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14 Nov 2022 at 02:01
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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 14 Nov 2022 at 02:01 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: ( fhcrc[Affiliation] OR fred hutchinson[Affiliation] OR Fred Hutchinson Cancer Research[Affiliation] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2022-09-18

Mossa F, Robesti D, Sumankalai R, et al (2022)

Subtype and site specific-induced metabolic vulnerabilities in prostate cancer.

Molecular cancer research : MCR pii:709237 [Epub ahead of print].

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive-variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759's inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone. Implications: These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.

RevDate: 2022-09-17

Trofimov A, Brouillard P, Larouche JD, et al (2022)

Two types of human TCR differentially regulate reactivity to self and non-self antigens.

iScience, 25(9):104968.

Based on analyses of TCR sequences from over 1,000 individuals, we report that the TCR repertoire is composed of two ontogenically and functionally distinct types of TCRs. Their production is regulated by variations in thymic output and terminal deoxynucleotidyl transferase (TDT) activity. Neonatal TCRs derived from TDT-negative progenitors persist throughout life, are highly shared among subjects, and are reported as disease-associated. Thus, 10%-30% of most frequent cord blood TCRs are associated with common pathogens and autoantigens. TDT-dependent TCRs present distinct structural features and are less shared among subjects. TDT-dependent TCRs are produced in maximal numbers during infancy when thymic output and TDT activity reach a summit, are more abundant in subjects with AIRE mutations, and seem to play a dominant role in graft-versus-host disease. Factors decreasing thymic output (age, male sex) negatively impact TCR diversity. Males compensate for their lower repertoire diversity via hyperexpansion of selected TCR clonotypes.

RevDate: 2022-10-07

De Angeli K, Gao S, Blanchard A, et al (2022)

Using ensembles and distillation to optimize the deployment of deep learning models for the classification of electronic cancer pathology reports.

JAMIA open, 5(3):ooac075.

Objective: We aim to reduce overfitting and model overconfidence by distilling the knowledge of an ensemble of deep learning models into a single model for the classification of cancer pathology reports.

Materials and Methods: We consider the text classification problem that involves 5 individual tasks. The baseline model consists of a multitask convolutional neural network (MtCNN), and the implemented ensemble (teacher) consists of 1000 MtCNNs. We performed knowledge transfer by training a single model (student) with soft labels derived through the aggregation of ensemble predictions. We evaluate performance based on accuracy and abstention rates by using softmax thresholding.

Results: The student model outperforms the baseline MtCNN in terms of abstention rates and accuracy, thereby allowing the model to be used with a larger volume of documents when deployed. The highest boost was observed for subsite and histology, for which the student model classified an additional 1.81% reports for subsite and 3.33% reports for histology.

Discussion: Ensemble predictions provide a useful strategy for quantifying the uncertainty inherent in labeled data and thereby enable the construction of soft labels with estimated probabilities for multiple classes for a given document. Training models with the derived soft labels reduce model confidence in difficult-to-classify documents, thereby leading to a reduction in the number of highly confident wrong predictions.

Conclusions: Ensemble model distillation is a simple tool to reduce model overconfidence in problems with extreme class imbalance and noisy datasets. These methods can facilitate the deployment of deep learning models in high-risk domains with low computational resources where minimizing inference time is required.

RevDate: 2022-11-09
CmpDate: 2022-11-09

Jones SMW (2022)

Financial worry in people with cancer: Relationship to employment and outcomes.

Psycho-oncology, 31(11):1835-1842.

BACKGROUND: People with cancer experience financial hardship. Most previous research has focused on material financial burden rather than financial worry. This study investigated employment predictors of financial worry and examined outcomes potentially affected by financial worry.

METHODS: Data from the 2018 National Health Interview Study was used and limited to people diagnosed with cancer and having complete data on relevant variables (n = 2049). Preliminary analyses indicated three dimensions of financial worry: healthcare; lifestyle; and basic needs. Outcomes included cost-related nonadherence, and presence of depressive symptoms and anxiety. Multivariable regressions examined the association of financial worry with cost-related nonadherence and mental health and employment characteristics (paid hourly; sick leave; employer size) with financial worry while controlling for demographics.

RESULTS: Mean age was 68.10 years (range: 20-85), and most had skin (33.6%), prostate (12.5%) or breast (21.4%) cancer. Hourly pay predicted more financial worry about affording healthcare (p < 0.001), basic needs (p < 0.001) and lifestyle (p < 0.001). Having paid sick leave predicted less worry about basic needs (p = 0.003). Worry about affording healthcare predicted more cost-related nonadherence (p < 0.001) even when controlling for other variables associated with financial hardship. Worry about lifestyle (p = 0.193) and basic needs (p = 0.688) were not associated with cost-related nonadherence. Worry about lifestyle (p < 0.001) predicted depression. Worry about affording healthcare (p = 0.042) and lifestyle (p < 0.001) predicted anxiety.

CONCLUSIONS: Research is needed to determine the value of financial worry screening, particularly about affording healthcare, as well as material financial hardship. Financial worry should be included as an outcome in policy evaluations and interventions for financial hardship.

RevDate: 2022-11-02
CmpDate: 2022-09-19

Ling W, Lu J, Zhao N, et al (2022)

Batch effects removal for microbiome data via conditional quantile regression.

Nature communications, 13(1):5418.

Batch effects in microbiome data arise from differential processing of specimens and can lead to spurious findings and obscure true signals. Strategies designed for genomic data to mitigate batch effects usually fail to address the zero-inflated and over-dispersed microbiome data. Most strategies tailored for microbiome data are restricted to association testing or specialized study designs, failing to allow other analytic goals or general designs. Here, we develop the Conditional Quantile Regression (ConQuR) approach to remove microbiome batch effects using a two-part quantile regression model. ConQuR is a comprehensive method that accommodates the complex distributions of microbial read counts by non-parametric modeling, and it generates batch-removed zero-inflated read counts that can be used in and benefit usual subsequent analyses. We apply ConQuR to simulated and real microbiome datasets and demonstrate its advantages in removing batch effects while preserving the signals of interest.

RevDate: 2022-11-10
CmpDate: 2022-09-19

Ansary AM, Stolla M, Corson J, et al (2022)

Effect of Ado-Trastuzumab Emtansine on Autologous Platelet Kinetics and Function.

JCO precision oncology, 6:e2200237.

PURPOSE: Ado-trastuzumab emtansine (T-DM1) treatment results in grade 3-4 thrombocytopenia in 8%-13% of patients. Prior in vitro studies reported T-DM1 inhibition of megakaryocyte maturation as the cause of decreased platelet production. The current observational study was initiated to evaluate causes of thrombocytopenia in patients with metastatic breast cancer.

MATERIALS AND METHODS: Patients with human epidermal growth factor receptor 2-positive metastatic breast cancer (N = 11) were enrolled in this postmarket safety study. 111-Indium- radiolabeled autologous platelet recoveries and survivals as well as serial platelet counts, bleeding time assays, and platelet aggregation responses to a wide range of agonists were performed at baseline (BL) and during two consecutive cycles of the drug (3.6 mg/kg IV once every 3 weeks).

RESULTS: Platelet nadirs occurred earlier in cycle 2 than in cycle 1. Average nadir counts (% BL) in cycles 1 and 2 were 116,000/µL (53% ± 6%) and 115,000/µL (51% ± 9%), respectively, with return to BL by D15 in both cycles. BL platelet survival averaged 8.8 (± 0.3) days but progressively shortened to 5.5 (± 0.5) days during cycle 1 and to 4.6 (± 0.3) days during cycle 2 (P < .001 compared with BL for both cycles). Aggregation responses to all agonists decreased during the study, both in cycle 1 and cycle 2.

CONCLUSION: Following T-DM1 administration, we observed statistically significant progressive decreases in platelet survivals and decreased platelet function from BL values. In distinction to published in vitro studies, these unexpected results indicate a direct toxic effect of T-DM1 on patients' autologous circulating platelets.

RevDate: 2022-11-08
CmpDate: 2022-10-10

Tegally H, San JE, Cotten M, et al (2022)

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Science (New York, N.Y.), 378(6615):eabq5358.

Investment in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing in Africa over the past year has led to a major increase in the number of sequences that have been generated and used to track the pandemic on the continent, a number that now exceeds 100,000 genomes. Our results show an increase in the number of African countries that are able to sequence domestically and highlight that local sequencing enables faster turnaround times and more-regular routine surveillance. Despite limitations of low testing proportions, findings from this genomic surveillance study underscore the heterogeneous nature of the pandemic and illuminate the distinct dispersal dynamics of variants of concern-particularly Alpha, Beta, Delta, and Omicron-on the continent. Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve while the continent faces many emerging and reemerging infectious disease threats. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century.

RevDate: 2022-10-28
CmpDate: 2022-10-04

Pagán AJ, Lee LJ, Edwards-Hicks J, et al (2022)

mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.

Cell, 185(20):3720-3738.e13.

Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.

RevDate: 2022-09-29
CmpDate: 2022-09-15

Barber B, Mair F, M Prlic (2022)

A path forward to improving the specificity of immunotherapies.

Clinical and translational medicine, 12(9):e1051.

RevDate: 2022-10-18
CmpDate: 2022-10-05

Devall MAM, Dampier CH, Eaton S, et al (2022)

Transcriptomic Response to Calcium in Normal Colon Organoids is Impacted by Colon Location and Sex.

Cancer prevention research (Philadelphia, Pa.), 15(10):679-688.

Observational studies indicate that calcium supplementation may protect against colorectal cancer. Stratified analyses suggest that this protective effect may differ based on anatomic subsite and sex, but these hypotheses have been difficult to test experimentally. Here, we exposed 36 patient-derived organoid lines derived from normal colon biopsies (21 right colons, 15 left colons) of unrelated subjects (18 female, 18 male) to moderate (1.66 mmol/L) or high (5.0 mmol/L) concentrations of calcium for 72 hours. We performed bulk RNA-sequencing to measure gene expression, and cell composition was inferred using single-cell deconvolution in CIBERSORTx. We tested for significant differences in gene expression using generalized linear models in DESeq2. Exposure to higher levels of calcium was associated with changes in cell composition (P < 0.05), most notably increased goblet and reduced stem cell populations, and differential expression of 485 genes (FDR < 0.05). We found that 40 of these differentially expressed genes mapped to genomic loci identified through colorectal cancer genome-wide association studies, suggesting a potential biologic overlap between calcium supplementation and inherited colorectal cancer risk. Stratified analyses identified more differentially expressed genes in colon organoids derived from right sided colon and male subjects than those derived from left sided colon and female subjects. We confirmed the presence of a stronger right-sided effect for one of these genes, HSD17B2 using qPCR in a subset of matched right and left colon organoids (n = 4). By relating our findings to genetic data, we provide new insights into how nutritional and genetic factors may interact to influence colorectal cancer risk.

PREVENTION RELEVANCE: A chemopreventive role for calcium in colorectal cancer is still unclear. Here, we identify mechanisms through which calcium supplementation may reduce risk. Calcium supplementation increased differentiation and altered expression of colorectal cancer-related genes in a large study of patient-derived colon organoids. These findings were influenced by colon location and sex.

RevDate: 2022-09-29

Ezenwa BN, Umoren R, Fajolu IB, et al (2022)

Using Mobile Virtual Reality Simulation to Prepare for In-Person Helping Babies Breathe Training: Secondary Analysis of a Randomized Controlled Trial (the eHBB/mHBS Trial).

JMIR medical education, 8(3):e37297.

BACKGROUND: Neonatal mortality accounts for approximately 46% of global under-5 child mortality. The widespread access to mobile devices in low- and middle-income countries has enabled innovations, such as mobile virtual reality (VR), to be leveraged in simulation education for health care workers.

OBJECTIVE: This study explores the feasibility and educational efficacy of using mobile VR for the precourse preparation of health care professionals in neonatal resuscitation training.

METHODS: Health care professionals in obstetrics and newborn care units at 20 secondary and tertiary health care facilities in Lagos, Nigeria, and Busia, Western Kenya, who had not received training in Helping Babies Breathe (HBB) within the past 1 year were randomized to access the electronic HBB VR simulation and digitized HBB Provider's Guide (VR group) or the digitized HBB Provider's Guide only (control group). A sample size of 91 participants per group was calculated based on the main study protocol that was previously published. Participants were directed to use the electronic HBB VR simulation and digitized HBB Provider's Guide or the digitized HBB Provider's Guide alone for a minimum of 20 minutes. HBB knowledge and skills assessments were then conducted, which were immediately followed by a standard, in-person HBB training course that was led by study staff and used standard HBB evaluation tools and the Neonatalie Live manikin (Laerdal Medical).

RESULTS: A total of 179 nurses and midwives participated (VR group: n=91; control group: n=88). The overall performance scores on the knowledge check (P=.29), bag and mask ventilation skills check (P=.34), and Objective Structured Clinical Examination A checklist (P=.43) were similar between groups, with low overall pass rates (6/178, 3.4% of participants). During the Objective Structured Clinical Examination A test, participants in the VR group performed better on the critical step of positioning the head and clearing the airway (VR group: 77/90, 86%; control group: 57/88, 65%; P=.002). The median percentage of ventilations that were performed via head tilt, as recorded by the Neonatalie Live manikin, was also numerically higher in the VR group (75%, IQR 9%-98%) than in the control group (62%, IQR 13%-97%), though not statistically significantly different (P=.35). Participants in the control group performed better on the identifying a helper and reviewing the emergency plan step (VR group: 7/90, 8%; control group: 16/88, 18%; P=.045) and the washing hands step (VR group: 20/90, 22%; control group: 32/88, 36%; P=.048).

CONCLUSIONS: The use of digital interventions, such as mobile VR simulations, may be a viable approach to precourse preparation in neonatal resuscitation training for health care professionals in low- and middle-income countries.

RevDate: 2022-10-14

Farrell AG, Dadonaite B, Greaney AJ, et al (2022)

Receptor binding domain (RBD) antibodies contribute more to SARS-CoV-2 neutralization when target cells express high levels of ACE2.

bioRxiv : the preprint server for biology.

Neutralization assays are experimental surrogates for the effectiveness of infection- or vaccine-elicited polyclonal antibodies and therapeutic monoclonal antibodies targeting SARS-CoV-2. However, the measured neutralization can depend on details of the experimental assay. Here we systematically assess how ACE2 expression in target cells affects neutralization by antibodies to different spike epitopes in lentivirus pseudovirus neutralization assays. For high ACE2-expressing target cells, receptor binding domain (RBD) antibodies account for nearly all neutralizing activity in polyclonal human sera. But for lower ACE2-expressing target cells, antibodies targeting regions outside the RBD make a larger (although still modest) contribution to serum neutralization. These serum-level results are mirrored for monoclonal antibodies: N-terminal domain (NTD) antibodies and RBD antibodies that do not compete for ACE2 binding incompletely neutralize on high ACE2-expressing target cells, but completely neutralize on cells with lower ACE2 expression. Our results show that ACE2 expression level in the target cells is an important experimental variable, and that high ACE2 expression emphasizes the role of a subset of RBD-directed antibodies.

RevDate: 2022-11-12

Navarro SL, Zheng Z, Randolph TW, et al (2022)

Lipidomics of cyclophosphamide 4-hydroxylation in patients receiving post-transplant cyclophosphamide.

Clinical and translational science, 15(11):2772-2780.

Biomarker-guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration-time curve (AUC) of CY and its metabolites are time- and resource-intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time-varying differences in CY formation clearance to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post-transplant CY (PT-CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre-HCT), before infusion of the donor allograft (pre-graft), before the first dose of PT-CY (pre-CY) and 24 h after the first dose of PT-CY (24-h post-CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT.

RevDate: 2022-09-21
CmpDate: 2022-09-13

Anwar MY, Baldassari AR, Polikowsky HG, et al (2022)

Genetic pleiotropy underpinning adiposity and inflammation in self-identified Hispanic/Latino populations.

BMC medical genomics, 15(1):192.

BACKGROUND: Concurrent variation in adiposity and inflammation suggests potential shared functional pathways and pleiotropic disease underpinning. Yet, exploration of pleiotropy in the context of adiposity-inflammation has been scarce, and none has included self-identified Hispanic/Latino populations. Given the high level of ancestral diversity in Hispanic American population, genetic studies may reveal variants that are infrequent/monomorphic in more homogeneous populations.

METHODS: Using multi-trait Adaptive Sum of Powered Score (aSPU) method, we examined individual and shared genetic effects underlying inflammatory (CRP) and adiposity-related traits (Body Mass Index [BMI]), and central adiposity (Waist to Hip Ratio [WHR]) in HLA participating in the Population Architecture Using Genomics and Epidemiology (PAGE) cohort (N = 35,871) with replication of effects in the Cameron County Hispanic Cohort (CCHC) which consists of Mexican American individuals.

RESULTS: Of the > 16 million SNPs tested, variants representing 7 independent loci were found to illustrate significant association with multiple traits. Two out of 7 variants were replicated at statistically significant level in multi-trait analyses in CCHC. The lead variant on APOE (rs439401) and rs11208712 were found to harbor multi-trait associations with adiposity and inflammation.

CONCLUSIONS: Results from this study demonstrate the importance of considering pleiotropy for improving our understanding of the etiology of the various metabolic pathways that regulate cardiovascular disease development.

RevDate: 2022-11-10
CmpDate: 2022-11-08

Schenk JM, Till C, Neuhouser ML, et al (2022)

Differential Biopsy Patterns Influence Associations between Multivitamin Use and Prostate Cancer Risk in the Selenium and Vitamin E Cancer Prevention Trial.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 31(11):2063-2069.

BACKGROUND: Multivitamin (MVI) use is a common health behavior but there is conflicting evidence from prospective studies about whether this behavior increases or decreases prostate cancer risk.

METHODS: Associations of MVI use and prostate cancer risk were evaluated using data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Cox proportional hazards models estimated associations of MVI use with risk of total, low-, and high-grade prostate cancer. Longitudinal data were used to evaluate screening and biopsy patterns. To account for differential biopsy patterns, the probability of prostate cancer was estimated for men with a positive screening value but no biopsy. Incidence density ratios were used to approximate HRs, and associations of MVI use with predicted prostate cancer risk were compared with observed.

RESULTS: Analyses of data from observed biopsies suggest a respective 19% (95% confidence interval, 10%-28%) and 21% (12%-31%) higher risk of high-grade prostate cancer for current and long-term MVI use, compared with no use. Current and long-term MVI use was associated with a shorter time to first on-study biopsy, indicating the potential for detection bias. After accounting for differential acceptance of biopsy, associations of MVI use with prostate cancer were attenuated and not statistically significant.

CONCLUSIONS: In SELECT, biopsy acceptance patterns differed by MVI use. Estimates of associations of MVI use with prostate cancer risk based on observed biopsy data may be biased by differential acceptance of biopsy.

IMPACT: Differential biopsy ascertainment may impact associations of risk factors and prostate cancer. Detailed screening and biopsy data can be used to analytically minimize such bias.

RevDate: 2022-09-13
CmpDate: 2022-09-12

Jyoti D, Gordon-Wylie SW, Reeves DB, et al (2022)

Distinguishing Nanoparticle Aggregation from Viscosity Changes in MPS/MSB Detection of Biomarkers.

Sensors (Basel, Switzerland), 22(17):.

Magnetic particle spectroscopy (MPS) in the Brownian relaxation regime, also termed magnetic spectroscopy of Brownian motion (MSB), can detect and quantitate very low, sub-nanomolar concentrations of molecular biomarkers. MPS/MSB uses the harmonics of the magnetization induced by a small, low-frequency oscillating magnetic field to provide quantitative information about the magnetic nanoparticles' (mNPs') microenvironment. A key application uses antibody-coated mNPs to produce biomarker-mediated aggregation that can be detected using MPS/MSB. However, relaxation changes can also be caused by viscosity changes. To address this challenge, we propose a metric that can distinguish between aggregation and viscosity. Viscosity changes scale the MPS/MSB harmonic ratios with a constant multiplier across all applied field frequencies. The change in viscosity is exactly equal to the multiplier with generality, avoiding the need to understand the signal explicitly. This simple scaling relationship is violated when particles aggregate. Instead, a separate multiplier must be used for each frequency. The standard deviation of the multipliers over frequency defines a metric isolating viscosity (zero standard deviation) from aggregation (non-zero standard deviation). It increases monotonically with biomarker concentration. We modeled aggregation and simulated the MPS/MSB signal changes resulting from aggregation and viscosity changes. MPS/MSB signal changes were also measured experimentally using 100 nm iron-oxide mNPs in solutions with different viscosities (modulated by glycerol concentration) and with different levels of aggregation (modulated by concanavalin A linker concentrations). Experimental and simulation results confirmed that viscosity changes produced small changes in the standard deviation and aggregation produced larger values of standard deviation. This work overcomes a key barrier to using MPS/MSB to detect biomarkers in vivo with variable tissue viscosity.

RevDate: 2022-11-10

Wagner MJ, Hennessy C, Beeghly A, et al (2022)

Demographics, Outcomes, and Risk Factors for Patients with Sarcoma and COVID-19: A CCC19-Registry Based Retrospective Cohort Study.

Cancers, 14(17):.

BACKGROUND: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19.

METHODS: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed.

RESULTS: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity.

CONCLUSIONS: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

RevDate: 2022-09-13

Amendola BE, Mahadevan A, Blanco Suarez JM, et al (2022)

An International Consensus on the Design of Prospective Clinical-Translational Trials in Spatially Fractionated Radiation Therapy for Advanced Gynecologic Cancer.

Cancers, 14(17):.

Despite the unexpectedly high tumor responses and limited treatment-related toxicities observed with SFRT, prospective multi-institutional clinical trials of SFRT are still lacking. High variability of SFRT technologies and methods, unfamiliar complex dose and prescription concepts for heterogeneous dose and uncertainty regarding systemic therapies present major obstacles towards clinical trial development. To address these challenges, the consensus guideline reported here aimed at facilitating trial development and feasibility through a priori harmonization of treatment approach and the full range of clinical trial design parameters for SFRT trials in gynecologic cancer. Gynecologic cancers were evaluated for the status of SFRT pilot experience. A multi-disciplinary SFRT expert panel for gynecologic cancer was established to develop the consensus through formal panel review/discussions, appropriateness rank voting and public comment solicitation/review. The trial design parameters included eligibility/exclusions, endpoints, SFRT technology/technique, dose/dosimetric parameters, systemic therapies, patient evaluations, and embedded translational science. Cervical cancer was determined as the most suitable gynecologic tumor for an SFRT trial. Consensus emphasized standardization of SFRT dosimetry/physics parameters, biologic dose modeling, and specimen collection for translational/biological endpoints, which may be uniquely feasible in cervical cancer. Incorporation of brachytherapy into the SFRT regimen requires additional pre-trial pilot investigations. Specific consensus recommendations are presented and discussed.

RevDate: 2022-09-29
CmpDate: 2022-09-13

Bleakley M, M Biernacki (2022)

MDM2 inhibition augments GVL effect.

Blood, 140(10):1064-1065.

RevDate: 2022-09-25

Lønning PE, Nikolaienko O, Pan K, et al (2022)

Constitutional BRCA1 Methylation and Risk of Incident Triple-Negative Breast Cancer and High-grade Serous Ovarian Cancer.

JAMA oncology [Epub ahead of print].

Importance: About 25% of all triple-negative breast cancers (TNBCs) and 10% to 20% of high-grade serous ovarian cancers (HGSOCs) harbor BRCA1 promoter methylation. While constitutional BRCA1 promoter methylation has been observed in normal tissues of some individuals, the potential role of normal tissue methylation as a risk factor for incident TNBC or HGSOC is unknown.

Objective: To assess the potential association between white blood cell BRCA1 promoter methylation and subsequent risk of incident TNBC and HGSOC.

This case-control study included women who were participating in the Women's Health Initiative study who had not received a diagnosis of either breast or ovarian cancer before study entrance. A total of 637 women developing incident TNBC and 511 women developing incident HGSOC were matched with cancer-free controls (1841 and 2982, respectively) in a nested case-control design. Cancers were confirmed after central medical record review. Blood samples, which were collected at entry, were analyzed for BRCA1 promoter methylation by massive parallel sequencing. The study was performed in the Mohn Cancer Research Laboratory (Bergen, Norway) between 2019 and 2022.

Main Outcomes and Measures: Associations between BRCA1 methylation and incident TNBC and incident HGSOC were analyzed by Cox proportional hazards regression.

Results: Of 2478 cases and controls in the TNBC group and 3493 cases and controls in the HGSOC group, respectively, 7 (0.3%) and 3 (0.1%) were American Indian or Alaska Native, 46 (1.9%) and 30 (0.9%) were Asian, 1 (0.04%) and 1 (0.03%) was Native Hawaiian or Pacific Islander, 326 (13.2%) and 125 (3.6%) were Black or African, 56 (2.3%) and 116 (3.3%) were Hispanic, 2046 (82.6%) and 3257 (93.2%) were White, and 35 (1.4%) and 35 (1.0%) were multiracial. Median (range) age at entry was 62 (50-79) years, with a median interval to diagnosis of 9 (TNBC) and 10 (HGSOC) years. Methylated BRCA1 alleles were present in 194 controls (5.5%). Methylation was associated with risk of incident TNBC (12.4% methylated; HR, 2.35; 95% CI, 1.70-3.23; P < .001) and incident HGSOC (9.4% methylated; HR, 1.93; 95% CI, 1.36-2.73; P < .001). Restricting analyses to individuals with more than 5 years between sampling and cancer diagnosis yielded similar results (TNBC: HR, 2.52; 95% CI, 1.75-3.63; P < .001; HGSOC: HR, 1.82; 95% CI, 1.22-2.72; P = .003). Across individuals, methylation was not haplotype-specific, arguing against an underlying cis-acting factor. Within individuals, BRCA1 methylation was observed on the same allele, indicating clonal expansion from a single methylation event. There was no association found between BRCA1 methylation and germline pathogenic variant status.

Conclusions and Relevance: The results of this case-control suggest that constitutional normal tissue BRCA1 promoter methylation is significantly associated with risk of incident TNBC and HGSOC, with potential implications for prediction of these cancers. These findings warrant further research to determine if constitutional methylation of tumor suppressor genes are pancancer risk factors.

RevDate: 2022-09-29
CmpDate: 2022-09-28

Sichel SR, Bratton BP, NR Salama (2022)

Distinct regions of H. pylori's bactofilin CcmA regulate protein-protein interactions to control helical cell shape.

eLife, 11:.

The helical shape of Helicobacter pylori cells promotes robust stomach colonization; however, how the helical shape of H. pylori cells is determined is unresolved. Previous work identified helical-cell-shape-promoting protein complexes containing a peptidoglycan-hydrolase (Csd1), a peptidoglycan precursor synthesis enzyme (MurF), a non-enzymatic homolog of Csd1 (Csd2), non-enzymatic transmembrane proteins (Csd5 and Csd7), and a bactofilin (CcmA). Bactofilins are highly conserved, spontaneously polymerizing cytoskeletal bacterial proteins. We sought to understand CcmA's function in generating the helical shape of H. pylori cells. Using CcmA deletion analysis, in vitro polymerization, and in vivo co-immunoprecipitation experiments, we identified that the bactofilin domain and N-terminal region of CcmA are required for helical cell shape and the bactofilin domain of CcmA is sufficient for polymerization and interactions with Csd5 and Csd7. We also found that CcmA's N-terminal region inhibits interaction with Csd7. Deleting the N-terminal region of CcmA increases CcmA-Csd7 interactions and destabilizes the peptidoglycan-hydrolase Csd1. Using super-resolution microscopy, we found that Csd5 recruits CcmA to the cell envelope and promotes CcmA enrichment at the major helical axis. Thus, CcmA helps organize cell-shape-determining proteins and peptidoglycan synthesis machinery to coordinate cell wall modification and synthesis, promoting the curvature required to build a helical cell.

RevDate: 2022-11-03
CmpDate: 2022-11-02

Kedmi R, Najar TA, Mesa KR, et al (2022)

A RORγt[+] cell instructs gut microbiota-specific Treg cell differentiation.

Nature, 610(7933):737-743.

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment[1,2]. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised[3,4]. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt[+] cells-probably type 3 innate lymphoid cells and/or Janus cells[5]-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.

RevDate: 2022-11-04
CmpDate: 2022-10-25

Du G, Jiang J, Henning NJ, et al (2022)

Exploring the target scope of KEAP1 E3 ligase-based PROTACs.

Cell chemical biology, 29(10):1470-1481.e31.

Targeted protein degradation (TPD) uses small molecules to recruit E3 ubiquitin ligases into the proximity of proteins of interest, inducing ubiquitination-dependent degradation. A major bottleneck in the TPD field is the lack of accessible E3 ligase ligands for developing degraders. To expand the E3 ligase toolbox, we sought to convert the Kelch-like ECH-associated protein 1 (KEAP1) inhibitor KI696 into a recruitment handle for several targets. While we were able to generate KEAP1-recruiting degraders of BET family and murine focal adhesion kinase (FAK), we discovered that the target scope of KEAP1 was narrow, as targets easily degraded using a cereblon (CRBN)-recruiting degrader were refractory to KEAP1-mediated degradation. Linking the KEAP1-binding ligand to a CRBN-binding ligand resulted in a molecule that induced degradation of KEAP1 but not CRBN. In sum, we characterize tool compounds to explore KEAP1-mediated ubiquitination and delineate the challenges of exploiting new E3 ligases for generating bivalent degraders.

RevDate: 2022-09-23
CmpDate: 2022-09-23

Qi L, Sun Y, Juraska M, et al (2022)

Neutralizing antibody correlates of sequence specific dengue disease in a tetravalent dengue vaccine efficacy trial in Asia.

Vaccine, 40(41):5912-5923.

In the CYD14 trial of the CYD-TDV dengue vaccine in 2-14 year-olds, neutralizing antibody (nAb) titers to the vaccine-insert dengue strains correlated inversely with symptomatic, virologically-confirmed dengue (VCD). Also, vaccine efficacy against VCD was higher against dengue prM/E amino acid sequences closer to the vaccine inserts. We integrated the nAb and sequence data types by assessing nAb titers as a correlate of sequence-specific VCD separately in the vaccine arm and in the placebo arm. In both vaccine and placebo recipients the correlation of nAb titer with sequence-specific VCD was stronger for dengue nAb contact site sequences closer to the vaccine (p = 0.005 and p = 0.012, respectively). The risk of VCD in vaccine (placebo) recipients was 6.7- (1.80)-fold lower at the 90th vs 10th percentile of nAb for viruses perfectly matched to CYD-TDV, compared to 2.1- (0.78)-fold lower at the 90th vs 10th percentile for viruses with five amino acid mismatches. The evidence for a stronger sequence-distance dependent correlate of risk for the vaccine arm indicates departure from the Prentice criteria for a valid sequence-distance specific surrogate endpoint and suggests that the nAb marker may affect dengue risk differently depending on whether nAbs arise from infection or also by vaccination. However, when restricting to baseline-seropositive 9-14 year-olds, the correlation pattern became more similar between the vaccine and placebo arms, supporting nAb titers as an approximate surrogate endpoint in this population. No sequence-specific nAb titer correlates of VCD were seen in baseline-seronegative participants. Integrated immune response/pathogen sequence data correlates analyses could help increase knowledge of correlates of risk and surrogate endpoints for other vaccines against genetically diverse pathogens. Trial registration: EU Clinical Trials Register 2014-001708-24; registration date 2014-05-26.

RevDate: 2022-10-12
CmpDate: 2022-10-10

Gulati R, YA Nyame (2022)

Editorial Comment.

The Journal of urology, 208(5):1027.

RevDate: 2022-09-06

Ogimi C, Krantz EM, Golob JL, et al (2022)

Exposure to antibiotics with anaerobic activity before respiratory viral infection is associated with respiratory disease progression after hematopoietic cell transplant.

Bone marrow transplantation [Epub ahead of print].

We examined associations between specific antibiotic exposures and progression to lower respiratory tract disease (LRTD) following individual respiratory viral infections (RVIs) after hematopoietic cell transplantation (HCT). We analyzed allogeneic HCT recipients of all ages with their first RVI during the first 100 days post-HCT. For the 21 days before RVI onset, we recorded any receipt of specific groups of antibiotics, and the cumulative sum of the number of antibiotics received for each day (antibiotic-days). We used Cox proportional hazards models to assess the relationship between antibiotic exposure and progression to LRTD. Among 469 patients with RVI, 124 progressed to LRTD. Compared to no antibiotics, use of antibiotics with broad anaerobic activity in the prior 21 days was associated with progression to LRTD after adjusting for age, virus type, hypoalbuminemia, neutropenia, steroid use, and monocytopenia (HR 2.2, 95% CI 1.1-4.1). Greater use of those antibiotics (≥7 antibiotic days) was also associated with LRTD in adjusted models (HR 2.2, 95% CI 1.1-4.3). Results were similar after adjusting for lymphopenia instead of monocytopenia. Antibiotic use is associated with LRTD after RVI across different viruses in HCT recipients. Prospective studies using anaerobe-sparing antibiotics should be explored to assess impact on LRTD in patients undergoing HCT.

RevDate: 2022-09-07

Kim JN, Meyer J, Kwon Y, et al (2022)

Breast Cancer Therapy and Huntington Disease: A Case Report.

Advances in radiation oncology, 7(6):101025.

RevDate: 2022-09-15
CmpDate: 2022-09-08

Wolfe AE, KA Markey (2022)

The contribution of the intestinal microbiome to immune recovery after HCT.

Frontiers in immunology, 13:988121.

Allogenic hematopoietic stem-cell transplantation (allo-HCT) is a curative-intent immunotherapy for high-risk hematological malignancies and immune deficiencies. Allo-HCT carries a high risk of treatment-related mortality (TRM), largely due to infection or graft-versus-host disease (GVHD). Robust immune recovery is essential for optimal patient outcomes, given the immunologic graft-versus-leukemia effect prevents relapse, and functional innate and adaptive immunity are both needed for the prevention and control of infection. Most simply, we measure immune recovery by enumerating donor lymphocyte subsets in circulation. In functional terms, ideal immune recovery is more difficult to define, and current lab techniques are limited to the measurement of specific vaccine-responses or mitogens ex vivo. Clinically, poor immune function manifests as problematic infection with viral, bacterial and fungal organisms. Furthermore, the ideal recovering immune system is capable of exerting graft-versus-tumor effects to prevent relapse, and does not induce graft-versus-host disease. Large clinical observational studies have linked loss of diversity within the gut microbiome with adverse transplant outcomes including decreased overall survival and increased acute and chronic GVHD. Furthermore, the correlation between intestinal microbial communities and numeric lymphocyte recovery has now been reported using a number of approaches. Large sets of clinically available white blood cell count data, clinical flow cytometry of lymphocyte subsets and bespoke flow cytometry analyses designed to capture microbiota-specific T cells (e.g. Mucosal-associated invariant T cells, subsets of the gd T cells) have all been leveraged in an attempt to understand links between the microbiota and the recovering immune system in HCT patients. Additionally, preclinical studies suggest an immunomodulatory role for bacterial metabolites (including butyrate, secondary bile acids, and indole derivatives from tryptophan metabolism) in transplant outcomes, though further studies are needed to unravel mechanisms relevant to the post-HCT setting. An understanding of mechanistic relationships between the intestinal microbiome and post-transplant outcomes is necessary for reduction of risk associated with transplant, to inform prophylactic procedures, and ensure optimal immune reconstitution without alloreactivity. Here, we summarize the current understanding of the complex relationship between bacterial communities, their individual members, and the metabolites they produce with immune function in both the allo-HCT and steady-state setting.

RevDate: 2022-11-12
CmpDate: 2022-11-07

Manjappa S, Phi HQ, Lee LW, et al (2022)

Humoral and Cellular Immune Response to Covid-19 Vaccination in Patients with Chronic Graft-versus-Host Disease on Immunosuppression.

Transplantation and cellular therapy, 28(11):784.e1-784.e9.

Chronic graft-versus-host disease (cGVHD) and its management with immunosuppressive therapies increase the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as well as progression to severe Coronavirus 19 disease (COVID-19). Vaccination against COVID-19 is strongly recommended, but efficacy data are limited in this patient population. In this study, responses to COVID-19 vaccination were measured at 3 time points-after the initial vaccine series, before the third dose, and after the third dose-in adults with cGVHD receiving immunosuppressive therapy. Humoral response was measured by quantitative anti-spike antibody and neutralizing antibody levels. Anti-nucleocapsid antibody levels were measured to detect natural infection. T cell response was evaluated by a novel immunosequencing technique combined with immune repertoire profiling from cryopreserved peripheral blood mononuclear cell samples. Present or absent T cell responses were determined by the relative proportion of unique SARS-CoV-2-associated T cell receptor sequences ("breadth") plus clonal expansion of the response ("depth") compared with those in a reference population. Based on both neutralizing antibody and T cell responses, patients were categorized as vaccine responders (both detected), nonresponders (neither detected), or mixed (one but not both detected). Thirty-two patients were enrolled for the initial series, including 17 (53%) positive responders, 7 (22%) mixed responders, and 8 (25%) nonresponders. All but one patient categorized as mixed responders had humoral responses while lacking T cell responses. No statistical differences were observed in patient characteristics among the 3 groups of patients categorized by immune response, although sample sizes were limited. Significant positive correlations were observed between the robustness of cellular and humoral responses after the initial series. Among the 20 patients with paired samples (pre- and post-third dose), a third vaccination resulted in increased neutralizing antibody titers. cGVHD worsened in 10 patients (26%; 6 after the initial series and 4 after the third dose), necessitating escalation of immunosuppressive doses in 5 patients, although 4 had been tapering immunosuppression and 5 had already worsening cGVHD at the time of vaccination, and a clear association between COVID-19 vaccination and cGVHD could not be drawn. Among the patients with cGVHD on immunosuppressive therapy, 72% demonstrated a neutralizing antibody response after a 2-dose primary COVID-19 vaccination, two-thirds of whom also developed a T cell response; 25% had neither a humoral nor a T cell response. A third dose further amplified the antibody response.

RevDate: 2022-10-06

Sharma A, Farnia S, Otegbeye F, et al (2022)

Nomenclature for Cellular and Genetic Therapies: A Need for Standardization.

As the field of cellular and genetic therapies transitions from a scientific concept to a clinical reality, it has become evident that there are several conflicting or imprecise nomenclatures to describe these novel therapeutic products. The lack of uniformity and accuracy in the terminology often creates regulatory, educational, administrative, and billing quagmires. Standardization of the nomenclature for these therapeutic products is essential for creation of a harmonized regulatory and developmental framework, development of training paradigms and educational programs, equitable and rational decisions about accessibility, and consistency in the billing and coding structures used for reimbursement. Here we propose an updated framework as a foundation for categorizing these cell-based and genetically modified therapies.

RevDate: 2022-10-10

Rashid N, Krakow EF, Yeh AC, et al (2022)

Late Effects of Severe Acute Graft-versus-Host Disease on Quality of Life, Medical Comorbidities, and Survival.

Transplantation and cellular therapy pii:S2666-6367(22)01594-9 [Epub ahead of print].

Grade III-IV acute graft-versus-host disease (aGVHD) is associated with high short-term morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). The long-term effects after recovery from grade III-IV aGVHD are unknown. This study aimed to analyze late medical comorbidities, quality of life, nonrelapse mortality, and survival in patients treated for grade III-IV aGVHD. Chart review identified late effects, and patients were asked to complete annual surveys to collect patient-reported outcomes. Outcomes were compared between patients with grade 0-I aGVHD and grade III-IV aGVHD who underwent HCT between 2001 and 2019 and survived for at least 1 year post-transplantation. Patients with a history of grade III-IV aGVHD (n = 192) had significantly higher rates of late medical comorbidities (P < .001) and worse physical (P = .01) and mental (P = .04) functioning compared with patients with grade 0-I aGVHD (n = 615). Patients who survived for >1 year post-transplantation and had prior grade III-IV aGVHD also had worse 5-year overall survival (77.5% versus 83.6%; P = .006) and higher nonrelapse mortality (19.2% versus 10.6%; P < .001) compared with those with a history of grade 0-I aGVHD. No between-group difference was found in cumulative incidence of chronic GVHD. Patients who recover from severe aGVHD remain vulnerable to developing late comorbidities. These patients would likely benefit from continued monitoring and supportive care in an attempt to prevent late effects and improve survival.

RevDate: 2022-09-02

Yu EY, Piulats JM, Gravis G, et al (2022)

Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study.

European urology pii:S0302-2838(22)02554-4 [Epub ahead of print].

BACKGROUND: Pembrolizumab and olaparib have shown single-agent activity in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC).

OBJECTIVE: To evaluate the efficacy and safety of pembrolizumab plus olaparib in mCRPC.

Cohort A of the phase 1b/2 KEYNOTE-365 study enrolled patients with molecularly unselected, docetaxel-pretreated mCRPC whose disease progressed within 6 mo of screening.

INTERVENTION: Pembrolizumab 200 mg intravenously every 3 wk plus olaparib 400-mg capsule or 300-mg tablet orally twice daily.

The primary endpoints were safety, confirmed prostate-specific antigen (PSA) response rate, and objective response rate (ORR) as per Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. The secondary endpoints included radiographic progression-free survival (rPFS) and overall survival (OS).

RESULTS AND LIMITATIONS: Of 104 enrolled patients, 102 were treated. The median age was 70 yr (interquartile range [IQR], 65-76), and 59 patients (58%) had measurable disease as per RECIST v1.1. The median time from the first dose to database cutoff was 24 mo (IQR, 22-47). The confirmed PSA response rate was 15%. The confirmed ORR was 8.5% (five partial responses) for patients with measurable disease. The median rPFS was 4.5 mo (95% confidence interval [CI], 4.0-6.5) and median OS was 14 mo (95% CI, 10.4-18.2). Clinical activity was consistent across the programmed death ligand 1 (PD-L1)-positive and homologous recombination repair mutation subgroups. Treatment-related adverse events (TRAEs) occurred in 93 patients (91%). Grade 3-5 TRAEs occurred in 49 patients (48%). Six deaths (5.9%) were due to adverse events; two (myocardial infarction and unknown cause) were attributed to treatment. Limitations of the study include the single-arm design.

CONCLUSIONS: Pembrolizumab plus olaparib had a safety profile consistent with the profiles of the individual agents and demonstrated antitumor activity in previously treated patients with molecularly unselected, docetaxel-pretreated mCRPC.

PATIENT SUMMARY: Pembrolizumab plus olaparib showed antitumor activity and expected safety in patients with metastatic castration-resistant prostate cancer.

RevDate: 2022-10-27
CmpDate: 2022-10-18

D'Silva M, Han HS, Liu R, et al (2022)

Limited liver resections in the posterosuperior segments: international multicentre propensity score-matched and coarsened exact-matched analysis comparing the laparoscopic and robotic approaches.

The British journal of surgery, 109(11):1140-1149.

BACKGROUND: Limited liver resections (LLRs) for tumours located in the posterosuperior segments of the liver are technically demanding procedures. This study compared outcomes of robotic (R) and laparoscopic (L) LLR for tumours located in the posterosuperior liver segments (IV, VII, and VIII).

METHODS: This was an international multicentre retrospective analysis of patients who underwent R-LLR or L-LLR at 24 centres between 2010 and 2019. Patient demographics, perioperative parameters, and postoperative outcomes were analysed; 1 : 3 propensity score matching (PSM) and 1 : 1 coarsened exact matching (CEM) were performed.

RESULTS: Of 1566 patients undergoing R-LLR and L-LLR, 983 met the study inclusion criteria. Before matching, 159 R-LLRs and 824 L-LLRs were included. After 1 : 3 PSM of 127 R-LLRs and 381 L-LLRs, comparison of perioperative outcomes showed that median blood loss (100 (i.q.r. 40-200) versus 200 (100-500) ml; P = 0.003), blood loss of at least 500 ml (9 (7.4 per cent) versus 94 (27.6 per cent); P < 0.001), intraoperative blood transfusion rate (4 (3.1 per cent) versus 38 (10.0 per cent); P = 0.025), rate of conversion to open surgery (1 (0.8 per cent) versus 30 (7.9 per cent); P = 0.022), median duration of Pringle manoeuvre when applied (30 (20-46) versus 40 (25-58) min; P = 0.012), and median duration of operation (175 (130-255) versus 224 (155-300); P < 0.001) were lower in the R-LLR group compared with the L-LLR group. After 1 : 1 CEM of 104 R-LLRs with 104 L-LLRs, R-LLR was similarly associated with significantly reduced blood loss and a lower rate of conversion to open surgery.

CONCLUSION: Based on a matched analysis of well selected patients, both robotic and laparoscopic access could be undertaken safely with good outcomes for tumours in the posterosuperior liver segments.

RevDate: 2022-09-28
CmpDate: 2022-09-08

Young WJ, Lahrouchi N, Isaacs A, et al (2022)

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways.

Nature communications, 13(1):5144.

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization.

RevDate: 2022-09-07

Thomas HMT, Hippe DS, Forouzannezhad P, et al (2022)

Radiation and immune checkpoint inhibitor-mediated pneumonitis risk stratification in patients with locally advanced non-small cell lung cancer: role of functional lung radiomics?.

Discover. Oncology, 13(1):85.

BACKGROUND: Patients undergoing chemoradiation and immune checkpoint inhibitor (ICI) therapy for locally advanced non-small cell lung cancer (NSCLC) experience pulmonary toxicity at higher rates than historical reports. Identifying biomarkers beyond conventional clinical factors and radiation dosimetry is especially relevant in the modern cancer immunotherapy era. We investigated the role of novel functional lung radiomics, relative to functional lung dosimetry and clinical characteristics, for pneumonitis risk stratification in locally advanced NSCLC.

METHODS: Patients with locally advanced NSCLC were prospectively enrolled on the FLARE-RT trial (NCT02773238). All received concurrent chemoradiation using functional lung avoidance planning, while approximately half received consolidation durvalumab ICI. Within tumour-subtracted lung regions, 110 radiomics features (size, shape, intensity, texture) were extracted on pre-treatment [[99m]Tc]MAA SPECT/CT perfusion images using fixed-bin-width discretization. The performance of functional lung radiomics for pneumonitis (CTCAE v4 grade 2 or higher) risk stratification was benchmarked against previously reported lung dosimetric parameters and clinical risk factors. Multivariate least absolute shrinkage and selection operator Cox models of time-varying pneumonitis risk were constructed, and prediction performance was evaluated using optimism-adjusted concordance index (c-index) with 95% confidence interval reporting throughout.

RESULTS: Thirty-nine patients were included in the study and pneumonitis occurred in 16/39 (41%) patients. Among clinical characteristics and anatomic/functional lung dosimetry variables, only the presence of baseline chronic obstructive pulmonary disease (COPD) was significantly associated with the development of pneumonitis (HR 4.59 [1.69-12.49]) and served as the primary prediction benchmark model (c-index 0.69 [0.59-0.80]). Discrimination of time-varying pneumonitis risk was numerically higher when combining COPD with perfused lung radiomics size (c-index 0.77 [0.65-0.88]) or shape feature classes (c-index 0.79 [0.66-0.91]) but did not reach statistical significance compared to benchmark models (p > 0.26). COPD was associated with perfused lung radiomics size features, including patients with larger lung volumes (AUC 0.75 [0.59-0.91]). Perfused lung radiomic texture features were correlated with lung volume (adj R[2] = 0.84-1.00), representing surrogates rather than independent predictors of pneumonitis risk.

CONCLUSIONS: In patients undergoing chemoradiation with functional lung avoidance therapy and optional consolidative immune checkpoint inhibitor therapy for locally advanced NSCLC, the strongest predictor of pneumonitis was the presence of baseline chronic obstructive pulmonary disease. Results from this novel functional lung radiomics exploratory study can inform future validation studies to refine pneumonitis risk models following combinations of radiation and immunotherapy. Our results support functional lung radiomics as surrogates of COPD for non-invasive monitoring during and after treatment. Further study of clinical, dosimetric, and radiomic feature combinations for radiation and immune-mediated pneumonitis risk stratification in a larger patient population is warranted.

RevDate: 2022-09-15
CmpDate: 2022-09-08

Núñez ER, M Triplette (2022)

Addressing Lung Cancer Screening Disparities: What Does It Mean to Be Centralized?.

Annals of the American Thoracic Society, 19(9):1457-1458.

RevDate: 2022-10-21
CmpDate: 2022-10-21

Gössling GCL, Zhen DB, Pillarisetty VG, et al (2022)

Combination immunotherapy for pancreatic cancer: challenges and future considerations.

Expert review of clinical immunology, 18(11):1173-1186.

INTRODUCTION: Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA.

AREAS COVERED: We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA.

EXPERT OPINION: Pancreatic cancers rarely benefit from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME include low- and poor-quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.

RevDate: 2022-11-07
CmpDate: 2022-11-07

Carpenter PA, Kang HJ, Yoo KH, et al (2022)

Ibrutinib Treatment of Pediatric Chronic Graft-versus-Host Disease: Primary Results from the Phase 1/2 iMAGINE Study.

Transplantation and cellular therapy, 28(11):771.e1-771.e10.

Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Clinical data surrounding cGVHD therapies in younger children are limited and critically needed. Primary endpoints were to determine the recommended pediatric equivalent dose (RPED) and assess pharmacokinetics (PK) and safety. Secondary endpoints included overall response rate (ORR; comprising complete response and partial response) according to the 2014 National Institutes of Health criteria at 24 weeks, overall survival, and duration of response (DOR). Here we present the primary results from the open-label, multicenter, international phase 1/2 iMAGINE study (PCYC-1146-IM), which evaluated the PK, safety, and efficacy of ibrutinib in patients age ≥1 to <22 years with treatment-naive (TN) or relapsed/refractory (R/R) moderate/severe cGVHD. Patients age <12 years received once-daily ibrutinib starting at 120 mg/m[2] and escalating to 240 mg/m[2] (full adult dose equivalent) after 14 days if free from ibrutinib-related grade ≥3 toxicity; patients age ≥12 years received once-daily ibrutinib 420 mg. Fifty-nine patients (12 TN and 47 with R/R cGVHD; median age, 13 years; range, 1 to 19 years) were enrolled. Plasma concentration-time profiles for ibrutinib 240 mg/m[2] (the RPED) were comparable to those observed in adults with cGVHD at a dose of 420 mg/day. Safety was consistent with the known profile of ibrutinib in cGVHD. ORR by 24 weeks was 64% (38 of 59), including 83% (10 of 12) for the TN subgroup and 60% (28 of 47) for R/R. Among 46 responders (median follow-up, 20 months; range, 2 to 32 months), 12-month DOR for each subgroup was 60% (95% confidence interval [CI], 25% to 83%) in TN patients and 58% (95% CI, 35% to 75%) in R/R patients. Responses were durable, with numerically higher rates than those previously observed with ibrutinib in adults, demonstrating that ibrutinib provides clinically meaningful activity with acceptable safety in children with moderate/severe cGVHD.

RevDate: 2022-10-16
CmpDate: 2022-09-02

Halford JL, Morrill VN, Choi SH, et al (2022)

Endophenotype effect sizes support variant pathogenicity in monogenic disease susceptibility genes.

Nature communications, 13(1):5106.

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P < 0.001 for each trait) and discriminate pathogenic from non-pathogenic variants (area under the curve 0.82-0.84 across endophenotypes). An effect size threshold of ≥ 0.5 times the endophenotype standard deviation nominates up to 35% of rare variants of uncertain significance or not in ClinVar in disease susceptibility genes with pathogenic potential. We propose that variant associations with quantitative endophenotypes for monogenic diseases can provide evidence supporting pathogenicity.

RevDate: 2022-09-12
CmpDate: 2022-09-02

Choudhary GS, Pellagatti A, Agianian B, et al (2022)

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations.

eLife, 11:.

Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood.

Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML.

Results: RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models.

Conclusions: SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.

Funding: This work was supported by Cincinnati Children's Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle's Angel Foundation for Cancer Research, and Edward P. Evans Foundation grants to DTS. AV is supported by Edward P. Evans Foundation, National Institute of Health (R01HL150832, R01HL139487, R01CA275007), Leukemia and Lymphoma Society, Curis and a gift from the Jane and Myles P. Dempsey family. AP and JB are supported by Blood Cancer UK (grants 13042 and 19004). GC is supported by a training grant from NYSTEM. We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420).

RevDate: 2022-11-06
CmpDate: 2022-11-04

Rodríguez-Arbolí E, Orvain C, Othus M, et al (2022)

Significance of measurable residual disease in adults with secondary acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

Bone marrow transplantation, 57(11):1732-1734.

RevDate: 2022-08-26

Davidson NE (2022)

In It for the Long Haul: Long-Term Benefit With Adjuvant Endocrine Therapy for Premenopausal Women With Early-Stage Steroid Receptor-Positive Breast Cancer.

RevDate: 2022-08-26

Wang A, Xu Y, Yu Y, et al (2022)

Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Human molecular genetics pii:6677341 [Epub ahead of print].

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

RevDate: 2022-11-12

Szulzewsky F, Arora S, Arakaki AKS, et al (2022)

Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice.

Genes & development [Epub ahead of print].

YAP1 is a transcriptional coactivator regulated by the Hippo signaling pathway, including NF2. Meningiomas are the most common primary brain tumors; a large percentage exhibit heterozygous loss of chromosome 22 (harboring the NF2 gene) and functional inactivation of the remaining NF2 copy, implicating oncogenic YAP activity in these tumors. Recently, fusions between YAP1 and MAML2 have been identified in a subset of pediatric NF2 wild-type meningiomas. Here, we show that human YAP1-MAML2-positive meningiomas resemble NF2 mutant meningiomas by global and YAP-related gene expression signatures. We then show that expression of YAP1-MAML2 in mice induces tumors that resemble human YAP1 fusion-positive and NF2 mutant meningiomas by gene expression. We demonstrate that YAP1-MAML2 primarily functions by exerting TEAD-dependent YAP activity that is resistant to Hippo signaling. Treatment with YAP-TEAD inhibitors is sufficient to inhibit the viability of YAP1-MAML2-driven mouse tumors ex vivo. Finally, we show that expression of constitutively active YAP1 (S127/397A-YAP1) is sufficient to induce similar tumors, suggesting that the YAP component of the gene fusion is the critical driver of these tumors. In summary, our results implicate YAP1-MAML2 as a causal oncogenic driver and highlight TEAD-dependent YAP activity as an oncogenic driver in YAP1-MAML2 fusion meningioma as well as NF2 mutant meningioma in general.

RevDate: 2022-09-25
CmpDate: 2022-09-16

Heldman MR, Wight DJ, Aiewsakun P, et al (2022)

Chromosome-Specific Human Herpesvirus 6 Integration and Hematologic Malignancies.

Journal of virology, 96(17):e0093722.

RevDate: 2022-10-11
CmpDate: 2022-10-10

Wong RL, EY Yu (2022)

Enfortumab vedotin in the treatment of urothelial cancers and beyond.

Future oncology (London, England), 18(27):3067-3084.

Enfortumab vedotin (EV) is the first antibody-drug conjugate approved for locally advanced or metastatic urothelial cancers (la/mUCs), a disease group historically associated with limited prognosis and therapeutic options. EV consists of monomethyl auristatin E, a microtubule-disrupting agent linked to an antibody targeting Nectin-4. In clinical trials, EV demonstrated high response rates and superior survival in the third-line setting for la/mUC compared with chemotherapy. Peripheral neuropathy and rash were among the most common serious adverse events. EV is currently approved in multiple countries for the treatment of la/mUC in the later-line setting. Ongoing trials seek to expand the indication for EV and to study therapeutic combinations with other agents.

RevDate: 2022-11-07
CmpDate: 2022-11-07

Holmberg LA, Linenberger M, L Connelly-Smith (2022)

Successful Mobilization of Autologous Hematopoietic Peripheral Blood Stem Cells after Salvage Chemotherapy in Patients with Low CD34 Blood Cell Counts.

Transplantation and cellular therapy, 28(11):754-759.

A major barrier for proceeding to autologous stem cell transplantation (ASCT) is an inability to mobilize and collect an adequate number of peripheral blood (PB) stem cells (PBSC) for the transplant graft. Plerixafor added to granulocyte colony stimulating factor (G-CSF) alone, without prior chemotherapy, significantly improves the mobilization of autologous PBSC in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). However, the efficacy of plerixafor and the best timing to give the drug to poorly mobilizing patients with very low PB CD34+ cell counts after salvage chemotherapy and G-CSF are not well defined. We hypothesized that PBSC mobilization and collection might be improved in heavily treated patients who mobilized very poorly after salvage chemotherapy and G-CSF by alternating the days of plerixafor administration and leukapheresis. A day of rest between plerixafor doses, while continuing G-CSF, could allow time for some replenishment of the marrow stem/progenitor cell pool before the next mobilization. A retrospective review of collection results in poorly mobilizing patients at our center was undertaken. Three cohorts were identified: those who got every-other-day plerixafor and leukapheresis, those who got sequential plerixafor and leukapheresis and those who got risk adapted plerixafor. Overall, 69% of patients with NHL and MM with PB CD34+ cell counts <5/µL after salvage chemotherapy and G-CSF were ultimately able to collect adequate CD34+ cells to support ASCT using daily plerixafor and leukapheresis. On the alternating plerixafor and leukapheresis schedule, all 17 patients achieved the cumulative CD34+ cell product goals required for ASCT. This positive observation after salvage chemotherapy and G-CSF led to the incorporation at our center of an alternate-day schedule of plerixafor and leukapheresis into our real-time risk adapted strategy for poor mobilizers. © 2023 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

RevDate: 2022-09-06

Heldman MR, Edlefsen KL, Pepper G, et al (2022)

Combined assessment of Epstein-Barr virus viral capsid antigen and Epstein-Barr virus nuclear antigen-1 serology for post-transplant lymphoproliferative disorder risk stratification in adult solid organ transplant recipients.

Transplant infectious disease : an official journal of the Transplantation Society [Epub ahead of print].

BACKGROUND: Epstein-Barr virus (EBV) seronegative solid organ transplant recipients (SOTRs) are at increased risk for post-transplant lymphoproliferative disorder (PTLD). Assays for EBV serostatus assess antibody to both EBV viral capsid antigen (VCA) and Epstein-Barr nuclear antigen-1 (EBNA-1), but PTLD risk among SOT recipients with discordant VCA and EBNA-1 results is unknown.

METHODS: We performed a retrospective, single-center cohort study to determine the risk of PTLD among adult (≥ 18 years) SOTRs with discordant pre-transplant VCA and EBNA-1 IgG compared to that of SOTRs with concordantly negative or concordantly positive serology using univariable and multivariable Cox-proportional hazards models.

RESULTS: Of 4106 SOTRs, the number (%) who were concordantly positive, concordantly negative, and discordant was 3787 (92.2%), 149 (3.6%), and 170 (4.2%), respectively. The adjusted hazard of PTLD was significantly higher among discordant SOTRs compared to concordantly positive SOTRs (aHR 2.6, 95% CI 1.04-6.6, p =.04) and lower compared to concordantly negative SOTRs (aHR 0.27, 95% CI 0.10-0.76, p <.001). The adjusted hazard of EBV+ PTLD among those with discordant serology was also significantly higher compared to the concordantly positive cohort (aHR 3.53, 95% CI 1.04-12.0, p =.04) and significantly lower compared to the concordantly negative cohort (aHR 0.23, 95% CI 0.06-0.82, p =.02).

CONCLUSIONS: Risk of PTLD among SOTRs with discordant VCA and EBNA-1 may be intermediate between those with concordantly positive and negative serology. If confirmed in future studies, revision of national EBV serology reporting to include both VCA and EBNA results may be needed to optimize PTLD risk stratification.

RevDate: 2022-09-28
CmpDate: 2022-09-09

Happi C, Adetifa I, Mbala P, et al (2022)

Urgent need for a non-discriminatory and non-stigmatizing nomenclature for monkeypox virus.

PLoS biology, 20(8):e3001769.

We propose a novel, non-discriminatory classification of monkeypox virus diversity. Together with the World Health Organization, we named three clades (I, IIa and IIb) in order of detection. Within IIb, the cause of the current global outbreak, we identified multiple lineages (A.1, A.2, A.1.1 and B.1) to support real-time genomic surveillance.

RevDate: 2022-08-23

Sonpavde GP, Maughan BL, McGregor BA, et al (2022)

Phase II trial of CV301 vaccine combined with atezolizumab in advanced urothelial carcinoma.

Cancer immunology, immunotherapy : CII [Epub ahead of print].

CV301 comprises recombinant poxviruses, Modified Vaccinia Ankara (MVA) and Fowlpox (FPV), encoding CEA, MUC-1, and co-stimulatory Molecules (TRICOM) ICAM-1, LFA-3, and B7-1. MVA-BN-CV301 is used for priming and FPV-CV301 is used for boosting. A Phase 2, single-arm trial was designed to evaluate CV301 plus atezolizumab as first-line treatment for cisplatin-ineligible advanced urothelial carcinoma (aUC) (Cohort 1) or progressing after platinum chemotherapy (Cohort 2). MVA-CV301 was given subcutaneously (SC) on Days 1 and 22 and FPV-CV301 SC from day 43 every 21 days for 4 doses, then tapered gradually over up to 2 years. Atezolizumab 1200 mg IV was given every 21 days. The primary endpoint was objective response rate (ORR). Overall, 43 evaluable patients received therapy: 19 in Cohort 1; 24 in Cohort 2; nine experienced ≥ Grade 3 therapy-related adverse events. In Cohort 1, one had partial response (PR) (ORR 5.3%, 90% CI 0.3, 22.6). In Cohort 2, 1 complete response and 1 PR were noted (ORR 8.3%, 90% CI 1.5, 24.0). The trial was halted for futility. Patients exhibiting benefit demonstrated T-cell response to CEA and MUC-1. The trial illustrates the challenges in the development of vaccines, which should be guided by robust preclinical data.

RevDate: 2022-11-12
CmpDate: 2022-11-10

Sucandy I, Rayman S, Lai EC, et al (2022)

Robotic Versus Laparoscopic Left and Extended Left Hepatectomy: An International Multicenter Study Propensity Score-Matched Analysis.

Annals of surgical oncology, 29(13):8398-8406.

BACKGROUND: Controversies exist among liver surgeons regarding clinical outcomes of the laparoscopic versus the robotic approach for major complex hepatectomies. The authors therefore designed a study to examine and compare the perioperative outcomes of laparoscopic left hepatectomy or extended left hepatectomy (L-LH/L-ELH) versus robotic left hepatectomy or extended left hepatectomy (R-LH/R-ELH) using a large international multicenter collaborative database.

METHODS: An international multicenter retrospective analysis of 580 patients undergoing L-LH/L-ELH or R-LH/R-ELH at 25 specialized hepatobiliary centers worldwide was undertaken. Propensity score-matching (PSM) was used at a 1:1 nearest-neighbor ratio according to 15 perioperative variables, including demographics, tumor characteristics, Child-Pugh score, presence of portal hypertension, multiple resections, histologic diagnosis, and Iwate difficulty grade.

RESULTS: Before the PSM, 190 (32 %) patients underwent R-LH/R-ELH, and 390 (68 %) patients underwent L-LH/L-ELH. After the matching, 164 patients were identified in each arm without significant differences in demographics, preoperative variables, medical history, tumor pathology, tumor characteristics, or Iwate score. Regarding intra- and postoperative outcomes, the rebotic approach had significantly less estimated blood loss (EBL) (100 ml [IQR 200 ml] vs 200 ml [IQR 235 ml]; p = 0.029), fewer conversions to open operations (n = 4 [2.4 %] vs n = 13, [7.9 %]; p = 0.043), and a shorter hospital stay (6 days [IQR 3 days] vs 7 days [IQR 3.3 days]; p = 0.009).

CONCLUSION: Both techniques are safe and feasible in major hepatic resections. Compared with L-LH/L-ELH, R-LH/R-ELH is associated with less EBL, fewer conversions to open operations, and a shorter hospital stay.

RevDate: 2022-10-19
CmpDate: 2022-09-23

Hayden RT, Su Y, Boonyaratanakornkit J, et al (2022)

Matrix Matters: Assessment of Commutability among BK Virus Assays and Standards.

Journal of clinical microbiology, 60(9):e0055522.

Quantitative testing of BK virus (BKPyV) nucleic acid has become the standard of care in transplant patients. While the relationship between interassay harmonization and commutability has been well characterized for other transplant-related viruses, it has been less well studied for BKPyV, particularly regarding differences in commutability between matrices. Here, interassay agreement was evaluated among six real-time nucleic acid amplification tests (NAATs) and one digital PCR (dPCR) BKPyV assay. Differences in the commutability of three quantitative standards was examined across all assays using a variety of statistical approaches. Panels, including 40 samples each of plasma and urine samples previously positive for BKPyV, together with one previously negative plasma sample and four previously negative urine samples, were tested using all assays, with each real-time NAAT utilizing its usual quantitative calibrators. Serial dilutions of WHO, National Institute for Standards and Technology (NIST), and commercially produced (Exact/Bio-Rad) reference materials were also run by each assay as unknowns. The agreement of the clinical sample values was assessed as a group and in a pairwise manner. The commutability was estimated using both relativistic and quantitative means. The quantitative agreement across assays in the urine samples was within a single log10 unit across all assays, while the results from the plasma samples varied by 2 to 3 log10 IU/mL. The commutability showed a similar disparity between the matrices. Recalibration using international standards diminished the resulting discrepancies in some but not all cases. Differences in the sample matrix can affect the commutability and interassay agreement of quantitative BKPyV assays. Differences in commutability between matrices may largely be due to factors other than those such as amplicon size, previously described as important in the case of cytomegalovirus. Continued efforts to standardize viral load measurements must address multiple sources of variability and account for differences in assay systems, quantitative standards, and sample matrices.

RevDate: 2022-10-25
CmpDate: 2022-09-26

Gilbert PB, Huang Y, deCamp AC, et al (2022)

Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition.

Nature medicine, 28(9):1924-1932.

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker-which quantifies the neutralization potency of antibodies in an individual's serum against an HIV-1 isolate-can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 <200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluatinon of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

RevDate: 2022-08-23
CmpDate: 2022-08-23

Talbert P, S Henikoff (2022)

Centromeres organize (epi)genome architecture.

Cell, 185(17):3083-3085.

In some plants and animals, microtubules attach across the length of the chromosome in mitosis, forming a holocentromere instead of a single centromeric locus. A new study in Cell shows that in the holocentric beak sedge Rhynchospora, holocentromeres also impact genomic architecture, epigenome organization, and karyotype evolution.

RevDate: 2022-10-01

Loh KP, McLaughlin EM, Krok-Schoen JL, et al (2022)

Correlates of common concerns in older cancer survivors of leukemia and lymphoma: results from the WHI LILAC study.

Journal of cancer survivorship : research and practice [Epub ahead of print].

PURPOSE: Older survivors of leukemia and lymphoma often experience long-term effects of chemotherapy. We described common concerns related to their cancer and treatment in older survivors of leukemia and non-Hodgkin lymphoma (NHL) and assessed correlates of these concerns.

METHODS: We utilized data from the Women's Health Initiative (WHI) Life and Longevity After Cancer (LILAC) study that recruited post-menopausal women aged 50-79. Participants diagnosed with leukemia and NHL were included (n = 420). They were asked about 14 areas of current concerns related to their cancer and treatment and to rate each from 0 (no concern) to 2 (major concern), with total scores ranging from 0 to 28. Linear regression was used to assess factors correlated with the concern score, and logistic regression for factors correlated with the three most common concerns.

RESULTS: Mean age at assessment was 81 years (range 69-99); 72% reported at least one concern, and median concern score among these survivors was 3.5 (Q1-Q3 2-5). Factors significantly correlated with concern scores were sadness, pain, distress, higher prior symptom count, and loneliness (all p < 0.05). Significant factors correlated with common concerns were (1) fatigue/sleep: sadness/depression, distress, higher prior symptom count, greater loneliness, and worse physical functioning; (2) physical functioning/activity: older age, public insurance, higher body mass index, pain, worse QoL, and higher treatment-related comorbidities; (3) memory/concentration: prior chemotherapy or radiation, worse QoL, higher prior symptom count, and greater loneliness (all p < 0.05).

Almost three-quarters of older survivors of leukemia and lymphoma reported at least one concern; a multifaceted intervention may be needed to address these concerns.

RevDate: 2022-10-13
CmpDate: 2022-08-26

Tokaz MC, Baik CS, Houghton AM, et al (2022)

New Immuno-oncology Targets and Resistance Mechanisms.

Current treatment options in oncology, 23(9):1201-1218.

OPINION STATEMENT: Immune checkpoint inhibition (ICI) has revolutionized the field of non-small cell lung cancer (NSCLC); currently, most patients with advanced disease receive upfront ICI either alone or in combination with chemotherapy. These advances have recently extended into early-stage NSCLC, with ICI incorporation into neoadjuvant and adjuvant treatment regimens. However, despite these successes, immunotherapy (IO) resistance remains a fundamental challenge in NSCLC, introducing a central quandary of how to precisely select the appropriate IO therapy or IO combination therapy for each individual patient. To address this vital need in the field, there has been an explosion of research in immuno-oncology to identify mechanisms of resistance, ranging from genomic alterations in the tumor to immunosuppressive conditions in the tumor microenvironment (TME). There remain many questions about how this complex interplay between the tumor and the immune microenvironment translates into clinical phenotypes of primary and acquired resistance. In NSCLC, a number of novel therapeutics are being developed to prevent and overcome resistance to ICI. Particular promise has been shown with therapeutics targeting novel T cell immune checkpoint inhibitors and targeting innate immune cells in the TME, chief among these cells are natural killer cells, neutrophils, and macrophages. Further research into tissue-based and non-invasive biomarkers that can be prospectively integrated into therapeutic trial design will be critical to advance the field's understanding of individual resistance patterns and enable the ultimate goal of precision immuno-oncology.

RevDate: 2022-09-28
CmpDate: 2022-09-28

Hatashima A, Karami M, M Shadman (2022)

Approved and emerging Bruton's tyrosine kinase inhibitors for the treatment of chronic lymphocytic leukemia.

Expert opinion on pharmacotherapy, 23(13):1545-1557.

INTRODUCTION: The Bruton's tyrosine kinase (BTK) pathway has proven to be an effective and transformative therapeutic target in the treatment of chronic lymphocytic leukemia (CLL), fueling the growth of BTK inhibitors (BTKis) and landmark approval of first-generation BTKi, ibrutinib. However, ibrutinib's side effect profile left an unmet need for BTKis with improved tolerability, thus spurring the subsequent development of second-generation acalabrutinib and zanubrutinib. The treatment landscape continues to evolve with studies using BTKi combination therapies, notably with venetoclax, with and without an anti-CD20 monoclonal antibody as well as third-generation BTKis aimed to overcome BTKi resistance.

AREAS COVERED: This article details the current literature highlighting the efficacy, toxicities, and potential therapeutic combinations of approved and preclinical BTKis.

EXPERT OPINION: BTKis have signaled the start of a new treatment paradigm in CLL and improved clinical outcomes, especially for patients with high-risk disease. However, drug resistance, low CR rates, and indefinite treatment necessitate the development of novel BTKis and fixed duration combination therapy. The results from recently completed and ongoing clinical trials are eagerly awaited with the potential promise of reduced treatment durations and financial burden while achieving durable remissions.

RevDate: 2022-11-08

Yenamandra AK, Smith RB, Senaratne TN, et al (2022)

Evidence-based review of genomic aberrations in diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS): Report from the cancer genomics consortium lymphoma working group.

Cancer genetics, 268-269:1-21 pii:S2210-7762(22)00108-9 [Epub ahead of print].

Diffuse large B cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type of non-Hodgkin lymphoma (NHL). The 2016 World Health Organization (WHO) classification defined DLBCL, NOS and its subtypes based on clinical findings, morphology, immunophenotype, and genetics. However, even within the WHO subtypes, it is clear that additional clinical and genetic heterogeneity exists. Significant efforts have been focused on utilizing advanced genomic technologies to further subclassify DLBCL, NOS into clinically relevant subtypes. These efforts have led to the implementation of novel algorithms to support optimal risk-oriented therapy and improvement in the overall survival of DLBCL patients. We gathered an international group of experts to review the current literature on DLBCL, NOS, with respect to genomic aberrations and the role they may play in the diagnosis, prognosis and therapeutic decisions. We comprehensively surveyed clinical laboratory directors/professionals about their genetic testing practices for DLBCL, NOS. The survey results indicated that a variety of diagnostic approaches were being utilized and that there was an overwhelming interest in further standardization of routine genetic testing along with the incorporation of new genetic testing modalities to help guide a precision medicine approach. Additionally, we present a comprehensive literature summary on the most clinically relevant genomic aberrations in DLBCL, NOS. Based upon the survey results and literature review, we propose a standardized, tiered testing approach which will help laboratories optimize genomic testing in order to provide the maximum information to guide patient care.

RevDate: 2022-10-04
CmpDate: 2022-09-02

Ensrud KE, Larson JC, Guthrie KA, et al (2022)

Changes in serum endogenous estrogen concentrations are mediators of the effect of low-dose oral estradiol on vasomotor symptoms.

Menopause (New York, N.Y.), 29(9):1014-1020.

OBJECTIVES: The aim of this study was to quantify changes in serum total estradiol (E2) and estrone (E1) concentrations with initiation of low-dose oral estradiol treatment and evaluate whether changes in concentrations mediate the effect of treatment in reducing vasomotor symptom (VMS) frequency.

METHODS: We analyzed baseline and week 8 (W8) data from 171 perimenopausal and postmenopausal women with VMS enrolled in low-dose 17β estradiol (n = 72) and placebo (n = 99) groups of a randomized clinical trial.

RESULTS: From baseline to W8, women in the low-dose estradiol group had a fourfold increase in E2, resulting in a W8 E2 of 23 pg/mL, and a fivefold increase in E1, resulting in a W8 E1 of 110.7 pg/mL. In contrast, E2 and E1 among women in the placebo group were unchanged from baseline to W8. Changes in E2 and E1 from baseline to W8 met criteria for mediating the effect of low-dose estradiol treatment on VMS frequency. With change in estrogen concentration added to treatment assignment in a regression model predicting W8 VMS frequency, the effect of treatment with low-dose estradiol versus placebo was attenuated, with change in E2 representing a 44.1% reduction (P = 0.03) and change in E1 representing a 69.5% reduction (P = 0.02) in total intervention effect.

CONCLUSION: Among perimenopausal and postmenopausal women with VMS, treatment with low-dose oral estradiol versus placebo results in four- to fivefold increases in serum E2 and E1. The increases in serum E2 and E1 with low-dose oral estradiol treatment seem to mediate in part the effect of treatment in reducing VMS frequency.

RevDate: 2022-09-08
CmpDate: 2022-08-16

Al-Nakouzi N, Wang CK, Oo HZ, et al (2022)

Reformation of the chondroitin sulfate glycocalyx enables progression of AR-independent prostate cancer.

Nature communications, 13(1):4760.

Lineage plasticity of prostate cancer is associated with resistance to androgen receptor (AR) pathway inhibition (ARPI) and supported by a reactive tumor microenvironment. Here we show that changes in chondroitin sulfate (CS), a major glycosaminoglycan component of the tumor cell glycocalyx and extracellular matrix, is AR-regulated and promotes the adaptive progression of castration-resistant prostate cancer (CRPC) after ARPI. AR directly represses transcription of the 4-O-sulfotransferase gene CHST11 under basal androgen conditions, maintaining steady-state CS in prostate adenocarcinomas. When AR signaling is inhibited by ARPI or lost during progression to non-AR-driven CRPC as a consequence of lineage plasticity, CHST11 expression is unleashed, leading to elevated 4-O-sulfated chondroitin levels. Inhibition of the tumor cell CS glycocalyx delays CRPC progression, and impairs growth and motility of prostate cancer after ARPI. Thus, a reactive CS glycocalyx supports adaptive survival and treatment resistance after ARPI, representing a therapeutic opportunity in patients with advanced prostate cancer.

RevDate: 2022-10-22
CmpDate: 2022-10-03

Desprez C, Riou J, Peterlin P, et al (2022)

Comparison of scoring systems evaluating suitability for intensive chemotherapy in adults with acute myeloid leukemia-a Grand Ouest Against Leukemia (GOAL) study.

Leukemia, 36(10):2408-2417.

Several scoring systems have been developed to assess suitability of individual patients for intensive acute myeloid leukemia (AML) therapy. We sought to compare the performance of these scores in a cohort of 428 consecutive adults with AML who received conventional induction chemotherapy in five academic centers in France. All scoring systems identified a subset of patients with increased 28 and 56-day mortality although the prediction accuracy was overall limited with C-statistics of ranging from 0.61 to 0.71 Overall survival (OS) prediction was more limited and restricted to scoring systems that include AML-related parameters. The outcome of 104 patients (24%) considered unsuitable for intensive chemotherapy based on criteria used in recent randomized trials was similar to that of the other 324 patients (28-day mortality, odds ratio [OR] = 1.88, P = 0.2; 56-day mortality, OR = 1.71, P = 0.21; event-free survival, hazard ratio [HR] = 1.08, P = 0.6; OS, HR = 1.25, P = 0.14) with low discrimination (C-statistic: 0.57, 0.56, 0.50, and 0.52 for 28-day, 56-day mortality, EFS, and OS, respectively). Together, our findings indicate that the accuracy of currently available approaches to identify patients at increased risk of early mortality and shortened survival after intensive AML therapy is relatively limited. Caution regarding the use of available scoring systems should be warranted in clinical decision-making.

RevDate: 2022-11-07
CmpDate: 2022-11-07

Al Achkar M, Basu Roy U, Manley E, et al (2022)

A qualitative study of interactions with oncologists among patients with advanced lung cancer.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 30(11):9049-9055.

INTRODUCTION: To support the care of lung cancer patients, oncologists have needed to stay current on treatment advancements and build relationships with a new group of survivors in an era where lung cancer survivorship has been re-defined. The objectives of the study were to (1) understand the perspectives of advanced lung cancer patients whose tumors have oncogenic alterations about their care experiences with their oncologist(s) and (2) describe the perceptions of advanced lung cancer patients about seeking second opinions and navigating care decisions.

METHODS: In this qualitative study, patients with advanced lung cancer (n = 25) on targeted therapies were interviewed to discuss their ongoing experience with their oncologists. We used deductive and inductive qualitative approaches in the coding of the data. We organized the data using the self-determination framework.

RESULTS: Patients described both positive and negative aspects of their care as related to autonomy, provider competency, and connectedness. Patients sought second opinions for three primary reasons: expertise, authoritative advice, and access to clinical trial opportunities. When there is disagreement in the treatment plan between the primary oncologist and the specialist, there can be confusion and tension, and patients have to make difficult choices about their path forward.

CONCLUSIONS: Patients value interactions that support their autonomy, demonstrate the competency of their providers, and foster connectedness. To ensure that patients receive quality and goal-concordant care, developing decision aids and education materials that help patients negotiate recommendations from two providers is an area that deserves further attention.

RevDate: 2022-10-29

Vy HMT, Lin BM, Gulamali FF, et al (2022)

Genome-Wide Epistatic Interaction between DEF1B and APOL1 High-Risk Genotypes for Chronic Kidney Disease.

RevDate: 2022-08-17
CmpDate: 2022-08-11

Matrajt L, Brown ER, Cohen MS, et al (2022)

Could widespread use of antiviral treatment curb the COVID-19 pandemic? A modeling study.

BMC infectious diseases, 22(1):683.

BACKGROUND: Despite the development of safe and effective vaccines, effective treatments for COVID-19 disease are still urgently needed. Several antiviral drugs have shown to be effective in reducing progression of COVID-19 disease.

METHODS: In the present work, we use an agent-based mathematical model to assess the potential population impact of the use of antiviral treatments in four countries with different demographic structure and current levels of vaccination coverage: Kenya, Mexico, United States (US) and Belgium. We analyzed antiviral effects on reducing hospitalization and death, and potential antiviral effects on reducing transmission. For each country, we varied daily treatment initiation rate (DTIR) and antiviral effect in reducing transmission (AVT).

RESULTS: Irrespective of location and AVT, widespread antiviral treatment of symptomatic adult infections (20% DTIR) prevented the majority of COVID-19 deaths, and recruiting 6% of all adult symptomatic infections daily reduced mortality by over 20% in all countries. Furthermore, our model projected that targeting antiviral treatment to the oldest age group (65 years old and older, DTIR of 20%) can prevent over 30% of deaths. Our results suggest that early antiviral treatment (as soon as possible after inception of infection) is needed to mitigate transmission, preventing 50% more infections compared to late treatment (started 3 to 5 days after symptoms onset). Our results highlight the synergistic effect of vaccination and antiviral treatment: as the vaccination rate increases, antivirals have a larger relative impact on population transmission. Finally, our model projects that even in highly vaccinated populations, adding antiviral treatment can be extremely helpful to mitigate COVID-19 deaths.

CONCLUSIONS: These results suggest that antiviral treatments can become a strategic tool that, in combination with vaccination, can significantly reduce COVID-19 hospitalizations and deaths and can help control SARS-CoV-2 transmission.

RevDate: 2022-10-09
CmpDate: 2022-09-09

Zhou M, Ko M, Hoge AC, et al (2022)

Patterns of structural variation define prostate cancer across disease states.

JCI insight, 7(17):.

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined 9 subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

RevDate: 2022-08-08

Bade B, Gwin M, Triplette M, et al (2022)

Comorbidity and life expectancy in shared decision making for lung cancer screening.

Seminars in oncology pii:S0093-7754(22)00057-4 [Epub ahead of print].

Shared decision making (SDM) is an important part of lung cancer screening (LCS) that includes discussing the risks and benefits of screening, potential outcomes, patient eligibility and willingness to participate, tobacco cessation, and tailoring a strategy to an individual patient. More than other cancer screening tests, eligibility for LCS is nuanced, incorporating the patient's age as well as tobacco use history and overall health status. Since comorbidities and multimorbidity (ie, 2 or more comorbidities) impact the risks and benefits of LCS, these topics are a fundamental part of decision-making. However, there is currently little evidence available to guide clinicians in addressing comorbidities and an individual's "appropriateness" for LCS during SDM visits. Therefore, this literature review investigates the impact of comorbidities and multimorbidity among patients undergoing LCS. Based on available evidence and guideline recommendations, we identify comorbidities that should be considered during SDM conversations and review best practices for navigating SDM conversations in the context of LCS. Three conditions are highlighted since they concomitantly portend higher risk of developing lung cancer, potentially increase risk of screening-related evaluation and treatment complications and can be associated with limited life expectancy: chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and human immunodeficiency virus infection.

RevDate: 2022-08-08

Ruvkun G, N Lehrbach (2022)

Regulation and Functions of the ER-Associated Nrf1 Transcription Factor.

Cold Spring Harbor perspectives in biology pii:cshperspect.a041266 [Epub ahead of print].

Nrf1 is a member of the nuclear erythroid 2-like family of transcription factors that regulate stress-responsive gene expression in animals. Newly synthesized Nrf1 is targeted to the endoplasmic reticulum (ER) where it is N-glycosylated. N-glycosylated Nrf1 is trafficked to the cytosol by the ER-associated degradation (ERAD) machinery and is subject to rapid proteasomal degradation. When proteasome function is impaired, Nrf1 escapes degradation and undergoes proteolytic cleavage and deglycosylation. Deglycosylation results in deamidation of N-glycosylated asparagine residues to edit the protein sequence encoded by the genome. This truncated and "sequence-edited" form of Nrf1 enters the nucleus where it induces up-regulation of proteasome subunit genes. Thus, Nrf1 drives compensatory proteasome biogenesis in cells exposed to proteasome inhibitor drugs and other proteotoxic insults. In addition to its role in proteasome homeostasis, Nrf1 is implicated in responses to oxidative stress, and maintaining lipid and cholesterol homeostasis. Here, we describe the conserved and complex mechanism by which Nrf1 is regulated and highlight emerging evidence linking this unusual transcription factor to development, aging, and disease.

RevDate: 2022-11-11
CmpDate: 2022-11-11

Duggan C, Tapsoba JD, Scheel J, et al (2022)

Weight loss reduces circulating micro-RNA related to obesity and breast cancer in postmenopausal women.

Epigenetics, 17(13):2082-2095.

Postmenopausal women with overweight or obesity have an increased risk of developing breast cancer but many of the mechanisms underlying this association remain to be elucidated. MicroRNAs (miRNAs), short non-coding single-stranded RNAs, regulate many physiological processes by controlling post-transcriptional regulation of mRNA. We measured circulating miRNA from 192 overweight/obese postmenopausal women (50-75 years) who were part of a randomized controlled trial, comparing independent and combined effects of a 12-month reduced-calorie weight-loss diet and exercise programme, versus control. RNA was extracted from stored plasma samples, and 23 a priori selected miRNA targets related to aetiology of breast cancer or obesity were measured using NanoString nCounter miRNA Expression assays. Changes from baseline to 12-months between controls and women in the diet/exercise weight loss arms were analysed using generalized estimating equations modification of linear regression, adjusted for confounders. We next examined changes in levels of circulating miRNA by amount of weight loss (0-10% versus ≥10%). Participants randomized to weight-loss interventions had statistically significantly greater reductions in miR-122 (-7.25%), compared to controls (+ 33.5%, P = 0.009), and miR-122 levels were statistically significantly correlated with weight loss (rho = 0.24; P = 0.001) Increasing weight loss was associated with greater reductions in miR-122 vs. controls (-11.7% (≥10% weight loss); +2.0% (0-10% weight loss) +33.5% (controls); Ptrend = 0.006), though this was not significant after correction for multiple testing (P = 0.05/23) Our study supports the effect of weight loss on regulation of miRNA.

RevDate: 2022-08-08

Yun J, Nakagawa R, K Tham (2022)

KRAS-targeted therapy in the treatment of non-small cell lung cancer.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners [Epub ahead of print].

OBJECTIVE: KRAS mutations are one of the most common driver mutations in non-small cell lung cancer. Though previously believed to be an undruggable target, recent advances in therapeutics have seen new targeted agents against KRAS mutations. The objective of this article is to review currently available and upcoming KRAS-targeted treatments.

DATA SOURCES: Currently available trials examining KRAS-targeted therapy in non-small cell lung cancer were examined by searching for the keyword "KRAS inhibitors." The pivotal trials for sotorasib and adagrasib were reviewed for this article.

DATA SUMMARY: Mutated KRAS can be challenging to target for a variety of reasons. In 2021, the US Food and Drug Administration approved sotorasib for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutation as determined by a Food and Drug Administration-approved test, who have received at least one prior systemic therapy. A multicenter, single-group, open-label, phase 2 trial was able to demonstrate that sotorasib was able to demonstrate objective response, progression-free survival, and overall survival in this patient population. A phase 3 trial comparing sotorasib to docetaxel in the subsequent-line treatment of KRAS G12C non-small cell lung cancer is currently ongoing. There are other KRAS-targeted agents currently under study, including adagrasib, with growing interest in targeting KRAS downstream pathways.

CONCLUSION: Further trials need to be conducted in order to identify other targeted agents for KRAS and the appropriate place in therapy among currently approved treatments for non-small cell lung cancer.

RevDate: 2022-08-06

Aroke H, Buchanan A, Katenka N, et al (2022)

Evaluating the Mediating Role of Recall of Intervention Knowledge in the Relationship Between a Peer-Driven Intervention and HIV Risk Behaviors Among People Who Inject Drugs.

AIDS and behavior [Epub ahead of print].

Peer-driven interventions can be effective in reducing HIV injection risk behaviors among people who inject drugs (PWID). We employed a causal mediation framework to examine the mediating role of recall of intervention knowledge in the relationship between a peer-driven intervention and subsequent self-reported HIV injection-related risk behavior among PWID in the HIV Prevention Trials Network (HPTN) 037 study. For each intervention network, the index participant received training at baseline to become a peer educator, while non-index participants and all participants in the control networks received only HIV testing and counseling; recall of intervention knowledge was measured at the 6-month visit for each participant, and each participant was followed to ascertain HIV injection-related risk behaviors at the 12-month visit. We used inverse probability weighting to fit marginal structural models to estimate the total effect (TE) and controlled direct effect (CDE) of the intervention on the outcome. The proportion eliminated (PE) by intervening to remove mediation by the recall of intervention knowledge was computed. There were 385 participants (47% in intervention networks) included in the analysis. The TE and CDE risk ratios for the intervention were 0.47 [95% confidence interval (CI): 0.28, 0.78] and 0.73 (95% CI: 0.26, 2.06) and the PE was 49%. Compared to participants in the control networks, the peer-driven intervention reduced the risk of HIV injection-related risk behavior by 53%. The mediating role of recall of intervention knowledge accounted for less than 50% of the total effect of the intervention, suggesting that other potential causal pathways between the intervention and the outcome, such as motivation and skill, self-efficacy, social norms and behavior modeling, should be considered in future studies.

RevDate: 2022-08-09
CmpDate: 2022-08-09

Chowdhury S, Wang R, Yu Q, et al (2022)

DAGBagM: learning directed acyclic graphs of mixed variables with an application to identify protein biomarkers for treatment response in ovarian cancer.

BMC bioinformatics, 23(1):321.

BACKGROUND: Applying directed acyclic graph (DAG) models to proteogenomic data has been shown effective for detecting causal biomarkers of complex diseases. However, there remain unsolved challenges in DAG learning to jointly model binary clinical outcome variables and continuous biomarker measurements.

RESULTS: In this paper, we propose a new tool, DAGBagM, to learn DAGs with both continuous and binary nodes. By using appropriate models, DAGBagM allows for either continuous or binary nodes to be parent or child nodes. It employs a bootstrap aggregating strategy to reduce false positives in edge inference. At the same time, the aggregation procedure provides a flexible framework to robustly incorporate prior information on edges.

CONCLUSIONS: Through extensive simulation experiments, we demonstrate that DAGBagM has superior performance compared to alternative strategies for modeling mixed types of nodes. In addition, DAGBagM is computationally more efficient than two competing methods. When applying DAGBagM to proteogenomic datasets from ovarian cancer studies, we identify potential protein biomarkers for platinum refractory/resistant response in ovarian cancer. DAGBagM is made available as a github repository at https://github.com/jie108/dagbagM .

RevDate: 2022-08-05

Yuan S, Peng L, Liu Y, et al (2022)

Low-dose anlotinib confers improved survival in combination with immune checkpoint inhibitor in advanced non-small cell lung cancer patients.

Cancer immunology, immunotherapy : CII [Epub ahead of print].

BACKGROUND: Anti-angiogenic drugs increase anti-tumor efficacy of immune checkpoint inhibitors (ICIs). However, the optimal dose of anti-angiogenic drugs remains unclear.

METHODS: We retrospectively analyzed efficacy and safety data from patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC) that received PD-1 blockade with low-doses of anlotinib, a highly selective receptor tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptors, as second or later line therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety profile. Univariate and multivariate analyses were used to identify prognostic factors.

RESULTS: A total of 40 eligible patients were included. The median PFS was 11.4 months. The median OS of the entire cohort was 27.0 months. ORR was achieved in 16 patients (40.0%) and DCR was maintained in 33 patients (82.5%). The overall incidence of adverse events (AEs) was 52.5%, and the most common all grade AE was gastrointestinal reactions, which occurred in four patients (10.0%). Treatment-related grade 3/4 toxicity was observed in one patient (2.5%). Conclusions Low-dose anlotinib may be an effective and well-tolerated anti-angiogenesis partner for combination therapy with ICIs in second-line and later settings for advanced NSCLC.

RevDate: 2022-08-09
CmpDate: 2022-08-09

Veatch JR, SR Riddell (2022)

Immune checkpoint blockade provokes resident memory T cells to eliminate head and neck cancer.

Cell, 185(16):2848-2849.

Immune checkpoint blockade is effective in treating many human cancers. In this issue of Cell, Luoma et al. show that tissue-resident memory T cells in head and neck cancers rapidly respond to immune checkpoint blockade, and they identify specific CD8[+] T cells in pretreatment blood that predict pathologic tumor regression.

RevDate: 2022-08-05

Vogtmann E, Hua X, Yu G, et al (2022)

The oral microbiome and lung cancer risk: An analysis of 3 prospective cohort studies.

Journal of the National Cancer Institute pii:6656358 [Epub ahead of print].

BACKGROUND: Previous studies suggested associations between the oral microbiome and lung cancer, but studies were predominantly cross-sectional and underpowered.

METHODS: Using a case-cohort design, 1,306 incident lung cancer cases were identified in the Agricultural Health Study, NIH-AARP Diet and Health Study, and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Referent subcohorts were randomly selected by strata of age, sex, and smoking history. DNA was extracted from oral wash specimens using the DSP DNA Virus Pathogen kit, the 16S rRNA gene V4 region was amplified and sequenced, and bioinformatics were conducted using QIIME 2. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using weighted Cox proportional hazards models.

RESULTS: Higher alpha diversity was associated with lower lung cancer risk (Shannon index HR 0.90; 95% CI: 0.84-0.96). Specific principal component vectors of the microbial communities were also significantly associated with lung cancer risk. After multiple testing adjustment, greater relative abundance of three genera and presence of one genus were associated with greater lung cancer risk, while presence of three genera were associated with lower risk. For example, every standard deviation increase in Streptococcus abundance was associated with 1.14 times the risk of lung cancer (95% CI: 1.06-1.22). Associations were strongest among squamous cell carcinoma cases and former smokers.

CONCLUSIONS: Multiple oral microbial measures were prospectively associated with lung cancer risk in three US cohort studies with associations varying by smoking history and histologic subtype. The oral microbiome may offer new opportunities for lung cancer prevention.

RevDate: 2022-08-06

Chang E, Holt S, Montgomery B, et al (2022)

Chemotherapy Utilization in Men with Advanced Penile Cancer.

Urology practice, 9(1):12-15.

Introduction: Although studies using mixed insurance populations suggest that chemotherapy use in men with advanced penile cancer (PC) is low, it is unclear what regimens are being utilized. In this study, we use a database of insured patients to better understand specific chemotherapy utilization in men with PC.

Methods: This is a retrospective cohort study of patients with stage IIIB or IV PC in the Surveillance, Epidemiology, and End Results-Medicare database (2004-2015). Standard of care (SOC) chemotherapy was defined by the National Comprehensive Cancer Network® guidelines: 4 cycles of paclitaxel, ifosfamide and cisplatin or 5-fluorouracil with cisplatin in the neoadjuvant, adjuvant or primary setting. We calculated what proportion of patients receive SOC or any chemotherapy within 2 years of diagnosis and analyzed what factors were associated with receiving chemotherapy.

Results: Our study included 147 patients-48 stage IIIB and 99 stage IV. Of these patients, 49 (33%) received chemotherapy. Less than 5% of men received SOC. About 10% received SOC chemotherapy but an insufficient number of cycles. Married men were more likely to undergo chemotherapy (OR 3.4, 95% CI 1.5-7.8). Less than 5% of the 24 Black or Hispanic patients received chemotherapy compared to 37% of white patients (p <0.001).

Conclusions: Only a third of men with stage IIIB/IV PC underwent chemotherapy. Less than 5% of men received complete guideline-based regimens. Whether this is driven primarily by patient or provider factors is unknown, although social determinants of health may play a role. These data highlight the difficulty for patients with PC to get chemotherapy.

RevDate: 2022-08-23
CmpDate: 2022-08-08

Shenoy MK, MA Koch (2022)

Twice the tolerance.

Science (New York, N.Y.), 377(6606):575-576.

A gut microbiota-derived antigen elicits distinct subsets of regulatory T cells to suppress inflammation in mice.

RevDate: 2022-11-04
CmpDate: 2022-11-03

Palmieri R, Othus M, Cheng GS, et al (2022)

Pulmonary function testing for fitness assessment in asymptomatic adults with newly diagnosed acute myeloid leukemia.

Haematologica, 107(11):2752-2755.

RevDate: 2022-08-04

Orvain C, Wilson JA, Fang M, et al (2022)

Relative impact of residual cytogenetic abnormalities and flow cytometric measurable residual disease on outcome after allogeneic hematopoietic cell transplantation in adult acute myeloid leukemia.

Haematologica [Epub ahead of print].

Measurable residual disease (MRD) before hematopoietic cell transplantation (HCT) is an independent established prognostic factor in patients with acute myeloid leukemia (AML). Several methods exist to evaluate the presence of residual leukemia cells, but how these are used best in combination is unclear. To examine how residual cytogenetic abnormalities and MRD testing by multiparameter flow cytometry (MFC) may refine risk assessment before HCT, we analyzed 506 adults with cytogenetically abnormal AML who underwent both routine karyotyping and MFC MRD testing before receiving a first allograft while in morphologic remission. Testing for residual cytogenetic abnormalities and MFC MRD identified four groups of patients with differential relapse-free survival (RFS, hazard ratio [HR]=1.63 for Cytoabnormal/MFCnegative [P=0.01, n=63], HR=3.24 for Cytonormal/MFCpositive [P.

RevDate: 2022-09-21
CmpDate: 2022-08-22

Tcheandjieu C, Zhu X, Hilliard AT, et al (2022)

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

Nature medicine, 28(8):1679-1692.

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

RevDate: 2022-11-09
CmpDate: 2022-09-28

Kiptinness C, Kuo AP, Reedy AM, et al (2022)

Examining the Use of HIV Self-Testing to Support PrEP Delivery: a Systematic Literature Review.

Current HIV/AIDS reports, 19(5):394-408.

PURPOSE OF REVIEW: HIV self-testing (HIVST) has the potential to expand access to and uptake of HIV pre-exposure prophylaxis (PrEP) delivery. We conducted a systematic literature review to understand the evidence on HIVST use for PrEP delivery.

RECENT FINDINGS: After screening 1055 records, we included eight: three randomized trials and five values and preferences studies. None measured PrEP initiation. Most studies occurred in Sub-Saharan Africa (7/8) and included different populations. One trial found that HIVST use between quarterly clinic visits as part of an adherence package with biofeedback slightly increased adherence; the other two trials found that HIVST use between or in lieu of quarterly clinic visits had no significant or non-inferior effects on adherence. HIVST to support PrEP delivery was acceptable, feasible, and preferred. HIVST use for PrEP continuation largely resulted in similar outcomes to standard-of-care delivery and was perceived acceptable and feasible. Further research is needed to optimize HIVST use within PrEP programming.

RevDate: 2022-07-31
CmpDate: 2022-07-28

Wang Z, Liang Y, Gong C, et al (2022)

Improved Dynamic Window Approach for Unmanned Surface Vehicles' Local Path Planning Considering the Impact of Environmental Factors.

Sensors (Basel, Switzerland), 22(14):.

The aim of local path planning for unmanned surface vehicles (USVs) is to avoid unknown dynamic or static obstacles. However, current relative studies have not fully considered the impact of ocean environmental factors which significantly increase the control difficulty and collision risk of USVs. Therefore, this work studies two ocean environmental factors, namely, wave and current, given that they both have a significant impact on USVs. Furthermore, we redesign a kinematic model of an USV and the evaluation function of a classical and practical local path planning method based on the dynamic window approach (DWA). As shown by the results of the simulations, the path length was impacted mainly by the intensity of the environmental load and slightly by the direction of the environmental load, but the navigation time was significantly influenced by both. Taking the situation in still water as a benchmark in terms of the intensity and direction of the environmental factors, the maximum change rates of the path length were 8.6% and 0.6%, respectively, but the maximum change rates of the navigating time were 17.9% and 25.6%, separately. In addition, the average calculation time of each cycle was only 0.0418 s, and the longest time did not exceed the simulation time corresponding to a single cycle of 0.1 s. This method has proven to be a good candidate for real-time local path planning of USVs since it systematically considers the impact of waves and currents on the navigation of USVs, and thus ensures that USVs can adjust to the planned path in time and avoid obstacles when navigating in the real ocean environment.

RevDate: 2022-07-31

Olson AT, Child SJ, AP Geballe (2022)

Antagonism of Protein Kinase R by Large DNA Viruses.

Pathogens (Basel, Switzerland), 11(7):.

Decades of research on vaccinia virus (VACV) have provided a wealth of insights and tools that have proven to be invaluable in a broad range of studies of molecular virology and pathogenesis. Among the challenges that viruses face are intrinsic host cellular defenses, such as the protein kinase R pathway, which shuts off protein synthesis in response to the dsRNA that accumulates during replication of many viruses. Activation of PKR results in phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α), inhibition of protein synthesis, and limited viral replication. VACV encodes two well-characterized antagonists, E3L and K3L, that can block the PKR pathway and thus enable the virus to replicate efficiently. The use of VACV with a deletion of the dominant factor, E3L, enabled the initial identification of PKR antagonists encoded by human cytomegalovirus (HCMV), a prevalent and medically important virus. Understanding the molecular mechanisms of E3L and K3L function facilitated the dissection of the domains, species-specificity, and evolutionary potential of PKR antagonists encoded by human and nonhuman CMVs. While remaining cognizant of the substantial differences in the molecular virology and replication strategies of VACV and CMVs, this review illustrates how VACV can provide a valuable guide for the study of other experimentally less tractable viruses.

RevDate: 2022-08-23

Torres-Blasco N, Costas-Muñiz R, Rosario L, et al (2022)

Psychosocial Intervention Cultural Adaptation for Latinx Patients and Caregivers Coping with Advanced Cancer.

Healthcare (Basel, Switzerland), 10(7):.

Latinx advanced cancer patients and caregivers are less likely to have adequate access to culturally congruent psychosocial interventions. Culturally relevant and adapted interventions are more effective within minority groups. We obtained patients' and caregivers' initial evaluations of the Caregivers-Patients Support to Latinx coping with advanced-cancer (CASA) protocol. A qualitative study was conducted, and an acceptance questionnaire and semi-structured interviews were conducted to culturally adapt the psychosocial intervention for Latinx coping with cancer. The semi-structured interview described and demonstrated intervention components and elicited feedback about each one. Latinx advanced cancer patients (Stage III and IV) and caregivers (n = 14 each) completed the acceptance survey, and N = 7 each completed semi-structured interviews. A total of 12 of the 14 patients and caregivers (85.7%) reported high acceptance of the goals and purposes of the intervention protocol. They also reported willingness to daily use of the content of the intervention components: Communication Skills, the Willingness of Meaning, Life has Meaning, Freedom of Will, Identity, Creative Sources of Meaning, and Homework. Most of the participants reported high acceptance (n = 9) of integrating family caregivers into therapy and the high acceptance (n = 10) of the length of the 4-session intervention.

RevDate: 2022-07-26

Necchi A, Spiess PE, Bandini M, et al (2022)

Advanced Squamous Cell Carcinomas of the Pelvic and Perineal Region: A Comprehensive Genomic Profiling Study.

The oncologist pii:6650150 [Epub ahead of print].

BACKGROUND: Advanced pelvic squamous cell carcinoma (pSCC) is a broad category of cancers affecting different pelvic organs and usually featuring unfavorable clinical outcomes. Thus, we aimed to assess genomic differences among pSCC cases and learn whether pSCC could potentially benefit from targeted therapies and/or immunotherapy.

MATERIALS AND METHODS: A total of 1917 advanced pSCCs, including penile (penSCC), male urethral (murthSCC), male anal (manSCC), female urethral (furthSCC), vulvar (vulSCC), cervical (crvSCC), female anal (fanSCC), and vaginal (vagSCC), underwent comprehensive genomic profiling (CGP). We used hybrid capture-based CGP to evaluate recurrent genomic alterations (GAs). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 95 loci. Programmed cell-death-ligand-1 (PD-L1) expression was determined by immunohistochemistry (IHC; Dako 22C3).

RESULTS: PIK3CA was the most frequently identified potentially "actionable" GA (22%-43%), followed by mTOR pathway [PTEN (0%-18%), FBXW7 (7%-29%)], and cell-cycle GAs. DNA-damage response (DDR) GAs and receptor-tyrosine kinase (RTK) targeted options were uncommon. NOTCH1 GAs were present in >15% of penSCC and vulvSCC. TMB ≥10 mut/Mb was >15% in manSCC, fanSCC, crvSCC, and vagSCC. PD-L1 high expression was >18% in all pSCC except urthSCC, manSCC, and vagSCC. HPV-16/18 detection was highest in manSCC, fanSCC, and crvSCC.

CONCLUSION: Despite similar histology, pSCCs can differ in GAs and HPV status. Overall, PIK3CA is the most frequent potentially "targetable" GA followed by mTOR and cell cycle pathway. RTK and DDR GAs are rare in pSCC. Immunotherapy could be considered for pSCC management based on TMB and PD-L1 expression.

RevDate: 2022-08-30

Greenlee H, Rillamas-Sun E, Cheng R, et al (2022)

Reply to M.S. Ewer et al.

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

RevDate: 2022-11-10
CmpDate: 2022-10-12

Lee CI, JG Elmore (2022)

Cancer Risk Prediction Paradigm Shift: Using Artificial Intelligence to Improve Performance and Health Equity.

Journal of the National Cancer Institute, 114(10):1317-1319.

RevDate: 2022-10-05
CmpDate: 2022-07-27

Lurain K, Uldrick TS, JT Navarro (2022)

Leveraging fine-needle aspiration to improve HIV-associated lymphoma diagnostic capacity in resource-limited settings.

AIDS (London, England), 36(10):1461-1463.

RevDate: 2022-09-02

Ortblad KF, Sekhon M, Wang L, et al (2022)

Acceptability Assessment in HIV Prevention and Treatment Intervention and Service Delivery Research: A Systematic Review and Qualitative Analysis.

AIDS and behavior [Epub ahead of print].

We reviewed the literature on the assessment of acceptability of HIV prevention and treatment interventions and service delivery strategies. Following PRISMA guidelines, we screened 601 studies published from 2015 to 2020 and included 217 in our review. Of 384 excluded studies, 21% were excluded because they relied on retention as the sole acceptability indicator. Of 217 included studies, only 16% were rated at our highest tier of methodological rigor. Operational definitions of acceptability varied widely and failed to comprehensively represent the suggested constructs in current acceptability frameworks. Overall, 25 studies used formal quantitative assessments (including four adapted measures used in prior studies) and six incorporated frameworks of acceptability. Findings suggest acceptability assessment in recent HIV intervention and service delivery research lacks harmonization and rigor. We offer guidelines for best practices and future research, which are timely and critical in this era of informed choice and novel options for HIV prevention and treatment.

RevDate: 2022-10-04
CmpDate: 2022-08-30

Fernandez AI, Starbird C, Davis-Reyes B, et al (2022)

Evaluating diversity, equity, and inclusion consultation requests.

Trends in molecular medicine, 28(9):707-709.

Diversity, equity, and inclusion (DEI) efforts have increased drastically as companies and institutions recognize their value in fostering innovative ideas for success. Individuals trained in these efforts can impart their knowledge and expertise in consultation, but this transaction should be mutually beneficial. Here, we provide recommendations to maximize consulting opportunities.

RevDate: 2022-10-09

Longini IM, Yang Y, Fleming TR, et al (2022)

A platform trial design for preventive vaccines against Marburg virus and other emerging infectious disease threats.

Clinical trials (London, England) [Epub ahead of print].

BACKGROUND: The threat of a possible Marburg virus disease outbreak in Central and Western Africa is growing. While no Marburg virus vaccines are currently available for use, several candidates are in the pipeline. Building on knowledge and experiences in the designs of vaccine efficacy trials against other pathogens, including SARS-CoV-2, we develop designs of randomized Phase 3 vaccine efficacy trials for Marburg virus vaccines.

METHODS: A core protocol approach will be used, allowing multiple vaccine candidates to be tested against controls. The primary objective of the trial will be to evaluate the effect of each vaccine on the rate of virologically confirmed Marburg virus disease, although Marburg infection assessed via seroconversion could be the primary objective in some cases. The overall trial design will be a mixture of individually and cluster-randomized designs, with individual randomization done whenever possible. Clusters will consist of either contacts and contacts of contacts of index cases, that is, ring vaccination, or other transmission units.

RESULTS: The primary efficacy endpoint will be analysed as a time-to-event outcome. A vaccine will be considered successful if its estimated efficacy is greater than 50% and has sufficient precision to rule out that true efficacy is less than 30%. This will require approximately 150 total endpoints, that is, cases of confirmed Marburg virus disease, per vaccine/comparator combination. Interim analyses will be conducted after 50 and after 100 events. Statistical analysis of the trial will be blended across the different types of designs. Under the assumption of a 6-month attack rate of 1% of the participants in the placebo arm for both the individually and cluster-randomized populations, the most likely sample size is about 20,000 participants per arm.

CONCLUSION: This event-driven design takes into the account the potentially sporadic spread of Marburg virus. The proposed trial design may be applicable for other pathogens against which effective vaccines are not yet available.

RevDate: 2022-07-23

Zhang X, Yamada Y, Sagayama H, et al (2022)

Human total, basal and activity energy expenditures are independent of ambient environmental temperature.

iScience, 25(8):104682.

Lower ambient temperature (Ta) requires greater energy expenditure to sustain body temperature. However, effects of Ta on human energetics may be buffered by environmental modification and behavioral compensation. We used the IAEA DLW database for adults in the USA (n = 3213) to determine the effect of Ta (-10 to +30°C) on TEE, basal (BEE) and activity energy expenditure (AEE) and physical activity level (PAL). There were no significant relationships (p > 0.05) between maximum, minimum and average Ta and TEE, BEE, AEE and PAL. After adjustment for fat-free mass, fat mass and age, statistically significant (p < 0.01) relationships between TEE, BEE and Ta emerged in females but the effect sizes were not biologically meaningful. Temperatures inside buildings are regulated at 18-25°C independent of latitude. Hence, adults in the US modify their environments to keep TEE constant across a wide range of external ambient temperatures.

RevDate: 2022-08-02
CmpDate: 2022-07-21

Boonyaratanakornkit J, Boeckh M, A Waghmare (2022)

Monoclonal antibodies for prophylaxis and treatment of respiratory viral infections.

Current opinion in infectious diseases, 35(4):280-287.

PURPOSE OF REVIEW: Monoclonal antibody (mAb) administration represents an important strategy for preventing and treating respiratory viral infections in vulnerable populations, including immunocompromised individuals. The purpose of this review is to provide an overview of mAbs in clinical use against respiratory viruses, highlight factors that modulate mAb clinical efficacy, and provide a perspective on future innovations in the field. This review focuses on publications from the last year.

RECENT FINDINGS: Historically, clinical development of a single mAb has taken over a decade. The COVID-19 pandemic has demonstrated that this timeframe can be reduced to less than a year and has catalyzed rapid innovations in the field. Several novel mAbs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have received emergency use authorization by the Food and Drug Administration (FDA) for the early treatment of mild to moderate COVID-19. However, the majority of these mAbs have ultimately failed due to the emergence of variants, highlighting an important lesson about predicting and countering resistance. Novel mAbs are also in clinical use or in late-stage development for the prevention of infection by SARS-CoV-2 and respiratory syncytial virus (RSV) in vulnerable populations. Several factors can be modulated to improve the clinical efficacy of mAbs. For example, Fc modifications can extend mAb half-life and increase respiratory tract bioavailability, both of which are attractive properties for achieving protection against respiratory viruses.

SUMMARY: The mAb landscape is rapidly evolving with numerous examples of success and failure. The armamentarium of clinically-available mAbs to protect vulnerable populations is expected to undergo continued growth.

RevDate: 2022-08-17

Gilbert PB, Fong Y, Kenny A, et al (2022)

A controlled effects approach to assessing immune correlates of protection.

Biostatistics (Oxford, England) pii:6644798 [Epub ahead of print].

An immune correlate of risk (CoR) is an immunologic biomarker in vaccine recipients associated with an infectious disease clinical endpoint. An immune correlate of protection (CoP) is a CoR that can be used to reliably predict vaccine efficacy (VE) against the clinical endpoint and hence is accepted as a surrogate endpoint that can be used for accelerated approval or guide use of vaccines. In randomized, placebo-controlled trials, CoR analysis is limited by not assessing a causal vaccine effect. To address this limitation, we construct the controlled risk curve of a biomarker, which provides the causal risk of an endpoint if all participants are assigned vaccine and the biomarker is set to different levels. Furthermore, we propose a causal CoP analysis based on controlled effects, where for the important special case that the biomarker is constant in the placebo arm, we study the controlled vaccine efficacy curve that contrasts the controlled risk curve with placebo arm risk. We provide identification conditions and formulae that account for right censoring of the clinical endpoint and two-phase sampling of the biomarker, and consider G-computation estimation and inference under a semiparametric model such as the Cox model. We add modular approaches to sensitivity analysis that quantify robustness of CoP evidence to unmeasured confounding. We provide an application to two phase 3 trials of a dengue vaccine indicating that controlled risk of dengue strongly varies with 50$\%$ neutralizing antibody titer. Our work introduces controlled effects causal mediation analysis to immune CoP evaluation.

RevDate: 2022-07-19

Ackerman SD, Singhvi A, L Bianchi (2022)

Editorial: Accessory Cells of Sensory Systems and Their Functional Roles.

Frontiers in neuroscience, 16:965580.

RevDate: 2022-11-08
CmpDate: 2022-08-30

Griffin JM, Finney Rutten LJ, Zhu X, et al (2022)

The COMPASS study: A prospective, randomized, multi-center trial testing the impact of a clinic-based intervention informing patients of colorectal cancer screening options on screening completion.

Contemporary clinical trials, 119:106852.

BACKGROUND: Colorectal cancer (CRC) screening is underutilized despite evidence that screening improves survival. Since healthcare provider recommendation is a strong predictor of CRC screening completion, providers are encouraged to engage eligible patients in collaborative decision-making that attends to patients' values, needs, and preferences for guideline-concordant screening modalities.

METHODS: This three-arm randomized controlled trial is testing the effectiveness of an evidence-based video intervention informing patients of screening choices delivered in a clinic prior to a healthcare appointment. We hypothesize that participants randomized to watch a basic video describing CRC and screening in addition to an informed choice video showing the advantages and disadvantages of fecal immunochemical test (FIT), stool DNA FIT (s-DNA FIT), and colonoscopy (Arm 3) will exhibit a greater proportion of time adherent to CRC screening guidelines after 1, 3 and 6 years than those who only watch the basic video (Arm 2) or no video at all (Arm 1). Primary care and Obstetrician/Gynecology clinics across the United States are recruiting 5280 patients, half who have never been screened and half who previously screened but are currently not guideline adherent. Participants complete surveys prior to and following an index appointment to self-report personal, cognitive, and environmental factors potentially associated with screening. Proportion of time adherent to screening guidelines will be assessed using medical record data and supplemented with annual surveys self-reporting screening.

CONCLUSION: Results will provide evidence on the effectiveness of informational and motivational videos to encourage CRC screening that can be easily integrated into clinical practice.


RevDate: 2022-08-18
CmpDate: 2022-08-15

Li SS, Hickey A, Shangguan S, et al (2022)

HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype.

Cell host & microbe, 30(8):1173-1185.e8.

Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific T cell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia.

RevDate: 2022-11-09
CmpDate: 2022-11-09

Mehta S, Buyanbat A, Kai Y, et al (2022)

Temporal resolution of gene derepression and proteome changes upon PROTAC-mediated degradation of BCL11A protein in erythroid cells.

Cell chemical biology, 29(8):1273-1287.e8.

Reactivation of fetal hemoglobin expression by the downregulation of BCL11A is a promising treatment for β-hemoglobinopathies. A detailed understanding of BCL11A-mediated repression of γ-globin gene (HBG1/2) transcription is lacking, as studies to date used perturbations by shRNA or CRISPR-Cas9 gene editing. We leveraged the dTAG PROTAC degradation platform to acutely deplete BCL11A protein in erythroid cells and examined consequences by nascent transcriptomics, proteomics, chromatin accessibility, and histone profiling. Among 31 genes repressed by BCL11A, HBG1/2 and HBZ show the most abundant and progressive changes in transcription and chromatin accessibility upon BCL11A loss. Transcriptional changes at HBG1/2 were detected in <2 h. Robust HBG1/2 reactivation upon acute BCL11A depletion occurred without the loss of promoter 5-methylcytosine (5mC). Using targeted protein degradation, we establish a hierarchy of gene reactivation at BCL11A targets, in which nascent transcription is followed by increased chromatin accessibility, and both are uncoupled from promoter DNA methylation at the HBG1/2 loci.

RevDate: 2022-07-29

Zhou LY, Zou F, W Sun (2022)

Prioritizing candidate peptides for cancer vaccines through predicting peptide presentation by HLA-I proteins.

Biometrics [Epub ahead of print].

Cancer (treatment) vaccines that are made of neoantigens, or peptides unique to tumor cells due to somatic mutations, have emerged as a promising method to reinvigorate the immune response against cancer. A key step to prioritizing neoantigens for cancer vaccines is computationally predicting which neoantigens are presented on the cell surface by a human leukocyte antigen (HLA). We propose to address this challenge by training a neural network using mass spectrometry (MS) data composed of peptides presented by at least one of several HLAs of a subject. We embed the neural network within a mixture model and train the neural network by maximizing the likelihood of the mixture model. After evaluating our method using data sets where the peptide presentation status was known, we applied it to analyze somatic mutations of 60 melanoma patients and identified a group of neoantigens more immunogenic in tumor cells than in normal cells. Moreover, neoantigen burden estimated by our method was significantly associated with a measurement of the immune system activity, suggesting these neoantigens could induce an immune response.

RevDate: 2022-10-05
CmpDate: 2022-07-15

Celum CL, Bukusi EA, Bekker LG, et al (2022)

PrEP use and HIV seroconversion rates in adolescent girls and young women from Kenya and South Africa: the POWER demonstration project.

Journal of the International AIDS Society, 25(7):e25962.

INTRODUCTION: HIV incidence remains high among African adolescent girls and young women (AGYW). The primary objective of this study is to assess pre-exposure prophylaxis (PrEP) initiation, use, persistence and HIV acquisition among African AGYW offered PrEP in order to inform PrEP scale-up.

METHODS: POWER was a prospective implementation science evaluation of PrEP delivery for sexually active HIV-negative AGYW ages 16-25 in family planning clinics in Kisumu, Kenya and youth and primary healthcare clinics in Cape Town and Johannesburg, South Africa. Follow-up visits occurred at month 1 and quarterly for up to 36 months. PrEP users were defined based on the month 1 refill. PrEP persistence through month 6 was assessed using Kaplan-Meier survival analysis among AGYW with a month 1 visit, defining non-persistence as an ≥15 day gap in PrEP availability for daily dosing. PrEP execution was evaluated in a subset with PrEP supply from the prior visit sufficient for daily dosing by measuring blood tenofovir diphosphate (TFV-DP) levels.

RESULTS: From June 2017 to September 2020, 2550 AGYW were enrolled (1000 in Kisumu, 787 in Cape Town and 763 in Johannesburg). Median age was 21 years, 66% had a sexual partner of unknown HIV status, and 29% had chlamydia and 10% gonorrhoea. Overall, 2397 (94%) initiated PrEP and 749 (31%) had a refill at 1 month. Of AGYW who could reach 6 months of post-PrEP initiation follow-up, 128/646 (20%) persisted with PrEP for 6 months and an additional 92/646 (14%) had a gap and restarted PrEP. TFV-DP levels indicated that 47% (91/193) took an average of ≥4 doses/week. Sixteen HIV seroconversions were observed (incidence 2.2 per 100 person-years, 95% CI 1.2, 3.5); 13 (81%) seroconverters either did not have PrEP dispensed in the study interval prior to seroconversion or TFV-DP levels indicated <4 doses/week in the prior 6 weeks.

CONCLUSIONS: In this study of PrEP integration with primary care and reproductive health services for African AGYW, demand for PrEP was high. Although PrEP use decreased in the first months, an important fraction used PrEP through 6 months. Strategies are needed to simplify PrEP delivery, support adherence and offer long-acting PrEP options to improve persistence and HIV protection.

RevDate: 2022-08-02
CmpDate: 2022-08-02

Pan K, Aragaki AK, Michael Y, et al (2022)

Long-term dietary intervention influence on physical activity in the Women's Health Initiative Dietary Modification randomized trial.

Breast cancer research and treatment, 195(1):43-54.

PURPOSE: In the Women's Health Initiative (WHI) Dietary Modification (DM) randomized trial, dietary intervention significantly reduced breast cancer mortality (P = 0.02). In observational studies, physical activity is associated with lower breast cancer incidence. Currently, dietary intervention influence on other health-related behaviors is unknown. Therefore, we evaluated whether the WHI dietary intervention influenced self-directed physical activity.

METHODS: Of 48,835 postmenopausal women, 19,541 were randomized to dietary intervention (18 nutritionist-led group sessions first year, then quarterly sessions throughout 8.5 years [median] intervention) and 29,294 to a usual diet comparison (written health-related materials only). Neither randomization group received specific or ongoing instructions to increase physical activity. Episodes per week of moderate or vigorous recreational physical activity (MVPA) were serially reported. Marginal longitudinal logistic regression models were used to assess physically inactive (MVPA = 0) or physically active (MVPA > 0) participants by randomization group. Marginal Poisson regression models estimated mean weekly MVPA.

RESULTS: At entry, 45.6% of all participants reported physical inactivity (MVPA = 0). In 43,760 women with MVPA information, throughout 15.9 years (median) cumulative follow-up, dietary intervention group participation was associated with 7% lower physical inactivity rate (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.91, 0.95, P < 0.001) and a 4% higher mean MVPA (ratio of means [RM] 1.04 95% CI 1.02, 1.06, P < 0.001), relative to the comparison group.

CONCLUSION: In a randomized trial setting, a low-fat dietary pattern intervention was associated with a long-term, favorable influence on self-directed recreational physical activity.



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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Curriculum Vitae for R J Robbins

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