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22 Oct 2020 at 01:44
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Bibliography on: Publications by FHCRC Researchers


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 22 Oct 2020 at 01:44 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2020-10-21

Du Y, Du Y, N Yao (2020)

Patient-provider relationships in China: A qualitative study on the perspectives of healthcare students and junior professionals.

PloS one, 15(10):e0240747 pii:PONE-D-20-17587.

BACKGROUND: Mistrust and conflicts in patient-provider relationships (PPR) have become prevalent in China. The frequency of verbal and physical violence against healthcare workers has been increasing, but few interventions seem to be effective. Limited prior research has focused on the perspectives of healthcare professionals in training. This paper aimed to understand their viewpoints and conceptualize potentially actionable areas for future policy interventions.

METHODS: We analyzed de-identified training registration data of a convenience sample of 151 healthcare students and 38 junior professionals from 20 provinces in China. One open-ended question in the registration form asked the participant to comment on PPRs in China. We used qualitative thematic coding to analyze the narrative data. All answers were categorized into three overarching frames: patients, providers, and external agencies/regulations. Frequently mentioned themes in each frame were evaluated to generate an overall theoretical framework.

FINDINGS: Although fewer than 25% indicated that current PPRs are "good" or acceptable, 98% of respondents were optimistic about the future improvement of these relationships. The leading factors of PPRs mentioned as patient-relevant were eroding trust in the physician, unrealistic expectations, and ineffective communication. The provider-relevant themes highlighted were poor service quality, ineffective communication, and heavy workload. Leading themes relevant to external agencies or regulations were dysfunctional administration system, negative media reports, and disparity in healthcare resource distribution.

INTERPRETATION: Healthcare professionals in training had a negative view of the current situation but had confidence in future improvement. Patient, provider, and societal factors all contributed to the tension between patients and providers. All aspects of the healthcare sector should be carefully considered when contemplating policy or social interventions to improve the patient-provider relationship.

RevDate: 2020-10-21

Hong S, Brazauskas R, Hebert KM, et al (2020)

Community health status and outcomes after allogeneic hematopoietic cell transplantation in the United States.

Cancer [Epub ahead of print].

BACKGROUND: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes.

METHODS: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied.

RESULTS: The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM.

CONCLUSIONS: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.

RevDate: 2020-10-21

Orozco JJ, Kenoyer AL, Lin Y, et al (2020)

Therapy of Myeloid Leukemia using Novel Bispecific Fusion Proteins Targeting CD45 and 90Y-DOTA.

Molecular cancer therapeutics pii:1535-7163.MCT-20-0306 [Epub ahead of print].

Pretargeted radioimmunotherapy (PRIT) has been investigated as a multi-step approach to decrease relapse and toxicity for high-risk acute myeloid leukemia (AML). Relevant factors including endogenous biotin and immunogenicity, however, have limited the use of PRIT with an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and radiolabeled DOTA-biotin. To overcome these limitations we designed anti-murine and anti-human CD45 bispecific antibody (Ab) constructs using 30F11 and BC8 Ab, respectively, combined with an anti-yttrium (Y)-DOTA single-chain variable fragment (C825) to capture a radiolabeled ligand. The bispecific construct targeting human CD45 (BC8-Fc-C825) had high uptake in leukemia HEL xenografts [7.8 ± 0.02% percent injected dose/gram of tissue (%ID/g)]. Therapy studies showed that 70% of mice with HEL human xenografts treated with BC8-Fc-C825 followed by 44.4 MBq (1200 µCi) of 90Y-DOTA-biotin survived at least 170 days after therapy, while all non-treated controls required euthanasia due to tumor progression by day 32. High uptake at sites of leukemia (spleen and bone marrow) was also seen with 30F11-IgG1-C825 in a syngeneic disseminated SJL murine leukemia model (spleen: 9.0 ± 1.5% ID/g, and bone marrow: 8.1 ± 1.2% ID/g), with minimal uptake in all other normal organs (<0.5% ID/g) at 24 hours after 90Y-DOTA injections. SJL leukemia mice treated with the bispecific 30F11-IgG1-C825 and 29.6 MBq (800 µCi) of 90Y-DOTA-biotin had a survival advantage compared to untreated leukemic mice (median 43 versus 30 days, respectively, p<0.0001). These data suggest bispecific Ab mediated PRIT may be highly effective for leukemia therapy and translation to human studies.

RevDate: 2020-10-21

Outlaw VK, Bovier FT, Mears MC, et al (2020)

Inhibition of Coronavirus Entry In Vitro and Ex Vivo by a Lipid-Conjugated Peptide Derived from the SARS-CoV-2 Spike Glycoprotein HRC Domain.

mBio, 11(5):.

The emergence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), the etiological agent of the 2019 coronavirus disease (COVID-19), has erupted into a global pandemic that has led to tens of millions of infections and hundreds of thousands of deaths worldwide. The development of therapeutics to treat infection or as prophylactics to halt viral transmission and spread is urgently needed. SARS-CoV-2 relies on structural rearrangements within a spike (S) glycoprotein to mediate fusion of the viral and host cell membranes. Here, we describe the development of a lipopeptide that is derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibits infection by SARS-CoV-2. The lipopeptide inhibits cell-cell fusion mediated by SARS-CoV-2 S and blocks infection by live SARS-CoV-2 in Vero E6 cell monolayers more effectively than previously described lipopeptides. The SARS-CoV-2 lipopeptide exhibits broad-spectrum activity by inhibiting cell-cell fusion mediated by SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) and blocking infection by live MERS-CoV in cell monolayers. We also show that the SARS-CoV-2 HRC-derived lipopeptide potently blocks the spread of SARS-CoV-2 in human airway epithelial (HAE) cultures, an ex vivo model designed to mimic respiratory viral propagation in humans. While viral spread of SARS-CoV-2 infection was widespread in untreated airways, those treated with SARS-CoV-2 HRC lipopeptide showed no detectable evidence of viral spread. These data provide a framework for the development of peptide therapeutics for the treatment of or prophylaxis against SARS-CoV-2 as well as other coronaviruses.IMPORTANCE SARS-CoV-2, the causative agent of COVID-19, continues to spread globally, placing strain on health care systems and resulting in rapidly increasing numbers of cases and mortalities. Despite the growing need for medical intervention, no FDA-approved vaccines are yet available, and treatment has been limited to supportive therapy for the alleviation of symptoms. Entry inhibitors could fill the important role of preventing initial infection and preventing spread. Here, we describe the design, synthesis, and evaluation of a lipopeptide that is derived from the HRC domain of the SARS-CoV-2 S glycoprotein that potently inhibits fusion mediated by SARS-CoV-2 S glycoprotein and blocks infection by live SARS-CoV-2 in both cell monolayers (in vitro) and human airway tissues (ex vivo). Our results highlight the SARS-CoV-2 HRC-derived lipopeptide as a promising therapeutic candidate for SARS-CoV-2 infections.

RevDate: 2020-10-20

Sichel SR, NR Salama (2020)

Bacterial Cell Biology: It Takes Two to Tango.

Current biology : CB, 30(20):R1258-R1260.

Work identifying how stalk morphogenesis in a species of Alphaproteobacteria is controlled unveils an interesting mechanism that other bacteria may utilize to generate the variety of bacterial cell morphologies found across the bacterial domain.

RevDate: 2020-10-20

Tosoian JJ, Trock BJ, Morgan TM, et al (2020)

Use of the MyProstateScore (MPS) Test to Rule Out Clinically-Significant Cancer: Validation of a Straightforward Clinical Testing Approach.

The Journal of urology [Epub ahead of print].

PURPOSE: The MyProstateScore (MPS) test was validated for improved detection of clinically-significant (Grade Group [GG] ≥2) prostate cancer relative to PSA-based risk calculators. We sought to validate an optimal MPS threshold for clinical use in ruling-out GG ≥2 cancer in men referred for biopsy.

MATERIALS AND METHODS: Biopsy-naïve men provided post-digital rectal examination (DRE) urine prior to biopsy. MPS was calculated using the validated, locked multivariable model including only serum PSA, urinary PCA3, and urinary TMPRSS2:ERG. The MPS threshold approximating 95% sensitivity for GG ≥2 cancer was identified in a training cohort, and performance was measured in two external validation cohorts. We assessed the (i) overall biopsy-referral population and (ii) population meeting guideline-based testing criteria (ie, PSA 3-10; or PSA <3 with suspicious DRE).

RESULTS: Validation cohorts were prospectively-enrolled from academic (n=977, median PSA 4.5 [IQR:3.1-6.0]) and community (n=548, median PSA 4.9 [IQR:3.7-6.8]) settings. In the overall validation population (n=1525), 338 men (22%) had GG ≥2 cancer on biopsy. The MPS threshold of 10 provided 97% sensitivity and 98% negative predictive value (NPV) for GG ≥2 cancer. MPS testing would have prevented 387 unnecessary biopsies (33%), while missing only ten GG ≥2 cancers (3.0%). In 1242 patients meeting guideline-based criteria, MPS ≤10 provided 96% sensitivity, 97% NPV, and would have prevented 32% of unnecessary biopsies, missing 3.7% of GG ≥2 cancers.

CONCLUSIONS: In a large, clinically-pertinent biopsy-referral population, MPS ≤10 provided exceptional sensitivity and NPV for ruling-out GG ≥2 cancer. This straightforward secondary testing approach would reduce the use of more costly and invasive procedures after screening with PSA.

RevDate: 2020-10-20

Brodersen LE, Gerbing RB, Pardo ML, et al (2020)

Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report.

Blood advances, 4(20):5050-5061.

Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The "difference from normal" (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable and multivariable analyses, and was predictive of relapse risk, disease-free survival, and treatment-related mortality. Clearance of MRD after a second round of chemotherapy did not improve survival. The morphologic definition of persistent disease (>15% AML) failed 27% of the time; those identified as MRD- had superior outcomes. Similarly, for patients not achieving morphologic remission (>5% blasts), 36% of patients were MRD- and had favorable outcomes compared with those who were MRD+ (P < .001); hence an increase in myeloid progenitor cells can be favorable when ΔN classifies them as phenotypically normal. Furthermore, ΔN reclassified 20% of patients in morphologic remission as having detectable MRD with comparable poor outcomes. Retrospective analysis using the relapse phenotype as a template demonstrated that 96% of MRD- patients had <0.02% of the relapse immunophenotype in their end of induction 1 marrow. Thus, the detection of abnormal myeloid progenitor cells by ΔN is both specific and sensitive, with a high predictive signal identifiable early in treatment. This trial was registered at www.clinicaltrials.gov as #NCT00372593.

RevDate: 2020-10-20

Denduluri N, Somerfield MR, Chavez-MacGregor M, et al (2020)

Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: The aim of this work is to update key recommendations of the ASCO guideline adaptation of the Cancer Care Ontario guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer and adjuvant targeted therapy for breast cancer.

METHODS: An Expert Panel conducted a targeted systematic literature review guided by a signals approach to identify new, potentially practice-changing data that might translate into revised guideline recommendations.

RESULTS: The Expert Panel reviewed abstracts from the literature review and identified one article for inclusion that reported results of the phase III, open-label KATHERINE trial. In the KATHERINE trial, patients with stage I to III human epidermal growth factor receptor 2 (HER2)-positive breast cancer with residual invasive disease in the breast or axilla after completing neoadjuvant chemotherapy and HER2-targeted therapy were allocated to adjuvant trastuzumab emtansine (T-DM1; n = 743) or to trastuzumab (n = 743). Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab arm (hazard ratio, 0.50; 95% CI, 0.39 to 0.64; P < .001), and risk of distant recurrence was lower in patients who received T-DM1 than in patients who received trastuzumab (hazard ratio, 0.60; 95% CI, 0.45 to 0.79). Grade 3 or higher adverse events occurred in 190 patients (25.7%) who received T-DM1 and in 111 patients (15.4%) who received trastuzumab.

RECOMMENDATIONS: Patients with HER2-positive breast cancer with pathologic invasive residual disease at surgery after standard preoperative chemotherapy and HER2-targeted therapy should be offered 14 cycles of adjuvant T-DM1, unless there is disease recurrence or unmanageable toxicity. Clinicians may offer any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars.Additional information can be found at www.asco.org/breast-cancer-guidelines.

RevDate: 2020-10-20

Lautz TB, Chi YY, Li M, et al (2020)

Benefit of delayed primary excision in rhabdomyosarcoma: A report from the Children's Oncology Group (COG).

Cancer [Epub ahead of print].

BACKGROUND: Most children with intermediate-risk rhabdomyosarcoma (RMS) have gross disease (group III) at the initiation of chemotherapy. Delayed primary excision (DPE) after induction chemotherapy allows for a reduction in adjuvant radiation dose, but with the risk of potential surgical morbidity. The objectives of this study were to compare outcomes in children with group III RMS who did and did not undergo DPE and to assess surgical morbidity.

METHODS: The study included 369 patients who had clinical group III RMS at sites amenable to DPE from intermediate-risk Children's Oncology Group studies D9803 (encouraged DPE) and ARST0531 (discouraged DPE).

RESULTS: The primary tumor site was bladder/prostate (136 patients; 37%), extremity (97 patients; 26%), trunk (24 patients; 7%), retroperitoneum (91 patients; 25%), or intrathoracic/perineum/perianal (21 patients; 6%). In total, 112 patients (53.9%) underwent DPE in D9803, and 26 patients (16.2%) underwent DPE in ARST0531 (P < .001), with loss of vital organ or function in 30 of 138 patients (22%). DPE allowed for a reduced radiation dose in 110 of 135 patients (81%; 51% were reduced to 36 Gy, and 30% were reduced to 42 Gy). Patients who underwent DPE had improved unadjusted overall survival (P = .013). In adjusted regression analysis, the risk of death (hazard ratio, 0.71; 95% CI 0.43-1.16) was similar for patients who did and did not undergo DPE and was improved for the subset of patients who had tumors of the trunk and retroperitoneum (hazard ratio, 0.44; 95% CI, 0.20-0.97).

CONCLUSIONS: Children with group III RMS have equivalent or improved outcomes with DPE and can receive a decreased radiation dose for definitive local control. The choice of local control modality should weigh the potential morbidity of surgery versus that of higher dose irradiation.

RevDate: 2020-10-20

Lüftner D, Lyman GH, Gonçalves J, et al (2020)

Correction to: Biologic Drug Quality Assurance to Optimize HER2+ Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

The article Biologic Drug Quality Assurance to Optimize HER2+ Breast Cancer Treatment: Insights from Development of the Trastuzumab Biosimilar SB3.

RevDate: 2020-10-20

Haynes BF, Corey L, Fernandes P, et al (2020)

Prospects for a safe COVID-19 vaccine.

Science translational medicine pii:scitranslmed.abe0948 [Epub ahead of print].

Rapid development of an efficacious vaccine against the viral pathogen SARS-CoV-2, the cause of the coronavirus disease-2019 (COVID-19) pandemic, is essential, but rigorous studies are required to determine the safety of candidate vaccines. Here, on behalf of the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) Working Group, we evaluate research on the potential risk of immune enhancement of disease by vaccines and viral infections, including coronavirus infections, together with emerging data about COVID-19 disease. Vaccine-associated enhanced disease has been rarely encountered with existing vaccines or viral infections. Although animal models of SARS-CoV-2 infection may elucidate mechanisms of immune protection, we need observations of enhanced disease in people receiving candidate COVID-19 vaccines to understand the risk of immune enhancement of disease. Neither principles of immunity nor preclinical studies provide a basis for prioritizing among the COVID-19 vaccine candidates with respect to safety at this time. Rigorous clinical trial design and post-licensure surveillance should provide a reliable strategy to identify adverse events, including the potential for enhanced severity of COVID-19 disease, following vaccination.

RevDate: 2020-10-19

Lau N, Waldbaum S, Parigoris R, et al (2020)

eHealth and mHealth psychosocial interventions for youths with chronic illnesses: A systematic review.

JMIR pediatrics and parenting [Epub ahead of print].

BACKGROUND: An estimated 12.8% of children and adolescents experience chronic health conditions which lead to poor quality of life, adjustment and coping issues, and concurrent mental health problems. Digital health deployment of psychosocial interventions to support youth with chronic illness has become increasingly popular with the advent of the technological advances in the Digital Age.

OBJECTIVE: To (1) systematically review published efficacy studies of eHealth (internet-based) and mHealth (mobile health) psychosocial interventions for youths with chronic illnesses; and, (2) review intervention theory and treatment components.

METHODS: PubMed, Embase, Web of Science, PsychInfo, and Cochrane Database of Systematic reviews were searched for studies published from 2008-2019 of eHealth and mHealth psychosocial interventions designed for children and adolescents with chronic illnesses in which efficacy outcomes were reported. We excluded studies of interventions for caregivers, healthy youth, disease and medication management, and telehealth interventions that function solely as a platform to connect patients to providers via phone, text, or videoconference.

RESULTS: We screened 2,551 articles, and 133 relevant full-text articles. Sixteen efficacy studies with psychosocial and health outcomes met inclusion criteria, which represented 12 unique interventions. Of the included studies, 12 were randomized controlled trials and four were prospective cohort studies with no comparison group. Most interventions were based in cognitive-behavioral theory and designed as eHealth interventions; only 2 were designed as an mHealth intervention. All but two interventions provided access to support staff via text, phone, email, or discussion forums. The significant heterogeneity in intervention content, intervention structure, medical diagnoses, and outcomes precluded meta-analysis. For example, measurement timepoints ranged from immediately post-completion of the mHealth program to 18-months later, and we identified 39 unique outcomes of interest. The majority of included studies (11/16, 68.75%) reported significant changes in measured health and/or psychosocial post-treatment outcomes, with small to large effect sizes.

CONCLUSIONS: Although the available literature on the efficacy of eHealth and mHealth psychosocial interventions for youth with chronic illnesses is limited, preliminary research suggests some evidence of positive treatment responses. Future studies should continue to evaluate whether digital health platforms may be a viable alternative model of delivery to traditional face-to-face approaches.

RevDate: 2020-10-19

Leisman DE, Ronner L, Pinotti R, et al (2020)

Cytokine elevation in severe and critical COVID-19: a rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes.

The Lancet. Respiratory medicine pii:S2213-2600(20)30404-5 [Epub ahead of print].

The description of a so-called cytokine storm in patients with COVID-19 has prompted consideration of anti-cytokine therapies, particularly interleukin-6 antagonists. However, direct systematic comparisons of COVID-19 with other critical illnesses associated with elevated cytokine concentrations have not been reported. In this Rapid Review, we report the results of a systematic review and meta-analysis of COVID-19 studies published or posted as preprints between Nov 1, 2019, and April 14, 2020, in which interleukin-6 concentrations in patients with severe or critical disease were recorded. 25 COVID-19 studies (n=1245 patients) were ultimately included. Comparator groups included four trials each in sepsis (n=5320), cytokine release syndrome (n=72), and acute respiratory distress syndrome unrelated to COVID-19 (n=2767). In patients with severe or critical COVID-19, the pooled mean serum interleukin-6 concentration was 36·7 pg/mL (95% CI 21·6-62·3 pg/mL; I2=57·7%). Mean interleukin-6 concentrations were nearly 100 times higher in patients with cytokine release syndrome (3110·5 pg/mL, 632·3-15 302·9 pg/mL; p<0·0001), 27 times higher in patients with sepsis (983·6 pg/mL, 550·1-1758·4 pg/mL; p<0·0001), and 12 times higher in patients with acute respiratory distress syndrome unrelated to COVID-19 (460 pg/mL, 216·3-978·7 pg/mL; p<0·0001). Our findings question the role of a cytokine storm in COVID-19-induced organ dysfunction. Many questions remain about the immune features of COVID-19 and the potential role of anti-cytokine and immune-modulating treatments in patients with the disease.

RevDate: 2020-10-18

Whaley RE, Ameny S, Arkatkar T, et al (2020)

Generation of a cost-effective cell line for support of high-throughput isolation of primary human B cells and monoclonal neutralizing antibodies.

Journal of immunological methods pii:S0022-1759(20)30195-2 [Epub ahead of print].

The isolation of human monoclonal antibodies (mAbs) arising from natural infection with human pathogens has proven to be a powerful technology, facilitating the understanding of the host response to infection at a molecular level. mAbs can reveal sites of vulnerability on pathogens and illuminate the biological function of the antigenic targets. Moreover, mAbs have the potential to be used directly for therapeutic applications such as passive delivery to prevent infection in susceptible target populations, and as treatment of established infection. The isolation of antigen-specific B cells from vaccine trials can also assist in deciphering whether the desired B cells are being targeted by a given vaccine. Several different processes have been developed to isolate mAbs, but all are generally labor-intensive and result in varying degrees of efficiency. Here, we describe the development of a cost-effective feeder cell line that stably expresses CD40-ligand, interleukin-2 and interleukin-21. Sorting of single B cells onto a layer of irradiated feeder cells sustained antibody production that permits functional screening of secreted antibodies in a manner that enables subsequent recovery of B cells for recombinant antibody cloning. As a proof of concept, we show that this approach can be used to isolate B cells that secrete antibodies that neutralize human papilloma virus (HPV) from participants of an HPV vaccine study.

RevDate: 2020-10-19

Signorelli M, Mason AG, Mul K, et al (2020)

Evaluation of blood gene expression levels in facioscapulohumeral muscular dystrophy patients.

Scientific reports, 10(1):17547 pii:10.1038/s41598-020-74687-5.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the expression of DUX4 in skeletal muscles. A number of therapeutic approaches are being developed to antagonize the events preceding and following DUX4 expression that leads to muscular dystrophy. Currently, the possibility to evaluate treatment response in clinical trials is hampered by the lack of objective molecular biomarkers connecting the disease cause to clinical performance. In this study we employed RNA-seq to examine gene expression in PAXgene tubes obtained from two independent cohorts of FSHD patients. Analysis of gene expression profiles did not lead to the identification of genes or pathways differentially expressed in FSHD patients, or associated with disease severity. In particular, we did not find evidence that the DUX4 and PAX7 signatures were differentially expressed. On the other hand, we were able to improve patient classification by including single genes or groups of genes in classification models. The best classifier was ROPN1L, a gene known to be expressed in testis, coincidentally the typical location of DUX4 expression. These improvements in patient classification hold the potential to enrich the FSHD clinical trial toolbox.

RevDate: 2020-10-19

Böhme J, Martinez N, Li S, et al (2020)

Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits.

Nature communications, 11(1):5225 pii:10.1038/s41467-020-19095-z.

Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3-/- mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.

RevDate: 2020-10-17

Eckel AM, HJ Deeg (2020)

Silver lining: reduced relapse with chronic GVHD after transplant for MDS.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-20-3583 [Epub ahead of print].

Chronic graft-versus-host disease (GVHD) following hematopoietic cell transplantation is associated with reduced relapse incidence in patients with leukemias. This impact has been investigated in myelodysplastic syndrome, showing a beneficial impact of limited chronic GVHD on transplant outcomes in a cohort of more than 3,000 patients.

RevDate: 2020-10-16

Parker MH, Stone D, Abrams K, et al (2020)

Anti-ICOS mAb Targets Pathogenic IL-17A-expressing Cells in Canine Model of Chronic GVHD.

Transplantation [Epub ahead of print].

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality in transplant patients. We have previously shown that 3 doses of an anti-ICOS mAb transiently ameliorated symptoms and extended survival of dogs affected by chronic GVHD over that of control dogs. The purpose of this study was to specifically correlate changes in T-cell populations in the peripheral blood with anti-ICOS treatment and chronic GVHD progression and regression in order to reach a better understanding of the mechanism of the disease and prioritize future studies.

METHODS: Peripheral blood cells from canines transplanted with DLA-mismatched bone marrow and PBMC to generate chronic GVHD were analyzed by flow cytometry using a panel of antibodies specific to helper and cytolytic T cells.

RESULTS: Chronic GVHD was specifically associated with an increase in CD4ICOS cells, ICOS cells expressing IL-17A, and CD8 cells generating granzyme B. Treatment with anti-ICOS mAb at onset of chronic GVHD symptoms specifically targeted IL-17A-expressing cells, transiently relieved symptoms, and lengthened survival but was unable to reduce the percentage of CD8 T-cells expressing granzyme B.

CONCLUSIONS: These studies suggested a role for both CD4 and CD8 T cells in pathogenesis of chronic GVHD in the canine model. We propose that future studies should focus on further extending survival by developing a treatment that would control both CD4 and CD8 T cells.

RevDate: 2020-10-16

Slyker JA, Guthrie B, Pankau M, et al (2020)

Cytomegalovirus and Epstein-Barr virus viremia are associated with HIV DNA levels in the reservoir of Kenyan infants on antiretroviral therapy.

The Journal of infectious diseases pii:5926738 [Epub ahead of print].

Identifying determinants of HIV reservoir levels may inform novel viral eradication strategies. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) co-infections were assessed as predictors of HIV proviral DNA level in 26 HIV RNA-suppressed Kenyan children starting antiretroviral therapy (ART) before 7 months of age. Earlier acquisition of CMV and EBV, and higher cumulative burden of systemic EBV DNA viremia were each associated with higher HIV DNA level in the reservoir after 24 months of ART, independent of HIV RNA levels over time. These data suggest delaying or containing CMV and EBV viremia may be novel strategies to limit HIV reservoir formation.

RevDate: 2020-10-19

Stoddard BL, ME Black (2019)

Letter to the Editor.

Neuro-oncology, 21(9):1210.

RevDate: 2020-10-16

McCune JS, McKiernan JS, van Maarseveen E, et al (2020)

Prediction of Acute Graft versus Host Disease and Relapse by Endogenous Metabolomic Compounds in Patients Receiving Personalized Busulfan-Based Conditioning.

Journal of proteome research [Epub ahead of print].

Busulfan-based conditioning is the most commonly used high-dose conditioning regimen for allogeneic hematopoietic cell transplant (HCT). The alkylating agent busulfan has a narrow therapeutic index, with busulfan doses personalized to a target plasma exposure (targeted busulfan). Using a global pharmacometabonomics approach, we sought to identify novel biomarkers of relapse or acute graft versus host disease (GVHD) in a cohort of 84 patients receiving targeted busulfan before allogeneic HCT. A total of 763 endogenous metabolomic compounds (EMCs) were quantitated in 230 longitudinal blood samples before, during, and shortly after intravenous busulfan administration. We performed both univariate linear regression and pathway enrichment analyses using global testing. The cysteine/methionine pathway and the glycine, serine, and threonine metabolism pathway were most associated with relapse. The latter be explained by the fact that glutathione S-transferases conjugate both busulfan and glutathione, which contains glycine as a component. The d-arginine and d-ornithine metabolism pathway and arginine and proline metabolism pathway were most associated with acute GVHD. None of these associations were significant after correcting for false discovery rate (FDR) with a strict cutoff of FDR-adjusted p < 0.1. Although larger studies are needed to substantiate these findings, the results show that EMCs may be used as predictive biomarkers in HCT patients.

RevDate: 2020-10-16

Hays M, Young JM, Levan PF, et al (2020)

A natural variant of the essential host gene MMS21 restricts the parasitic 2-micron plasmid in Saccharomyces cerevisiae.

eLife, 9: pii:62337 [Epub ahead of print].

Antagonistic coevolution with selfish genetic elements (SGEs) can drive evolution of host resistance. Here, we investigated host suppression of 2-micron (2m) plasmids, multicopy nuclear parasites that have co-evolved with budding yeasts. We developed SCAMPR (Single-Cell Assay for Measuring Plasmid Retention) to measure copy number heterogeneity and 2m plasmid loss in live cells. We identified three S. cerevisiae strains that lack endogenous 2m plasmids and reproducibly inhibit mitotic plasmid stability. Focusing on the Y9 ragi strain, we determined that plasmid restriction is heritable and dominant. Using bulk segregant analysis, we identified a high-confidence Quantitative Trait Locus (QTL) with a single variant of MMS21 associated with increased 2m instability. MMS21 encodes a SUMO E3 ligase and an essential component of the Smc5/6 complex, involved in sister chromatid cohesion, chromosome segregation, and DNA repair. Our analyses leverage natural variation to uncover a novel means by which budding yeasts can overcome highly successful genetic parasites.

RevDate: 2020-10-16

Morrison ML, Iwata A, Wick ML, et al (2020)

Iodine Redistribution During Trauma, Sepsis, and Hibernation: An Evolutionarily Conserved Response to Severe Stress.

Critical care explorations, 2(10):e0215.

Objective: We performed these studies to learn how iodine in the form of free iodide behaves during stress.

Design: Prospective observational trial using samples obtained from human trauma patients and retrospective observational study using remnant samples from human sepsis patients and arctic ground squirrels. Preclinical interventional study using hind-limb ischemia and reperfusion injury in mice.

Setting: Level I trauma center emergency room and ICU and animal research laboratories.

Subjects: Adult human sepsis and trauma patients, wild-caught adult arctic ground squirrels, and sexually mature laboratory mice.

Interventions: Ischemia and reperfusion injury was induced in mice by temporary application of tourniquet to one hind-limb. Iodide was administered IV just prior to reperfusion.

Measurements and Main Results: Free iodide was measured using ion chromatography. Relative to iodide in plasma from normal donors, iodide was increased 17-fold in plasma from trauma patients and 26-fold in plasma from sepsis patients. In arctic ground squirrels, iodide increases over three-fold during hibernation. And during ischemia/reperfusion injury in mice, iodide accumulates in ischemic tissue and reduces both local and systemic tissue damage.

Conclusions: Iodide redistributes during stress and improves outcome after injury. Essential functions of iodide may have contributed to its evolutionary selection and be useful as a therapeutic intervention for human patients.

RevDate: 2020-10-16

Gordon DE, Hiatt J, Bouhaddou M, et al (2020)

Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.

Science (New York, N.Y.) pii:science.abe9403 [Epub ahead of print].

The COVID-19 (Coronavirus disease-2019) pandemic, caused by the SARS-CoV-2 coronavirus, is a significant threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and MERS-CoV. Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analysis for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 Orf9b, an interaction we structurally characterized using cryo-EM. Combining genetically-validated host factors with both COVID-19 patient genetic data and medical billing records identified important molecular mechanisms and potential drug treatments that merit further molecular and clinical study.

RevDate: 2020-10-16

Golob JL, SS Minot (2020)

In silico benchmarking of metagenomic tools for coding sequence detection reveals the limits of sensitivity and precision.

BMC bioinformatics, 21(1):459 pii:10.1186/s12859-020-03802-0.

BACKGROUND: High-throughput sequencing can establish the functional capacity of a microbial community by cataloging the protein-coding sequences (CDS) present in the metagenome of the community. The relative performance of different computational methods for identifying CDS from whole-genome shotgun sequencing is not fully established.

RESULTS: Here we present an automated benchmarking workflow, using synthetic shotgun sequencing reads for which we know the true CDS content of the underlying communities, to determine the relative performance (sensitivity, positive predictive value or PPV, and computational efficiency) of different metagenome analysis tools for extracting the CDS content of a microbial community. Assembly-based methods are limited by coverage depth, with poor sensitivity for CDS at < 5X depth of sequencing, but have excellent PPV. Mapping-based techniques are more sensitive at low coverage depths, but can struggle with PPV. We additionally describe an expectation maximization based iterative algorithmic approach which we show to successfully improve the PPV of a mapping based technique while retaining improved sensitivity and computational efficiency.

CONCLUSION: Our benchmarking approach reveals the trade-offs of assembly versus alignment-based approaches and the relative performance of specific implementations when one wishes to extract the protein coding capacity of microbial communities.

RevDate: 2020-10-15

Guo X, Lin W, Wen W, et al (2020)

Identifying novel susceptibility genes for colorectal cancer risk from a transcriptome-wide association study of 125,478 subjects.

Gastroenterology pii:S0016-5085(20)35243-4 [Epub ahead of print].

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (TCGA, n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in four novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In nine known GWAS-identified loci, we uncovered nine genes that have not been previously reported, whereas four genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < 0.01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

CONCLUSION: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

RevDate: 2020-10-15

Rout ED, Moore AR, Burnett RC, et al (2020)

Polyclonal B-cell lymphocytosis in English bulldogs.

Journal of veterinary internal medicine [Epub ahead of print].

BACKGROUND: English bulldogs disproportionally develop an expansion of small B-cells, which has been interpreted as B-cell chronic lymphocytic leukemia (BCLL). However, clonality testing in these cases has often not been supportive of neoplasia.

HYPOTHESIS: English bulldogs have a syndrome of nonneoplastic B-cell expansion.

ANIMALS: Eighty-four English bulldogs with small-sized CD21+ B-cell lymphocytosis in the blood as determined by flow cytometry.

METHODS: This is a retrospective study. We characterized this syndrome by assessing B-cell clonality, clinical presentation, flow cytometric features, and immunoglobulin gammopathy patterns. We identified 84 cases with CD21+ lymphocytosis among 195 English bulldogs with blood samples submitted to the Colorado State University-Clinical Immunology laboratory for immunophenotyping between 2010 and 2019. Flow cytometry features were compared to normal B-cells and BCLL cases. PCR for antigen receptor rearrangements (PARR) by multiple immunoglobulin primers was performed to assess B-cell clonality. A subset of cases with gammopathy were examined by protein electrophoresis, immunofixation, and immunoglobulin subclass ELISA quantification.

RESULTS: Seventy percent (58/83) of cases had polyclonal or restricted polyclonal immunoglobulin gene rearrangements, suggesting nonmalignant B-cell expansion. The median age of all dogs in the study was 6.8 years and 74% were male. The median (range) lymphocyte count was 22 400/μL (2000-384 400/μL) and B-cells had low expression of class II MHC and CD25. Splenomegaly or splenic masses were detected in 57% (26/46) of cases and lymphadenopathy in 11% (7/61). Seventy-one percent (52/73) of cases had hyperglobulinemia and 77% (23/30) with globulin characterization had IgA ± IgM polyclonal or restricted polyclonal gammopathy patterns.

Polyclonal B-cell lymphocytosis in English bulldogs is characterized by low B-cell class II MHC and CD25 expression, splenomegaly and hyperglobulinemia consisting of increased IgA ± IgM. We hypothesize that this syndrome has a genetic basis.

RevDate: 2020-10-15

Haddad N, Delyon J, Trabelsi Messai S, et al (2020)

Clinical response to immune checkpoint inhibition in patients with advanced skin cancers receiving concurrent ruxolitinib therapy for hematologic malignancy.

Patients who are being treated with Janus-Kinase (JAK) inhibitors for hematologic conditions have a higher risk of developing non-melanoma skin cancers (NMSC) with an aggressive course1,2 . This has been attributed to relative immune-suppression that can accompany the use of JAK inhibitors, from their effects on T-cell signaling pathways3 . Acquired inactivating mutations in JAK 1 and JAK 2 genes have been reported to lead to a loss of programmed death ligand-1 (PD-L1) expression and a lack of response to interferon-γ (IFN-γ) in melanoma, contributing to acquired resistance to anti-programmed death 1 (PD-1) treatment4 .

RevDate: 2020-10-15

Bick AG, Weinstock JS, Nandakumar SK, et al (2020)

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature pii:10.1038/s41586-020-2819-2 [Epub ahead of print].

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2-4 and coronary heart disease5-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

RevDate: 2020-10-16

Zhao X, Qiao D, Yang C, et al (2020)

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Nature communications, 11(1):5182 pii:10.1038/s41467-020-18334-7.

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

RevDate: 2020-10-16

Tam CS, Robak T, Ghia P, et al (2020)

Zanubrutinib monotherapy for patients with treatment naïve chronic lymphocytic leukemia and 17p deletion.

Haematologica, Online ahead of print:.

Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma whose tumors carry deletion of chromosome 17p13.1 [del(17p)] have an unfavorable prognosis and respond poorly to standard chemoimmunotherapy. Zanubrutinib is a selective next-generation Bruton tyrosine kinase inhibitor. We evaluated the safety and efficacy of zanubrutinib 160 mg twice daily in treatment-naïve patients with del(17p) disease enrolled in a dedicated, nonrandomized cohort (Arm C) of the phase 3 SEQUOIA trial. A total of 109 patients (median age, 70 years; range, 42 - 86) with centrally confirmed del(17p) were enrolled and treated. After a median of 18.2 months (range, 5.0 - 26.3), seven patients had discontinued study treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent. The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete hematologic recovery. The estimated 18-month progression-free survival rate was 88.6% (95% CI, 79.0 - 94.0) and the estimated 18-month overall survival rate was 95.1% (95% CI, 88.4 - 98.0). Most common all-grade adverse events included contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), and diarrhea (16.5%). Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%). An adverse event of atrial fibrillation was reported in three patients (2.8%). Zanubrutinib was active and well tolerated in this large, prospectively enrolled treatment cohort of previously untreated patients with del(17p) chronic lymphocytic leukemia/small lymphocytic lymphoma. This trial was registered at ClinicalTrials.gov as #NCT03336333.

RevDate: 2020-10-16

Stephens DM, Boucher K, Kander E, et al (2020)

Hodgkin lymphoma arising in patients with chronic lymphocytic leukemia: outcomes from a large multi-center collaboration.

Haematologica, Online ahead of print:.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

RevDate: 2020-10-16

Granot N, R Storb (2020)

History of hematopoietic cell transplantation: challenges and progress.

Haematologica, Online ahead of print:2716-2729.

After more than 60 years of research in allogeneic hematopoietic cell transplantation (HCT), this therapy has advanced from one that was declared dead in the 1960s to a standard treatment of otherwise fatal malignant and non-malignant blood diseases. To date, close to 1.5 million hematopoietic cell transplants have been performed in more than 1,500 transplantation centers worldwide. This review will highlight the enormous efforts by numerous investigators throughout the world who have brought the experimental field of HCT to clinical reality, examine ongoing challenges, and provide insights for the future.

RevDate: 2020-10-16

Hongjiao Li , Yi Wang , Xingchen Pang , et al (2020)

Elevated TWIST1 expression in myelodysplastic syndromes/acute myeloid leukemia reduces efficacy of hypomethylating therapy with decitabine.

Haematologica, 105(10):e502.

RevDate: 2020-10-14

Camacho-Bydume C, Wang T, Sees JA, et al (2020)

Specific class I HLA supertypes but not HLA zygosity or expression are associated with outcomes following HLA-matched allogeneic hematopoietic cell transplant: HLA supertypes impact allogeneic HCT outcomes.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30664-9 [Epub ahead of print].

Maximizing the probability of antigen presentation to T cells through diversity in human leukocyte antigens (HLA) can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with AML, MDS, ALL, and NHL who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (HR=0.79, 95% CI 0.69 - 0.90, P=0.00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR=1.21, 95% CI, 1.10-1.32, P=0.00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibition does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes.

RevDate: 2020-10-14

Lin YR, Parks KR, Weidle C, et al (2020)

HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors.

Immunity, 53(4):840-851.e6.

Activating precursor B cell receptors of HIV-1 broadly neutralizing antibodies requires specifically designed immunogens. Here, we compared the abilities of three such germline-targeting immunogens against the VRC01-class receptors to activate the targeted B cells in transgenic mice expressing the germline VH of the VRC01 antibody but diverse mouse light chains. Immunogen-specific VRC01-like B cells were isolated at different time points after immunization, their VH and VL genes were sequenced, and the corresponding antibodies characterized. VRC01 B cell sub-populations with distinct cross-reactivity properties were activated by each immunogen, and these differences correlated with distinct biophysical and biochemical features of the germline-targeting immunogens. Our study indicates that the design of effective immunogens to activate B cell receptors leading to protective HIV-1 antibodies will require a better understanding of how the biophysical properties of the epitope and its surrounding surface on the germline-targeting immunogen influence its interaction with the available receptor variants in vivo.

RevDate: 2020-10-14

Piccart MJ, Hilbers FS, Bliss JM, et al (2020)

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

RevDate: 2020-10-14

Bast RC, Lu Z, Han CY, et al (2020)

Biomarkers and Strategies for Early Detection of Ovarian Cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1057 [Epub ahead of print].

Early detection of ovarian cancer remains an important unmet medical need. Effective screening could reduce mortality by 10-30%. Used individually, neither serum CA125 nor transvaginal sonography (TVS) is sufficiently sensitive or specific. Two stage strategies have proven more effective, where a significant rise above a woman's baseline CA125 prompts TVS and an abnormal sonogram prompts surgery. Two major screening trials have documented that this strategy has adequate specificity, but sensitivity for early stage (I-II) disease must improve to have a greater impact on mortality. To improve the first stage, different panels of protein biomarkers have detected cases missed by CA125. Autoantibodies against TP53 have detected 20% of early stage ovarian cancers 8 months prior to elevation of CA125 and 22 months prior to clinical diagnosis. Panels of autoantibodies and antigen-autoantibody complexes are being evaluated with the goal of detecting >90% of early stage ovarian cancers, alone or in combination with CA125, while maintaining 98% specificity in control subjects. Other biomarkers, including micro-RNAs, ctDNA, methylated DNA, and combinations of ctDNA alterations are being tested to provide an optimal first stage test. New technologies are also being developed with greater sensitivity than TVS to image small volumes of tumor.

RevDate: 2020-10-14

Li Y, Bai L, Yu H, et al (2020)

Epigenetic inactivation of α-internexin accelerates microtubule polymerization in colorectal cancer.

Cancer research pii:0008-5472.CAN-20-1590 [Epub ahead of print].

DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in colorectal cancer patients. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer.

RevDate: 2020-10-13

Kugel S, SR Hingorani (2020)

Cholesterol Biosynthesis Influences Subtype Specificity and Plasticity in Pancreas Cancer.

Cancer cell, 38(4):443-445.

Cellular plasticity contributes to intratumoral heterogeneity, metastatic spread, and treatment resistance of cancers. In this issue of Cancer Cell, Gabitova-Cornell et al. identify the potential to inadvertently develop an undifferentiated and more aggressive pancreas cancer with agents commonly prescribed to manage heart disease risk.

RevDate: 2020-10-13

Bleakley M (2020)

Naive T-cell depletion in stem cell transplantation.

Blood advances, 4(19):4980.

Allogeneic hematopoietic stem cell transplantation (HCT) is curative in many patients with advanced hematopoietic malignancies. Donor T cells not only facilitate engraftment and protect against opportunistic pathogens and residual disease, but can also cause graft-versus-host disease (GVHD), with significant morbidity and mortality. Complete T-cell depletion can not only substantially reduce GVHD rates but can also delay immune reconstitution and increase rates of opportunistic infections and relapse. Murine models have shown that naive T cells (TNs) consistently cause severe GVHD, whereas memory T cells cause milder or no GVHD and have critical graft-versus-tumor function. Informed by experiments performed in murine models of HCT, clinical trials are being conducted to evaluate TN-depleted peripheral blood stem cell (PBSC) grafts. These trials are showing very low rates of chronic GVHD and of serious acute GVHD in the HLA-matched HCT setting, with lower frequencies of opportunistic infections than after fully T-cell-depleted HCT and no apparent increase in relapse rates. Randomized clinical trials are ongoing, comparing standard unselected HCT with TN-depleted PBSCs and other promising GVHD-reduction strategies. Correlative laboratory studies will clarify how antitumor function is retained in TN-depleted HCT and inform strategies to further augment graft-versus-leukemia in patients at a high risk of relapse. TN depletion of donor lymphocyte infusions and of haploidentical stem cell grafts is also being investigated.

RevDate: 2020-10-13

Voso MT, Larson RA, Jones D, et al (2020)

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial.

Blood advances, 4(19):4945-4954.

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.

RevDate: 2020-10-13

van der Ploeg K, Le Luduec JB, Stevenson PA, et al (2020)

HLA-A alleles influencing NK cell function impact AML relapse following allogeneic hematopoietic cell transplantation.

Blood advances, 4(19):4955-4964.

HLA-B allotypes exhibiting the Bw4 epitope trigger variable inhibitory signaling of KIR3DL1 receptor types, where strong inhibitory HLA-B and KIR3DL1 allele combinations are associated with increased risk for relapse of acute myelogenous leukemia (AML) following allogeneic hematopoietic cell transplantation (HCT). Several HLA-A allotypes also exhibit the Bw4 epitope. Studies with natural killer (NK) cell clones have demonstrated NK inhibition via KIR3DL1 by HLA-A Bw4+ allotypes, but did not delineate strengths of inhibition or hierarchies of NK education. Using primary NK cells from healthy donors, we demonstrate that HLA-A*23, HLA-A*24, and HLA-A*32 proteins are expressed at different densities and exhibit different capacities to educate and inhibit KIR3DL1-expressing NK cells in vitro. Among the HLA-A Bw4+ allotypes, HLA-A*24 and HLA-A*32 demonstrate the strongest inhibitory capacity. To determine if HLA-A allotypes with strong inhibitory capacity have similar negative impact in allogeneic HCT as HLA-B Bw4+ allotypes, we performed a retrospective analysis of 1729 patients with AML who received an allogeneic HCT from a 9/10 or 10/10 HLA allele-matched unrelated donor. Examination of the donor-recipient pairs whose Bw4 epitope was exclusively contributed from HLA-A*24 and A*32 allotypes revealed that patients with HLA-A*24 who received an allograft from a KIR3DL1+ donor experienced a higher risk of disease relapse (hazard ratio, 1.65; 95% confidence interval, 1.17-2.32; P = .004) when compared with patients without a Bw4 epitope. These findings indicate that despite weak affinity interactions with KIR3DL1, common HLA-A allotypes with the Bw4 epitope can interact with KIR3DL1+ donor NK cells with clinically meaningful impact and provide additional insight to donor NK alloreactivity in HLA-matched HCT.

RevDate: 2020-10-13

Montes de Oca M, de Labastida Rivera F, Winterford C, et al (2020)

IL-27 signalling regulates glycolysis in Th1 cells to limit immunopathology during infection.

PLoS pathogens, 16(10):e1008994 pii:PPATHOGENS-D-20-01240 [Epub ahead of print].

Inflammation is critical for controlling pathogens, but also responsible for symptoms of infectious diseases. IL-27 is an important regulator of inflammation and can limit development of IFNγ-producing Tbet+ CD4+ T (Th1) cells. IL-27 is thought to do this by stimulating IL-10 production by CD4+ T cells, but the underlying mechanisms of these immunoregulatory pathways are not clear. Here we studied the role of IL-27 signalling in experimental visceral leishmaniasis (VL) caused by infection of C57BL/6 mice with the human pathogen Leishmania donovani. We found IL-27 signalling was critical for the development of IL-10-producing Th1 (Tr1) cells during infection. Furthermore, in the absence of IL-27 signalling, there was improved control of parasite growth, but accelerated splenic pathology characterised by the loss of marginal zone macrophages. Critically, we discovered that IL-27 signalling limited glycolysis in Th1 cells during infection that in turn attenuated inflammation. Furthermore, the modulation of glycolysis in the absence of IL-27 signalling restricted tissue pathology without compromising anti-parasitic immunity. Together, these findings identify a novel mechanism by which IL-27 mediates immune regulation during disease by regulating cellular metabolism.

RevDate: 2020-10-13

Coelho CH, Nadakal ST, Gonzales Hurtado PA, et al (2020)

Antimalarial antibody repertoire defined by plasma IG proteomics and single B cell IG sequencing.

JCI insight pii:143471 [Epub ahead of print].

Plasma antimalarial antibody can mediate anti-parasite immunity but has not previously been characterized at the molecular level. Here, we develop an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IG) or antibodies with those expressed on B cells as part of BcR. We applied this strategy to define plasma IG and determine variable V gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25. First, using proteomic tools coupled with bulk immunosequencing data, we determined human F(ab')2 peptide sequences from plasma IG of adults who received four doses of Pfs25-EPA/Alhydrogel. Specifically, Pfs25 antigen-specific F(ab')2 peptides (Pfs25-IG) were aligned to cDNA sequences of IGH complementarity determining region 3 (CDR3) from a dataset generated by total peripheral B cell immunosequencing of the entire vaccinated population. IGHV4 was the most commonly identified IGHV subgroup of Pfs25-IG, a pattern that was corroborated by VH/VL sequencing of Pfs25-specific single B cells from five vaccinees and by matching plasma Pfs25-IG peptides and V-(D)-J sequences of Pfs25-specific single B cells from the same donor. Among 13 recombinant human mAbs generated from IG sequences of Pfs25-specific single B cells, a single IGHV4 mAb displayed strong neutralizing activity, reducing the number of P. falciparum oocysts in infected mosquitoes by more than 80% at 100 μg/mL. Our approach characterizes the human plasma antibody repertoire in response to the Pfs25-EPA/Alhydrogel vaccine and will be useful to study circulating antibodies in response to other vaccines as well as those induced during infections or autoimmune disorders.

RevDate: 2020-10-13

Richard MA, Brown AL, Belmont JW, et al (2020)

Genetic variation in the body mass index of adult survivors of childhood acute lymphoblastic leukemia: A report from the Childhood Cancer Survivor Study and the St. Jude Lifetime Cohort.

Cancer [Epub ahead of print].

BACKGROUND: Treatment characteristics such as cranial radiation therapy (CRT) do not fully explain adiposity risk in childhood acute lymphoblastic leukemia (ALL) survivors. This study was aimed at characterizing genetic variation related to adult body mass index (BMI) among survivors of childhood ALL.

METHODS: Genetic associations of BMI among 1458 adult survivors of childhood ALL (median time from diagnosis, 20 years) were analyzed by multiple approaches. A 2-stage genome-wide association study in the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort Study (SJLIFE) was performed. BMI was a highly polygenic trait in the general population. Within the known loci, the BMI percent variance explained was estimated, and additive interactions (chi-square test) with CRT in the CCSS were evaluated. The role of DNA methylation in CRT interaction was further evaluated in a subsample of ALL survivors.

RESULTS: In a meta-analysis of the CCSS and SJLIFE, 2 novel loci associated with adult BMI among survivors of childhood ALL (LINC00856 rs575792008 and EMR1 rs62123082; PMeta < 5E-8) were identified. It was estimated that the more than 700 known loci explained 6.2% of the variation in adult BMI in childhood ALL survivors. Within the known loci, significant main effects for 23 loci and statistical interactions with CRT at 9 loci (P < 7.0E-5) were further identified. At 2 CRT-interacting loci, DNA methylation patterns may have differed by age.

CONCLUSIONS: Adult survivors of childhood ALL have genetic heritability for BMI similar to that observed in the general population. This study provides evidence that treatment with CRT can modify the effect of genetic variants on adult BMI in childhood ALL survivors.

RevDate: 2020-10-13

Galletti G, De Simone G, Mazza EMC, et al (2020)

Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans.

Nature immunology pii:10.1038/s41590-020-0791-5 [Epub ahead of print].

T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.

RevDate: 2020-10-13

Addetia A, Lin MJ, Peddu V, et al (2020)

Sensitive recovery of complete SARS-CoV-2 genomes from clinical samples using Swift Biosciences' SARS-CoV-2 multiplex amplicon sequencing panel.

Whole genome sequencing (WGS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a better understanding of the virus's origin, transmission, and evolution (1-6).….

RevDate: 2020-10-13

Rusert JM, Juarez EF, Brabetz S, et al (2020)

Functional precision medicine identifies new therapeutic candidates for medulloblastoma.

Cancer research pii:0008-5472.CAN-20-1655 [Epub ahead of print].

Medulloblastoma (MB) is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most MB patients receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each MB patient is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patient tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most MB do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for MB, was active against PDX representing Group 3 MB, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor.

RevDate: 2020-10-12

Farhadfar N, Burns LJ, Mupfudze T, et al (2020)

Hematopoietic Cell Transplantation: Practice predictions for the Year 2023.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30658-3 [Epub ahead of print].

BACKGROUND: Research priorities are best determined by the most pressing scientific questions, in the context of current knowledge. However, definitive research studies take time while real-world experience accumulates. Adoption of new practices before adequate comparison to current treatments threaten successful study conduct and may expose patients to what is ultimately learned to be inferior treatment. We conducted a survey to understand the Hematopoietic Cell Transplant (HCT) community's predictions about (a) future practice trends in the HCT field and (b) results of ongoing Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials to gauge how the HCT community views the treatments being studied.

METHOD: The survey was distributed between February and March 2019 to an electronic mailing list maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR) of HCT clinicians practicing in the United States.

RESULTS: Of 986 clinicians surveyed, 315 responded (32%). They predicted an increase in the number of HCTs performed for malignant hematologic diseases and benign diseases such as sickle cell, autoimmune and genetic disorders. The majority (63%) predicted that matched related donors (MRD) will remain the preferred donor source for adult HCT recipients in 2023 but 21% predicted haploidentical (Haplo) and 17% predicted matched unrelated donors (MUD) would be the preferred donors. Most respondents (65%) predicted a decrease in the use of umbilical cord blood (UCB) as a graft source for HCT. Most respondents also predicted that calcineurin-based graft-versus-host disease (GVHD) prophylaxis would be replaced by post-transplant cyclophosphamide (PTCy) (55%), biomarker use would become standard practice to guide GVHD therapy (73%), and steroids would be combined with other agents for first line therapy for newly diagnosed acute and (53%) chronic GVHD (54%). In ongoing BMT CTN trials where outcomes are not yet known, 60% to 92% of respondents had an opinion about which arm they thought would be superior. However, not all respondents predicted the same outcome with a range of 44% to 88% choosing the same arm. There was not a clear relationship between the proportion predicting the same arm would win and accrual to the trial.

CONCLUSION: Survey respondents are optimistic about growth in the volume of transplant procedures, and they also expect significant changes in the practice of HCT over the next few years including wider adoption of PTCy GVHD prophylaxis, increased use of biomarkers to guide GVHD therapy, and decreased use of UCB HCT. The degree of equipoise in the community about the relative efficacy of therapies being studied did not seem to affect accrual to current BMT CTN trials but this is an area that needs further investigation.

RevDate: 2020-10-12

Karcher MD, Carvalho LM, Suchard MA, et al (2020)

Estimating effective population size changes from preferentially sampled genetic sequences.

PLoS computational biology, 16(10):e1007774 pii:PCOMPBIOL-D-19-00490 [Epub ahead of print].

Coalescent theory combined with statistical modeling allows us to estimate effective population size fluctuations from molecular sequences of individuals sampled from a population of interest. When sequences are sampled serially through time and the distribution of the sampling times depends on the effective population size, explicit statistical modeling of sampling times improves population size estimation. Previous work assumed that the genealogy relating sampled sequences is known and modeled sampling times as an inhomogeneous Poisson process with log-intensity equal to a linear function of the log-transformed effective population size. We improve this approach in two ways. First, we extend the method to allow for joint Bayesian estimation of the genealogy, effective population size trajectory, and other model parameters. Next, we improve the sampling time model by incorporating additional sources of information in the form of time-varying covariates. We validate our new modeling framework using a simulation study and apply our new methodology to analyses of population dynamics of seasonal influenza and to the recent Ebola virus outbreak in West Africa.

RevDate: 2020-10-12

Marchand A, Kervarrec T, Bhatia S, et al (2020)

Pembrolizumab and other immune checkpoint inhibitors in locally advanced or metastatic merkel cell carcinoma: safety and efficacy.

Expert review of anticancer therapy [Epub ahead of print].

INTRODUCTION: Merkel Cell Carcinoma (MCC) is a rare aggressive skin cancer, mostly affecting elderly patients. Until recently, patients with advanced disease were treated with cytotoxic chemotherapies despite rapid chemoresistance and high toxicity. As with other cancers, immune checkpoint inhibitors (CPI), including pembrolizumab, allow durable responses with a manageable safety profile in these patients.

AREAS COVERED: This review describes the rationale for using PD-1/PD-L1 inhibitors in MCC, as well as efficacy and safety results from the 3 open-label trials investigating pembrolizumab or other PD-1/PD-L1 inhibitors in patients with advanced MCC. Real-life experience and predictive pre-treatment biomarkers are discussed to assess which patients are likely to be candidates for such strategies. Ongoing fields of research include the use of CPI in the adjuvant or neoadjuvant setting and combined strategies in refractory patients. Expert opinion: CPI have become the standard of care for frontline treatment in patients with advanced MCC. Earlier introduction of CPI in the disease course, including neo-adjuvant and adjuvant settings, is likely to improve the outcomes further. Given the rarity of this cancer, we still need to harmonize efforts in order to conduct large scale trials and efficiently identify best optimal care.

RevDate: 2020-10-12

Alshiekh S, Maziarz M, Geraghty DE, et al (2020)

High-resolution genotyping suggests that children with type 1 diabetes and celiac disease share three HLA class II loci in DRB3, DRB4, and DRB5 genes.

HLA [Epub ahead of print].

BACKGROUND AND OBJECTIVES: The aim was to compare extended HLA-class II genes in children with T1D, CD, and in a subgroup with both diseases (T1D w/CD) for differences and shared polymorphisms.

MATERIALS AND METHODS: Next-generation targeted sequencing (NGTS) of HLA-DRB3, DRB4, DRB5, DRB1, DQA1and DQB1alleles were analysed in 68 children with T1D, 219 children with CD, and in seven children with T1D w/CD and compared with 636 previously HLA-genotyped controls selected from the Swedish general population.

RESULTS: In CD children, DRB3*01:01:02 allele occurred more frequently in CD as compared to controls (OR=7.87; 95% CI, (6.17, 10.03), P=4.24x10-71), but less frequently in T1D. DRB4*01:03:01 was the most frequent allele in 55% of T1D children higher than control group (OR =3.86; 95% CI (2.69, 5.55), P=1.07x10-14) and had similar increased frequency in 71.4% of T1D w/CD compared to controls (OR=7.84; 95% CI (2.24, 34.5), P=0.0002). DRB3*02:02:01 showed a significant negative association in 4.6% of CD and nearly similar to T1D compared to control but not significant in T1D w/CD (P ≥ .05). The most significant allelic differences between T1D, CD and T1D w/ CD children was estimated for DRB4*01:03:01, which occurred more frequently in T1D (OR=2.58; 95% CI (1.74, 3.83), P =1.59x10-06) and in T1D w/ CD (OR=5.41; 95% CI (1.53, 24.06), P=0.003) as compared to CD children. The contrary was true for DRB3*01:01:02, which occurred less frequently in both T1D (OR=0.31; 95% CI (0.21, 0.47), P=7.17x10-09) and T1D w/CD (OR=0.11; 95% CI (0.01, 0.51), P=0.001) compared to CD children, respectively.

CONCLUSION: Differences in the HLA allelic distribution between T1D and CD children are mainly accounted for DRB3*01:01:02, DRB3*02:02:01 and DRB4*01:03:01. Children having both diseases show shared polymorphisms more similar to T1D than CD. This article is protected by copyright. All rights reserved.

RevDate: 2020-10-12

Williamson BD, Gilbert PB, Carone M, et al (2020)

Nonparametric variable importance assessment using machine learning techniques.

Biometrics [Epub ahead of print].

In a regression setting, it is often of interest to quantify the importance of various features in predicting the response. Commonly, the variable importance measure used is determined by the regression technique employed. For this reason, practitioners often only resort to one of a few regression techniques for which a variable importance measure is naturally defined. Unfortunately, these regression techniques are often sub-optimal for predicting the response. Additionally, because the variable importance measures native to different regression techniques generally have a different interpretation, comparisons across techniques can be difficult. In this work, we study a variable importance measure that can be used with any regression technique, and whose interpretation is agnostic to the technique used. This measure is a property of the true data-generating mechanism. Specifically, we discuss a generalization of the ANOVA variable importance measure, and discuss how it facilitates the use of machine learning techniques to flexibly estimate the variable importance of a single feature or group of features. The importance of each feature or group of features in the data can then be described individually, using this measure. We describe how to construct an efficient estimator of this measure as well as a valid confidence interval. Through simulations, we show that our proposal has good practical operating characteristics, and we illustrate its use with data from a study of risk factors for cardiovascular disease in South Africa. This article is protected by copyright. All rights reserved.

RevDate: 2020-10-13

Connelly ZM, Jin R, Zhang J, et al (2020)

FOXA2 promotes prostate cancer growth in the bone.

American journal of translational research, 12(9):5619-5629.

Bone metastasis frequently occurs in advanced-stage prostate cancer (PCa) patients. Understanding the mechanisms that promote PCa-mediated bone destruction is important for the identification of therapeutic targets against this lethal disease. We found that forkhead box A2 (FOXA2) is expressed in a subset of PCa bone metastasis specimens. To determine the functional role of FOXA2 in PCa metastasis, we knocked down the expression of FOXA2 in PCa PC3 cells, which can grow in bones and elicit an osteolytic reaction. The PC3/FOXA2-knockdown cells generated fewer bone lesions following intra-tibial injection compared to control cells. Further, we found that FOXA2 knockdown decreased the expression of PTHLH, which encodes PTHrP, a well-established factor that regulates bone remodeling. These results indicate that FOXA2 is involved in PCa bone metastasis.

RevDate: 2020-10-13

Kuderer NM, Wulff-Burchfield E, Rubinstein SM, et al (2020)

Cancer and COVID-19 - Authors' reply.

Lancet (London, England), 396(10257):1067-1068.

RevDate: 2020-10-10

Dimou NL, Papadimitriou N, Mariosa D, et al (2020)

Circulating adipokine concentrations and risk of five obesity-related cancers: a Mendelian randomization study.

International journal of cancer [Epub ahead of print].

Obesity is considered a chronic inflammatory state characterised by continued secretion of adipokines and cytokines. Experimental and epidemiological evidence indicates that circulating adipokines may be associated with the development of obesity-related cancers, but it is unclear if these associations are causal or confounded. We examined potential causal associations of specific adipokines [adiponectin, leptin, soluble leptin receptor (sOB-R), and plasminogen activator inhibitor-1 (PAI-1)] with five obesity-related cancers (colorectal, pancreatic, renal cell carcinoma, ovarian, and endometrial) using Mendelian randomization (MR) methods. We used summary-level data from large genetic consortia for 114 530 cancer cases and 245 284 controls. We constructed genetic instruments using 18 genetic variants for adiponectin, 2 for leptin, and 4 for both sOB-R and PAI-1 (P-value for inclusion<5 ˟ 10-8). Causal estimates were obtained using two-sample MR methods. In the inverse-variance weighted models, we found an inverse association between adiponectin and risk of colorectal cancer [odds ratio (OR) per 1 μg/mL increment in adiponectin concentration: 0.90 (95% confidence interval [CI]: 0.84-0.97); P: 0.01]; but, evidence of horizontal pleiotropy was detected and the association was not present when this was taken into consideration. No association was found for adiponectin and risks of pancreatic cancer, renal cell carcinoma, ovarian cancer, and endometrial cancer. Leptin, sOB-R and PAI-1 were also similarly unrelated to risk of obesity-related cancers. Despite the large sample size, our MR analyses do not support causal effects of circulating adiponectin, leptin, sOB-R, and PAI-1 concentrations on the development of five obesity-related cancers. This article is protected by copyright. All rights reserved.

RevDate: 2020-10-10

Patel S, Issaka RB, Chen E, et al (2020)

Colorectal Cancer Screening and COVID-19.

The American journal of gastroenterology [Epub ahead of print].

RevDate: 2020-10-10

Chow EJ, Doody DR, Di C, et al (2020)

Feasibility of a behavioral intervention using mobile health applications to reduce cardiovascular risk factors in cancer survivors: a pilot randomized controlled trial.

Journal of cancer survivorship : research and practice pii:10.1007/s11764-020-00949-w [Epub ahead of print].

PURPOSE: Determine the feasibility of a remotely delivered mobile health (mHealth)-supported intervention to improve diet and physical activity in hematologic malignancy survivors.

METHODS: Pilot randomized controlled trial of a 16-week intervention for improving diet and physical activity: individualized goal-setting (daily steps, sodium, saturated fat, added sugar intake) per feedback from mHealth trackers (Fitbit for activity; Healthwatch360 for diet), supplemented by a Facebook peer support group. Controls accessed the trackers without goal-setting or peer support. Everyone received standardized survivorship counseling with tailored advice from a clinician. Actigraphy and food frequency questionnaires assessed activity and diet at baseline and follow-up.

RESULTS: Forty-one participants (51.2% male; median age 45.1 years; 7.0 years from treatment) were randomized (24 intervention; 17 control). Fitbit and Healthwatch360 use were more common among intervention versus control participants (75.0% versus 70.6% and 50.0% versus 17.7% of eligible days, respectively). Most intervention participants (66.7%) engaged with Facebook; overall, 91.7% interacted with the study's mHealth applications. While no comparisons in activity or dietary outcomes between intervention versus control group met statistical significance, the intervention was associated with greater reductions in the targeted dietary factors and improvements in Healthy Eating Index-2015 score, moderate-vigorous physical activity time, and daily steps. Participant retention at 6 months was 90.2%.

CONCLUSIONS: An intervention for cardiovascular risk reduction based on individualized goal-setting enhanced by mHealth and social media peer support was feasible and acceptable among cancer survivors.

Effective and easily disseminated strategies that improve diet and physical activity in this population are needed.

TRIAL REGISTRATION: Registered in ClinicalTrials.gov (NCT03574012) on June 29, 2018.

RevDate: 2020-10-12

Rozot V, Nemes E, Geldenhuys H, et al (2020)

Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines.

Communications biology, 3(1):563 pii:10.1038/s42003-020-01288-3.

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection.

RevDate: 2020-10-12

Bauer M, Nascakova Z, Mihai AI, et al (2020)

The ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress.

Nature communications, 11(1):5117 pii:10.1038/s41467-020-18857-z.

Exposure of gastric epithelial cells to the bacterial carcinogen Helicobacter pylori causes DNA double strand breaks. Here, we show that H. pylori-induced DNA damage occurs co-transcriptionally in S-phase cells that activate NF-κB signaling upon innate immune recognition of the lipopolysaccharide biosynthetic intermediate β-ADP-heptose by the ALPK1/TIFA signaling pathway. DNA damage depends on the bi-functional RfaE enzyme and the Cag pathogenicity island of H. pylori, is accompanied by replication fork stalling and can be observed also in primary cells derived from gastric organoids. Importantly, H. pylori-induced replication stress and DNA damage depend on the presence of co-transcriptional RNA/DNA hybrids (R-loops) that form in infected cells during S-phase as a consequence of β-ADP-heptose/ ALPK1/TIFA/NF-κB signaling. H. pylori resides in close proximity to S-phase cells in the gastric mucosa of gastritis patients. Taken together, our results link bacterial infection and NF-κB-driven innate immune responses to R-loop-dependent replication stress and DNA damage.

RevDate: 2020-10-09

Park J, Frizzell H, Zhang H, et al (2020)

Flt3-L enhances trans-epithelial migration and antigen presentation of dendritic cells adoptively transferred to genital mucosa.

Journal of controlled release : official journal of the Controlled Release Society pii:S0168-3659(20)30583-6 [Epub ahead of print].

Dendritic cells (DCs) play a critical role in shaping adaptive immunity. Systemic transfer of DCs by intravenous injection has been widely investigated to inform the development of immunogenic DCs for use as cellular therapies. Adoptive transfer of DCs to mucosal sites has been limited but serves as a valuable tool to understand the role of the microenvironment on mucosal DC activation, maturation and antigen presentation. Here, we show that chitosan facilitates transmigration of DCs across the vaginal epithelium in the mouse female reproductive tract (FRT). In addition, ex vivo programming of DCs with fms-related tyrosine kinase 3 ligand (Flt3-L) was found to enhance translocation of intravaginally administered DCs to draining lymph nodes (dLNs) and stimulate in vivo proliferation of both antigen-specific CD4+ and CD8+ T cells (cross-presentation). Mucosal priming with chitosan and DC programming may hold great promise to enhance efficacy of DC-based vaccination to the female genital mucosa.

RevDate: 2020-10-09

Gounder M, Schöffski P, Jones RL, et al (2020)

Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study.

The Lancet. Oncology pii:S1470-2045(20)30451-4 [Epub ahead of print].

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma.

METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing.

FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths.

INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941).

FUNDING: Epizyme.

RevDate: 2020-10-09

Armstrong WS, Agwu AL, Barrette EP, et al (2020)

Innovations in HIV care delivery during the COVID-19 pandemic: Policies to strengthen the Ending the Epidemic Initiative - A Policy Paper of the Infectious Diseases Society of America and the HIV Medicine Association.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5920317 [Epub ahead of print].

The goal of the Ending the HIV Epidemic Initiative is to reduce new infections in the US by 90% by 2030. Success will require fundamentally changing HIV prevention and care delivery to engage more persons with HIV and at-risk of HIV in treatment. While the COVID-19 pandemic reduced in-person visits to care facilities and led to concern about interruptions in care, it also accelerated growth of alternative options, bolstered by additional funding support. These included the use of telehealth, medication delivery to the home and increased flexibility facilitating access to Ryan White HIV/AIDS Program services. While the outcomes of these programs must be studied, many have improved accessibility during the pandemic. As the pandemic wanes, long term policy changes are needed to preserve these options for those who benefit from them. These new care paradigms may provide a roadmap for progress for those with other chronic health issues as well.

RevDate: 2020-10-11

Huang Y, S Dasgupta (2019)

Likelihood-Based Methods for Assessing Principal Surrogate Endpoints in Vaccine Trials.

Statistics in biosciences, 11(3):504-523.

When evaluating principal surrogate biomarkers in vaccine trials, missingness in potential outcomes requires prediction using auxiliary variables and/or augmented study design with a close-out placebo vaccination (CPV) component. The estimated likelihood approach, which separates the estimation of biomarker distribution from the maximization of the estimated likelihood, has often been adopted. Here we develop a likelihood-based approach that jointly estimates the two parts and describe the methods for selecting auxiliary variables as risk predictors and/or biomarker predictors. Through numerical studies, we observe that in a standard trial design without a CPV component, the two methods achieve similar performance in estimation of the risk model and the marker model. However, for trials augmented with a CPV component, using the likelihood-based method achieves better estimation performance compared to the estimated likelihood method. Moreover, in the presence of a large number of covariates from which to select, the ML method achieves comparable or better performance compared to the EL method in both designs. While the CPV component has not yet been implemented in existing vaccine trials, our results have applications in the planning of future vaccine trials. We illustrate the method using data from a dengue vaccine trial.

RevDate: 2020-10-09

Chu HY, Boeckh M, Englund JA, et al (2020)

The Seattle Flu Study: a multiarm community-based prospective study protocol for assessing influenza prevalence, transmission and genomic epidemiology.

BMJ open, 10(10):e037295 pii:bmjopen-2020-037295.

INTRODUCTION: Influenza epidemics and pandemics cause significant morbidity and mortality. An effective response to a potential pandemic requires the infrastructure to rapidly detect, characterise, and potentially contain new and emerging influenza strains at both an individual and population level. The objective of this study is to use data gathered simultaneously from community and hospital sites to develop a model of how influenza enters and spreads in a population.

METHODS AND ANALYSIS: Starting in the 2018-2019 season, we have been enrolling individuals with acute respiratory illness from community sites throughout the Seattle metropolitan area, including clinics, childcare facilities, Seattle-Tacoma International Airport, workplaces, college campuses and homeless shelters. At these sites, we collect clinical data and mid-nasal swabs from individuals with at least two acute respiratory symptoms. Additionally, we collect residual nasal swabs and data from individuals who seek care for respiratory symptoms at four regional hospitals. Samples are tested using a multiplex molecular assay, and influenza whole genome sequencing is performed for samples with influenza detected. Geospatial mapping and computational modelling platforms are in development to characterise the regional spread of influenza and other respiratory pathogens.

ETHICS AND DISSEMINATION: The study was approved by the University of Washington's Institutional Review Board (STUDY00006181). Results will be disseminated through talks at conferences, peer-reviewed publications and on the study website (www.seattleflu.org).

RevDate: 2020-10-11

Manrique-Saide P, Dean NE, Halloran ME, et al (2020)

The TIRS trial: protocol for a cluster randomized controlled trial assessing the efficacy of preventive targeted indoor residual spraying to reduce Aedes-borne viral illnesses in Merida, Mexico.

Trials, 21(1):839.

BACKGROUND: Current urban vector control strategies have failed to contain dengue epidemics and to prevent the global expansion of Aedes-borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in sustaining effective ABV control emerges from the paucity of evidence regarding the epidemiological impact of any Aedes control method. A strategy for which there is limited epidemiological evidence is targeted indoor residual spraying (TIRS). TIRS is a modification of classic malaria indoor residual spraying that accounts for Aedes aegypti resting behavior by applying residual insecticides on exposed lower sections of walls (< 1.5 m), under furniture, and on dark surfaces.

METHODS/DESIGN: We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). The trial will be conducted in the city of Merida, Yucatan State, Mexico (population ~ 1million), where we will prospectively follow 4600 children aged 2-15 years at enrollment, distributed in 50 clusters of 5 × 5 city blocks each. Clusters will be randomly allocated (n = 25 per arm) using covariate-constrained randomization. A "fried egg" design will be followed, in which all blocks of the 5 × 5 cluster receive the intervention, but all sampling to evaluate the epidemiological and entomological endpoints will occur in the "yolk," the center 3 × 3 city blocks of each cluster. TIRS will be implemented as a preventive application (~ 1-2 months prior to the beginning of the ABV season). Active monitoring for symptomatic ABV illness will occur through weekly household visits and enhanced surveillance. Annual sero-surveys will be performed after each transmission season and entomological evaluations of Ae. aegypti indoor abundance and ABV infection rates monthly during the period of active surveillance. Epidemiological and entomological evaluation will continue for up to three transmission seasons.

DISCUSSION: The findings from this study will provide robust epidemiological evidence of the efficacy of TIRS in reducing ABV illness and infection. If efficacious, TIRS could drive a paradigm shift in Aedes control by considering Ae. aegypti behavior to guide residual insecticide applications and changing deployment to preemptive control (rather than in response to symptomatic cases), two major enhancements to existing practice.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04343521 . Registered on 13 April 2020. The protocol also complies with the WHO International Clinical Trials Registry Platform (ICTRP) (Additional file 1).

PRIMARY SPONSOR: National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID).

RevDate: 2020-10-08

Feofanova EV, Chen H, Dai Y, et al (2020)

A Genome-wide Association Study Discovers 46 Loci of the Human Metabolome in the Hispanic Community Health Study/Study of Latinos.

American journal of human genetics pii:S0002-9297(20)30323-2 [Epub ahead of print].

Variation in levels of the human metabolome reflect changes in homeostasis, providing a window into health and disease. The genetic impact on circulating metabolites in Hispanics, a population with high cardiometabolic disease burden, is largely unknown. We conducted genome-wide association analyses on 640 circulating metabolites in 3,926 Hispanic Community Health Study/Study of Latinos participants. The estimated heritability for 640 metabolites ranged between 0%-54% with a median at 2.5%. We discovered 46 variant-metabolite pairs (p value < 1.2 × 10-10, minor allele frequency ≥ 1%, proportion of variance explained [PEV] mean = 3.4%, PEVrange = 1%-22%) with generalized effects in two population-based studies and confirmed 301 known locus-metabolite associations. Half of the identified variants with generalized effect were located in genes, including five nonsynonymous variants. We identified co-localization with the expression quantitative trait loci at 105 discovered and 151 known loci-metabolites sets. rs5855544, upstream of SLC51A, was associated with higher levels of three steroid sulfates and co-localized with expression levels of SLC51A in several tissues. Mendelian randomization (MR) analysis identified several metabolites associated with coronary heart disease (CHD) and type 2 diabetes. For example, two variants located in or near CYP4F2 (rs2108622 and rs79400241, respectively), involved in vitamin E metabolism, were associated with the levels of octadecanedioate and vitamin E metabolites (gamma-CEHC and gamma-CEHC glucuronide); MR analysis showed that genetically high levels of these metabolites were associated with lower odds of CHD. Our findings document the genetic architecture of circulating metabolites in an underrepresented Hispanic/Latino community, shedding light on disease etiology.

RevDate: 2020-10-08

Chow VA, Gopal AK, Gauthier J, et al (2020)

Axicabtagene ciloleucel for relapsed or refractory lymphoma after prior treatment with a different CD19-directed CAR T-cell therapy.

Blood advances, 4(19):4869-4872.

RevDate: 2020-10-08

Ganapathi SS, Havard ME, Ferguson M, et al (2020)

Extramedullary Hematopoiesis in the Dura Mater During Treatment of a CNS Embryonal Tumor.

Journal of pediatric hematology/oncology [Epub ahead of print].

Extramedullary hematopoiesis (EMH) is hematopoiesis occurring outside of the bone marrow. It has been reported to develop in abdominal organs or lymph nodes after chemotherapy. Here, the authors describe a patient with a localized central nervous system embryonal tumor who, during intensive chemotherapy, developed dural nodules. Biopsy revealed these nodules to be EMH. Without a pathologic diagnosis, this may have been considered disease progression, altering the patient's treatment plan. This report intends to serve as a reminder that EMH should be included in the differential diagnosis of suspicious lesions and highlights the importance of their biopsy because of potential management implications.

RevDate: 2020-10-08

Palmieri R, Othus M, Halpern AB, et al (2020)

Accuracy of SIE/SIES/GITMO Consensus Criteria for Unfitness to Predict Early Mortality After Intensive Chemotherapy in Adults With AML or Other High-Grade Myeloid Neoplasm.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: With increasing therapeutic alternatives available, there is growing interest in tools that accurately identify patients most suitable for intensive acute myeloid leukemia (AML) chemotherapy. Nowadays, conceptual criteria proposed by an Italian panel of experts are widely used for this purpose. How accurately these Ferrara criteria predict fitness for intensive chemotherapy is unknown.

PATIENTS AND METHODS: We assessed the fitness of adults undergoing intensive AML therapy based on Ferrara criteria and determined the accuracy of this assessment for early mortality and survival prediction.

RESULTS: Among 655 adults who received curative-intent induction or reinduction chemotherapy with 7 days of standard-dose cytarabine and 3 days of an anthracycline ("7+3") CLAG-M (cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone), or reduced-dose CLAG-M, 197 (30%) met at least one of the criteria defining unfitness for intensive chemotherapy (F-unfit). Compared with F-fit patients, the overall survival of F-unfit patients was significantly shorter (median, 4.8 months; 95% CI, 3.6 to 6.5 months v 36.8 months; 95% CI, 27.4 to 73.0 months; P < .001). When used alone, the Ferrara unfitness assessment was more accurate in predicting day 28 and day 100 mortality than the treatment-related mortality score we developed previously (used binary, ≤ 13.1 v > 13.1), as indicated by area under the receiver operating characteristic curve (AUC) values of 0.76 and 0.79 versus 0.66 and 0.62. The predictive accuracy of the Ferrara unfitness assessment could be significantly improved by including additional covariates such as performance status and albumin, yielding AUCs as high as 0.84-0.85 for the prediction of day 28 or day 100 mortality. Prediction of overall survival was less accurate, yielding a c-statistic value as high as 0.75 in multivariable models.

CONCLUSION: Ferrara unfitness criteria provide a good prediction tool for shorter-term mortality after intensive AML chemotherapy. Our data may serve as a benchmark for expected outcomes with intensive chemotherapy in F-fit and F-unfit patients.

RevDate: 2020-10-08

Short NJ, Zhou S, Fu C, et al (2020)

Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.

JAMA oncology pii:2771199 [Epub ahead of print].

Importance: Measurable residual disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.

Objective: To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.

Data Sources: Clinical studies on AML published between January 1, 2000, and October 1, 2018, were identified via searches of PubMed, Embase, and MEDLINE.

Study Selection: Literature search and study screening were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies that assessed DFS or OS by MRD status in patients with AML were included. Reviews, non-English-language articles, and studies reporting only outcomes after hematopoietic cell transplantation or those with insufficient description of MRD information were excluded.

Data Extraction and Synthesis: Study sample size, median patient age, median follow-up time, MRD detection method, MRD assessment time points, AML subtype, specimen source, and survival outcomes were extracted. Meta-analyses were performed separately for DFS and OS using bayesian hierarchical modeling.

Main Outcomes and Measures: Meta-analyses of survival probabilities and hazard ratios (HRs) were conducted for OS and DFS according to MRD status.

Results: Eighty-one publications reporting on 11 151 patients were included. The average HR for achieving MRD negativity was 0.36 (95% bayesian credible interval [CrI], 0.33-0.39) for OS and 0.37 (95% CrI, 0.34-0.40) for DFS. The estimated 5-year DFS was 64% for patients without MRD and 25% for those with MRD, and the estimated OS was 68% for patients without MRD and 34% for those with MRD. The association of MRD negativity with DFS and OS was significant for all subgroups, with the exception of MRD assessed by cytogenetics or fluorescent in situ hybridization.

Conclusions and Relevance: The findings of this meta-analysis suggest that achievement of MRD negativity is associated with superior DFS and OS in patients with AML. The value of MRD negativity appears to be consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and MRD detection methods. These results support MRD status as an end point that may allow for accelerated evaluation of novel therapies in AML.

RevDate: 2020-10-08

McKay RR, Hafron JM, Ferro C, et al (2020)

A Retrospective Observational Analysis of Overall Survival with Sipuleucel-T in Medicare Beneficiaries Treated for Advanced Prostate Cancer.

Advances in therapy pii:10.1007/s12325-020-01509-5 [Epub ahead of print].

INTRODUCTION: Since sipuleucel-T approval in 2010, the treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) now includes the androgen-receptor signaling pathway inhibitors (ASPIs) abiraterone acetate or enzalutamide. In 2013 and 2014, these oral agents were approved for use in men with metastatic prostate cancer who had minimal to no symptoms. We compared overall survival (OS) in men who received their first mCRPC treatment using the Medicare Fee-for-Service 100% administrative claims research dataset with patient-level linkage to the National Death Index.

METHODS: This retrospective cohort analysis (January 2013 to December 2017) included men who were chemo-naïve at treatment start in 2014 and who had continuous Medicare Parts A, B, and D eligibility during the 3-year observation period. We compared: first-line sipuleucel-T vs. first-line ASPIs and any-line sipuleucel-T vs. any-line ASPIs (without sipuleucel-T). We used a multivariable regression model to help control for potentially confounding factors while assessing survival outcomes.

RESULTS: The model included 6044 eligible men (average age 75-78 years) with similar disease severity; > 80% were white. Median OS, presented as sipuleucel-T vs. ASPI, was 35.2 vs. 20.7 months (n, 906 vs. 5092; any-line cohort) and 34.9 vs. 21.0 months (n, 647 vs. 4810; first-line cohort). Model outcomes indicated sipuleucel-T was associated with significantly prolonged OS compared with ASPIs: adjusted hazard ratio, 0.59 (95% CI 0.527-0.651) and 0.56 (0.494-0.627) for the any-line and first-line cohorts, respectively.

CONCLUSION: This analysis suggests use of sipuleucel-T at any time was associated with improved OS compared with ASPI use alone. Of note, these analyses are intended as descriptive rather than definitive as this dataset contains limited data on key clinical factors. While selection bias is a risk in secondary claims data, this research provides important insight into real-world treatment outcomes.

RevDate: 2020-10-08

Suzuki T, Uruno A, Yumoto A, et al (2020)

Author Correction: Nrf2 contributes to the weight gain of mice during space travel.

Communications biology, 3(1):566 pii:10.1038/s42003-020-01292-7.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2020-10-08

Stinn T, Kuntz S, Varon D, et al (2020)

Subclinical genital herpes shedding in HIV/HSV-2 co-infected women during antiretroviral therapy (ART) is associated with an increase in HIV tissue reservoirs and potentially promotes HIV evolution.

Journal of virology pii:JVI.01606-20 [Epub ahead of print].

Antigen (Ag)-specific immune responses to chronic infections, such as herpes simplex virus type-2 (HSV), in HIV/HSV co-infected persons may sustain HIV tissue reservoirs by promoting T-cell proliferation but are poorly studied in women on antiretroviral therapy (ART). Mixed anogenital swabs and cervical secretions were self-collected by nine HIV/HSV-2 co-infected women during ART for 28 days to establish subclinical HSV DNA shedding rates and detection of HIV RNA by real-time PCR. Typical herpes lesion site (TLSB) and cervical biopsies were collected at the end of the daily sampling period. Nucleic acids (NA) isolated from biopsies had HIV quantified, HIV envC2-V5 single-genome amplification (SGA), and TCR repertoires assessed. Women had a median CD4 count of 537 cells/uL ((IQR): 483-741) at enrollment and HIV plasma viral loads <40copies/mL. HSV DNA was detected on 12% of days (IQR: 2-25%) from anogenital specimens. Frequent subclinical HSV DNA shedding was associated with increased HIV DNA tissue concentrations and increased divergence from the most recent common ancestor (MRCA), an indicator of HIV replication. Distinct predominant TCR clones were detected in cervix and TLSB in a woman with frequent HSV DNA shedding, with mixing of minor variants between her tissues; more limited TCR repertoire mixing was observed in two women with less frequent subclinical HSV DNA shedding. Subclinical HSV shedding in HIV/HSV co-infected women during ART may sustain HIV tissue reservoirs via Ag-exposure or HIV replication. This study provides evidence supporting further study of interventions targeting suppression of Ag-specific immune responses as a component of HIV cure strategies.IMPORTANCE Persons with HIV infection are frequently co-infected with chronic herpes viruses, which periodically replicate and produce viable herpes virions, particularly in anogenital and cervical tissues. Persistent protein expression results in proliferation of CD8+ and CD4+ T cells; the latter could potentially expand and sustain HIV tissue reservoirs. We found HSV genital shedding rates were positively correlated with HIV DNA concentrations and HIV divergence from ancestral sequences in tissues. Our work suggests that immune responses to common co-infections, such as herpes viruses, may sustain HIV tissue reservoirs during suppressive ART, suggesting future cure strategies should study interventions to suppress replication or reactivation of chronic herpes infections.

RevDate: 2020-10-10

Lloyd EC, Sallis HM, Verplanken B, et al (2020)

Understanding the nature of association between anxiety phenotypes and anorexia nervosa: a triangulation approach.

BMC psychiatry, 20(1):495.

BACKGROUND: Evidence from observational studies suggests an association between anxiety disorders and anorexia nervosa (AN), but causal inference is complicated by the potential for confounding in these studies. We triangulate evidence across a longitudinal study and a Mendelian randomization (MR) study, to evaluate whether there is support for anxiety disorder phenotypes exerting a causal effect on AN risk.

METHODS: Study One assessed longitudinal associations of childhood worry and anxiety disorders with lifetime AN in the Avon Longitudinal Study of Parents and Children cohort. Study Two used two-sample MR to evaluate: causal effects of worry, and genetic liability to anxiety disorders, on AN risk; causal effects of genetic liability to AN on anxiety outcomes; and the causal influence of worry on anxiety disorder development. The independence of effects of worry, relative to depressed affect, on AN and anxiety disorder outcomes, was explored using multivariable MR. Analyses were completed using summary statistics from recent genome-wide association studies.

RESULTS: Study One did not support an association between worry and subsequent AN, but there was strong evidence for anxiety disorders predicting increased risk of AN. Study Two outcomes supported worry causally increasing AN risk, but did not support a causal effect of anxiety disorders on AN development, or of AN on anxiety disorders/worry. Findings also indicated that worry causally influences anxiety disorder development. Multivariable analysis estimates suggested the influence of worry on both AN and anxiety disorders was independent of depressed affect.

CONCLUSIONS: Overall our results provide mixed evidence regarding the causal role of anxiety exposures in AN aetiology. The inconsistency between outcomes of Studies One and Two may be explained by limitations surrounding worry assessment in Study One, confounding of the anxiety disorder and AN association in observational research, and low power in MR analyses probing causal effects of genetic liability to anxiety disorders. The evidence for worry acting as a causal risk factor for anxiety disorders and AN supports targeting worry for prevention of both outcomes. Further research should clarify how a tendency to worry translates into AN risk, and whether anxiety disorder pathology exerts any causal effect on AN.

RevDate: 2020-10-09

Godwin CD, Zhou Y, Othus M, et al (2020)

Acute Myeloid Leukemia Measurable Residual Disease Detection by Flow Cytometry in Peripheral Blood Versus Bone Marrow.

Blood pii:464167 [Epub ahead of print].

RevDate: 2020-10-07

Prentice RL, Aragaki AK, Chlebowski RT, et al (2020)

Randomized Trial Evaluation of Benefits and Risks of Menopausal Hormone Therapy Among Women Aged 50-59.

American journal of epidemiology pii:5918691 [Epub ahead of print].

The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy post-menopausal women aged 50-79 at 40 U.S. clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens, and 16,608 participants with uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over an 18-year (median) follow-up period (1993-2016) risk for a global index, defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality, is reduced with conjugated equine estrogens with hazard ratio (95% confidence interval) of 0.82 (0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (0.95, 1.19) were non-significant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

RevDate: 2020-10-09

Petitprez F, Levy S, Sun CM, et al (2020)

The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression.

Genome medicine, 12(1):86.

Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer's disease.

RevDate: 2020-10-06

Wenger DS, Triplette M, Shahrir S, et al (2020)

Associations of marijuana with markers of chronic lung disease in people living with HIV.

HIV medicine [Epub ahead of print].

OBJECTIVES: The relationship between marijuana use and markers of chronic lung disease in people living with HIV (PLWH) is poorly understood.

METHODS: We performed a cross-sectional analysis of the Examinations of HIV-Associated Lung Emphysema (EXHALE) study, including 162 HIV-positive patients and 138 participants without HIV. We modelled marijuana exposure as: (i) current daily or weekly marijuana smoking vs. monthly or less often; or (ii) cumulative marijuana smoking (joint-years). Linear and logistic regression estimated associations between marijuana exposure and markers of lung disease, adjusted for tobacco smoking and other factors.

RESULTS: In PLWH, current daily or weekly marijuana use was associated with a larger forced vital capacity (FVC), larger total lung capacity and increased odds of radiographic emphysema compared with marijuana non-smokers in adjusted models; these associations were not statistically significant in participants without HIV. Marijuana joint-years were associated with higher forced expiratory volume in 1 s and FVC in PLWH but not with emphysema.

CONCLUSIONS: In PLWH, marijuana smoking was associated with higher lung volumes and potentially with radiographic emphysema. No consistently negative associations were observed between marijuana and measures of chronic lung health.

RevDate: 2020-10-06

Unger JM, Hershman DL, Till C, et al (2020)

"When offered to participate:" A systematic review and meta-analysis of patient agreement to participate in cancer clinical trials.

Journal of the National Cancer Institute pii:5918345 [Epub ahead of print].

BACKGROUND: Patient participation in clinical trials is vital for knowledge advancement and outcomes improvement. Few adult cancer patients participate in trials. Although patient decision-making about trial participation has been frequently examined, the participation rate for patients actually offered a trial is unknown.

METHODS: A systematic review and meta-analysis using 3 major search engines was undertaken. We identified studies from 1/1/2000-1/1/2020 that examined clinical trial participation in the U.S. Studies must have specified the numbers of patients offered a trial and the number enrolled. A random effects model of proportions was used. All statistical tests were two-sided.

RESULTS: We identified 35 studies (30 about treatment trials and 5 about cancer control trials) among which 9,759 patients were offered trial participation. Overall, 55.0% (95% CI: 49.4% to 60.5%) of patients agreed to enroll. Participation rates did not differ between treatment (55.0%, 95% CI: 48.9% to 60.9%) and cancer control trials (55.3%, 95% CI: 38.9% to 71.1%, p=.98). Black patients participated at similar rates (58.4%, 95% CI: 46.8% to 69.7%) compared to White patients (55.1%, 95% CI: 44.3% to 65.6%, p=.88). The main reasons for non-participation were treatment choice or lack of interest.

CONCLUSIONS: More than half of all cancer patients offered a clinical trial do participate. These findings upend several conventional beliefs about cancer clinical trial participation, including that Black patients are less likely to agree to participate and that patient decision-making is the primary barrier to participation. Policies and interventions to improve clinical trial participation should focus more on modifiable systemic structural and clinical barriers, such as improving access to available trials and broadening eligibility criteria.

RevDate: 2020-10-06

Watabayashi K, Steelquist J, Overstreet KA, et al (2020)

A Pilot Study of a Comprehensive Financial Navigation Program in Patients With Cancer and Caregivers.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(10):1366-1373 pii:jnccn19485.

BACKGROUND: Few studies have engaged patients and caregivers in interventions to alleviate financial hardship. We collaborated with Consumer Education and Training Services (CENTS), Patient Advocate Foundation (PAF), and Family Reach (FR) to assess the feasibility of enrolling patient-caregiver dyads in a program that provides financial counseling, insurance navigation, and assistance with medical and cost of living expenses.

METHODS: Patients with solid tumors aged ≥18 years and their primary caregiver received a financial education video, monthly contact with a CENTS counselor and PAF case manager for 6 months, and referral to FR for help with unpaid cost of living bills (eg, transportation or housing). Patient financial hardship and caregiver burden were measured using the Comprehensive Score for Financial Toxicity-Patient-Reported Outcomes (COST-PRO) and Caregiver Strain Index (CSI) measures, respectively, at baseline and follow-up.

RESULTS: Thirty patients (median age, 59.5 years; 40% commercially insured) and 18 caregivers (67% spouses) consented (78% dyad participation rate). Many participants faced cancer-related financial hardships prior to enrollment, such as work change or loss (45% of patients; 39% of caregivers) and debt (64% of patients); 39% of caregivers reported high levels of financial burden at enrollment. Subjects received $11,000 in assistance (mean, $772 per household); 66% of subjects with income ≤$50,000 received cost-of-living assistance. COST-PRO and CSI scores did not change significantly.

CONCLUSIONS: Patient-caregiver dyads were willing to participate in a financial navigation program that addresses various financial issues, particularly cost of living expenses in lower income participants. Future work should address financial concerns at diagnosis and determine whether doing so improves patient and caregiver outcomes.

RevDate: 2020-10-06

Deininger MW, Shah NP, Altman JK, et al (2020)

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 18(10):1385-1415 pii:jnccnGLS1810.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

RevDate: 2020-10-06

Mollura DJ, Culp MP, Pollack E, et al (2020)

Artificial Intelligence in Low- and Middle-Income Countries: Innovating Global Health Radiology.

Radiology [Epub ahead of print].

Scarce or absent radiology resources impede adoption of artificial intelligence (AI) for medical imaging by resource-poor health institutions. They face limitations in local equipment, personnel expertise, infrastructure, data-rights frameworks, and public policies. The trustworthiness of AI for medical decision making in global health and low-resource settings is hampered by insufficient data diversity, nontransparent AI algorithms, and resource-poor health institutions' limited participation in AI production and validation. RAD-AID's three-pronged integrated strategy for AI adoption in resource-poor health institutions is presented, which includes clinical radiology education, infrastructure implementation, and phased AI introduction. This strategy derives from RAD-AID's more-than-a-decade experience as a nonprofit organization developing radiology in resource-poor health institutions, both in the United States and in low- and middle-income countries. The three components synergistically provide the foundation to address health care disparities. Local radiology personnel expertise is augmented through comprehensive education. Software, hardware, and radiologic and networking infrastructure enables radiology workflows incorporating AI. These educational and infrastructure developments occur while RAD-AID delivers phased introduction, testing, and scaling of AI via global health collaborations.

RevDate: 2020-10-06

Parast L, Garcia TP, Prentice RL, et al (2020)

Robust methods to correct for measurement error when evaluating a surrogate marker.

Biometrics [Epub ahead of print].

The identification of valid surrogate markers of disease or disease progression has the potential to decrease the length and costs of future studies. Most available methods that assess the value of a surrogate marker ignore the fact that surrogates are often measured with error. Failing to adjust for measurement error can erroneously identify a useful surrogate marker as not useful or vice versa. We investigate and propose robust methods to correct for the effect of measurement error when evaluating a surrogate marker using multiple estimators developed for parametric and nonparametric estimates of the proportion of treatment effect explained by the surrogate marker. In addition, we quantify the attenuation bias induced by measurement error and develop inference procedures to allow for variance and confidence interval estimation. Through a simulation study, we show that our proposed estimators correct for measurement error in the surrogate marker and that our inference procedures perform well in finite samples. We illustrate these methods by examining a potential surrogate marker which is measured with error, hemoglobin A1c, using data from the Diabetes Prevention Program clinical trial. This article is protected by copyright. All rights reserved.

RevDate: 2020-10-08

Algazi AP, Othus M, Daud AI, et al (2020)

Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial.

Nature medicine, 26(10):1564-1568.

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.

RevDate: 2020-10-08

De Boeck A, Ahn BY, D'Mello C, et al (2020)

Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression.

Nature communications, 11(1):4997 pii:10.1038/s41467-020-18569-4.

Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.

RevDate: 2020-10-05

Horn DL, Bettcher LF, Navarro SL, et al (2020)


The journal of trauma and acute care surgery [Epub ahead of print].

BACKGROUND: Following trauma, persistent inflammation, immunosuppression, and catabolism may characterize delayed recovery or failure to recover. Understanding the metabolic response associated with these adverse outcomes may facilitate earlier identification and intervention. We characterized the metabolic profiles of trauma victims who died or developed chronic critical illness (CCI), and hypothesized that differences would be evident within one-week post-injury.

METHODS: Venous blood samples from trauma victims with shock who survived at least seven days were analyzed using mass spectrometry. Subjects who died or developed CCI (ICU LOS ≥ 14 days with persistent organ dysfunction) were compared to subjects who recovered rapidly (ICU LOS ≤ 7 days), and uninjured controls. We used Partial Least Squares Discriminant Analysis (PLS-DA), t-tests, linear mixed effects regression, and pathway enrichment analyses to make broad comparisons and identify differences in metabolite concentrations and pathways.

RESULTS: We identified 27 patients who died or developed CCI, and 33 who recovered rapidly. Subjects were predominantly male (65%) with a median age of 53 years and injury severity score of 36. Healthy controls (n=48) had similar age and sex distributions. Overall, from the 163 metabolites detected in the samples, 56 metabolites and 21 pathways differed between injury outcome groups, and PLS-DA models distinguished injury outcome groups as early as 1-day post-injury. Differences were observed in tryptophan, phenylalanine, and tyrosine metabolism; metabolites associated with oxidative stress via methionine metabolism; inflammatory mediators including kynurenine, arachidonate, and glucuronic acid; and products of the gut microbiome including indole-3-propionate.

CONCLUSIONS: The metabolic profiles in subjects who ultimately die or develop CCI differ from those who have recovered. In particular, we have identified differences in markers of inflammation, oxidative stress, amino acid metabolism and alterations in the gut microbiome. Targeted metabolomics has the potential to identify important metabolic changes post-injury to improve early diagnosis and targeted intervention.

LEVEL OF EVIDENCE: Prognostic/Epidemiologic Level III.

RevDate: 2020-10-13

Hughes SM, Levy CN, Calienes FL, et al (2020)

Treatment with Commonly Used Antiretroviral Drugs Induces a Type I/III Interferon Signature in the Gut in the Absence of HIV Infection.

Cell reports. Medicine, 1(6):100096.

Tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) are used for HIV treatment and prevention. Previously, we found that topical rectal tenofovir gel caused immunological changes in the mucosa. Here, we assess the effect of oral TDF/FTC in three HIV pre-exposure prophylaxis trials, two with gastrointestinal and one with cervicovaginal biopsies. TDF/FTC induces type I/III interferon-related (IFN I/III) genes in the gastrointestinal tract, but not blood, with strong correlations between the two independent rectal biopsy groups (Spearman r = 0.91) and between the rectum and duodenum (r = 0.81). Gene set testing also indicates stimulation of the type I/III pathways in the ectocervix and of cellular proliferation in the duodenum. mRNA sequencing, digital droplet PCR, proteomics, and immunofluorescence confirm IFN I/III pathway stimulation in the gastrointestinal tract. Thus, oral TDF/FTC stimulates an IFN I/III signature throughout the gut, which could increase antiviral efficacy but also cause chronic immune activation in HIV prevention and treatment settings.

RevDate: 2020-10-06

Wise DR, Schneider JA, Armenia J, et al (2020)

Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer.

JCO precision oncology, 4:.

PURPOSE: Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets.

METHODS: Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models. Epigenetic studies were carried out in a rapid autopsy cohort.

RESULTS: Dickkopf-1 (DKK1) expression is increased in DNPC relative to prostate-specific antigen (PSA)-expressing mCRPC in the Stand Up to Cancer/Prostate Cancer Foundation discovery cohort (11.2 v 0.28 reads per kilobase per million mapped reads; q < 0.05; n = 117) and in the University of Washington/Fred Hutchinson Cancer Research Center cohort (9.2 v 0.99 fragments per kilobase of transcript per million mapped reads; P < .0001). DKK1 expression can be regulated by activated Wnt signaling in vitro and correlates with activating canonical Wnt signaling mutations and low PSA mRNA in mCRPC biopsies (P < .05). DKK1 hypomethylation was associated with increased DKK1 mRNA expression (Pearson r = -0.66; P < .0001) in a rapid autopsy cohort (n = 7). DKK1-high mCRPC biopsies are infiltrated with significantly higher numbers of quiescent natural killer (NK) cells (P < .005) and lower numbers of activated NK cells (P < .0005). Growth inhibition of the human PCa model PC3 by the anti-DKK1 monoclonal antibody DKN-01 depends on the presence of NK cells in a severe combined immunodeficient xenograft mouse model.

CONCLUSION: These results support DKK1 as a contributor to the immunosuppressive tumor microenvironment of DNPC. These data have provided the rationale for a clinical trial targeting DKK1 in mCRPC (ClinicalTrials.gov identifier: NCT03837353).

RevDate: 2020-10-07

Wilson DR, Jin C, Ibrahim JG, et al (2020)

ICeD-T Provides Accurate Estimates of Immune Cell Abundance in Tumor Samples by Allowing for Aberrant Gene Expression Patterns.

Journal of the American Statistical Association, 115(531):1055-1065.

Immunotherapies have attracted lots of research interests recently. The need to understand the underlying mechanisms of immunotherapies and to develop precision immunotherapy regimens has spurred great interest in characterizing immune cell composition within the tumor microenvironment. Several methods have been developed to estimate immune cell composition using gene expression data from bulk tumor samples. However, these methods are not flexible enough to handle aberrant patterns of gene expression data, e.g., inconsistent cell type-specific gene expression between purified reference samples and tumor samples. We propose a novel statistical method for expression deconvolution called ICeD-T (Immune Cell Deconvolution in Tumor tissues). ICeD-T automatically identifies aberrant genes whose expression are inconsistent with the deconvolution model and down-weights their contributions to cell type abundance estimates. We evaluated the performance of ICeD-T versus existing methods in simulation studies and several real data analyses. ICeD-T displayed comparable or superior performance to these competing methods. Applying these methods to assess the relationship between immunotherapy response and immune cell composition, ICeD-T is able to identify significant associations that are missed by its competitors.

RevDate: 2020-10-05

Lee MS, Carcone AI, Ko L, et al (2020)

Managing Outliers in Adolescent Food Frequency Questionnaire Data.

Journal of nutrition education and behavior pii:S1499-4046(20)30551-0 [Epub ahead of print].

OBJECTIVE: The goal of this study was to explore the impact of 5 decision rules for removing outliers from adolescent food frequency questionnaire (FFQ) data.

DESIGN: This secondary analysis used baseline and 3-month data from a weight loss intervention clinical trial.

PARTICIPANTS: African American adolescents (n = 181) were recruited from outpatient clinics and community health fairs.

VARIABLES MEASURED: Data collected included self-reported FFQ and mediators of weight (food addiction, depressive symptoms, and relative reinforcing value of food), caregiver-reported executive functioning, and objectively measured weight status (percentage overweight).

ANALYSIS: Descriptive statistics examined patterns in study variables at baseline and follow-up. Correlational analyses explored the relationships between FFQ data and key study variables at baseline and follow-up.

RESULTS: Compared with not removing outliers, using decision rules reduced the number of cases and restricted the range of data. The magnitude of baseline FFQ-mediator relationships was attenuated under all decision rules but varied (increasing, decreasing, and reversing direction) at follow-up. Decision rule use increased the magnitude of change in FFQ estimated energy intake and significantly strengthened its relationship with weight change under 2 fixed range decision rules.

CONCLUSIONS AND IMPLICATIONS: Results suggest careful evaluation of outliers and testing and reporting the effects of different outlier decision rules through sensitivity analyses.

RevDate: 2020-10-09

Dean NE, Pastore Y Piontti A, Madewell ZJ, et al (2020)

Ensemble forecast modeling for the design of COVID-19 vaccine efficacy trials.

Vaccine [Epub ahead of print].

To rapidly evaluate the safety and efficacy of COVID-19 vaccine candidates, prioritizing vaccine trial sites in areas with high expected disease incidence can speed endpoint accrual and shorten trial duration. Mathematical and statistical forecast models can inform the process of site selection, integrating available data sources and facilitating comparisons across locations. We recommend the use of ensemble forecast modeling - combining projections from independent modeling groups - to guide investigators identifying suitable sites for COVID-19 vaccine efficacy trials. We describe an appropriate structure for this process, including minimum requirements, suggested output, and a user-friendly tool for displaying results. Importantly, we advise that this process be repeated regularly throughout the trial, to inform decisions about enrolling new participants at existing sites with waning incidence versus adding entirely new sites. These types of data-driven models can support the implementation of flexible efficacy trials tailored to the outbreak setting.

RevDate: 2020-10-03

Bejanyan N, Zhang M, Bo-Subait K, et al (2020)

Myeloablative Conditioning for Allogeneic Transplantation Results in Superior Disease-Free Survival for Acute Myeloid Leukemia and Myelodysplastic Syndromes with Low/Intermediate, but not High Disease Risk Index: A CIBMTR Study: Superior DFS with MAC compared to RIC HCT in AML/MDS with low/intermediate risk DRI.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(20)30618-2 [Epub ahead of print].

Myeloablative (MAC) as compared to reduced-intensity conditioning (RIC) is generally associated with lower relapse risk after allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). However, disease specific risk factors in AML/MDS can further inform when MAC vs. RIC may yield differential outcomes. We analyzed HCT outcomes stratified by the disease risk index (DRI) in 4387 adults (age 40-65 years) to identify the impact of conditioning intensity. In the low/intermediate risk DRI cohort, RIC was associated with lower non-relapse mortality (NRM) (HR=0.74, 95% CI 0.62-0.88; p<0.001), but significantly higher relapse risk (HR=1.54, 95% CI 1.35-1.76; p<0.001) and thus inferior disease-free survival (DFS) (HR=1.19, 95% CI 1.07-1.33; p=0.001). In the high/very high risk DRI cohort, RIC resulted in marginally lower NRM (HR=0.83, 95% CI 0.68-1.00; p=0.051), and significantly higher relapse risk (HR=1.23, 95% CI 1.08-1.41; p=0.002) leading to similar DFS using either RIC or MAC. These data support MAC over RIC as the preferred conditioning intensity for AML/MDS with low/intermediate risk DRI, but similar benefit to RIC in high/very high risk DRI. Novel MAC regimens with less toxicity could benefit all, but more potent anti-neoplastic approaches are needed for the high/very high risk DRI group.

RevDate: 2020-10-13

Baden LR, Stieh DJ, Sarnecki M, et al (2020)

Safety and immunogenicity of two heterologous HIV vaccine regimens in healthy, HIV-uninfected adults (TRAVERSE): a randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study.

The lancet. HIV, 7(10):e688-e698.

BACKGROUND: Bioinformatically designed mosaic antigens increase the breadth of HIV vaccine-elicited immunity. This study compared the safety, tolerability, and immunogenicity of a newly developed, tetravalent Ad26 vaccine with the previously tested trivalent formulation.

METHODS: This randomised, parallel-group, placebo-controlled, double-blind, phase 1/2a study (TRAVERSE) was done at 11 centres in the USA and one centre in Rwanda. Eligible participants were adults aged 18 to 50 years, who were HIV-uninfected, healthy at screening based on their medical history and a physical examination including laboratory assessment and vital sign measurements, and at low risk of HIV infection in the opinion of study staff, who applied a uniform definition of low-risk guidelines that was aligned across sites. Enrolled participants were randomly assigned at a 2:1 ratio to tetravalent and trivalent groups. Participants in tetravalent and trivalent groups were then further randomly assigned at a 5:1 ratio to adenovirus 26 (Ad26)-vectored vaccine and placebo subgroups. Randomisation was stratified by region (USA and Rwanda) and based on a computer-generated schedule using randomly permuted blocks prepared under the sponsor's supervision. We masked participants and investigators to treatment allocation throughout the study. On day 0, participants received a first injection of tetravalent vaccine (Ad26.Mos4.HIV or placebo) or trivalent vaccine (Ad26.Mos.HIV or placebo), and those injections were repeated 12 weeks later. At week 24, vaccine groups received a third dose of tetravalent or trivalent together with clade C gp140, and this was repeated at week 48, with placebos again administered to the placebo group. All study vaccines and placebo were administered by intramuscular injection in the deltoid muscle. We assessed adverse events in all participants who received at least one study injection (full analysis set) and Env-specific binding antibodies in all participants who received at least the first three vaccinations according to the protocol-specified vaccination schedule, had at least one measured post-dose blood sample collected, and were not diagnosed with HIV during the study (per-protocol set). This study is registered with Clinicaltrials.gov, NCT02788045.

FINDINGS: Of 201 participants who were enrolled and randomly assigned, 198 received the first vaccination: 110 were in the tetravalent group, 55 in the trivalent group, and 33 in the placebo group. Overall, 185 (93%) completed two scheduled vaccinations per protocol, 180 (91%) completed three, and 164 (83%) completed four. Solicited, self-limiting local, systemic reactogenicity and unsolicited adverse events were similar in vaccine groups and higher than in placebo groups. All participants in the per-protocol set developed clade C Env binding antibodies after the second vaccination, with higher total IgG titres after the tetravalent vaccine than after the trivalent vaccine (10 413 EU/mL, 95% CI 7284-14 886 in the tetravalent group compared with 5494 EU/mL, 3759-8029 in the trivalent group). Titres further increased after the third and fourth vaccinations, persisting at least through week 72. Other immune responses were also higher with the tetravalent vaccine, including the magnitude and breadth of binding antibodies against a cross-clade panel of Env antigens, and the magnitude of IFNγ ELISPOT responses (median 521 SFU/106 peripheral blood mononuclear cells [PBMCs] in the tetravalent group and median 282 SFU/106 PBMCs in the trivalent group after the fourth vaccination) and Env-specific CD4+ T-cell response rates after the third and fourth vaccinations. No interference by pre-existing Ad26 immunity was identified.

INTERPRETATION: The tetravalent vaccine regimen was generally safe, well-tolerated, and found to elicit higher immune responses than the trivalent regimen. Regimens that use this tetravalent vaccine component are being advanced into field trials to assess efficacy against HIV-1 infection.

FUNDING: National Institutes of Health, Henry M Jackson Foundation for Advancement of Military Medicine and the US Department of Defense, Ragon Institute of MGH, MIT, & Harvard, Bill & Melinda Gates Foundation, and Janssen Vaccines & Prevention.

RevDate: 2020-10-03

Hurwitz LM, Agalliu I, Albanes D, et al (2020)

Recommended definitions of aggressive prostate cancer for etiologic epidemiologic research.

Journal of the National Cancer Institute pii:5917632 [Epub ahead of print].

BACKGROUND: In the era of widespread prostate-specific antigen testing, it is important to focus etiologic research on the outcome of aggressive prostate cancer, but studies have defined this outcome differently. We aimed to develop an evidence-based consensus definition of aggressive prostate cancer using clinical features at diagnosis for etiologic epidemiologic research.

METHODS: Among prostate cancer cases diagnosed in 2007 in the U.S. SEER-18 database with follow-up through 2017, we compared the performance of categorizations of aggressive prostate cancer in discriminating fatal prostate cancer within 10 years of diagnosis, placing the most emphasis on sensitivity and positive predictive value (PPV).

RESULTS: In our case population (n = 55,900), 3,073 men died of prostate cancer within 10 years. Among 12 definitions that included TNM stage and Gleason score, sensitivities ranged from 0.64 to 0.89 and PPVs ranged from 0.09 to 0.23. We propose defining aggressive prostate cancer as diagnosis of stage T4 or N1 or M1 or Gleason score ≥8 prostate cancer, as this definition had one of the higher PPVs (0.23, 95% confidence interval [CI] 0.22-0.24) and reasonable sensitivity (0.66, 95% CI 0.64-0.67) for prostate cancer death within 10 years. Results were similar across sensitivity analyses.

CONCLUSIONS: We recommend that etiologic epidemiologic studies of prostate cancer report results for this definition of aggressive prostate cancer. We also recommend that studies separately report results for advanced stage (T4 or N1 or M1), high grade (Gleason score ≥8), and fatal prostate cancer. Use of this comprehensive set of endpoints will facilitate comparison of results from different studies and help elucidate prostate cancer etiology.

RevDate: 2020-10-03

Kwon OJ, Zhang L, Jia D, et al (2020)

De novo induction of lineage plasticity from human prostate luminal epithelial cells by activated AKT1 and c-Myc.

Oncogene pii:10.1038/s41388-020-01487-6 [Epub ahead of print].

Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that either develops de novo or arises from prostate adenocarcinoma as a result of treatment resistance. Although the prostate basal cells have been shown to directly generate tumor cells with neuroendocrine features when transduced with oncogenic signaling, the identity of the cell-of-origin for de novo NEPC remains unclear. We show that the TACSTD2high human prostate luminal epithelia cells highly express SOX2 and are relatively enriched in the transition zone prostate. Both TACSTD2high and TACSTD2low luminal cells transduced by constitutively activated AKT1 (caAKT1), and c-Myc can form organoids containing versatile clinically relevant tumor cell lineages with regard to the expression of AR and the neuroendocrine cell markers Synaptophysin and Chromogranin A. Tumor organoid cells derived from the TACSTD2high luminal cells are more predisposed to neuroendocrine differentiation along passaging and are relatively more castration-resistant. Knocking down TACSTD2 and SOX2 both attenuate neuroendocrine differentiation of tumor organoid cells. This study demonstrates de novo neuroendocrine differentiation of the human prostate luminal epithelial cells induced by caAKT1 and c-Myc and reveals an impact of cellular status on initiation of lineage plasticity.

RevDate: 2020-10-03

Haidar G, Garner W, JA Hill (2020)

Infections after anti-CD19 chimeric antigen receptor T-cell therapy for hematologic malignancies: timeline, prevention, and uncertainties.

Current opinion in infectious diseases [Epub ahead of print].

PURPOSE OF REVIEW: Data on the infectious complications of anti-CD19 chimeric antigen receptor-modified T-cell (CAR-T-cell) therapies are scant. The approaches to preventing and managing infections among CAR-T-cell recipients are extrapolated from those of patients with other hematological malignancies. Understanding the incidence and risk factors of infections in these patients will improve clinical outcomes.

RECENT FINDINGS: Infections occur in 23-42% of CAR-T-cell recipients and are most frequent in the first month after infusion, declining sharply thereafter. Risk factors include preinfusion (e.g., prior hematopoietic cell transplant, underlying malignancy) and postinfusion variables (e.g., cytokine release syndrome [CRS], neutropenia). Neutropenic fever after CAR-T-cell therapy is nearly universal but is confounded by CRS. The timeline of infections can be divided into preinfusion (because of the preparative regimen); 0-30 days after infusion, when bacterial infections predominate; and 30 days onwards, when respiratory viral infections predominate. Fungal and herpesviridae infections are uncommon.

SUMMARY: Recent studies have shed light on the epidemiology of infections after CAR-T-cell therapy. Future efforts should focus on identifying modifiable risk factors for infection, defining neutropenic fever in the setting of CRS, determining the benefit of antimold prophylaxis, and identifying the optimal approach to viral monitoring, vaccination, and immunoglobulin replacement.

RevDate: 2020-10-10

Neumeyer S, Hua X, Seibold P, et al (2020)

Genetic variants in the regulatory T cell related pathway and colorectal cancer prognosis.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-0714 [Epub ahead of print].

BACKGROUND: High numbers of lymphocytes in tumor tissue, including T regulatory cells (Treg), have been associated with better colorectal cancer (CRC) survival. Tregs, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer and therefore variants in genes related to Treg differentiation and function could be associated with CRC prognosis.

METHODS: In a prospective German cohort of 3 593 CRC patients, we assessed the association of 771 SNPs in 58 T-reg related genes with overall and CRC-specific survival using Cox regression models. Effect modification by microsatellite instability (MSI) status was also investigated since tumors with MSI show greater lymphocytic infiltration and have been associated with better prognosis. Replication of significant results was attempted in 2 047 CRC patients of the International Survival Analysis in Colorectal cancer Consortium (ISACC).

RESULTS: A significant association of the TGFBR3 SNP rs7524066 with more favorable CRC-specific survival (hazard ratio (HR) per minor allele: 0.83, 95% confidence interval (CI): 0.74-0.94, p-value: 0.0033) was replicated in ISACC (HR: 0.82, 95% CI 0.68-0.98, p-value: 0.03). Suggestive evidence for association was found with two IL7 SNPs, rs16906568 and rs7845577. Thirteen SNPs with differential associations with overall survival according to MSI in the discovery analysis were not confirmed.

CONCLUSIONS: Common genetic variation in the Treg pathway implicating genes such as TGFBR3 and IL7 was shown to be associated with prognosis of CRC patients.

IMPACT: The implicated genes warrant further investigation.

RevDate: 2020-10-13

Wrenn ED, Yamamoto A, Moore BM, et al (2020)

Regulation of Collective Metastasis by Nanolumenal Signaling.

Cell pii:S0092-8674(20)31087-4 [Epub ahead of print].

Collective metastasis is defined as the cohesive migration and metastasis of multicellular tumor cell clusters. Disrupting various cell adhesion genes markedly reduces cluster formation and colonization efficiency, yet the downstream signals transmitted by clustering remain largely unknown. Here, we use mouse and human breast cancer models to identify a collective signal generated by tumor cell clusters supporting metastatic colonization. We show that tumor cell clusters produce the growth factor epigen and concentrate it within nanolumina-intercellular compartments sealed by cell-cell junctions and lined with microvilli-like protrusions. Epigen knockdown profoundly reduces metastatic outgrowth and switches clusters from a proliferative to a collective migratory state. Tumor cell clusters from basal-like 2, but not mesenchymal-like, triple-negative breast cancer cell lines have increased epigen expression, sealed nanolumina, and impaired outgrowth upon nanolumenal junction disruption. We propose that nanolumenal signaling could offer a therapeutic target for aggressive metastatic breast cancers.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

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Curriculum Vitae for R J Robbins

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