI severity was determined by hospitalization for UTI in the prior year. Multivariate regression compared these factors across groups.

RESULTS: UTIs were least frequent in Void followed by pads/condom, CIC, and IDC (all p ≤ 0.001). UTI severity followed a similar pattern. Controlling for covariates, the adjusted odds of UTI frequency (Void = reference) were 2.28 (1.38-3.76) for pads/condom, 3.42 (2.25-5.18) for CIC, and 4.3 (2.59-6.70) for IDC (all p ≤ 0.001).

CONCLUSIONS: Patient subjective assessment of UTI frequency is highest with IDC, followed by CIC, pads/condom, and lowest with spontaneous voiding. The odds of hospitalization for UTI were three times higher for IDC than spontaneous voiding. UTI risk should be considered when counseling patients about bladder management options. These associations do not imply causation but warrant further investigation in a prospective manner.

SPONSORSHIP: Patient-Centered Outcomes Research Institute (PCORI) Award (CER14092138).

RevDate: 2020-03-12

Guo T, Chen Z, Xu J, et al (2020)

Change of Pathological Type to Metaplastic Squamous Cell Carcinoma of the Breast During Disease Recurrence: Case Report and Literature Review.

Frontiers in oncology, 10:32.

Background: Metaplastic squamous cell carcinoma (SCC) of the breast is a rare and heterogeneous group of primary breast malignancies. The etiology, pathogenesis, and proper treatment for this kind rare breast cancer are still unclear. Case presentation: We reported a case of a 55-year-old woman with a palpable lump in the inner quadrant of the right breast. She underwent a right breast mass resection and sentinel lymph node biopsy, which revealed that the tumor was an invasive ductal carcinoma, followed by four cycles of doxorubicin plus cyclophosphamide and four cycles of docetaxel as adjuvant chemotherapy, and then simultaneous integrated boost intensity modulated radiotherapy to the whole right breast. After 2 years' follow-up, she had biopsy-proven disease recurrence in the right breast, which revealed SCC, and a mammogram showed abnormalities in the lower inner quadrant of the right breast and left axillary lymph nodes. Then we performed bilateral breast modified radical mastectomy, which confirmed that the recurrent tumors were metaplastic SCC, followed by adjuvant chemotherapy and adjuvant radiotherapy of the left supraclavicular and apical axillary regions. There has been no recurrent or metastatic evidence in the 16 months' follow-up since the second surgery. Conclusion: This case report shows that evolution of pathology type in recurrent breast cancer after initial treatment is possible. Detailed pathologic and immunohistochemical analyses are needed for identification of this change. Surgery and adjuvant radiation and chemotherapy are appropriate treatments for recurrent primary SCC of the breast.

RevDate: 2020-03-11

Egawa C, Yanai A, Yanagawa T, et al (2019)

[Long-Term Survival in a Case of Breast Cancer with Brain Metastases and No Other Distant Metastases Treated by Surgical Removal and Gamma Knife Radiosurgery].

Gan to kagaku ryoho. Cancer & chemotherapy, 46(13):2063-2065.

A 44-year-oldwoman was diagnosedwith right breast cancer andund erwent mastectomy andaxillary lymph node dissection in February 2006. She was pathologically diagnosed with invasive ductal carcinoma without lymph node metastasis. Immunohistochemical examination showedthat the tumor was estrogen receptor positive, progesterone receptor negative, andhada HER2 status score of 0. She received 4 cycles of AC, followedby leuprorelin andtamoxifen. Several metastases were identified in the right supraclavicular lymph nodes in August 2008 during the endocrine therapy. Then, she received S-1 as the first-line chemotherapy. Although metastases showed complete response, she developed an eye disorder caused by S-1 and thus the treatment agent was changedto leuprorelin andanastrozole. She complainedof headache andright homonymous hemianopsia in November 2013. MRI showeda 42mm diameter tumor in the left occipital lobe, suspectedto be brain metastasis from breast cancer. Craniotomy was performedto remove the brain tumor, which was pathologically diagnosedas metastasis from breast cancer. In the brain tumor, the estrogen receptor status hadchangedto negative, but the HER2 status remained unchanged, showing a score of 0. Vinorelbine was administered after the brain surgery. Unfortunately, brain metastasis was foundin the dura mater near the surgical cavity, andgamma knife radiosurgery was performedin January 2014. Thereafter, brain metastases were repeatedly found, and gamma knife radiosurgery was again performed in January 2015, September 2016, and February 2017. In addition, a large tumor appearedin the left occipital lobe andwas surgically removed in June 2016. No other distant metastases were found, andvinorelbine was continueduntil February 2018. Because the patient developed dyslexia caused by gamma knife-induced radiation necrosis, bevacizumab was administered between November 2018 and April 2019. MRI showed that the edema due to radiation necrosis reduced and dyslexia symptoms improved. As of now, she has survivedfor 5 years and 6 months after the diagnosis of brain metastases.

RevDate: 2020-03-12
CmpDate: 2020-03-12

Nasir A, Lehrke HD, Mounajjed T, et al (2019)

Albumin In Situ Hybridization Can Be Positive in Adenocarcinomas and Other Tumors From Diverse Sites.

American journal of clinical pathology, 152(2):190-199.

OBJECTIVES: Albumin messenger RNA (mRNA) expression is a marker of hepatocellular differentiation. Most published data are from review of tissue microarrays, and albumin in situ hybridization (ISH) expression across several tumor types is incompletely characterized.

METHODS: Sections from 221 tumors were evaluated for albumin mRNA. Immunohistochemistry was used to confirm diagnoses. Albumin ISH was performed according to manufacturer-provided instructions. Fifty-nine cases were evaluated with both commercial ISH assays.

RESULTS: Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Lung (20%), gallbladder (39%), hepatoid pancreatic (n = 1 of 1) adenocarcinoma, breast invasive ductal carcinoma (18%), yolk sac tumor (25%), and acinar cell carcinoma (29%) showed expression. Both assays were concordant in 93% of cases.

CONCLUSIONS: Albumin ISH was expressed in all HCCs studied. It was also positive in intrahepatic cholangiocarcinoma and patchy positive in gallbladder adenocarcinoma and a subset of other neoplasms, which can be a potential pitfall.

RevDate: 2020-03-06

Sun T, Yang W, Toprani SM, et al (2020)

Induction of immunogenic cell death in radiation-resistant breast cancer stem cells by repurposing anti-alcoholism drug disulfiram.

Cell communication and signaling : CCS, 18(1):36 pii:10.1186/s12964-019-0507-3.

BACKGROUND: The current successful clinical use of agents promoting robust anti-tumor immunity in cancer patients warrants noting that radiation therapy (RT) induces immunogenic cell death (ICD) of tumor cells, which can generate anti-tumor immune responses. However, breast cancer stem cells (BCSCs) are resistant to RT and RT alone usually failed to mount an anti-tumor immune response.

METHODS: High aldehyde dehydrogenase activity (ALDH)bright and CD44+/CD24-/ESA+ cancer cells, previously shown to have BCSC properties, were isolated from human MDA-MB-231 and UACC-812 breast cancer cell lines by flow cytometer. Flow sorted BCSCs and non-BCSCs were further tested for their characteristic of stemness by mammosphere formation assay. Induction of ICD in BCSCs vs. non-BCSCs in response to different in vitro treatments was determined by assessing cell apoptosis and a panel of damage-associated molecular pattern molecules (DAMPs) by flow and enzyme-linked immunosorbent assay (ELISA).

RESULTS: We found that ionizing radiation (IR) triggered a lower level of ICD in BCSCs than non-BCSCs. We then investigated the ability of disulfiram/cooper (DSF/Cu) which is known to preferentially induce cancer stem cells (CSCs) apoptosis to enhance IR-induced ICD of BCSCs. The results indicate that DSF/Cu induced a similar extent of IDC in both BCSCs and non-BCSCs and rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. IR and DSF/Cu induced ICD of BCSCs could be partly reversed by pre-treatment of BCSCs with a reactive oxygen species (ROS) scavenger and XBP1s inhibitors.

CONCLUSION: DSF/Cu rendered IR-resistant BCSCs as sensitive as non-BCSCs to IR-induced ICD. Our data demonstrate the potential of IR and DSF/Cu to induce ICD in BCSCs and non-BCSCs leading to robust immune responses against not only differentiated/differentiating breast cancer cells but also BCSCs, the root cause of cancer formation, progression and metastasis.

RevDate: 2020-03-04
CmpDate: 2020-03-04

Jakharia-Shah A, Wheatley H, M Beesley (2019)

Reminder of an important clinical lesson: breast cancer metastasis to the parotid gland.

BMJ case reports, 12(10): pii:12/10/e226494.

A 59-year-old woman presented to an otolaryngology clinic with an 8-week history of a painless lump over her left parotid gland. Her medical history included an invasive ductal carcinoma (33 mm) and a ductal carcinoma in situ (70 mm) of the right breast, for which she had a mastectomy and various adjuvant therapies. The primary tumour presented 8 years prior to the metachronous metastasis. This patient was a non-smoker and had no significant family history. Post-superficial parotidectomy pathology revealed the parotid gland tumour to be oestrogen receptor-positive and HER2 receptor-positive, thus ruling out the initial differential diagnosis of a pleomorphic adenoma. A consequential total parotidectomy with a posterolateral neck dissection was performed with sparing of the facial nerve. The patient recovered well having only encountered a self-resolving salivary fistula. She portrayed no signs of facial nerve palsy and subsequent imaging scans showed no abnormalities.

RevDate: 2020-03-04
CmpDate: 2020-03-04

Sokol ES, Feng YX, Jin DX, et al (2019)

Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer.

Annals of oncology : official journal of the European Society for Medical Oncology, 30(1):115-123.

Background: Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed.

Patients and methods: Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes.

Results: Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays. Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; P < 0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%).

Conclusions: This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors.

RevDate: 2020-03-03
CmpDate: 2020-03-03

Walzer KA, Fradin H, Emerson LY, et al (2019)

Latent transcriptional variations of individual Plasmodium falciparum uncovered by single-cell RNA-seq and fluorescence imaging.

PLoS genetics, 15(12):e1008506.

Malaria parasites follow a complex life cycle that consists of multiple stages that span from the human host to the mosquito vector. Among the species causing malaria, Plasmodium falciparum is the most lethal, with clinical symptoms manifesting during the intraerythrocytic developmental cycle (IDC). During the IDC, P. falciparum progresses through a synchronous and continuous cascade of transcriptional programming previously established using population analyses. While individual parasites are known to exhibit transcriptional variations to evade the host immune system or commit to a sexual fate, such rare expression heterogeneity is largely undetectable on a population level. Therefore, we combined single-cell RNA-sequencing (scRNA-seq) on a microfluidic platform and fluorescence imaging to delineate the transcriptional variations among individual parasites during late asexual and sexual stages. The comparison between asexual and sexual parasites uncovered a set of previously undefined sex-specific genes. Asexual parasites were segregated into three distinct clusters based on the differential expression of genes encoding SERAs, rhoptry proteins, and EXP2 plus transporters. Multiple pseudotime analyses revealed that these stage-specific transitions are distinct. RNA fluorescent in situ hybridization of cluster-specific genes validated distinct stage-specific expression and transitions during the IDC and defined the highly variable transcriptional pattern of EXP2. Additionally, these analyses indicated huge variations in the stage-specific transcript levels among parasites. Overall, scRNA-seq and RNA-FISH of P. falciparum revealed distinct stage transitions and unexpected degrees of heterogeneity with potential impact on transcriptional regulation during the IDC and adaptive responses to the host.

RevDate: 2020-03-03
CmpDate: 2020-03-03

Santos Junior OR, da Costa Rocha MO, Rodrigues de Almeida F, et al (2019)

Speckle tracking echocardiographic deformation indices in Chagas and idiopathic dilated cardiomyopathy: Incremental prognostic value of longitudinal strain.

PloS one, 14(8):e0221028.

BACKGROUND: Chagas cardiomyopathy (CDC) is associated with a poor prognosis compared to other cardiomyopathies. Speckle tracking echocardiography (STE), which provides direct assessment of myocardial fiber deformation, may be useful in predicting prognosis.

OBJECTIVE: This study assessed STE in CDC and compared with idiopathic cardiomyopathy (IDC), and also examined the incremental prognostic information of STE over left ventricular ejection fraction (LVEF) in these patients.

METHODS: We enrolled 112 patients, age of 56.7 ± 11.8 years, 81 with CDC and 31 with IDC. STE indices were obtained at baseline in all patients. The endpoint was a composite of death, hospitalization for heart failure, or need for heart transplantation.

RESULTS: Patients with IDC had worse LV systolic function compared to CDC, with LVEF of 34.5% vs 41.3%, p = 0.004, respectively. After adjustment for LVEF, there were no differences in STE values between CDC and IDC. During a median follow-up of 18.2 months (range, 11 to 22), 26 patients met the composite end point (24%). LV longitudinal strain was a strong predictor of adverse events, incremental to LVEF and E/e' ratio (HR 1.463, 95% CI 1.130-1.894; p = 0.004). The risk of cardiac events increased significantly in patients with GLS > - 12% (log-rank p = 0.035).

CONCLUSIONS: STE indices were abnormal in patients with dilated cardiomyopathy, without differences between CDC and IDC. LV longitudinal strain was a powerful predictor of outcome, adding prognostic information beyond that provided by LVEF and E/e' ratio.

RevDate: 2020-02-27
CmpDate: 2020-02-27

Lee JY, Schizas M, Geyer FC, et al (2019)

Lobular Carcinomas In Situ Display Intralesion Genetic Heterogeneity and Clonal Evolution in the Progression to Invasive Lobular Carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research, 25(2):674-686.

PURPOSE: Lobular carcinoma in situ (LCIS) is a preinvasive lesion of the breast. We sought to define its genomic landscape, whether intralesion genetic heterogeneity is present in LCIS, and the clonal relatedness between LCIS and invasive breast cancers.Experimental Design: We reanalyzed whole-exome sequencing (WES) data and performed a targeted amplicon sequencing validation of mutations identified in 43 LCIS and 27 synchronous more clinically advanced lesions from 24 patients [9 ductal carcinomas in situ (DCIS), 13 invasive lobular carcinomas (ILC), and 5 invasive ductal carcinomas (IDC)]. Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic trees were defined using validated computational methods.

RESULTS: WES of 43 LCIS lesions revealed a genomic profile similar to that previously reported for ILCs, with CDH1 mutations present in 81% of the lesions. Forty-two percent (18/43) of LCIS were found to be clonally related to synchronous DCIS and/or ILCs, with clonal evolutionary patterns indicative of clonal selection and/or parallel/branched progression. Intralesion genetic heterogeneity was higher among LCIS clonally related to DCIS/ILC than in those nonclonally related to DCIS/ILC. A shift from aging to APOBEC-related mutational processes was observed in the progression from LCIS to DCIS and/or ILC in a subset of cases.

CONCLUSIONS: Our findings support the contention that LCIS has a repertoire of somatic genetic alterations similar to that of ILCs, and likely constitutes a nonobligate precursor of breast cancer. Intralesion genetic heterogeneity is observed in LCIS and should be considered in studies aiming to develop biomarkers of progression from LCIS to more advanced lesions.

RevDate: 2020-02-26
CmpDate: 2020-02-26

McQuerry JA, Jenkins DF, Yost SE, et al (2019)

Pathway activity profiling of growth factor receptor network and stemness pathways differentiates metaplastic breast cancer histological subtypes.

BMC cancer, 19(1):881.

BACKGROUND: Gene expression profiling of rare cancers has proven challenging due to limited access to patient materials and requirement of intact, non-degraded RNA for next-generation sequencing. We customized a gene expression panel compatible with degraded RNA from formalin-fixed, paraffin-embedded (FFPE) patient cancer samples and investigated its utility in pathway activity profiling in patients with metaplastic breast cancer (MpBC).

METHODS: Activity of various biological pathways was profiled in samples from nineteen patients with MpBC and 8 patients with invasive ductal carcinoma with triple negative breast cancer (TNBC) phenotype using a custom gene expression-based assay of 345 genes.

RESULTS: MpBC samples of mesenchymal (chondroid and/or osteoid) histology demonstrated increased SNAI1 and BCL2L11 pathway activity compared to samples with non-mesenchymal histology. Additionally, late cornified envelope and keratinization genes were downregulated in MpBC compared to TNBC, and epithelial-to-mesenchymal transition (EMT) and collagen genes were upregulated in MpBC. Patients with high activity of an invasiveness gene expression signature, as well as high expression of the mesenchymal marker and extracellular matrix glycoprotein gene SPARC, experienced worse outcomes than those with low invasiveness activity and low SPARC expression.

CONCLUSIONS: This study demonstrates the utility of gene expression profiling of metaplastic breast cancer FFPE samples with a custom counts-based assay. Gene expression patterns identified by this assay suggest that, although often histologically triple negative, patients with MpBC have distinct pathway activation compared to patients with invasive ductal TNBC. Incorporation of targeted therapies may lead to improved outcome for MpBC patients, especially in those patients expressing increased activity of invasiveness pathways.

RevDate: 2020-02-26
CmpDate: 2020-02-26

Downes MR, Xu B, TH van der Kwast (2019)

Gleason grade patterns in nodal metastasis and corresponding prostatectomy specimens: impact on patient outcome.

Histopathology, 75(5):715-722.

AIMS: Lymph node metastases at the time of prostatectomy are an infrequent finding. The correlation of the pattern of nodal metastases with patient outcome has yet to be explored.

METHODS AND RESULTS: Lymph node-positive prostatectomies were retrospectively reviewed. The presence of cribriform carcinoma (CC), intraductal carcinoma (IDC) and ISUP grade (G) were documented. The largest nodal metastasis was assessed for the morphological patterns present. G was assigned to the metastasis based on percentage morphological patterns present. Statistical analysis used spss to assess disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS). One hundred and ten cases were identified: G5 (n = 52), G4 (n = 8), G3 (n = 34), G2 (n = 10) and no G (n = 6; treatment effect). IDC or CC was present in 103 (94%) specimens. More than one positive node correlated with worse DFS [P = 0.012, hazard ratio (HR) = 1.951, 95% confidence interval (CI) = 1.142-3.331] and DMFS (P = 0.009, HR = 2.647, 95% CI = 1.239-5.651). G in the prostate and nodal metastasis were poorly correlated (kappa = 0.073, P = 0.195). The presence of pattern 5 was seen in 33 nodes (30%) and correlated with DFS (P = 0.020, HR = 1.903, 95% CI = 1.091-3.320), DSS (P = 0.021, HR = 5.937, 95% CI = 1.084-32.533) and DMFS (P = 0.007, HR = 2.695, 95% CI = 1.269-5.726). Nodal cribriform pattern showed no prognostic correlation and pattern 3 metastasis showed a significant trend towards better outcome (DMFS P = 0.033, HR = 0.431, 95% CI = 0.194-0.958).

CONCLUSIONS: IDC or CC is identified in 94% of node-positive prostate cancers. Although G in the largest nodal metastasis has prognostic significance, its G does not reflect that of the primary prostatic adenocarcinoma.

RevDate: 2020-02-25
CmpDate: 2020-02-25

Shimmura H, Kuramochi H, Jibiki N, et al (2019)

Dramatic response of FOLFIRINOX regimen in a collision pancreatic adenocarcinoma patient with a germline BRCA2 mutation: a case report.

Japanese journal of clinical oncology, 49(11):1049-1054.

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history-her mother died of pancreatic adenocarcinoma at age 48-we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

RevDate: 2020-02-25
CmpDate: 2020-02-25

D'Iorio A, Maggi G, Vitale C, et al (2019)

Prospective memory in Parkinson's disease: the role of the motor subtypes.

Journal of neurology, 266(10):2505-2511.

BACKGROUND: Prospective memory (PM) is defined as memory for future intentions and it is typically divided into time-based and event-based PM. Deficit of PM has been reported in patients with Parkinson's disease (PD) but no study has yet explored the association between motor subtypes (tremor dominant and rigidity/bradykinesia dominant) and performance on PM tasks. The aim of the study was to explore the role of motor subtypes in the defect of PM.

METHODS: Consecutive outpatients with tremor dominant (TD-PD) or rigidity/bradykinesia dominant (PIGD-PD) PD and healthy subjects (HCs) were enrolled and underwent a neuropsychological battery assessing PM, verbal memory and executive functions and questionnaires assessing apathy, functional autonomy, and perceived memory disturbances.

RESULTS: We enrolled 28 patients with TD-PD, 28 patients with PIGD-PD and 50 HCs. The three groups did not differ on demographic and cognitive variables. Patients with TD-PD performed worse on time-based PM tasks than patients with PIGD-PD and HCs; no significant difference was found among the three groups on event-based PM tasks. Executive dysfunctions contributed to reduced time-based PM scores in TD-PD. Moreover, severe deficit of time-based and more frequency of perceived failures of PM contributed to reduced functional autonomy in TD-PD.

CONCLUSION: The finding of a poorer performance of patients with TD-PD than ones with PIGD-PD and HCs suggests a selective deficit of time-based PM abilities in TD-PD group; therefore, deficit of time-based PM might be considered as a distinctive non-motor symptom of TD-PD and it might affect the functional autonomy in this subtype of PD.

RevDate: 2020-02-19
CmpDate: 2020-02-19

Quagliarini F, Mir AA, Balazs K, et al (2019)

Cistromic Reprogramming of the Diurnal Glucocorticoid Hormone Response by High-Fat Diet.

Molecular cell, 76(4):531-545.e5.

The glucocorticoid receptor (GR) is a potent metabolic regulator and a major drug target. While GR is known to play integral roles in circadian biology, its rhythmic genomic actions have never been characterized. Here we mapped GR's chromatin occupancy in mouse livers throughout the day and night cycle. We show how GR partitions metabolic processes by time-dependent target gene regulation and controls circulating glucose and triglycerides differentially during feeding and fasting. Highlighting the dominant role GR plays in synchronizing circadian amplitudes, we find that the majority of oscillating genes are bound by and depend on GR. This rhythmic pattern is altered by high-fat diet in a ligand-independent manner. We find that the remodeling of oscillatory gene expression and postprandial GR binding results from a concomitant increase of STAT5 co-occupancy in obese mice. Altogether, our findings highlight GR's fundamental role in the rhythmic orchestration of hepatic metabolism.

RevDate: 2020-02-19
CmpDate: 2020-02-19

Xu Q, Rangaswamy US, Wang W, et al (2020)

Evaluation of Newcastle disease virus mediated dendritic cell activation and cross-priming tumor-specific immune responses ex vivo.

International journal of cancer, 146(2):531-541.

We have developed an oncolytic Newcastle disease virus (NDV) that has potent in vitro and in vivo anti-tumor activities and attenuated pathogenicity in chickens. In this ex vivo study using the same recombinant NDV backbone with GFP transgene (NDV-GFP, designated as rNDV), we found that rNDV induces maturation of monocyte-derived immature dendritic cells (iDCs) by both direct and indirect mechanisms, which promote development of antigen-specific T cell responses. Addition of rNDV directly to iDCs culture induced DC maturation, as demonstrated by the increased expression of costimulatory and antigen-presenting molecules as well as the production of type I interferons (IFNs). rNDV infection of the HER-2 positive human breast cancer cell line (SKBR3) resulted in apoptotic cell death, release of proinflammatory cytokines, and danger-associated molecular pattern molecules (DAMPs) including high-mobility group protein B1 (HMGB1) and heat shock protein 70 (HSP70). Addition of rNDV-infected SKBR3 cells to iDC culture resulted in greatly enhanced upregulation of the maturation markers and release of type I IFNs by DCs than rNDV-infected DCs only. When co-cultured with autologous T cells, DCs pre-treated with rNDV-infected SKBR3 cells cross-primed T cells in an antigen-specific manner. Altogether, our data strongly support the potential of oncolytic NDV as efficient therapeutic agent for cancer treatment.

RevDate: 2020-02-18
CmpDate: 2020-02-18

Chen WR, Deng JP, Wang J, et al (2019)

Impact of 21-Gene Recurrence Score on Chemotherapy Decision in Invasive Ductal Carcinoma of Breast with Nodal Micrometastases.

Cancer research and treatment : official journal of Korean Cancer Association, 51(4):1437-1448.

PURPOSE: The purpose of this study was to investigate the effect of 21-gene recurrence score (RS) on predicting prognosis and chemotherapy decision in node micrometastases (N1mi) breast invasive ductal carcinoma (IDC). Methods Patients with stage T1-2N1mi and estrogen receptor-positive IDC diagnosed between 2004 and 2015 were included. The associations of 21-gene RS with breast cancer-specific survival (BCSS), chemotherapy decision, and benefit of chemotherapy were analyzed.

RESULTS: We identified 4,758 patients including 1,403 patients (29.5%) treated with adjuvant chemotherapy. In the traditional RS cutoffs, 2,831 (59.5%), 1,634 (34.3%), and 293 (6.2%) patients were in the low-, intermediate-, and high-risk RS groups, respectively. In 3,853 patients with human epidermal growth factor receptor-2 (HER2) status available, most patients were HER2-negative disease (98.3%). A higher RS was independently related to chemotherapy receipt, and 14.0%, 47.7%, and 77.8% of patients in the low-, intermediate-, and high-risk RS groups received chemotherapy, respectively. The multivariate analysis indicated that a higher RS was related to worse BCSS (p < 0.001). The 5-year BCSS rates were 99.3%, 97.4%, and 91.9% in patients with low-, intermediate-, and high-risk RS groups, respectively (p < 0.001). However, chemotherapy receipt did not correlate with better BCSS in low-, intermediate-, or high-risk RS groups. There were similar trends using Trial Assigning Individualized Options for Treatment RS cutoffs.

CONCLUSION: The 21-gene RS does predict outcome and impact on chemotherapy decision of N1mi breast IDC. Large cohort and long-term outcomes studies are needed to identify the effects of chemotherapy in N1mi patients by different 21-gene RS groups.

RevDate: 2020-02-14
CmpDate: 2020-02-14

Sun Y, Lei B, Q Huang (2019)

SOX18 Affects Cell Viability, Migration, Invasiveness, and Apoptosis in Hepatocellular Carcinoma (HCC) Cells by Participating in Epithelial-to-Mesenchymal Transition (EMT) Progression and Adenosine Monophosphate Activated Protein Kinase (AMPK)/Mammalian Target of Rapamycin (mTOR).

Medical science monitor : international medical journal of experimental and clinical research, 25:6244-6254.

BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies around the world. It has been verified that the expression of SOX18 is correlated to poor clinical prognosis in patients with ovarian cancer, non-small cell lung cancer, or breast invasive ductal carcinoma. However, the expression pattern and biological function of SOX18 in HCC tissues remains unclear. In this study, we set out to investigate the associated biological function and potential molecular mechanism of the SOX18 gene in HCC cells. MATERIAL AND METHODS The mRNA and protein expression levels of experimental related genes were detected by real-time polymerase chain reaction and western blotting assay, respectively. The MTT method was used to assess cell viability, and cell apoptosis analysis was performed by means of FACScan flow cytometry. Wound-healing assay and Transwell analysis were performed to evaluate the ability of cell migration and invasiveness, respectively. RESULTS SOX18 was highly expressed in various HCC cell lines. In addition, SOX18 promoted cell viability, migration, and invasion and simultaneously induce cell apoptosis. SOX18 promoted epithelial-to-mesenchymal transition (EMT) progression, and SOX18 downregulation activated the autophagy signaling pathway AMPK/mTOR in HCC cells. CONCLUSIONS SOX18 downregulation in HCC cells suppressed cell viability and metastasis, induced cell apoptosis and hindered the occurrence and progression of tumor cells by participating in the EMT process and regulating the autophagy signaling pathway AMPK/mTOR.

RevDate: 2020-02-11
CmpDate: 2020-02-11

Shee K, Muller KE, Marotti J, et al (2019)

Ductal Carcinoma in Situ Biomarkers in a Precision Medicine Era: Current and Future Molecular-Based Testing.

The American journal of pathology, 189(5):956-965.

Historically, ductal carcinoma in situ (DCIS) of the breast has been managed aggressively with surgery and radiotherapy because of a risk of progression to invasive ductal carcinoma. However, this treatment paradigm has been challenged by overtreatment concerns and evidence that suggests that DCIS can be stratified according to risk of recurrence or risk of progression to invasive disease. Traditional methods of risk stratification include histologic grade and hormone receptor status. Recent technological advancements have enabled an era of precision medicine, where DCIS can be molecularly analyzed by tools, such as next-generation DNA and RNA sequencing, to identify molecular biomarkers for risk stratification. These findings have led to the development of tools such as the Oncotype DX Breast DCIS Score, a gene expression-based assay with the potential to prevent overtreatment in low-risk disease.

RevDate: 2020-02-11
CmpDate: 2020-02-11

Hannafon BN, WQ Ding (2019)

Functional Role of miRNAs in the Progression of Breast Ductal Carcinoma in Situ.

The American journal of pathology, 189(5):966-974.

miRNAs are small RNAs that influence gene expression by targeting mRNAs. Depending on the function of their target genes, miRNAs may regulate the expression of oncogenes and tumor suppressors, thereby contributing to the promotion or inhibition of tumor progression. Ductal carcinoma in situ (DCIS), although often diagnosed as breast cancer, is a potential precursor to invasive ductal carcinoma. Many of the genetic events required for the invasive progression of DCIS occur at the preinvasive stage, and these events include changes in the expression of miRNAs. Aberrant expression of miRNAs can influence specific oncogenic or tumor-suppressive pathways required for breast cancer progression. miRNAs in DCIS have been shown to influence hormone signaling, cell-cell adhesion, epithelial-to-mesenchymal transition, transforming growth factor β signaling, maintenance of cancer stem cells, and modulation of the extracellular matrix. Additionally, extracellular DCIS miRNAs, such as those found in exosomes, may promote invasive progression by modifying the tumor microenvironment. Here, we review the miRNAs that have been identified in DCIS and how they may contribute to the progression to invasive disease. We also touch on the current state of miRNA therapy development, including the current challenges, and discuss the key future perspectives for research into miRNA function for the purpose of miRNA therapy development for DCIS.

RevDate: 2020-02-07

Aminian A, Zajichek A, Arterburn DE, et al (2020)

Predicting 10-Year Risk of End-Organ Complications of Type 2 Diabetes With and Without Metabolic Surgery: A Machine Learning Approach.

Diabetes care pii:dc19-2057 [Epub ahead of print].

OBJECTIVE: To construct and internally validate prediction models to estimate the risk of long-term end-organ complications and mortality in patients with type 2 diabetes and obesity that can be used to inform treatment decisions for patients and practitioners who are considering metabolic surgery.

RESEARCH DESIGN AND METHODS: A total of 2,287 patients with type 2 diabetes who underwent metabolic surgery between 1998 and 2017 in the Cleveland Clinic Health System were propensity-matched 1:5 to 11,435 nonsurgical patients with BMI ≥30 kg/m2 and type 2 diabetes who received usual care with follow-up through December 2018. Multivariable time-to-event regression and random forest machine learning models were built and internally validated using fivefold cross-validation to predict the 10-year risk for four outcomes of interest. The prediction models were programmed to construct user-friendly web-based and smartphone applications of Individualized Diabetes Complications (IDC) Risk Scores for clinical use.

RESULTS: The prediction tools demonstrated the following discrimination ability based on the area under the receiver operating characteristic curve (1 = perfect discrimination and 0.5 = chance) at 10 years in the surgical and nonsurgical groups, respectively: all-cause mortality (0.79 and 0.81), coronary artery events (0.66 and 0.67), heart failure (0.73 and 0.75), and nephropathy (0.73 and 0.76). When a patient's data are entered into the IDC application, it estimates the individualized 10-year morbidity and mortality risks with and without undergoing metabolic surgery.

CONCLUSIONS: The IDC Risk Scores can provide personalized evidence-based risk information for patients with type 2 diabetes and obesity about future cardiovascular outcomes and mortality with and without metabolic surgery based on their current status of obesity, diabetes, and related cardiometabolic conditions.

RevDate: 2020-01-31
CmpDate: 2020-01-31

Farsang A, Bódi I, Fölker O, et al (2019)

Avian coronavirus infection induces mannose-binding lectin production in dendritic cell precursors of chicken lymphoid organs.

Acta veterinaria Hungarica, 67(2):183-196.

The aim of this immunocytochemical study was to compare mannose-binding lectin (MBL) production induced by avian coronavirus in the spleen and caecal tonsil (CT). One-day-old specific-pathogen-free (SPF) chickens were experimentally infected with six QX field isolates and the H120 vaccine strain. In the negative control birds, the spleen was MBL negative, while the CT showed scattered MBL-positive cells in close proximity and within the surface epithelium and germinal centre (GC)-like cell clusters. MBL was detectable in the ellipsoid-associated cells (EACs) and cell clusters in the periarterial lymphoid sheath (PALS) by 7 days post infection (dpi). In both organs, the MBL-positive cells occupy antigen-exposed areas, indicating that GC formation depends on resident precursors of dendritic cells. The majority of MBL-positive EACs express the CD83 antigen, providing evidence that coronavirus infection facilitated the maturation of dendritic cell precursors. Surprisingly, co-localisation of MBL and CD83 was not detectable in the CT. In the spleen (associated with circulation), the EACs producing MBL and expressing CD83 are a common precursor of both follicular (FDC) and interdigitating dendritic cells (IDC). In the CT (gut-associated lymphoid tissue, GALT) the precursors of FDC and IDC are MBL-producing cells and CD83-positive cells, respectively. In the CT the two separate precursors of lymphoid dendritic cells provide some 'autonomy' for the GALT.

RevDate: 2020-01-31
CmpDate: 2020-01-31

Dianatinasab M, Fararouei M, Daneshi N, et al (2019)

Heterogeneity in risk factors for ductal and lobular breast carcinomas: A case-control study.

International journal of cancer, 145(11):2917-2925.

Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of the breast are the most common histological subtypes of breast cancer. However, the associations and heterogeneity between histological subtypes and their risk factors are not well established. This study aimed to investigate risk factors for IDC and ILC. This case-control study included 1,009 incident breast cancer cases and 1,009 hospital controls, frequency-matched by age. Data were obtained from the patients' medical files and an interview administered via a questionnaire. Multinomial logistic regression was used and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The heterogeneity of the associations was assessed using the Wald test. Family history of breast cancer was associated with IDC (OR 2.64, 95% CI: 1.97-3.55) but not ILC (OR 0.81, 95% CI: 0.42-1.57; p for heterogeneity <0.001). Conversely, a history of miscarriage was associated with ILC (OR 1.71, 95% CI: 1.17-2.51) but not IDC (OR 1.18, 95% CI: 0.95-1.46; p for heterogeneity = 0.04). Similarly, type 2 diabetes was associated with ILC but not IDC (p for heterogeneity = 0.02). Age at first delivery and breastfeeding were significantly associated with IDC but not ILC, though p values for heterogeneity did not reach the significance level. Deliberate weight loss and age at menarche were significantly associated with ILC but not IDC (p for heterogeneity ≥0.27). Smoking, history of benign breast disease and BMI were associated with both subtypes. The present study supports the hypothesis that IDC and ILC are etiologically distinct tumours.

RevDate: 2020-01-29

Assefa T, Zhang J, Chowda-Reddy RV, et al (2020)

Deconstructing the genetic architecture of iron deficiency chlorosis in soybean using genome-wide approaches.

BMC plant biology, 20(1):42 pii:10.1186/s12870-020-2237-5.

BACKGROUND: Iron (Fe) is an essential micronutrient for plant growth and development. Iron deficiency chlorosis (IDC), caused by calcareous soils or high soil pH, can limit iron availability, negatively affecting soybean (Glycine max) yield. This study leverages genome-wide association study (GWAS) and a genome-wide epistatic study (GWES) with previous gene expression studies to identify regions of the soybean genome important in iron deficiency tolerance.

RESULTS: A GWAS and a GWES were performed using 460 diverse soybean PI lines from 27 countries, in field and hydroponic iron stress conditions, using more than 36,000 single nucleotide polymorphism (SNP) markers. Combining this approach with available RNA-sequencing data identified significant markers, genomic regions, and novel genes associated with or responding to iron deficiency. Sixty-nine genomic regions associated with IDC tolerance were identified across 19 chromosomes via the GWAS, including the major-effect quantitative trait locus (QTL) on chromosome Gm03. Cluster analysis of significant SNPs in this region deconstructed this historically prominent QTL into four distinct linkage blocks, enabling the identification of multiple candidate genes for iron chlorosis tolerance. The complementary GWES identified SNPs in this region interacting with nine other genomic regions, providing the first evidence of epistatic interactions impacting iron deficiency tolerance.

CONCLUSIONS: This study demonstrates that integrating cutting edge genome wide association (GWA), genome wide epistasis (GWE), and gene expression studies is a powerful strategy to identify novel iron tolerance QTL and candidate loci from diverse germplasm. Crops, unlike model species, have undergone selection for thousands of years, constraining and/or enhancing stress responses. Leveraging genomics-enabled approaches to study these adaptations is essential for future crop improvement.

RevDate: 2020-01-29
CmpDate: 2020-01-29

Sethy C, Goutam K, Nayak D, et al (2020)

Clinical significance of a pvrl 4 encoded gene Nectin-4 in metastasis and angiogenesis for tumor relapse.

Journal of cancer research and clinical oncology, 146(1):245-259.

PURPOSE: In the present study, we have systematically examined the clinical significance of Nectin-4 (encoded by the PVRL-4 gene), a marker for breast cancer stem cells (CSCs), in cancer metastasis and angiogenesis using a variety of human specimens, including invasive duct carcinoma (IDC) with multiple grades, several types of primary tumors to local and distant relapses, lymph node metastases and circulating tumor cells (CTCs).

METHODS: Nectin-4 was overexpressed in more than 92% of samples with 65.2% Nectin-4-positive cells. The level of expression was increased with increasing tumor grade (GI-III) and size (T1-4) of IDC specimens.

RESULTS: More induction of Nectin-4 was noted in relapsed samples from a variety of tumors (colon, tongue, liver, kidney, ovary, buccal mucosa) in comparison to primary tumors, while paired adjacent normal tissues do not express any Nectin-4. A high expression of Nectin-4 along with other representative markers in CTCs and lymph node metastasis was also observed in cancer specimens. An increased level of Nectin-4 along with representative metastatic (CD-44, Sca1, ALDH1, Nanog) and angiogenic (Ang-I, Ang-II, VEGF) markers were noted in metastatic tumors (local and distant) in comparison to primary tumors that were correlated with different grades of tumor progression. In addition, greater expression of Nectin-4 was observed in secondary tumors (distant metastasis, e.g., breast to liver or stomach to gall bladder) in comparison to primary tumors.

CONCLUSION: Our study demonstrated a significant correlation between Nectin-4 expression and tumor grade as well as stages (p < 0.001), suggesting its association with tumor progression. Nectin-4 was overexpressed at all stages of metastasis and angiogenesis, thus appearing to play a major role in tumor relapse through the PI3K-Akt-NFκβ pathway.

RevDate: 2020-01-24
CmpDate: 2020-01-24

Tan X, Li Z, Ren S, et al (2019)

Dynamically decreased miR-671-5p expression is associated with oncogenic transformation and radiochemoresistance in breast cancer.

Breast cancer research : BCR, 21(1):89 pii:10.1186/s13058-019-1173-5.

BACKGROUND: Understanding the molecular alterations associated with breast cancer (BC) progression may lead to more effective strategies for both prevention and management. The current model of BC progression suggests a linear, multistep process from normal epithelial to atypical ductal hyperplasia (ADH), to ductal carcinoma in situ (DCIS), and then invasive ductal carcinoma (IDC). Up to 20% ADH and 40% DCIS lesions progress to invasive BC if left untreated. Deciphering the molecular mechanisms during BC progression is therefore crucial to prevent over- or under-treatment. Our previous work demonstrated that miR-671-5p serves as a tumor suppressor by targeting Forkhead box protein M1 (FOXM1)-mediated epithelial-to-mesenchymal transition (EMT) in BC. Here, we aim to explore the role of miR-671-5p in the progression of BC oncogenic transformation and treatment.

METHODS: The 21T series cell lines, which were originally derived from the same patient with metastatic BC, including normal epithelia (H16N2), ADH (21PT), primary DCIS (21NT), and cells derived from pleural effusion of lung metastasis (21MT), and human BC specimens were used. Microdissection, miRNA transfection, dual-luciferase, radio- and chemosensitivity, and host-cell reactivation (HCR) assays were performed.

RESULTS: Expression of miR-671-5p displays a gradual dynamic decrease from ADH, to DCIS, and to IDC. Interestingly, the decreased expression of miR-671-5p detected in ADH coexisted with advanced lesions, such as DCIS and/or IDC (cADH), but not in simple ADH (sADH). Ectopic transfection of miR-671-5p significantly inhibited cell proliferation in 21NT (DCIS) and 21MT (IDC), but not in H16N2 (normal) and 21PT (ADH) cell lines. At the same time, the effect exhibited in time- and dose-dependent manner. Interestingly, miR-671-5p significantly suppressed invasion in 21PT, 21NT, and 21MT cell lines. Furthermore, miR-671-5p suppressed FOXM1-mediated EMT in all 21T cell lines. In addition, miR-671-5p sensitizes these cell lines to UV and chemotherapeutic exposure by reducing the DNA repair capability.

CONCLUSIONS: miR-671-5p displays a dynamic decrease expression during the oncogenic transition of BC by suppressing FOXM1-mediated EMT and DNA repair. Therefore, miR-671-5p may serve as a novel biomarker for early BC detection as well as a therapeutic target for BC management.

RevDate: 2020-01-24
CmpDate: 2020-01-24

Malik SS, Baig M, Khan MB, et al (2019)

Survival analysis of breast cancer patients with different treatments: a multicentric clinicopathological study.

JPMA. The Journal of the Pakistan Medical Association, 69(7):976-980.

OBJECTIVE: To explore and better understand clinic pathological details of breast cancer patients and analyse their survival rate among different treatment groups.

Methods: The prospective cohort, multi-centric study was conducted from September, 2014, to February, 2018, at five hospitals in Rawalpindi and Islamabad, Pakistan, and comprised histo-pathologically confirmed breast cancer cases. Patient characteristics and medical history were collected using a detailed questionnaire. All the subjects were followed up, and information regarding their current health and treatment status was collected. Data was analysed using SPSS 24.

RESULTS: There were 347 subjects with a mean age of 44.3±12.2 years and body mass index of 27.9±4.0 kg/m2. Younger age, increased body mass index, consanguinity and family history were major contributing factors in breast cancer development (p<0.05). Overall, 267(77%) had invasive ductal carcinoma and Grade II tumour 234(67%) was more frequent. A total of 221(64%) cases had positive lymph nodes and 97(28%) had metastasis to different body organs. Overall survival analysis showed statistically significant role (p<0.0001) of all treatment options.

CONCLUSIONS: Combination of different treatments can provide more promising health outcomes in breast cancer cases.

RevDate: 2020-01-21
CmpDate: 2020-01-21

Arabpour M, Rasolmali R, Talei AR, et al (2019)

Granzyme B production by activated B cells derived from breast cancer-draining lymph nodes.

Molecular immunology, 114:172-178.

B lymphocytes with regulatory or effector functions synthesize granzyme B (GZMB). We investigated the frequency and phenotype of GZMB-producing B cells in breast tumor-draining lymph nodes (TDLNs). Mononuclear cells were isolated from 48 axillary lymph nodes and were stimulated with anti-BCR (B cell receptor), recombinant interleukin (IL)-21 and CD40 L alone or in combination. Flow cytometry was used to evaluate the expression of GZMB in B cells, and in 4 samples the phenotype of GZMB+ B cells was determined. B cells produced GZMB only when stimulated with a combination of IL-21 and anti-BCR for at least 16 h. Adding CD40 L to IL-21 and anti-BCR stimuli resulted in lower GZMB production in B cells. A small fraction of B cells was able to produce perforin in all stimulation conditions, and the majority of GZMB+ B cells were perforin-negative. Both naïve (CD24lowCD27-) and active/memory (CD24hiCD27+) B cells expressed GZMB. In patients with invasive ductal carcinoma, the frequency of GZMB+ B cells was significantly lower in metastatic compared to non-metastatic lymph nodes. The frequency of GZMB+ B cells did not significantly correlate with prognostic factors such as stage, tumor size or Her2 expression. In summary, a subpopulation of both naïve and memory B cells expressed GZMB in breast TDLNs. Our findings underscore the need to investigate the function of GZMB+ B cells in breast tumor immunity.

RevDate: 2020-01-20
CmpDate: 2020-01-20

Yamashita H, Kurita A, Azuma S, et al (2019)

Usefulness of immunohistochemical staining for MUC5AC in differentiating primary pancreatic cancer from pancreatic metastasis of breast cancer.

Diagnostic cytopathology, 47(10):1037-1041.

Diagnosis of pancreatic ductal adenocarcinoma (PDAC) and its differentiation from metastases to the pancreas from other organs remains challenging. We report a case in which immunohistochemical staining for MUC5AC was useful in distinguishing primary pancreatic cancer from breast cancer metastasis. A 51-year-old Japanese woman who underwent curative resection of her breast cancer was referred to our hospital with a pancreatic head tumor. Although we surmised her pancreatic tumor to be metastatic breast cancer based on her past history and imaging studies, she was subsequently diagnosed with PDAC on the basis of immunohistochemical staining for MUC5AC using specimens obtained by endoscopic ultrasound-fine-needle aspiration. Thus, MUC5AC may be a useful diagnostic marker for discriminating PDAC from a secondary malignancy.

RevDate: 2020-01-20
CmpDate: 2020-01-20

Shah RB, Shore KT, Yoon J, et al (2019)

PTEN loss in prostatic adenocarcinoma correlates with specific adverse histologic features (intraductal carcinoma, cribriform Gleason pattern 4 and stromogenic carcinoma).

The Prostate, 79(11):1267-1273.

BACKGROUND: The loss of PTEN tumor suppressor gene is one of the most common somatic genetic aberrations in prostate cancer (PCa) and is frequently associated with high-risk disease. Deletion or mutation of at least one PTEN allele has been reported to occur in 20% to 40% of localized PCa and up to 60% of metastases. The goal of this study was to determine if somatic alteration detected by PTEN immunohistochemical loss of expression is associated with specific histologic features.

METHODS: Two hundred sixty prostate core needle biopsies with PCa were assessed for PTEN loss using an analytically validated immunohistochemical assay. Blinded to PTEN status, each tumor was assessed for the Grade Group (GG) and the presence or absence of nine epithelial features. Presence of stromogenic PCa was also assessed and defined as grade 3 reactive tumor stroma as previously described: the presence of carcinoma associated stromal response with epithelial to stroma ratio of greater than 50% reactive stroma.

RESULTS: Eight-eight (34%) cases exhibited PTEN loss while 172 (66%) had intact PTEN. PTEN loss was significantly (P < 0.05) associated with increasing GG, poorly formed glands (74% of total cases with loss vs 49% of intact), and three well-validated unfavorable pathological features: intraductal carcinoma of the prostate (IDC-P) (69% of total cases with loss vs 12% of intact), cribriform Gleason pattern 4 (38% of total cases with loss vs 10% of intact) and stromogenic PCa (23% of total cases with loss vs 6% of intact). IDC-P had the highest relative risk (4.993, 95% confidence interval, 3.451-7.223, P < 0.001) for PTEN loss. At least one of these three unfavorable pathological features were present in 67% of PCa exhibiting PTEN loss, while only 11% of PCa exhibited PTEN loss when none of these three unfavorable pathological features were present.

CONCLUSIONS: PCa with PTEN loss demonstrates a strong correlation with known unfavorable histologic features, particularly IDC-P. This is the first study showing the association of PTEN loss with stromogenic PCa.

RevDate: 2020-01-14
CmpDate: 2020-01-14

Nie L, Pan X, Zhang M, et al (2019)

The expression profile and heterogeneity analysis of ERG in 633 consecutive prostate cancers from a single center.

The Prostate, 79(8):819-825.

BACKGROUND: Overexpression of ERG protein resulting from TMPRSS2:ERG rearrangement is highly specific for prostate cancer (PCa). However, the biological function of this fusion protein and its relationship with clinicopathological features still remain controversial.

METHOD: In this study, we evaluated ERG protein expression/gene rearrangement and heterogeneity by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in a cohort of 633 consecutive PCa initially diagnosed by core-needle biopsy in the West China Hospital.

RESULT: Overall, ERG protein expression was detected in 16.7% (106 of 633) cases, and frequently observed in PCa patients less than 60 years of age (31.9% vs 15.5%, P = 0.004) and in PCa with Gleason score less than 8 (20.0% vs 13.4%, P = 0.027), but infrequently observed in cases with intraductal carcinoma of the prostate (IDC-P) (10.0% vs 18.6%, P = 0.012). Follow-up analysis found that patients who progressed to castration-resistant prostate cancer (CRPC) have a lower frequency of ERG protein expression at initial biopsies compared to androgen deprivation therapy (ADT)-sensitive cases (14.1% vs 23.5%, P = 0.042), but Kaplan-Meier curve showed that ERG protein expression was not an independent prognostic marker. Of all the 106 ERG-positive cases, eight cases (7.5%) exhibited heterogeneous expression of ERG protein, in which ERG was only positive in tumors with Gleason pattern 3, but negative in Gleason pattern 4. The FISH analysis was consistent with IHC in six of these cases. In the other two cases, ERG rearrangement was detected in tumors with both Gleason pattern 3 and 4 by FISH, despite the negative protein expression in Gleason pattern 4. In case 1, a repeated biopsy was performed when the disease progressed to CRPC, and no ERG-positive cells were identified neither by IHC nor FISH.

CONCLUSION: This was by far the largest series of ERG expression and heterogeneity analysis in Chinese PCa. The ERG rearrangement seemed to be frequently expressed in patients with relatively younger age and lower Gleason score and infrequently expressed in PCa with the IDC-P. PCa with positive ERG were less frequently to progress to CRPC, but there was no prognostic significance of ERG expression. In heterogeneous cases, ERG protein was detectable only in tumors with Gleason pattern 3 but not in pattern 4. Tumor cells with positive ERG expression/rearrangement seemed easily response to ADT.

RevDate: 2020-01-13
CmpDate: 2020-01-13

Sheaffer WW, Gray RJ, Wasif N, et al (2019)

Predictive factors of upstaging DCIS to invasive carcinoma in BCT vs mastectomy.

American journal of surgery, 217(6):1025-1029.

BACKGROUND: Upstaging from DCIS to invasive ductal carcinoma varies widely from 0 to 59%. We aim to identify risk factors associated with upstaging in all DCIS patients and based on specific surgical intervention.

METHODS: Patients with a pre-operative diagnosis of DCIS undergoing BCT or mastectomy were reviewed. Multivariable analysis was performed to identify risk factors for upstaging.

RESULTS: In total, 623 patients had a preoperative diagnosis of DCIS. Upstaging occurred in 74 patients (12%) overall. There was no difference in upstaging rates between mastectomy and BCT (11% v 14% p = 0.27). Sentinel lymph node biopsy was positive in 4/212 patients (1%). Multivariable analysis revealed suspicion of microinvasion (OR 5.7 95%CI2.2-14.9), surgeon suspicion of invasive disease (OR 2.7, 95% CI 1.2-6.4) and larger size/multicentric/extensive tumor (OR 1.9 95% CI 1.1-3.4) increase risk of upstaging.

CONCLUSIONS: Suspicion of microinvasion, surgeon suspicion, and tumor size can be used to help guide the use of sentinel lymph node biopsy. For patients without these high risk characteristics, it is hard to justify the use of concurrent SLN biopsy for patients who undergo BCT.

RevDate: 2020-01-09
CmpDate: 2020-01-09

Petridis C, Arora I, Shah V, et al (2019)

Frequency of pathogenic germline variants in BRCA1, BRCA2, PALB2, CHEK2 and TP53 in ductal carcinoma in situ diagnosed in women under the age of 50 years.

Breast cancer research : BCR, 21(1):58 pii:10.1186/s13058-019-1143-y.

INTRODUCTION: Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age.

METHODS: After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls.

RESULTS: Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 × 10-10) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 × 10-6), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively.

CONCLUSIONS: This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.

RevDate: 2020-01-09
CmpDate: 2020-01-09

Griggs RB, Santos DF, Laird DE, et al (2019)

Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes.

Neurobiology of disease, 127:76-86.

Painful diabetic neuropathy (PDN) is a devastating neurological complication of diabetes. Methylglyoxal (MG) is a reactive metabolite whose elevation in the plasma corresponds to PDN in patients and pain-like behavior in rodent models of type 1 and type 2 diabetes. Here, we addressed the MG-related spinal mechanisms of PDN in type 2 diabetes using db/db mice, an established model of type 2 diabetes, and intrathecal injection of MG in conventional C57BL/6J mice. Administration of either a MG scavenger (GERP10) or a vector overexpressing glyoxalase 1, the catabolic enzyme for MG, attenuated heat hypersensitivity in db/db mice. In C57BL/6J mice, intrathecal administration of MG produced signs of both evoked (heat and mechanical hypersensitivity) and affective (conditioned place avoidance) pain. MG-induced Ca2+ mobilization in lamina II dorsal horn neurons of C57BL/6J mice was exacerbated in db/db, suggestive of MG-evoked central sensitization. Pharmacological and/or genetic inhibition of transient receptor potential ankyrin subtype 1 (TRPA1), adenylyl cyclase type 1 (AC1), protein kinase A (PKA), or exchange protein directly activated by cyclic adenosine monophosphate (Epac) blocked MG-evoked hypersensitivity in C57BL/6J mice. Similarly, intrathecal administration of GERP10, or inhibitors of TRPA1 (HC030031), AC1 (NB001), or Epac (HJC-0197) attenuated hypersensitivity in db/db mice. We conclude that MG and sensitization of a spinal TRPA1-AC1-Epac signaling cascade facilitate PDN in db/db mice. Our results warrant clinical investigation of MG scavengers, glyoxalase inducers, and spinally-directed pharmacological inhibitors of a MG-TRPA1-AC1-Epac pathway for the treatment of PDN in type 2 diabetes.

RevDate: 2020-01-06

Sultan G, Zubair S, Tayubi IA, et al (2019)

Towards the early detection of ductal carcinoma (a common type of breast cancer) using biomarkers linked to the PPAR(γ) signaling pathway.

Bioinformation, 15(11):799-805 pii:97320630015799.

Breast cancer is a leading cause of morbidity and mortality among women comprising about 12% females worldwide. The underlying alteration in the gene expression, molecular mechanism and metabolic pathways responsible for incidence and progression of breast tumorigenesis are yet not completely understood. In the present study, potential biomarker genes involved in the early progression for early diagnosis of breast cancer has been detailed. Regulation and Gene profiling of Ductal Carcinoma In-situ (DCIS), Invasive Ductal Carcinoma (IDC) and healthy samples have been analyzed to follow their expression pattern employing normalization, statistical calculation, DEGs annotation and Protein-Protein Interaction (PPI) network. We have performed a comparative study on differentially expressed genes among Healthy vs DCIS, Healthy vsIDC and DCIS vs IDC. We found MCM102 and SLC12A8as consistently over-expressed and LEP, SORBS1, SFRP1, PLIN1, FABP4, RBP4, CD300LG, ID4, CRYAB, ECRG4, G0S2, FMO2, ADAMTS5, CAV1, CAV2, ABCA8, MAMDC2, IGFBP6, CLDN11, TGFBR3as under-expressed genes in all the 3 conditions categorized for pre-invasive and invasive ductal breast carcinoma. These genes were further studied for the active pathways where PPAR(γ) signaling pathway was found to be significantly involved. The gene expression profile database can be a potential tool in the early diagnosis of breast cancer.

RevDate: 2020-01-06
CmpDate: 2020-01-06

Nkinda L, Patel K, Njuguna B, et al (2019)

C - reactive protein and interleukin - 6 levels among human immunodeficiency virus -infected patients with dysglycemia in Tanzania.

BMC endocrine disorders, 19(1):77 pii:10.1186/s12902-019-0407-y.

BACKGROUND: Chronic inflammation has been associated with dysglycemia among people living with HIV (PLHIV). There is however, limited data regarding this phenomenon in sub-Sahara Africa (SSA). Therefore we assessed the levels of C-reactive protein (CRP) and Interleukin 6 (IL-6) on a cohort of PLHIV and its associations with dysglycemia in Tanzania.

METHODS: We conducted a cross-sectional study at the Infectious Disease Clinic (IDC) in Tanzania from March to May 2018. Purposive sampling was used to identify participants who had an undetectable viral load, were on 1st line anti-retroviral therapy (ART) and had an overnight fast. The WHO stepwise approach for non-communicable disease (NCD) surveillance was used to collect data. Fasting blood glucose and blood glucose after 75 g oral glucose load was measured, and Enzyme-linked immunosorbent assay (ELISA) was used to test for inflammatory markers (IL-6 and CRP). Associations were explored using the Chi square test and binary logistic regression was performed to estimate the odds ratios. A p-value less than 0.05 was considered statistically significant.

RESULTS: A total of 240 participants were enrolled. Forty two percent were overweight/obese (> 25 kg/m2), 89% had a high waist to height ratio. The median ART duration was 8(5-10) years. The prevalence of dysglycemia among our cohort of PLHIV was 32%. High CRP was associated with a 2.05 increased odds of having dysglycemia OR 2.05 (1.15-3.65) (p = 0.01). Taking stavudine was associated with a 1.99 odds of having dysglycemia OR 1.99 (1.04-3.82) (p = 0.03).We did not find a significant association between IL-6 and dysglycemia.

CONCLUSION: High CRP and taking stavudine were significantly associated with dysglycemia among PLHIV with undetectable viral load.

RevDate: 2020-01-06
CmpDate: 2020-01-06

Wolff G, Taranko AE, Meln I, et al (2019)

Diet-dependent function of the extracellular matrix proteoglycan Lumican in obesity and glucose homeostasis.

Molecular metabolism, 19:97-106.

OBJECTIVE: Extracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications.

METHODS: Whole body ablation of Lumican (Lum-/-) gene and adeno-associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling.

RESULTS: Lumican was found to be particularly enriched in the stromal cells isolated from murine gonadal white adipose tissue. Likewise murine and human visceral fat showed a robust increase in Lumican as compared to fat from the subcutaneous depot. Lumican null female mice exhibited moderately increased fat mass, decreased insulin sensitivity and increased liver triglycerides in a diet-dependent manner. These changes coincided with inflammation in adipose tissue and no overt effects in adipose expandability, i.e. adipocyte formation and hypertrophy. Lumican over-expression in visceral fat and liver resulted in improved insulin sensitivity and glucose clearance.

CONCLUSIONS: These data indicate that Lumican may represent a functional link between the extracellular matrix, glucose homeostasis, and features of the metabolic syndrome.

RevDate: 2020-01-01
CmpDate: 2020-01-01

Kim SJ, JY Kim (2019)

An Unusual Cutaneous Recurrence of Carcinoma in the Mastectomy Bed and Its Imaging Features: A Case Report.

The American journal of case reports, 20:800-805 pii:916609.

BACKGROUND Chest wall recurrences of carcinoma after mastectomy usually involve subcutaneous tissue or the deep muscular layer. Recurrences arising in the skin are rare, and there are few reports of the associated radiologic features. This report presents an unusual case of cutaneous recurrence in the mastectomy bed and demonstrates its radiologic features using sonography and magnetic resonance imaging (MRI). CASE REPORT A 44-year-old woman presented with a palpable lump in the inferomedial area of the right chest wall. Six years ago, she had undergone total mastectomy for ductal carcinoma in situ in her right breast. Sonography showed an indistinct, oval, heterogeneous echoic mass measuring 0.9 cm, confined within the skin layer, corresponding to the palpable lump. A color Doppler sonogram showed minimal, spotted vascularity in and around the mass. Sonography-guided fine-needle aspiration biopsy was performed, revealing multiple clusters of atypical cells, suggestive of ductal carcinoma. On subsequent breast MRI, the mass, measuring 1.3 cm, was again localized to the skin; dynamic contrast-enhanced scans showed a circumscribed margin, oval shape, and rim enhancement (morphology) and slow initial enhancement and persistent delayed enhancement (kinetics). The mass was surgically excised and the pathological examination confirmed the diagnosis as recurrent invasive ductal carcinoma in the dermis. CONCLUSIONS Cutaneous recurrence in the mastectomy bed can manifest as a mass with suspicious radiologic features: indistinct margin on the sonogram and rim enhancement on the MRI. Awareness of such radiologic features may aid in differentiating between the various cutaneous manifestations encountered after mastectomy.

RevDate: 2019-12-31
CmpDate: 2019-12-31

Murakami W, Tozaki M, Nakamura S, et al (2019)

The clinical impact of MRI screening for BRCA mutation carriers: the first report in Japan.

Breast cancer (Tokyo, Japan), 26(5):552-561.

BACKGROUND: There is no consensus on the appropriate surveillance for high-risk women with breast cancer in Japan. We investigated their imaging features and pathological characteristics to build a proper surveillance system for asymptomatic high-risk individuals in the future.

METHODS: We retrospectively reviewed 93 female (median age 43 years) BRCA1 and BRCA2 mutation carriers from our institutional clinical database from 2011 to 2017. The study population was composed of 112 breast cancers. Mammography and MRI were reviewed by examiners blinded to patients' clinical history. Final surgical or biopsy histopathology served as the reference standard in all the patients.

RESULTS: Fifty-nine breast cancers met selection criteria; of these, 30 were BRCA1-associated tumors, and 29 were BRCA2-associated tumors. Invasive ductal carcinoma was the most prevalent type in both BRCA1 and BRCA2. There were statistically significant differences in phenotype, nuclear grade, and Ki-67 labeling index between BRCA1 and BRCA2 mutation carriers. Additionally, imaging findings on mammography and MRI were statistically different. Tumors in BRCA2 carriers demonstrated mammographic calcifications more frequently, while those in BRCA1 carriers demonstrated a mass or architectural distortion (P < 0.001). Enhancement pattern on MRI also significantly differed between the two subgroups (P = 0.006). The size of MRI-detected lesions was statistically smaller than the size of those detected by other modalities (P = 0.004).

CONCLUSIONS: The imaging and histological characteristics of BRCA1/2 mutation carriers were consistent with other countries' studies. MRI-detected lesions were significantly smaller than lesions detected by non-MRI modality. All lesions in BRCA1 mutation carriers could be detected by MRI.

RevDate: 2019-12-31
CmpDate: 2019-12-31

Guo Q, Li VZ, Nichol JN, et al (2019)

MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ.

Cancer research, 79(7):1646-1657.

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. SIGNIFICANCE: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.

RevDate: 2019-12-31
CmpDate: 2019-12-31

Alkhasawneh A, Nassri A, I John (2019)

Dedifferentiated Melanoma With Expression of Cytokeratin and GATA3 in a Patient With History of Breast Carcinoma.

The American Journal of dermatopathology, 41(7):502-504.

Melanoma is one of the great mimickers in pathology because it has diverse morphologies and can be mistaken for carcinoma or sarcoma. In most cases, immunochemistry is helpful in supporting the diagnosis and excluding other differentials. However, metastatic melanoma may lose immunohistochemical melanocytic markers and express nonmelanocytic lineage markers, which often poses a diagnostic dilemma and may be misdiagnosed as a poorly differentiated carcinoma or sarcoma. We report the case of a 52-year-old woman who had a history of recurrent melanoma on her right shoulder with axillary lymph node metastasis (BRAF V600K-mutated melanoma) and right-side breast-invasive ductal carcinoma (stage pT1b N0sn). One year later, she presented with a left-sided chest wall mass and enlarging left axillary lymph nodes. Needle core biopsies were obtained from both lesions, and histologic examination showed a poorly differentiated tumor with pleomorphic/anaplastic morphology and necrosis. The tumor cells were strongly immunoreactive for GATA-3 without expression of melanocytic markers (S100, Melan A, HMB45, SOX10, MITF, and tyrosinase). The history of melanoma prompted molecular analysis, and the lesion was found to harbor the BRAF V600K mutation, consistent with metastatic dedifferentiated melanoma. Recognition of metastatic dedifferentiated melanoma is important to avoid misdiagnosis of carcinoma, especially in patients with a previous history of carcinoma.

RevDate: 2019-12-27
CmpDate: 2019-12-27

Tan W, Tao L, Zhou Z, et al (2019)

Tumor-to-tumor metastasis: a rare case of breast carcinoma metastasizing to a pheochromocytoma, and a literature review.

Diagnostic pathology, 14(1):46 pii:10.1186/s13000-019-0816-2.

BACKGROUND: Tumor-to-tumor metastasis is a well-recognized but uncommon entity. Breast carcinoma is one of the most common metastatic donors. Breast carcinoma metastasizes commonly to adrenal glands. However, the co-existence of a metastatic lesion with an existing adrenal tumor is a rare finding.

CASE PRESENTATION: A 35-year-old woman was diagnosed with pheochromocytoma using computed tomography and ultrasound examinations. The tumor was surgically removed. Histological and immunohistochemical staining suggested that there were two components in the tumor: pheochromocytoma and metastatic cancer.

CONCLUSION: This is the second published case of pheochromocytoma with tumor-to-tumor metastasis from an invasive ductal carcinoma of the breast. Furthermore, we highlight the importance of awareness of tumor-to-tumor metastasis in pathological diagnosis.

RevDate: 2019-12-26

Phan Sy O, Rouchy RC, De Leiris N, et al (2019)

FDG PET/CT of a Supraclavicular Silicone Granuloma at Follow-up of a Breast Carcinoma.

Clinical nuclear medicine [Epub ahead of print].

We report herein the case of a 33-year-old woman who was referred for FDG PET/CT staging prior to pregnancy after a 4-year lost to follow-up for a breast invasive ductal carcinoma (pT2N1 SBRII). FDG PET/CT revealed right supraclavicular lymphadenopathy potentially caused by breast carcinoma recurrence. No additional site was involved. Supraclavicular ultrasonography showed typical "snowstorm" appearance. MRI revealed signs of breast implant intracapsular rupture and signal intensity of silicone within a supraclavicular node. Fine-needle aspiration and microbiopsy of adenopathy finally confirmed silicone granuloma and ruled out breast cancer recurrence.

RevDate: 2019-12-23
CmpDate: 2019-12-23

Campo-Sánchez SM, Camargo-Trillos J, Calle-Ramírez JA, et al (2019)

Colorectal cancer survival at an oncologic center in Colombia. A historic cohort study.

Revista de gastroenterologia de Mexico, 84(2):174-184.

INTRODUCTION AND AIMS: In Colombia, cancer of the colon is the third most frequent cancer in relation to incidence and mortality. Five-year survival depends on stage at diagnosis, albeit that rate is not known for the country. The aim of the present study was to characterize the overall survival and disease-free survival rates in an adult population with colorectal cancer treated at an oncology center in Medellín, Colombia.

MATERIALS AND METHODS: A retrospective cohort study was conducted. The case records of patients with a histologic diagnosis of colorectal cancer, seen within the time frame of 2011 and 2015, were reviewed. The overall survival and disease-free survival curves were calculated using the Kaplan-Meier method.

RESULTS: A total of 824 (54.9%) patients with cancer of the colon and 676 (45.1%) with cancer of the rectum were treated. Mean patient age was 63.3 years, female sex predominated (56.3%), and 98.1% of the tumors were adenocarcinomas. The majority of the lesions were stage iii (31.9% in the colon and 35.5% in the rectum) at the time of diagnosis. Surgery was the most frequent treatment in the colon (85.2%) and radiotherapy was the most frequent in the rectum (75.4%). Overall survival at the median follow-up (27.3 months) was 66.7% for cancer of the colon and 63.9% for cancer of the rectum. Disease-free survival at the median follow-up (18.6 months in colon and 14.9 in rectum) was 72.5 and 68.9%, respectively.

CONCLUSIONS: The clinical characteristics and treatment of patients were similar to those found in other studies. Two-year survival was higher than in other Colombian reports and 5-year survival was lower than that observed in developed countries.

RevDate: 2019-12-17

Redell M, Sierra-Hoffman M, Assi M, et al (2019)

The CHROME Study, a Real-world Experience of Single- and Multiple-Dose Oritavancin for Treatment of Gram-Positive Infections.

Open forum infectious diseases, 6(11):ofz479 pii:ofz479.

Background: Oritavancin (ORI) is a long-acting lipoglycopeptide indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSIs) caused or suspected to be caused by susceptible Gram-positive (GP) pathogens.

Methods: Data collected from a retrospective observational program (2014-2017), Clinical and Historic Registry and Orbactiv Medical Evaluation (CHROME), describe the utilization, outcomes, and adverse events (AEs) associated with ORI in 440 patients treated at 26 US sites for ABSSSI and other GP infections.

Results: Clinical success in evaluable patients receiving at least 1 dose of oritavancin was 88.1% (386/438). In a subgroup of patients who received ORI for skin and soft tissue infections (n = 401) and bacteremia (n = 7), clinical success was achieved in 89.0% and 100%, respectively. A cohort of 32 patients received 2-10 ORI doses separated by no more than 14 days for complicated GP infections. Clinical success was observed in 30 of 32 patients (93.8%), including 10 of 11 (90.9%) patients with bone and joint infections and 7 of 8 (87.5%) patients with osteomyelitis. In the safety evaluable population, the overall rate of AEs was 6.6%.

Conclusions: We describe results from a real-world program that includes the largest multicenter, retrospective, observational study in patients who received at least 1 dose of ORI for the treatment of GP infections. This study confirms that ORI is an effective, well-tolerated antibiotic used in single and multiple doses for the treatment of ABSSSIs and complicated GP infections.

RevDate: 2019-12-17

Christopher OC, NC Charles (2019)

Cancer Mortality in the Niger Delta Region of Nigeria: A Case Study of the University of Port Harcourt Teaching Hospital.

Nigerian medical journal : journal of the Nigeria Medical Association, 60(5):262-266.

Aim: The aim of this study is to determine the pattern of cancer mortality (CM) seen in the University of Port Harcourt Teaching Hospital (UPTH) which is a cancer reference center in the Niger Delta Region.

Methodology: This is a 6-year retrospective study of cancer-related deaths in UPTH using patients' admission registers in all the wards and emergency units. Furthermore, the death certificates of cases were reviewed.

Results: Three hundred and sixteen cases of cancer-related deaths occurred, involving 174 females and 142 males, in a female-to-male sex ratio of 1.2:1. All age groups were affected, with age group 40-49 years accounting for the majority (20.6%). CM was seen in all the systems, except the central nervous system. Cancers of the gastrointestinal tract and its accessory organs (liver and gall bladder) caused most mortality (27.9%), in a female-to-male ratio of 0.8:1. The single most involved organ in CM is the female breast (20.6%), distantly followed by mortality due to prostate cancers and hematolymphoid cancers which accounted for 9.2% each. Colorectal cancers accounted for 7.3% of cancer deaths and ranked 4th. Cancers of both cervix and stomach each accounted for 5.7% of mortality. The major histologic diagnoses were carcinomas (adenocarcinoma; 36.7%, invasive ductal carcinoma; 20.3%, squamous cell carcinomas; 8.2% and hepatocellular carcinomas; 4.4%). Leukemias and lymphomas accounted for 9.2% of cases, whereas sarcomas accounted for 5.1% of cases.

Conclusion: Infection-related and noninfection-related cancers cause most mortality in UPTH. The 5th decade was the most commonly affected, while female breast was the single most involved organ. Breast, prostate and hematolymphoid malignancies are common causes of CM with death from breast occurring earliest. Majority of the deceased were educated, working-class urban dwellers. More advocacies on public acceptance of cancer screening and cancer preventive lifestyles as well as governments' improvement on workforce training and treatment infrastructure will improve the current CM profile in Port Harcourt.

RevDate: 2019-12-17
CmpDate: 2019-12-12

Arabpour M, Ghods A, Shariat M, et al (2019)

Correlation of 4-1BBL+ B Cells in Tumor Draining Lymph Nodes with Pathological Characteristics of Breast Cancer.

Iranian journal of immunology : IJI, 16(2):108-116.

BACKGROUND: B cells can increase the expression of granzyme B in CD8+ T cells through 4-1BBL/4-1BB interaction and promote anti-tumor immunity.

OBJECTIVE: To investigate the expression of 4-1BBL on B cells in the breast tumor draining lymph nodes (TDLNs) and its association with disease parameters.

METHODS: Using Ficoll-Hypaque gradient centrifugation, mononuclear cells were isolated from axillary lymph nodes of 42 patients. Cells received 4 hours of PMA/Ionomycin stimulation, in vitro. Both unstimulated and stimulated cells were stained with anti‒CD19 and anti‒4-1BBL antibodies and subjected to flow cytometry.

RESULTS: 4-1BBL expression was detected on 2.8 ± 1.7% of unstimulated B cells, while 27.4 ± 11.9% of B cells expressed this co-stimulatory molecule following stimulation. In steady state, the percentage of 4-1BBL+ B cells was not associated with cancer characteristics. However, in patients with invasive ductal carcinoma, the percentage of 4-1BBL expressing B cells in stimulated condition had a decreasing trend in grade III, compared to grade II+I. In addition, significantly higher frequency of 4-1BBL+ B cells was seen in the TDLNs of ER+ or PR+ compared with ER‒ or PR‒ patients (p=0.021 and p=0.015, respectively). No significant associations were observed between the frequency of 4-1BBL+ B cells and the number of involved LNs, Her2 expression or disease stage.

CONCLUSIONS: The frequency of 4-1BBL+ B cells significantly increased following a short time activation, and showed relative and significant associations with tumor grade and estrogen receptor status, respectively. More investigations are required to evaluate the potential of 4-1BBL+ B cells for use in immunotherapy.

RevDate: 2019-12-17
CmpDate: 2019-12-17

Ciurea AI, Boca I, Rogojan L, et al (2019)

Pectoralis muscle metastases from breast cancer in a young patient detected by automated breast ultrasound.

Medical ultrasonography, 21(2):200-203.

Metastases to the skeletal muscle from breast cancer represent an unusual and rare condition. We present the case of a 27-year-old female with left breast cancer (IDC NST G3) who underwent neoadjuvant chemotherapy followed by conservativesurgery (sectorectomy and lymphadenectomy) and radiation therapy. Two months after the end of radiotherapy she presented with a 2 mm skin lesion and she was referred for a screening ultrasound. The screening automated breast ultrasound (ABUS) revealed local recurrence and pectoralis metastases, lesions evaluated also by magnetic resonance imaging. The diagnosis was confirmed by the ultrasound-guided biopsy.

RevDate: 2019-12-17
CmpDate: 2019-12-13

Grimm LJ, Saha A, Ghate SV, et al (2019)

Relationship between Background Parenchymal Enhancement on High-risk Screening MRI and Future Breast Cancer Risk.

Academic radiology, 26(1):69-75.

RATIONALE AND OBJECTIVES: To determine if background parenchymal enhancement (BPE) on screening breast magnetic resonance imaging (MRI) in high-risk women correlates with future cancer.

MATERIALS AND METHODS: All screening breast MRIs (n = 1039) in high-risk women at our institution from August 1, 2004, to July 30, 2013, were identified. Sixty-one patients who subsequently developed breast cancer were matched 1:2 by age and high-risk indication with patients who did not develop breast cancer (n = 122). Five fellowship-trained breast radiologists independently recorded the BPE. The median reader BPE for each case was calculated and compared between the cancer and control cohorts.

RESULTS: Cancer cohort patients were high-risk because of a history of radiation therapy (10%, 6 of 61), high-risk lesion (18%, 11 of 61), or breast cancer (30%, 18 of 61); BRCA mutation (18%, 11 of 61); or family history (25%, 15 of 61). Subsequent malignancies were invasive ductal carcinoma (64%, 39 of 61), ductal carcinoma in situ (30%, 18 of 61) and invasive lobular carcinoma (7%, 4of 61). BPE was significantly higher in the cancer cohort than in the control cohort (P = 0.01). Women with mild, moderate, or marked BPE were 2.5 times more likely to develop breast cancer than women with minimal BPE (odds ratio = 2.5, 95% confidence interval: 1.3-4.8, P = .005). There was fair interreader agreement (κ = 0.39).

CONCLUSIONS: High-risk women with greater than minimal BPE at screening MRI have increased risk of future breast cancer.

RevDate: 2019-12-02
CmpDate: 2019-12-02

Yilmaz R, Akpinar Y, Ozyavuz I, et al (2019)

Synchronous metastatic leiomyosarcoma and primer invasive ductal carcinoma tumors in the same breast: Mammography, ultrasonography, and magnetic resonance imaging findings.

The breast journal, 25(2):310-311.

RevDate: 2019-11-28
CmpDate: 2019-11-28

Koc-Günel S, Tekeli N, Smaczny C, et al (2019)

A Case of Lymphangioleiomyomatosis (LAM) of the Lung in a Patient with a History of Breast Cancer.

The American journal of case reports, 20:390-393 pii:914355.

BACKGROUND Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions. CASE REPORT A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms. CONCLUSIONS A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.

RevDate: 2019-11-27
CmpDate: 2019-11-27

Koren D, Rothschild-Yakar L, Lacoua L, et al (2019)

Attenuated psychosis and basic self-disturbance as risk factors for depression and suicidal ideation/behaviour in community-dwelling adolescents.

Early intervention in psychiatry, 13(3):532-538.

BACKGROUND AND AIMS: Adolescents at clinical high risk (CHR) for psychosis, as defined by the presence of attenuated psychosis symptoms (APS), exhibit increased levels of suicidal ideation and behaviour. However, no research thus far has examined the link between basic self-disturbances (SDs), an established marker for CHR, and suicidality/self-harm in this population. The goal of this pilot study was to assess the association between SD, depression and suicidal ideation and behaviour among non-help-seeking adolescents from the community.

METHOD: A total of 100 community-dwelling adolescents (age range: 13-16) were assessed using the Examination of Anomalous Self-experience, Prodromal Questionnaire, Structured Interview for Prodromal Syndromes, Mood and Anxiety Symptom Questionnaire and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). The K-SADS was used to derive a binary diagnosis of unipolar depression, as well as to measure suicidal ideation and behaviour and self-harm.

RESULTS: In a multiple regression analysis, SD accounted for variance in depressive symptoms and suicidality/self-harm over and above that accounted for by APS. Moreover, SD accounted for variance in suicidality/self-harm over and above that accounted for by depression symptoms.

CONCLUSIONS: These pilot results suggest that SD might be a unique dimension of vulnerability to depression and suicidality/self-harm in adolescence. Also, they encourage assessment of SD as part of a suicide risk assessment, particularly in the context of risk for subsequent psychosis.

RevDate: 2019-11-25
CmpDate: 2019-11-25

Lee J, Kim HE, Song YS, et al (2019)

miR-106b-5p and miR-17-5p could predict recurrence and progression in breast ductal carcinoma in situ based on the transforming growth factor-beta pathway.

Breast cancer research and treatment, 176(1):119-130.

PURPOSE: Ductal carcinoma in situ (DCIS) is well-known precursor of invasive ductal carcinoma (IDC). Parts of patients show recurrence as DCIS or IDC after local treatment, but there are no established markers predicting relapse. We analyzed changes in miRNA and oncogene expression during DCIS progression/evolution to identify potential markers predicting recurrence.

METHODS: Forty archival tissues diagnosed as primary or recurrent DCIS and DCIS adjacent to IDC were analyzed. MiRNA hierarchical clustering showed up-regulation of miR-17-5p and miR-106b-5p in recurrent DCIS and DCIS adjacent to IDC. Target genes were predicted based on pre-formed miRNA databases and PanCancer Pathway panel. MiRNAs were transfected into MCF-10A and MCF-7 cells; western blot analysis was performed with MCF-7 cell line to evaluate the effects on TGF-β downstream pathway.

RESULTS: miRNA hierarchical clustering showed 17 dysregulated miRNAs, including miR-17-5p and miR-106b-5p. Based on miRNA database and nCounter Pancancer pathway analysis, TGFβRII was selected as target of miR-106b-5p and miR-17-5p. MiR-106b-5p- and miR-17-5p-transfected MCF-7 cells showed decreased expression of TGFβRII, especially in cells transfected with both miRNAs.

CONCLUSION: miR-106b-5p and miR-17-5p might have a role in breast cancer recurrence and progression by suppressing TGF-β activity, leading to early breast cancer carcinogenesis.

RevDate: 2019-11-20
CmpDate: 2019-11-20

Zhu S, Ward BM, Yu J, et al (2018)

IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma.

JCI insight, 3(8):.

Pleomorphic invasive lobular carcinoma (PILC) is an aggressive variant of invasive lobular breast cancer that is associated with poor clinical outcomes. Limited molecular data are available to explain the mechanistic basis for PILC behavior. To address this issue, targeted sequencing was performed to identify molecular alterations that define PILC. This sequencing analysis identified genes that distinguish PILC from classic ILC and invasive ductal carcinoma by the incidence of their genomic changes. In particular, insulin receptor substrate 2 (IRS2) is recurrently mutated in PILC, and pathway analysis reveals a role for the insulin receptor (IR)/insulin-like growth factor-1 receptor (IGF1R)/IRS2 signaling pathway in PILC. IRS2 mutations identified in PILC enhance invasion, revealing a role for this signaling adaptor in the aggressive nature of PILC.

RevDate: 2019-11-18
CmpDate: 2019-11-18

Yang M, Xu Z, Zhang QZ, et al (2019)

A breast one-patient panel of heterogeneous genomes reveals genetic alterations driving DCIS into invasive lesions.

Future oncology (London, England), 15(14):1565-1576.

Aim: Utilize breast cancer samples in the same patient to indicate breast cancer development. Patients & methods: We performed whole-exome analysis of spatially independent ductal carcinoma in situ (DCIS) and invasive ductal carcinoma samples from the same breast. Results: In VEGF pathway, we observed two genes disrupted in DCIS, while another four (including ACTN2) mutated in invasive ductal carcinoma. When looked up TCGA database, we identified seven breast cancer patients with ACTN2 somatic mutations and observed a dramatic decrease in the overall survival time in ACTN2 mutant patients (p = 0.0182). A further finding in the TCGA database shows that breast cancer patients with ≥2 mutated genes in VEGF pathways showed worse prognosis (p = 0.0013). Conclusion: TCGA database and special case could inform each other to reveal DCIS developmental rules.

RevDate: 2019-11-18
CmpDate: 2019-11-18

Dong Y, Zhang WW, Wang J, et al (2019)

The 21-gene recurrence score and effects of adjuvant radiotherapy after breast conserving surgery in early-stage breast cancer.

Future oncology (London, England), 15(14):1629-1639.

Aim: To investigate the associations with the 21-gene recurrence score (RS) and effect of adjuvant radiotherapy (RT) for early-stage breast cancer after breast conserving surgery. Methods: We included 13,246 patients in the SEER database. Results: Patients with a higher RS were independently related to nonreceipt of RT (p < 0.001). In both the traditional and Trial Assigning Individualized Options for Treatment (TAILORx) RS cut-offs, the receipt of RT was not related to better breast cancer-specific survival in low- and high-risk RS groups, but was independently related to better breast cancer-specific survival in intermediate-risk RS group before (p = 0.029) and after (p = 0.001) propensity score matching. Conclusion: The 21-gene-RS may impact the decision-making of adjuvant RT in early-stage breast cancer after breast conserving surgery. The survival benefit of adjuvant RT may be limited to patients with intermediate-risk RS.

RevDate: 2019-11-18
CmpDate: 2019-11-18

Owen WA, Brazeal HA, Shaw HL, et al (2019)

Focal breast pain: imaging evaluation and outcomes.

Clinical imaging, 55:148-155.

OBJECTIVES: To determine the number and characteristics of cancers detected and the optimal imaging evaluation in women presenting with focal breast pain (FBP).

MATERIALS AND METHODS: We performed a retrospective review of 4720 women who underwent imaging for FBP from 2001 to 2013. Women 18 and over with one or two foci of breast pain and no concurrent breast symptoms were included. 944 patients met criteria. We recorded the imaging work-up, presence and type of finding at the site of pain, BI-RADS® assessment, and pathological outcomes. Subsequent imaging and clinical follow up was recorded.

RESULTS: Imaging evaluation consisted of sonogram alone in 286 women, mammogram alone in 231 women, and both in 427 women. 113 women had an imaging finding at the site of pain; 103 were designated benign or probably benign. 12 biopsies of corresponding findings were performed: 9 benign, 1 invasive lobular carcinoma, 1 invasive ductal carcinoma, 1 ductal carcinoma in situ. All three malignancies were seen mammographically; 2 had an ultrasound correlate. At initial evaluation, 4 incidental breast cancers were diagnosed remote from the site of FBP. All were seen on mammogram and 2 of 4 had an ultrasound correlate. On follow up evaluation, 9 cancers were diagnosed at the site of pain and 13 incidental cancers were diagnosed.

CONCLUSION: FBP is rarely associated with malignancy. Targeted ultrasound may be deferred in women 40 and older with FBP, no other clinical findings, and a negative mammogram.

RevDate: 2019-11-18
CmpDate: 2019-11-18

Nagle AM, Levine KM, Tasdemir N, et al (2018)

Loss of E-cadherin Enhances IGF1-IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors.

Clinical cancer research : an official journal of the American Association for Cancer Research, 24(20):5165-5177.

Purpose: Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin (CDH1) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and response to anti-IGF1R/insulin receptor (InsR) therapies in breast cancer.Experimental Design: Breast cancer cell lines were used to assess how altered E-cadherin levels regulate IGF1R signaling and response to two anti-IGF1R/InsR therapies. In situ proximity ligation assay (PLA) was used to define interaction between IGF1R and E-cadherin. TCGA RNA-seq and RPPA data were used to compare IGF1R/InsR activation in estrogen receptor-positive (ER+) invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) tumors. ER+ ILC cell lines and xenograft tumor explant cultures were used to evaluate efficacy to IGF1R pathway inhibition in combination with endocrine therapy.Results: Diminished functional E-cadherin increased both activation of IGF1R signaling and efficacy to anti-IGF1R/InsR therapies. PLA demonstrated a direct endogenous interaction between IGF1R and E-cadherin at points of cell-cell contact. Increased expression of IGF1 ligand and levels of IGF1R/InsR phosphorylation were observed in E-cadherin-deficient ER+ ILC compared with IDC tumors. IGF1R pathway inhibitors were effective in inhibiting growth in ER+ ILC cell lines and synergized with endocrine therapy and similarly IGF1R/InsR inhibition reduced proliferation in ILC tumor explant culture.Conclusions: We provide evidence that loss of E-cadherin hyperactivates the IGF1R pathway and increases sensitivity to IGF1R/InsR targeted therapy, thus identifying the IGF1R pathway as a potential novel target in E-cadherin-deficient breast cancers. Clin Cancer Res; 24(20); 5165-77. ©2018 AACR.

RevDate: 2019-11-14
CmpDate: 2019-11-14

Klomek AB (2019)

Prevention of postpartum suicidality in Israel.

Israel journal of health policy research, 8(1):77.

Postpartum suicidality in Israel had not been systematically studied until the recent important investigation by Glasser and colleagues. The authors review rates, trends, and characteristics of postpartum women who considered, attempted, or completed suicide in Israel. This commentary argues that, although postpartum suicidality is relatively rare, it is extremely tragic-not just for the women, but for the entire family and community. The main aim of this commentary is to emphasize that preventive efforts should continue and expand, especially among at-risk groups. At-risk groups include the youngest age group, postpartum Arab women, and postpartum former Soviet Union immigrants. Identification of women at risk or suffering from postpartum depression (PPD) is mandated in Israel. Efforts should include broader screening for various types of suicide ideation and behavior. Assessments should specifically include passive suicide ideation, active suicide ideation with method, intent, and plan, as well as various types of suicide attempts and preparatory behaviors. In addition, specific interventions formulated on evidence-based psychotherapies should be provided in family practice, obstetric, and pediatric settings. These settings are less stigmatized in comparison to mental health settings. Potential therapies can be (among others) Cognitive Behavioral Therapy (CBT) and Interpersonal Psychotherapy (IPT), which are effective in preventing perinatal depression.

RevDate: 2019-11-11
CmpDate: 2019-11-11

Autenshlyus AI, Davletova KI, Studenikina AA, et al (2019)

[Cytokine production by blood immune cells, tumor and its microenvironment, characteristic of extracellular matrix in patients with invasive ductal carcinoma of no special type].

Biomeditsinskaia khimiia, 65(5):424-431.

The aim of this research was to study cytokine production by blood immune cells, tumor, and its microenvironment, and characterize extracellular matrix of patients with invasive ductal carcinoma of no special type and lymphatic metastases. Spontaneous and polyclonal activators stimulated production of cytokines by blood immune cells, tumor and its microenvironment were studied in 95 patients with invasive ductal carcinoma of no special type. The concentration of IL-2, IL-4, IL-6, IL-8, IL-10, IL-17, IL-18, IL-1β, IL-1Ra, TNF-α, IFN-γ, G-CSF, GM-CSF, VEGF and MCP-1 was determined by the solid-phase enzyme-linked immunosorbent assay. The condition of fibrous component and presence of neutral glycoproteins and sulfated glycosaminoglycans were evaluated during the research of extracellular matrix. Regional lymphatic metastases were detected in 35 of 95 patients. It was shown that in the presence or absence of lymphatic metastases index of polyclonal activators influence on the production of cytokines by blood immune cells was different for IL-6, IL-8, and IL-1β; while in the case of cytokine production by tumor and its microenvironment the index of influence was different for IL-2 and IL-17. The presence of lymphatic metastases corresponded with the rise of cytokines spontaneous production, while the absence of lymphatic metastases corresponded with the rise of cytokines production stimulated by polyclonal activators. The value of indices of polyclonal activators influence on the production of cytokines by blood immune cells pointed to the highly stimulating effect of polyclonal activators while the value of indices of polyclonal activators influence on cytokines production by tumor and its microenvironments pointed to the low and sometimes even absent effect of polyclonal activators. Basing on these data we propose a ratio of indices of polyclonal activators influence for the better evaluation of the probability of lymphatic metastases during preoperative period. After characterizing extracellular matrix we found out a point threshold, which, in 100% of cases, predicted the presence of lymphatic metastases basing on the condition of extracellular matrix. Using the data acquired, we are proposing a risk group for metastasis among women with no lymphatic metastases in the moment of check-up.

RevDate: 2019-11-08
CmpDate: 2019-11-08

Jacob T, J Bracha (2019)

Identification of Signs and Symptoms of Axillary Web Syndrome and Breast Seroma During a Course of Physical Therapy 7 Months After Lumpectomy: A Case Report.

Physical therapy, 99(2):229-239.

Background and Purpose: Axillary web syndrome (AWS) and seroma are common and function-limiting side effects following treatments for breast cancer. Studies of AWS and seroma are rare, and there are no guidelines for physical therapy in these cases.

Case Description: After left breast lumpectomy due to invasive ductal carcinoma, a 65-year-old female patient underwent intraoperative radiation therapy and whole breast radiation. Seven months later, during treatment for breast swelling, AWS and breast seroma were identified by a physical therapist certified in lymphedema treatment. Treatment goals were to reduce breast swelling and pain and to improve shoulder movements. Interventions included manual lymph drainage, left arm stretching, and instruction about self-lymphatic-drainage and stretching exercise. Also, a compression bra was ordered, and continued daily activities and physical activity were recommended.

Outcomes: Improvement in shoulder movement, breast swelling, and pain.

Discussion: Because evidence for treatment guidelines following treatments for breast cancer is lacking, close follow-up for treatment-related complications is recommended. Management should be chosen according to signs and symptoms. Realistic expectations can reduce patient frustration and improve coping strategies and compliance with self-treatment demands. Clinical studies to support these conclusions are required.

RevDate: 2019-10-29
CmpDate: 2019-10-29

Maida A, Zota A, Vegiopoulos A, et al (2018)

Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance.

The Journal of nutritional biochemistry, 57:189-196.

Recent studies have demonstrated that dietary protein dilution (PD) can promote metabolic inefficiency and improve glucose metabolism. However, whether PD can promote other aspects of metabolic health, such as improve systemic lipid metabolism, and mechanisms therein remains unknown. Mouse models of obesity, such as high-fat-diet-fed C57Bl/6 N mice, and New Zealand Obese mice were fed normal (i.e., 20%P) and protein-dilute (i.e., 5%EP) diets. FGF21-/- and Cd36-/- and corresponding littermate +/+ controls were also studied to examine gene-diet interactions. Here, we show that chronic PD retards the development of hypertrigylceridemia and fatty liver in obesity and that this relies on the induction of the hepatokine fibroblast growth factor 21 (FGF21). Furthermore, PD greatly enhances systemic lipid homeostasis, the mechanisms by which include FGF21-stimulated, and cluster of differentiation 36 (CD36) mediated, fatty acid clearance by oxidative tissues, such as heart and brown adipose tissue. Taken together, our preclinical studies demonstrate a novel nutritional strategy, as well as highlight a role for FGF21-stimulated systemic lipid metabolism, in combating obesity-related dyslipidemia.

RevDate: 2019-10-17
CmpDate: 2019-10-17

Abu-Sbeih H, Ali FS, Luo W, et al (2018)

Importance of endoscopic and histological evaluation in the management of immune checkpoint inhibitor-induced colitis.

Journal for immunotherapy of cancer, 6(1):95.

BACKGROUND: Immune checkpoint inhibitors (ICPI) are efficacious treatments for advanced malignancies but can result in immune mediated diarrhea and colitis (IDC). Currently, the guidelines for the treatment of IDC depend only on clinical symptoms. Endoscopic and histologic features of such adverse events are not well studied in a manner that can help to gauge treatment plans. We aimed to characterize endoscopic and histologic features of IDC and to assess their association with clinical outcomes.

METHODS: Our study included patients who had undergone endoscopy for IDC (1/2010 to 3/2018). Patients with GI infection at time of onset were excluded. High-risk endoscopic features were ulcers deeper than 2 mm, larger than 1 cm, and extensive colonic involvement. Univariate and multivariate logistic regression were performed to assess the association of endoscopic and histological features with clinical outcomes.

RESULTS: A total of 182 patients was included; most were white (92%), males (65%) with a mean age of 60 years. Median time from ICPI initiation to IDC was 7 weeks. Fifty-three percent had grade 3-4 diarrhea, and 32% grade 3-4 colitis. Forty-nine patients had mucosal ulcerations, 66 non-ulcerative inflammation and 67 normal endoscopy. Calprotectin was higher in patients with ulceration (P = 0.04). The sensitivity of lactoferrin to detect histologic and endoscopic inflammation was 90% and 70% respectively. Patients who underwent endoscopy earlier than 7 days after IDC onset had shorter duration of IDC symptoms and duration of steroid treatment than those who underwent endoscopy after 7 days of IDC onset (P = 0.026 and P = 0.053, respectively). Patients who underwent endoscopy > 30 days of symptom onset required longer duration of steroids (P = 0.02), had more recurrent symptoms (P < 0.01) and received later infliximab/vedolizumab add-on therapy than did those who underwent endoscopy ≤30 days (P = 0.03). High-risk features were associated with more frequent (P = 0.03) and longer duration (P = 0.02) hospitalization and infliximab/vedolizumab requirement (P < 0.01). Patients with active histological inflammation had more recurrence (P < 0.01) and repeat endoscopy (P < 0.01). Repeat endoscopy was required in 47 patients. A multivariate logistic regression revealed that longer ICPI treatment was associated with more frequent hospitalizations (OR 1.00; 95%CI 1.00-1.01; P < 0.01) and high-risk endoscopic features were associated with the requirement of infliximab/vedolizumab (OR 3.89; 95%CI 1.68-9.01; P < 0.01).

CONCLUSION: High risk endoscopic features and active histologic inflammation represent important markers of disease severity with clinical implications and should be used in a timely manner to devise IDC-focused treatment algorithms.

RevDate: 2019-10-16
CmpDate: 2019-10-16

Dodson A, Parry S, Ibrahim M, et al (2018)

Breast cancer biomarkers in clinical testing: analysis of a UK national external quality assessment scheme for immunocytochemistry and in situ hybridisation database containing results from 199 300 patients.

The journal of pathology. Clinical research, 4(4):262-273.

We describe a collated data set of results from clinical testing of breast cancers carried out between 2009 and 2016 in the United Kingdom and Republic of Ireland. More than 199 000 patient biomarker data sets, together with clinicopathological parameters were collected. Our analyses focused on human epidermal growth factor receptor-2 (HER2), oestrogen receptor (ER) and progesterone receptor (PR), with the aim of the study being to provide robust confirmatory evidence on known associations in these biomarkers and to uncover new data on previously undescribed or unconfirmed associations, thus strengthening the evidence-base in clinical breast cancer testing. Overall, 13.1% of tumours were HER2-positive; 10.6% in ER-positive tumours, and 25.5% in ER-negative tumours. Higher rates of HER2 positivity were significantly associated with patient age <56 years versus age ≥56 years, symptomatic versus screen-detected tumours, testing of involved axillary node versus primary breast cancer, invasive ductal carcinoma (not otherwise specified) versus other histological types, higher histological grade, increasing tumour size, increasing nodal involvement, ER-negative versus ER-positive tumour status, PR-negative versus PR-positive tumour status. Where ER status was known, 82.7% of tumours were ER-positive; 80.9% in women age <56 years, and 83.6% in those age ≥56 years (ER-positive cut-off ≥1.0% positive tumour cells or equivalent). Where PR status was known, 64.9% of tumours were PR-positive; 65.8% in women age <56 years, and 64.4% in women age ≥56 years (PR-positive cut off ≥10.0% or equivalent). These analyses of clinical test results provide contemporary benchmarking data for HER2, ER and PR positive rates.

RevDate: 2019-10-15
CmpDate: 2019-10-15

Sen U, Saxena H, Khurana J, et al (2018)

Plasmodium falciparum RUVBL3 protein: a novel DNA modifying enzyme and an interacting partner of essential HAT protein MYST.

Scientific reports, 8(1):10917.

RUVBLs constitute a conserved group of ATPase proteins that play significant role in a variety of cellular processes including transcriptional regulation, cell cycle and DNA damage repair. Three RUVBL homologues, namely, PfRUVBL1, PfRUVBL2 and PfRUVBL3 have been identified in P. falciparum, unlike its eukaryotic counterparts, which have two RUVBL proteins (RUVBL1 & RUVBL2). The present study expands our understanding of PfRUVBL3 protein and thereby basic biology of Plasmodium in general. Here, we have shown that parasite PfRUVBL3 is a true homolog of human/yeast RUVBL2 protein. Our result show that PfRUVBL3 constitutively expresses throughout the stages of intra-erythrocytic cycle (IDC) with varied localization. In addition to ATPase and oligomerization activity, we have for the first time shown that PfRUVBL3 possess DNA cleavage activity which interestingly is dependent on its insertion domain. Furthermore, we have also identified RUVBL3 to be an interacting partner of an essential chromatin remodeling protein PfMYST and together they colocalize with H3K9me1 histone in parasitophorous vacuole during the ring stage of IDC suggesting their potential involvement in chromatin remodeling and gene transcription.

RevDate: 2019-10-15
CmpDate: 2019-10-15

Du T, Zhu L, Levine KM, et al (2018)

Invasive lobular and ductal breast carcinoma differ in immune response, protein translation efficiency and metabolism.

Scientific reports, 8(1):7205.

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer following invasive ductal carcinoma (IDC). ILC differs from IDC in a number of histological and clinical features, such as single strand growth, difficulty in detection, and frequent late recurrences. To understand the molecular pathways involved in the clinical characteristics of ILC, we compared the gene expression profiles of luminal A ILC and luminal A IDC using data from TCGA and utilized samples from METABRIC as a validation data set. Top pathways that were significantly enriched in ILC were related to immune response. ILC exhibited a higher activity of almost all types of immune cells based on cell type-specific signatures compared to IDC. Conversely, pathways that were less enriched in ILC were related to protein translation and metabolism, which we functionally validated in cell lines. The higher immune activity uncovered in our study highlights the currently unexplored potential of a response to immunotherapy in a subset of patients with ILC. Furthermore, the lower rates of protein translation and metabolism - known features of tumor dormancy - may play a role in the late recurrences of ILC and lower detection rate in mammography and PET scanning.

RevDate: 2019-10-08
CmpDate: 2019-10-08

Esmaeili SA, Mahmoudi M, Rezaieyazdi Z, et al (2018)

Generation of tolerogenic dendritic cells using Lactobacillus rhamnosus and Lactobacillus delbrueckii as tolerogenic probiotics.

Journal of cellular biochemistry, 119(9):7865-7872.

Systemic lupus erythematosus (SLE) concurs with excessive uncontrolled inflammatory immune responses that lead to the loss of immune tolerance. Dendritic cells (DCs) are important and determinant immune cells that regulate immune responses. Tolerogenic DCs with regulatory markers and cytokines could induce regulatory immune cells and responses. Tolerogenic probiotics are capable of producing regulatory DCs from monocytes in in vitro conditions. The purpose of this study was to evaluate the effect of Lactobacillus delbrueckii and Lactobacillus rhamnosus on the production of DCs in an in vitro condition. Peripheral blood mononuclear cells were isolated from the healthy and SLE donors. Monocytes were cultured with optimized concentrations of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) to produce immature DCs (IDCs). An IDC uptake assay was performed, and IDCs of healthy and SLE donors were divided into three subgroups following 48 hours of treatment with GM-CSF and IL-4, along with L. delbrueckii, L. rhamnosus, and mixed probiotics for the production of tolerogenic DCs. The surface expression of Human Leukocyte Antigen-antigen D Related (HLA-DR), CD86, CD80, CD83, CD1a, and CD14 was analyzed using flow cytometry, and the gene expression levels of indoleamine 2,3-dioxygenase (IDO), IL-10, and IL-12 were measured using real-time polymerase chain reaction. We observed significantly reduced expression of costimulatory molecules and other surface markers in the probiotic-induced mature DCs (MDCs) in both healthy and SLE donor groups in comparison with lipopolysaccharide (LPS)-induced MDCs. In addition, the expression of IDO and IL-10 increased, whereas IL-12 decreased significantly in probiotic-induced MDCs compared with LPS-induced MDCs. IDCs and especially mature tolerogenic DC of SLE patients highly expressed IDO. The results of the current study suggested that live probiotics could modify properties of DCs to modulatory cells, which might contribute to the induction of tolerance and renovation of immune hemostasis.

RevDate: 2019-10-08
CmpDate: 2019-10-08

Dong C, Liu Y, Jiang K, et al (2018)

The Nogo-B receptor promotes human hepatocellular carcinoma cell growth via the Akt signal pathway.

Journal of cellular biochemistry, 119(9):7738-7746.

Nogo-B receptor (NgBR) is a type I receptor with a single transmembrane domain and specifically binds to ligand Nogo-B. A previous study demonstrated that NgBR was highly expressed in human breast invasive ductal carcinoma and promoted epithelial-mesenchymal transition in breast tumor cells. Our recent work found that NgBR expression was associated with a poor prognosis in human patients with hepatocellular carcinoma (HCC). Here, we elucidate that the increased expression of NgBR contributes toward the increased cell growth of human HCC cells both in vitro and in vivo. Cell viability and clonogenic survival analysis results demonstrated that knockdown of NgBR inhibits the cell growth in human HCC cells, which correlates with a reduction in the phosphorylation of Akt levels. Furthermore, overexpression of NgBR by the cotransfected pIRES-NgBR plasmid together with NgBR siRNA in human HCC cells can rescue impaired phosphorylation of Akt levels in NgBR knockdown human HCC cells. In addition, cell viability analyses showed that NgBR overexpression can rescue the cell growth inhibition presented in human HCC NgBR knockdown cells. Taken together, our results suggest that NgBR potentially acts as an oncogene in HCC by increasing Akt activity. Thus, NgBR may represent a new potential diagnostic and therapeutic target for the treatment of HCC.

RevDate: 2019-10-07
CmpDate: 2019-10-02

Montironi R, Zhou M, Magi-Galluzzi C, et al (2018)

Features and Prognostic Significance of Intraductal Carcinoma of the Prostate.

European urology oncology, 1(1):21-28.

CONTEXT: Intraductal carcinoma of the prostate (IDC-P) is an intraglandular/ductal neoplastic growth of glandular epithelial cells characterized by marked abnormality of the glandular architecture and/or cytological atypia that exceeds what is typically seen in high-grade prostatic intraepithelial neoplasia (HPGIN). It has been shown that IDC-P is a strong independent indicator of poor prognosis for prostate carcinoma (PCa).

OBJECTIVE: To review the pathological and genetic features, diagnostic criteria and differential diagnosis, and clinical significance of IDC-P.

EVIDENCE ACQUISITION: PubMed was searched using keywords including prostate carcinoma, intraductal carcinoma, IDC, histology, diagnostic criteria, and prognosis. The references in relevant articles were also reviewed.

EVIDENCE SYNTHESIS: IDC-P is a distinct entity with characteristic morphological and genetic features. It is strongly associated with aggressive PCa with high Gleason score/grade groups and large tumor volume, and portends unfavorable clinical outcomes. Morphological diagnostic criteria have been established to distinguish it from other lesions with similar histological features. IDC-P is an uncommon finding in prostate biopsies, and is even rarer as an isolated finding without concomitant PCa. However, patients with isolated IDC-P in biopsy specimens are recommended to have either definitive treatment or immediate repeat biopsy.

CONCLUSIONS: It is critical to recognize and report IDC-P, especially in prostate biopsies, where the clinical impact of such a diagnosis is greatest.

PATIENT SUMMARY: Intraductal carcinoma is a unique form of aggressive prostate cancer. In this report, we review its pathological and genetic features and poor prognostic significance. It is critical for pathologists to recognize and report this lesion in prostate specimens, especially in prostate biopsies for patient management.

RevDate: 2019-10-02

Marsili C, Wilson CM, N Gura (2019)

Prospective Surveillance Screenings to Identify Physical Therapy Needs During Breast Cancer Diagnosis and Surviviorship: A Case Report.

Cureus, 11(7):e5265.

Breast cancer and its treatments can cause detrimental effects to function and quality of life (QoL). These patients do not conventionally receive physical therapy services until impairments and functional limitations have become extensive. Emerging treatment models advocate for early rehabilitation screenings and proactive interventions, which are termed prospective surveillance. The purpose of this case report was to describe two prospective surveillance screenings at initial diagnosis and survivorship and subsequent physical therapy episodes of care for a patient with breast cancer. A 39-year-old female was diagnosed with invasive ductal carcinoma of the right breast. Approximately three months after the initial diagnosis, the patient had a right nipple-sparing mastectomy and immediate reconstruction with an expander. In addition, one lymph node was removed and underwent a biopsy, which was negative for metastases. The patient was screened by a physical therapist after her initial cancer diagnosis at the breast multidisciplinary clinic. This was after her mastectomy with an expander; the therapist recommended an episode of outpatient physical therapy due to impairments in pain, fatigue, loss of range of motion, weakness, and limitations in performance of her activities of daily living. The patient was seen initially for five visits. She underwent her final reconstructive surgery one month after discharge from physical therapy. Six months after her final reconstructive surgery, she was screened by the same physical therapist in the cancer survivorship clinic. Once again, therapy was recommended due to pain as well as deficits to her range of motion, strength, and functional status. The second episode of care lasted 14 visits and the patient showed improvements in pain, range of motion, shoulder strength and gains in the patient-specific functional scale and upper extremity functional index. This case reflects the importance of prospective surveillance screenings to overall patient outcomes. This patient may not have otherwise received physical therapy and its associated benefits without the prospective screenings by the physical therapist.

RevDate: 2019-09-25
CmpDate: 2019-09-25

Vergine M, Musella A, Gulotta E, et al (2018)

Paget's disease of the male breast: case report and a point of view from actual literature.

Il Giornale di chirurgia, 39(2):114-117.

INTRODUCTION: Paget disease of the nipple in man is a very rare breast cancer, and there are not standard procedures or guidelines. In any cases, a Paget's disease could hide an invasive ductal breast cancer.

CASE DESCRIPTION: We report the case of a 77-years old man affected by Alzheimer's disease, who presented to our attention because of an ulcerated palpable mass in the right nipple. A biopsy of the lesion showed "intra-epidermic proliferation of epitelioid cells, associated with linfo-plasmacellular infiltration of superficial dermis, compatible with Paget's disease (pTis)". We discussed the case in the multidisciplinary meeting and decided to subject the patient to surgery, so a right mastectomy plus sentinel lymph node biopsy (SLNB) were performed. Histo-pathological examination revealed "invasive ductal carcinoma of the breast, associated with a small component of in situ ductal carcinoma and Paget's disease of the nipple with superficial ulceration". Resection margins were free. Sentinel lymph node was negative. Biological features were as follows: ER 95%, PR 60%, Her-2/neu 1+, Ki-67 35%. The patient was discharged in the third post-operative day in good conditions. In the following weeks the patient's healing process was good and free of complications.

CONCLUSIONS: Clinical recognition of Paget's disease is very important also in man, because it can be the alarm bell for an underlying invasive ductal breast cancer, often more aggressive than in woman.

RevDate: 2019-09-25
CmpDate: 2019-09-24

Babaei R, Schuster M, Meln I, et al (2018)

Jak-TGFβ cross-talk links transient adipose tissue inflammation to beige adipogenesis.

Science signaling, 11(527): pii:11/527/eaai7838.

The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways.

RevDate: 2019-09-20
CmpDate: 2019-09-20

Zhou T, Xu D, Tang B, et al (2018)

Expression of programmed death ligand-1 and programmed death-1 in samples of invasive ductal carcinoma of the breast and its correlation with prognosis.

Anti-cancer drugs, 29(9):904-910.

The aim of the current study is to investigate programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) expressions and to analyze the relationship between the expression of PD-L1 and PD-1 proteins and the molecular type, clinicopathological factors, and prognosis of invasive ductal carcinoma. We enrolled 136 patients with invasive ductal carcinoma of the breast. The expression of PD-L1 in tumor cells and that of PD-1 on paratumor-infiltrating immune cells was detected by immunohistochemistry, and the data were analyzed using SPSS software. The positive expression rates of PD-L1 and PD-1 in triple-negative breast cancer (TNBC) were 47.8 and 43.5%, which were higher than those of other subtypes (P<0.05). The expression of PD-L1 in tumor cells was correlated with the expression of estrogen receptor, progesterone receptor, and Ki-67 (P<0.05). The expression of PD-1 in the tumor-infiltrating immune cells was correlated with the expression of estrogen receptor, progesterone receptor, and Ki-67 and the histological grade (P<0.05). The expression of PD-L1 in tumor cells was correlated with the expression of PD-1 in paratumor-infiltrating immune cells (P<0.001). The expression of PD-L1 in tumor cells was found to be an independent prognostic risk factor with the progression-free survival rate for breast invasive ductal carcinoma (P=0.003). These results indicate that PD-L1 and PD-1 were highly expressed in TNBC which suggests that patients with TNBC may benefit from targeted immune therapies to a greater degree than patients with other subtypes. PD-L1 expression is an independent risk factor for breast invasive ductal carcinoma and expression of PD-L1 is expected to be a prognostic factor for breast cancer.

RevDate: 2019-09-19
CmpDate: 2019-09-19

Oliveira RV, Souza VB, Souza PC, et al (2018)

Detection of Putative Stem-cell Markers in Invasive Ductal Carcinoma of the Breast by Immunohistochemistry: Does It Improve Prognostic/Predictive Assessments?.

Applied immunohistochemistry & molecular morphology : AIMM, 26(10):760-768.

INTRODUCTION: Experimental evidences from the last 2 decades supports the existence of a special type of neoplastic cell with stem-like features [cancer stem cell (CSC)] and their role in the pathophysiology and therapeutic resistance of breast cancer. However, their clinical value in human breast cancer has not been fully determined.

MATERIALS AND METHODS: An immunohistochemistry panel of 10 putative CSC markers (CD34, C-KIT, CD10, SOX-2, OCT 3/4, p63, CD24, CD44, CD133, and ESA/EPCAM) was applied to 74 cases of breast cancer, followed in a Regional Cancer Center of Minas Gerais State, Brazil, from 2004 to 2006. Possible associations between CSC markers and classic variables of clinicopathologic relevance were investigated.

RESULTS: The most frequently positive CSC markers were CD44, CD24, CD133, and ESA (the others were present in <15% of the cases). Two CSC profiles were defined: CD24/CD44 (CSC-1) and CD133/ESA (CSC-2). CSC-1 was significantly associated to patients older than 40 years, tumors of <2.0 cm in diameter, early clinical stages (P<0.05), and increased death risk of 4 times (P=0.03; 95% confidence interval, 1.09-14.41). CSC-2 was related to increased relapse risk of 3.75 times (P=0.04; 95% confidence interval, 1.02-13.69).

CONCLUSION: The detection of the most frequently positive CSC markers by immunohistochemistry is of clinicopathologic and prognostic relevance.

RevDate: 2019-09-18
CmpDate: 2019-09-18

Ngara M, Palmkvist M, Sagasser S, et al (2018)

Exploring parasite heterogeneity using single-cell RNA-seq reveals a gene signature among sexual stage Plasmodium falciparum parasites.

Experimental cell research, 371(1):130-138.

The malaria parasite has a complex lifecycle, including several events of differentiation and stage progression, while actively evading immunity in both its mosquito and human hosts. Important parasite gene expression and regulation during these events remain hidden in rare populations of cells. Here, we combine a capillary-based platform for cell isolation with single-cell RNA-sequencing to transcriptionally profile 165 single infected red blood cells (iRBCs) during the intra-erythrocytic developmental cycle (IDC). Unbiased analyses of single-cell data grouped the cells into eight transcriptional states during IDC. Interestingly, we uncovered a gene signature from the single iRBC analyses that can successfully discriminate between developing asexual and sexual stage parasites at cellular resolution, and we verify five, previously undefined, gametocyte stage specific genes. Moreover, we show the capacity of detecting expressed genes from the variable gene families in single parasites, despite the sparse nature of data. In total, the single parasite transcriptomics holds promise for molecular dissection of rare parasite phenotypes throughout the malaria lifecycle.

RevDate: 2019-09-13
CmpDate: 2019-09-13

Santangelo G, Vitale C, Baiano C, et al (2018)

Interoceptive processing deficit: A behavioral marker for subtyping Parkinson's disease.

Parkinsonism & related disorders, 53:64-69.

BACKGROUND: Non-motor symptoms in Parkinson's disease (PD), such as cognitive, emotional, autonomic and somatosensory alterations, are not ubiquitous but vary between the tremor dominant (TD) and postural instability/gait difficulty (PIGD) subtypes of the syndrome. Non-motor phenomena (e.g., anxiety, depression and apathy) have been related to representation of autonomic and somatosensory sensations (interoception), and recent findings suggest interoceptive deficits in PD.

OBJECTIVES: To test whether interoceptive processing is differently affected in TD and PIGD phenotypes, by assessing both interoceptive accuracy and sensibility in PD patients with TD and PIGD subtypes, and in healthy controls.

METHODS: Interoceptive accuracy was measured by the heartbeat perception task requiring participants to count their own heartbeats in a given time interval. A time-estimation, control task was also administered asking participants to count the seconds in a set period of time. Interoceptive sensibility was assessed by a questionnaire of subjective interoception. Finally, the patients underwent measures of anxiety, depression, apathy and anhedonia, and impulsive-compulsive disturbances.

RESULTS: The main results showed reduced interoceptive accuracy and sensibility in TD patients relative to both PIGD patients and healthy controls. Reduced interoceptive accuracy of TD group was a reliable result since their performance on the time estimation control task was comparable to that of both PIGD patients and healthy controls.

CONCLUSIONS: These findings demonstrate that the behavioural assessment of different aspects of interoceptive processing can provide with a further marker for subtyping patients with PD.

RevDate: 2019-09-12

Ali Mlees M (2019)

Diagnosis and surgical treatment of pathologic nipple discharge using ultrasound-guided wire localization of focal ductal dilatation.

The breast journal [Epub ahead of print].

Nipple discharge is the third breast complaint after pain and lumps. The modern high-resolution ultrasound techniques are becoming more sensitive for the visualization of intraductal changes especially focal ductal dilatation (FDD), hypothesized as a radiographic manifestation of the lesion itself and that ultrasound-guided wire localization of this finding would enable identification and excision of the causative lesion. The aim of this study was to evaluate the safety, feasibility, efficiency and outcome of ultrasound-guided wire localization of FDD as possible cause of pathological nipple discharge (PND). The present study was conducted on 56 patients with PND presented to Surgical Oncology Unit at General Surgery Department, Tanta University Hospital from January 2018 to January 2019. The patients subjected to ultrasound-guided wire localization of FDD on the day of surgery, the involved duct was cannulated with a lacrimal duct probe, the targeted tissue was excised, and the specimen was sent for histopathological examination. The patients' age ranged between 26 and 71 years with a mean age of 48 years. The bloody nipple discharge was the commonest presenting symptom in 44 out of 56 patients (78.5%). The duct dilatation on study ultrasound ranged from 2.1 to 3.7 mm with a mean of 2.6 mm. Preoperative ultrasound-guided wire localization of the site of FDD was successfully performed in all cases. Papilloma alone founded in 40 out of 56 patients (71.4%), papilloma + ductal carcinoma in situ (DCIS) in six patients (10.7%), papilloma + invasive ductal carcinoma in six patients (10.7%), DCIS in two patients (3.6%) and duct ectasia in two patients (3.6%). Ultrasound-guided wire localization of FDD is an easy and safe technique for evaluation, precise localization, and targeted excision of the underlying lesions of PND.

RevDate: 2019-09-12
CmpDate: 2019-09-12

Guillamat-Prats R, Rami M, Herzig S, et al (2019)

Endocannabinoid Signalling in Atherosclerosis and Related Metabolic Complications.

Thrombosis and haemostasis, 119(4):567-575.

Endocannabinoids are a group of arachidonic acid-derived lipid mediators binding to cannabinoid receptors CB1 and CB2. An overactivity of the endocannabinoid system plays a pathophysiological role in the development of visceral obesity and insulin resistance. Moreover, elevated circulating endocannabinoid levels are also prevalent in atherosclerosis. The pathophysiological increase of endocannabinoid levels is due to an altered expression of endocannabinoid synthesizing and degrading enzymes induced by inflammatory mediators such as cytokines or lipids. Emerging experimental evidence suggests that enhanced endocannabinoid signalling affects atherosclerosis via multiple effects, including a modulation of vascular inflammation, leukocyte recruitment, macrophage cholesterol metabolism and consequently atherosclerotic plaque stability. In addition, recent findings in various metabolic disease models highlight the relevance of peripheral CB1 cannabinoid receptors in adipose tissue, liver and pancreas, which crucially regulate lipid and glucose metabolism as well as macrophage properties in these organs. This suggests that targeting the endocannabinoid system in the vasculature and peripheral organs might have a therapeutic potential for atherosclerosis by inhibiting vascular inflammation and improving metabolic risk factors. This review will provide a brief update on the effects of endocannabinoid signalling in atherosclerosis and related metabolic complications.

RevDate: 2019-09-11

Couto MSA, Firme VAC, Guerra MR, et al (2019)

The effect of redistribution of ill-defined causes of death on the mortality rate of breast cancer in Brazil.

Ciencia & saude coletiva, 24(9):3517-3528 pii:S1413-81232019000903517.

The relevance of breast cancer for women has driven research about mortality of this disease. However, these studies are affected by problems generated by deaths due to ill-defined causes (IDC). To highlight distortions caused by IDC in studies that evaluate mortality, we calculated the age-standardized mortality rates of breast cancer, with and without adjustment for IDC for the years 1990, 2000, and 2010. Then, panel data regression models were estimated and enabled us to identify that the adjustment for IDC: has elevated breast cancer mortality rate of Brazilian municipalities by 9% in the period considered; has drawn mortality rates of the South, Southeast, Northeast and North regions closer; has reduced the increasing trend of mortality by almost 60%, mainly in the Southeast and South regions; has increased, more sharply, the mortality in cities with less than 5 thousand inhabitants; has curbed the significance of most factors associated with breast cancer; has revealed that the effect of longevity and the public health expenditure may be overestimated. These results highlight the importance of adjustment for IDC in producing reliable mortality indicators.

RevDate: 2019-09-11
CmpDate: 2019-09-11

DeVaux RS, JI Herschkowitz (2018)

Beyond DNA: the Role of Epigenetics in the Premalignant Progression of Breast Cancer.

Journal of mammary gland biology and neoplasia, 23(4):223-235.

Ductal Carcinoma in Situ (DCIS) is an early breast cancer lesion that is considered a nonobligate precursor to development of invasive ductal carcinoma (IDC). Although only a small subset of DCIS lesions are predicted to progress into a breast cancer, distinguishing innocuous from minacious DCIS lesions remains a clinical challenge. Thus, patients diagnosed with DCIS will undergo surgery with the potential for radiation and hormone therapy. This has led to a current state of overdiagnosis and overtreatment. Interrogating the transcriptome alone has yet to define clear functional determinants of progression from DCIS to IDC. Epigenetic changes, critical for imprinting and tissue specific development, in the incorrect context can lead to global signaling rewiring driving pathological phenotypes. Epigenetic signaling pathways, and the molecular players that interpret and sustain their signals, are critical to understanding the underlying pathology of breast cancer progression. The types of epigenetic changes, as well as the molecular players, are expanding. In addition to DNA methylation, histone modifications, and chromatin remodeling, we must also consider enhancers as well as the growing field of noncoding RNAs. Herein we will review the epigenetic interactions that have been uncovered in early stage lesions that impact breast cancer progression, and how these players may be utilized as biomarkers to mitigate overdiagnosis and overtreatment.

RevDate: 2019-09-11
CmpDate: 2019-09-11

Uemura MI, French JT, Hess KR, et al (2018)

Development of CNS metastases and survival in patients with inflammatory breast cancer.

Cancer, 124(11):2299-2305.

BACKGROUND: Inflammatory breast cancer (IBC) is associated with a poor prognosis and high risk of central nervous system (CNS) metastases.

METHODS: We retrospectively reviewed stage III-IBC patients compared with noninflammatory invasive ductal carcinoma (NI-IDC) patients treated between January 1, 1984, and December 31, 2011, who began primary treatment within 1 year of diagnosis and had been followed up for at least 1 year before the development of CNS metastasis or death. Cumulative CNS metastasis incidence and post-CNS metastasis overall survival (OS) estimates were computed. Multivariable Cox proportional hazard models explored factors for post-CNS metastasis survival.

RESULTS: A total of 2323 patients were identified (589-IBC/1734-NI-IDC). Eighty-one IBC patients developed CNS metastasis, versus 154 NI-IDC patients. The 2-, 5-, and 10-year cumulative CNS metastasis incidence rates in IBC and NI-IDC were 9.8%, 15.8%, 17.4% and 6.5%, 10.1%, and 12.7%, respectively. This was significantly different between IBC and NI-IDC patients (P = .0037). Multicovariate competing risk regression models in IBC and NI-IDC patients showed no statistically significant associations with the risk of developing CNS metastasis, except neoadjuvant taxane use in NI-IDC patients (hazard ratio, 0.45; 95% confidence interval, 0.24-0.83; P = .011). The median follow-up was 7.2 years, and the median post-CNS metastasis OS was not significantly different between IBC (7.6 months) and NI-IDC (5.6 months) patients. One hundred ninety patients with CNS metastasis died. HER2-positive patients had better OS, with a median 14.1 versus 4.3 months (P < .0001). Age >50 years (P = .012) but not IBC status was a significant predictor of post-CNS metastasis survival.

CONCLUSION: IBC patients demonstrated higher CNS metastasis incidence rates but OS following CNS metastases is similar in both groups. HER2 status and age may play prognostic roles. Cancer 2018;124:2299-305. © 2018 American Cancer Society.

RevDate: 2019-09-09
CmpDate: 2019-09-09

Lahav-Kadmiel Z, A Brunstein-Klomek (2018)

Bullying victimization and depressive symptoms in adolescence: The moderating role of parent-child conflicts among boys and girls.

Journal of adolescence, 68:152-158.

INTRODUCTION: The association between bullying victimization and depressive symptoms has been studied extensively over the years. Among the variables studied as having an impact on this association were different characteristics of the parent-child relationship. The current study was the first to specifically examine parent-child conflicts as a moderator in the association between victimization and depressive symptoms among adolescents. In addition, it was the first to examine the roles of the child and parent's gender in this moderation.

METHODS: 505 7th-9th graders from two schools in two different cities across Israel (mean age = 12.736, SD = 0.8154) participated in this study. 223 (44.2%) of the participants were male. The participants filled out a battery of self-report questionnaires assessing the different study's variables.

RESULTS: Significant gender differences were found: among girls, the association between bullying victimization and depressive symptoms was stronger when the level of parent-child conflicts was high, while among boys, it was stronger when the level of conflicts was low.

CONCLUSIONS: Our results indicate that the psychological outcomes for victims depend on their relationship with their parents. Bullying intervention programs should include the victims' parents. Furthermore, intervention programs should be designed to fit the different needs of girls and boys.

RevDate: 2019-09-06
CmpDate: 2019-09-06

Nuñez NN, Khuu C, Babu CS, et al (2018)

The Zinc Linchpin Motif in the DNA Repair Glycosylase MUTYH: Identifying the Zn2+ Ligands and Roles in Damage Recognition and Repair.

Journal of the American Chemical Society, 140(41):13260-13271.

The DNA base excision repair (BER) glycosylase MUTYH prevents DNA mutations by catalyzing adenine (A) excision from inappropriately formed 8-oxoguanine (8-oxoG):A mismatches. The importance of this mutation suppression activity in tumor suppressor genes is underscored by the association of inherited variants of MUTYH with colorectal polyposis in a hereditary colorectal cancer syndrome known as MUTYH-associated polyposis, or MAP. Many of the MAP variants encompass amino acid changes that occur at positions surrounding the two-metal cofactor-binding sites of MUTYH. One of these cofactors, found in nearly all MUTYH orthologs, is a [4Fe-4S]2+ cluster coordinated by four Cys residues located in the N-terminal catalytic domain. We recently uncovered a second functionally relevant metal cofactor site present only in higher eukaryotic MUTYH orthologs: a Zn2+ ion coordinated by three Cys residues located within the extended interdomain connector (IDC) region of MUTYH that connects the N-terminal adenine excision and C-terminal 8-oxoG recognition domains. In this work, we identified a candidate for the fourth Zn2+ coordinating ligand using a combination of bioinformatics and computational modeling. In addition, using in vitro enzyme activity assays, fluorescence polarization DNA binding assays, circular dichroism spectroscopy, and cell-based rifampicin resistance assays, the functional impact of reduced Zn2+ chelation was evaluated. Taken together, these results illustrate the critical role that the "Zn2+ linchpin motif" plays in MUTYH repair activity by providing for proper engagement of the functional domains on the 8-oxoG:A mismatch required for base excision catalysis. The functional importance of the Zn2+ linchpin also suggests that adjacent MAP variants or exposure to environmental chemicals may compromise Zn2+ coordination, and ability of MUTYH to prevent disease.

RevDate: 2019-08-02

Ogunleye AJ, Olanrewaju AJ, Arowosegbe M, et al (2019)

Molecular docking based screening analysis of GSK3B.

Bioinformation, 15(3):201-208 pii:97320630015201.

GSK3B has been an interesting drug target in the pharmaceutical industry. Its dysfunctional expression has prognostic significance in the top 3 cause of death associated with non-communicable diseases (cancer, Alzheimer's disease and type 2 diabetes). Previous studies have shown clearly that inhibiting GSK3B has proven therapeutic significance in Alzheimer's disease, but its contribution to various cancers has not been clearly resolved. In this study we report the contribution and prognostic significance of GSK3B to two breast cancer subtypes; ductal carcinoma in-situ (DCIS) and invasive ductal carcinoma (IDC) using the Oncomine platform. We performed high throughput screening using molecular docking. We identified BT-000775, a compound that was subjected to further computational hit optimization protocols. Through computational predictions, BT-000775 is a highly selective GSK3B inhibitor, with superior binding affinity and robust ADME profiles suitable for the patho-physiological presentations.

RevDate: 2019-07-28

Zacharioudakis K, Kontoulis T, Vella JX, et al (2019)

Can we see what is invisible? The role of MRI in the evaluation and management of patients with pathological nipple discharge.

Breast cancer research and treatment pii:10.1007/s10549-019-05321-w [Epub ahead of print].

INTRODUCTION: The aim of this study was to determine the ability of MRI to identify and assess the extent of disease in patients with pathological nipple discharge (PND) with an occult malignancy not evident on standard pre-operative evaluation with mammography and ultrasound.

METHODS: Patients presenting to the breast unit of Imperial College Healthcare NHS Trust between December 2009 and December 2018 with PND and normal imaging were enrolled in the study. Pre-operative bilateral breast MRI was performed in all patients as part of our protocol and all patients were offered diagnostic microdochectomy.

RESULTS: A total of 82 patients fulfilled our selection criteria and were enrolled in our study. The presence of an intraductal papilloma (IDP) was identified as the cause of PND in 38 patients (46.3%), 14 patients had duct ectasia (DE-17%) and 5 patients had both an IDP and DE. Other benign causes were identified in 11 patients (13.4%). Despite normal mammography and ultrasound a malignancy was identified in 14 patients (17%). Eleven patients had DCIS (13.4%), two had invasive lobular carcinoma and one patient had an invasive ductal carcinoma. The sensitivity of MRI in detecting an occult malignancy was 85.71% and the specificity was 98.53%. The positive predictive value was 92.31% and the negative predictive value was 97.1%.

CONCLUSIONS: Although a negative MRI does not exclude the presence of an occult malignancy the high sensitivity and specificity of this diagnostic modality can guide the surgeon and alter the management of patients with PND.

RevDate: 2019-08-20

Fang A, Dong J, R Zhang (2019)

Simulation of Heavy Metals Migration in Soil-Wheat System of Mining Area.

International journal of environmental research and public health, 16(14): pii:ijerph16142550.

Heavy metals in the soil of mining areas have become a primary source of pollution, which could cause deleterious health effects in people exposed through soil-plant systems via multi-pathways. A long-term field experiment under natural conditions was carried out to explore the distribution characteristic and migration law of heavy metals in a soil-wheat system of a mining area in Xuzhou. According to the second level standard of environmental quality standards for soils of China (GB 15618-1995), 30.8 g of CrCl3·6H2O, 8.3 g of Pb(CH3COO)2·3H2O, and 16.5 g of ZnSO4·7H2O were added into the soil of three experimental sites, respectively. The other experimental site with no additional compounds was used as the control site. The Cr, Pb, and Zn concentrations in the soil-wheat system were counted and their corresponding migration models were constructed. From 2014 to 2017, the mean concentrations of Cr (49.09 mg·kg-1), Pb (20.08 mg·kg-1), and Zn (39.11 mg·kg-1) in the soil of the addition sites were higher than that of the control site. The mean concentrations of Cr, Pb, and Zn in wheat of the addition sites were greater than that of the control site with the values of 3.29, 0.06, and 29 mg·kg-1. In comparison, the Cr, Pb, and Zn concentrations in the soil of all experimental sites were lower than the second level standard of environmental quality standards for soils of China (GB 15618-1995), whereas the Cr concentration exceeded its corresponding soil background value of Xuzhou in 2017. The Pb concentration in soil of the addition site was greater than its corresponding background value from 2014 to 2016. The Pb and Zn concentrations in wheat of all experimental sites were lower than the national hygienic standard for grains of China (GB2715-2005) and the national guidelines for cereals of China (NY 861-2004), but the Cr concentration significantly exceeded the national guidelines for cereals of China (NY 861-2004). By constructing the Identical-Discrepant-Contrary (IDC) gray connection models, the result showed that there was a non-linear relationship of Cr, Pb, and Zn concentrations in the soil-wheat system, and the absolute values of most correlation coefficients r were lower than 0.5 and the values of greyness f G (r) were more than 0.5. The curvilinear regression models could not reflect the relationship of Cr, Pb, and Zn concentrations in the soil-wheat system with the regression coefficient r 2 values far less than 1. Due to the values of regression coefficient r 2 being close to 1, this study suggested that the allocation estimation models could be used for simulating the Cr, Pb, and Zn migration in the soil-wheat system of a mining area in Xuzhou.

RevDate: 2019-07-24
CmpDate: 2019-07-24

Traoré B, Koulibaly M, Diallo A, et al (2019)

Molecular profile of breast cancers in Guinean oncological settings.

The Pan African medical journal, 33:22 pii:PAMJ-33-22.

Breast cancer is a complex disease characterized by the accumulation of multiple molecular alterations giving each tumor phenotype and an own evolutionary potential. This study aimed to describe the distribution of the profile and molecular subtypes of breast cancers followed at Surgical Oncology Unit of Donka National Hospital. This was retrospective and descriptive study on cases of breast cancer in which the hormone receptor status and expression of the Her2 oncogene have been performed from 2007 to 2016. We recorded 58 cases including 56 (96.6%) women and 2 (3.4%) men. The average age was 48.2 ± 10.9. Invasive ductal carcinoma accounted for 50 (86.2%) cases. The SBR grade was II in 31(53.4%) cases, III in 21 (36.2%) cases and I in 6 (10.3%) cases. The tumor was classified as T4 in 36 (62.1%) cases; it was metastatic in 11(19.0%) cases. Estrogen receptors were positive in 29 (50.0%) cases, progesterone receptors positive in 25 (43.1%) cases, the Her2 oncogene was positive in 22 (39.3%) cases. The distribution of molecular sub-types was: 20 (34.5%) luminal A, 15 (25.9%) triple negative, 13 (22.4%) Her2 overexpressed, 8 (13.8%) luminal B and 2 (3.2%) undetermined. This preliminary study showed the poor accessibility of immunohistochemistry for the molecular diagnosis of breast cancer in our country. Luminal A subtypes and triple negatives were more common. The determination of molecular subtypes is a rational basis for hormone therapy and targeted therapy, thus personalizing the treatment of breast cancer.

RevDate: 2019-07-07

Simeunovic D, Odanovic N, Pljesa-Ercegovac M, et al (2019)

Glutathione Transferase P1 Polymorphism Might Be a Risk Determinant in Heart Failure.

Disease markers, 2019:6984845.

Disturbed redox balance in heart failure (HF) might contribute to impairment of cardiac function, by oxidative damage, or by regulation of cell signaling. The role of polymorphism in glutathione transferases (GSTs), involved both in antioxidant defense and in regulation of apoptotic signaling pathways in HF, has been proposed. We aimed to determine whether GST genotypes exhibit differential risk effects between coronary artery disease (CAD) and idiopathic dilated cardiomyopathy (IDC) in HF patients. GSTA1, GSTM1, GSTP1, and GSTT1 genotypes were determined in 194 HF patients (109 CAD, 85 IDC) and 274 age- and gender-matched controls. No significant association was found for GSTA1, GSTM1, and GSTT1 genotypes with HF occurrence due to either CAD or IDC. However, carriers of at least one variant GSTP1∗Val (rs1695) allele were at 1.7-fold increased HF risk than GSTP1∗Ile/Ile carriers (p = 0.031), which was higher when combined with the variant GSTA1∗B allele (OR = 2.2, p = 0.034). In HF patients stratified based on the underlying cause of disease, an even stronger association was observed in HF patients due to CAD, who were carriers of a combined GSTP1(rs1695)/GSTA1 "risk-associated" genotype (OR = 2.8, p = 0.033) or a combined GSTP1∗Ile/Val+Val/Val (rs1695)/GSTP1∗AlaVal+∗ValVal (rs1138272) genotype (OR = 2.1, p = 0.056). Moreover, these patients exhibited significantly decreased left ventricular end-systolic diameter compared to GSTA1∗AA/GSTP1∗IleIle carriers (p = 0.021). Higher values of ICAM-1 were found in carriers of the GSTP1∗IleVal+∗ValVal (rs1695) (p = 0.041) genotype, whereas higher TNFα was determined in carriers of the GSTP1∗AlaVal+∗ValVal genotype (rs1138272) (p = 0.041). In conclusion, GSTP1 polymorphic variants may determine individual susceptibility to oxidative stress, inflammation, and endothelial dysfunction in HF.

RevDate: 2019-07-13

Ghaderi F, Mehdipour F, Hosseini A, et al (2019)

Establishment and Characterization of a New Triple Negative Breast Cancer Cell Line from an Iranian Breast Cancer Tissue.

Asian Pacific journal of cancer prevention : APJCP, 20(6):1683-1689.

RevDate: 2019-07-04

Zwarts I, van Zutphen T, Kruit JK, et al (2019)

Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR.

Scientific reports, 9(1):9299 pii:10.1038/s41598-019-45803-x.

Fructose has become a major constituent of our modern diet and is implicated as an underlying cause in the development of metabolic diseases. The fructose transporter GLUT5 (SLC2A5) is required for intestinal fructose absorption. GLUT5 expression is induced in the intestine and skeletal muscle of type 2 diabetes (T2D) patients and in certain cancers that are dependent on fructose metabolism, indicating that modulation of GLUT5 levels could have potential in the treatment of these diseases. Using an unbiased screen for transcriptional control of the human GLUT5 promoter we identified a strong and specific regulation by liver X receptor α (LXRα, NR1H3). Using promoter truncations and site-directed mutagenesis we identified a functional LXR response element (LXRE) in the human GLUT5 promoter, located at -385 bp relative to the transcriptional start site (TSS). Finally, mice treated with LXR agonist T0901317 showed an increase in Glut5 mRNA and protein levels in duodenum and adipose tissue, underscoring the in vivo relevance of its regulation by LXR. Together, our findings show that LXRα regulates GLUT5 in mice and humans. As a ligand-activated transcription factor, LXRα might provide novel pharmacologic strategies for the selective modulation of GLUT5 activity in the treatment of metabolic disease as well as cancer.

RevDate: 2019-06-26

Shenkman G, Pardo Aviv L, Hain D, et al (2019)

The moderation of attachment in the association between depressive symptoms and self-harm among a clinical sample.

Journal of mental health (Abingdon, England) [Epub ahead of print].

Background: Self-harm is a severe health problem worldwide and in particular in clinical settings. The association of depression and self-harm has been extensively studied alongside various variables that have been examined as moderating this association. However, no previous study has examined the moderating role of attachment in this association. Aim: We explored the role of attachment orientation in moderating the association between depressive symptoms and self-harm among a sample of patients in a community mental health clinic. Method: This study was a de-identified archival study of patients' medical charts, and used a convenience sample of 199 patients, which completed self-report measures following the initial intake appointment as part of clinic procedures. Results: Findings showed that both attachment anxiety and avoidance moderated the association between depressive symptoms and self-harm, such that depressive symptoms were positively associated with self-harm only when attachment anxiety scores were high, and attachment avoidance scores were high or average. Conclusions: Attachment anxiety and avoidance should be assessed in the initial intake of patients as it has a contribution to understanding self-harm vulnerability among new patients. Future studies should explore this moderation longitudinally so causality could be inferred.

RevDate: 2019-08-08

Cao L, Basudan A, Sikora MJ, et al (2019)

Frequent amplifications of ESR1, ERBB2 and MDM4 in primary invasive lobular breast carcinoma.

Cancer letters, 461:21-30.

Invasive lobular carcinoma (ILC) is the second most common histological subtype of breast cancer following invasive ductal carcinoma (IDC). To identify potential genetic drivers of ILC progression, we used NanoString nCounter technology to investigate the DNA copy number (CN) in 70 well-curated primary ILC samples. We confirmed prior observations of frequent amplification of CCND1 (33%), and MYC (17%) in ILC, but additionally identified a substantial subset of ILCs with ESR1 and ERBB2 (19%) amplifications. Of interest, tumors with ESR1 CN gains (14%) and amplification (10%) were more likely to recur compared to those with normal CN. Finally, we observed that MDM4 (MDMX) was amplified in 17% of ILC samples. MDM4 knockdown in TP53 wild-type ILC cell lines caused increased apoptosis, decreased proliferation associated with cell cycle arrest, and concomitant activation of TP53 target genes. Similar effects were seen in TP53 mutant cells, indicting a TP53-independent role for MDM4 in ILC. To conclude, amplification of ESR1 and MDM4 are potential genetic drivers of ILC. These amplifications may represent actionable, targetable tumor dependencies, and thus have potential clinical implications and warrant further study.

RevDate: 2019-06-21
CmpDate: 2019-06-21

Bao Y, Wang L, Shi L, et al (2019)

Transcriptome profiling revealed multiple genes and ECM-receptor interaction pathways that may be associated with breast cancer.

Cellular & molecular biology letters, 24:38 pii:162.

Background: Exploration of the genes with abnormal expression during the development of breast cancer is essential to provide a deeper understanding of the mechanisms involved. Transcriptome sequencing and bioinformatics analysis of invasive ductal carcinoma and paracancerous tissues from the same patient were performed to identify the key genes and signaling pathways related to breast cancer development.

Methods: Samples of breast tumor tissue and paracancerous breast tissue were obtained from 6 patients. Sequencing used the Illumina HiSeq platform. All. Only perfectly matched clean reads were mapped to the reference genome database, further analyzed and annotated based on the reference genome information. Differentially expressed genes (DEGs) were identified using the DESeq R package (1.10.1) and DEGSeq R package (1.12.0). Using KOBAS software to execute the KEGG bioinformatics analyses, enriched signaling pathways of DEGs involved in the occurrence of breast cancer were determined. Subsequently, quantitative real time PCR was used to verify the accuracy of the expression profile of key DEGs from the RNA-seq result and to explore the expression patterns of novel cancer-related genes on 8 different clinical individuals.

Results: The transcriptomic sequencing results showed 937 DEGs, including 487 upregulated and 450 downregulated genes in the breast cancer specimens. Further quantitative gene expression analysis was performed and captured 252 DEGs (201 downregulated and 51 upregulated) that showed the same differential expression pattern in all libraries. Finally, 6 upregulated DEGs (CST2, DRP2, CLEC5A, SCD, KIAA1211, DTL) and 6 downregulated DEGs (STAC2, BTNL9, CA4, CD300LG, GPIHBP1 and PIGR), were confirmed in a quantitative real time PCR comparison of breast cancer and paracancerous breast tissues from 8 clinical specimens. KEGG analysis revealed various pathway changes, including 20 upregulated and 21 downregulated gene enrichment pathways. The extracellular matrix-receptor (ECM-receptor) interaction pathway was the most enriched pathway: all genes in this pathway were DEGs, including the THBS family, collagen and fibronectin. These DEGs and the ECM-receptor interaction pathway may perform important roles in breast cancer.

Conclusion: Several potential breast cancer-related genes and pathways were captured, including 7 novel upregulated genes and 76 novel downregulated genes that were not found in other studies. These genes are related to cell proliferation, movement and adhesion. They may be important for research into breast cancer mechanisms, particularly CST2 and CA4. A key signaling pathway, the ECM-receptor interaction signal pathway, was also identified as possibly involved in the development of breast cancer.

RevDate: 2019-08-09

Hamzah JL, Ong KW, BY Tan (2019)

Isolated invasive ductal carcinoma of the nipple-areolar complex: A rare occurrence yet to be reported in current literature.

The breast journal, 25(4):706-708.

Invasive ductal carcinoma of the nipple-areolar complex is exceedingly rare. Patients who present with bloody nipple discharge with or without the presence of Paget's disease constitute one-third of all symptomatic in situ patients. Only rarely does an invasive cancer cause nipple discharge in the absence of a clinical mass. Even more obscure is the case of the invasive cancer involving solely the nipple-areolar complex. Sir James Paget first described 'an eczematous change in the skin of the nipple preceding an underlying mammary cancer' in 1874, which is now known as Paget's disease, considered to be ductal carcinoma in situ of the nipple-areolar region. There are two competing theories as to the pathogenesis of Paget's disease of the breast-one suggests that Pagetoid cells are keratinocytes that have undergone malignant transformation. According to this theory, Paget's disease of the breast represents an in situ carcinoma of the skin-and that overlying skin changes and underlying malignancy are discontinuous. The second theory suggests that cells migrate along basement membranes and enter the epidermis and dermis of the nipple-areola complex. Pagetoid cells and underlying carcinomas demonstrate similar immunohistochemical staining patterns.

RevDate: 2019-06-19
CmpDate: 2019-06-17

Haythorne E, Rohm M, van de Bunt M, et al (2019)

Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells.

Nature communications, 10(1):2474 pii:10.1038/s41467-019-10189-x.

Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic βV59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 β-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

RevDate: 2019-08-20

Zhu J, Sun K, Xu X, et al (2019)

A Preliminary Attempt of Nonintervention in the Treatment of Patients with Intervertebral Disc Calcification Combined with Ossification of the Posterior Longitudinal Ligament.

World neurosurgery, 129:181-185.

BACKGROUND: Calcification of intervertebral disc is a common impairment, which has been considered as the degenerative condition of the spine. In clinical practice, we note that the onset of intervertebral disc calcification (IDC) and ossification of the posterior longitudinal ligament (OPLL) can exist simultaneously in some cases, especially in younger children. However, only 8 cases have been reported in detail previously. In addition, controversy remains in terms of the best way to treat this condition.

CASE DESCRIPTION: An 8-year-old female child was referred to our department in March 2018 complaining of severe back pain and neck pain with a sign of neurologic dysfunction. Computed tomography and magnetic resonance imaging revealed the calcified intervertebral disc and OPLL at the C5-C6 level and spinal cord compression. We performed a noninterventional strategy for the patient. The patient's symptom recovered significantly in approximately 1 month. At 6 months of follow-up, the patient felt no discomfort, and computed tomography revealed the complete resorption of ossified lesion. Magnetic resonance imaging also showed no sign of compression on the spinal cord and nerve root at the involved segment.

CONCLUSIONS: Pediatric IDC accompanied with OPLL is much less frequent, but we must be aware of this disease. Since the distribution of this disease is age-specific and sex-specific, further research is necessary. Treatment for IDC combined with OPLL needs to follow the treatment principles as described in the text.