Publications by authors named "Yu Shyr"

378 Publications

Podocyte-Related Mechanisms Underlying Survival Benefit of Long-Term Angiotensin Receptor Blocker.

Int J Mol Sci 2022 May 27;23(11). Epub 2022 May 27.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

We previously found that short-term treatment (week 8 to 12 after injury) with high-dose angiotensin receptor blocker (ARB) induced the regression of existing glomerulosclerosis in 5/6 nephrectomy rats. We therefore assessed the effects of long-term intervention with ARB vs. nonspecific antihypertensives in this study. Adult rats underwent 5/6 nephrectomy and renal biopsy 8 weeks later. The rats were then divided into three groups with equivalent renal function and glomerular sclerosis and treated with high-dose losartan (ARB), nonspecific antihypertensive triple-therapy (TRX), or left untreated (Control) until week 30. We found that blood pressure, serum creatinine levels, and glomerulosclerosis were lower at sacrifice in ARB and TRX vs. Control. Only ARB reduced proteinuria and maintained the density of WT-1-positive podocytes. Glomerular tufts showed more double-positive cells for CD44, a marker of activated parietal epithelial cells, and synaptopodin after ARB vs. TRX or Control. ARB treatment reduced aldosterone levels. ARB-treated rats had significantly improved survival when compared with TRX or Control. We conclude that both long-term ARB and triple-therapy ameliorate progression, but do not sustain the regression of glomerulosclerosis. ARB resulted in the superior preservation of podocyte integrity and decreased proteinuria and aldosterone, linked to increased survival in the uremic environment.
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http://dx.doi.org/10.3390/ijms23116018DOI Listing
May 2022

Dysregulated Ligand-receptor interactions from single cell transcriptomics.

Bioinformatics 2022 Apr 28. Epub 2022 Apr 28.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.

Motivation: Intracellular communication is crucial to many biological processes, such as differentiation, development, homeostasis, and inflammation. Single cell transcriptomics provides an unprecedented opportunity for studying cell-cell communications mediated by ligand-receptor interactions. Although computational methods have been developed to infer cell type-specific ligand-receptor interactions from one single cell transcriptomics profile, there is lack of approaches considering ligand and receptor simultaneously to identifying dysregulated interactions across conditions from multiple single cell profiles.

Results: We developed scLR, a statistical method for examining dysregulated ligand-receptor interactions between two conditions. scLR models the distribution of the product of ligands and receptors expressions and accounts for inter-sample variances and small sample sizes. scLR achieved high sensitivity and specificity in simulation studies. scLR revealed important cytokine signaling between macrophages and proliferating T cells during severe acute COVID-19 infection, and activated TGF-β signaling from alveolar type II cells in the pathogenesis of pulmonary fibrosis.

Availability: scLR is freely available at https://github.com/cyhsuTN/scLR.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btac294DOI Listing
April 2022

Endogenous sex hormones, aromatase activity and lung cancer risk in postmenopausal never-smoking women.

Int J Cancer 2022 Mar 26. Epub 2022 Mar 26.

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.

Although reproductive factors have been repeatedly associated with lung cancer risk, no study to date has directly evaluated the relationship with endogenous sex hormones nor with aromatase activity in postmenopausal never-smoking women. A case-control study of 397 incident lung cancer cases and their individually matched controls, nested within the Shanghai Women's Health Study, was conducted among postmenopausal women who were lifetime never smokers. Prediagnostic concentrations of sex hormones was quantitated using LC-MS/MS assays in plasma. The product-substrate molar ratio of estrone to androstenedione was used as an index of aromatase activity (IAA). Multivariable conditional logistic regression models were used to calculate odds ratios (ORs) for lung cancer. Baseline concentrations of estradiol, free testosterone and IAA were inversely associated with subsequent risk of lung cancer in multivariable-adjusted models. When further adjusted for body mass index, the inverse association with estradiol was attenuated and no longer statistically significant, but the association with free testosterone and IAA remained. In analyses confined to participants having never used menopausal hormone therapy in 376 case-control pairs, the inverse association with free testosterone and IAA was slightly strengthened. OR for the highest vs the lowest quartile of free testosterone was 0.55 (95% CI = 0.34-0.90; P  = .03), and the corresponding OR for IAA was 0.57 (95% CI = 0.34-0.96; P  = .04). Our study, for the first time, suggests that higher levels of circulating free testosterone and estimated aromatase activity may be associated with lower lung cancer risk in postmenopausal never-smoking women.
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http://dx.doi.org/10.1002/ijc.34005DOI Listing
March 2022

Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19.

Blood Cancer Discov 2022 05;3(3):181-193

Division of Hematology, McGill University, Jewish General Hospital, Montreal, Quebec, Canada.

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19.

Significance: Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171.
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http://dx.doi.org/10.1158/2643-3230.BCD-22-0013DOI Listing
May 2022

Comprehensive evaluation of noise reduction methods for single-cell RNA sequencing data.

Brief Bioinform 2022 03;23(2)

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Normalization and batch correction are critical steps in processing single-cell RNA sequencing (scRNA-seq) data, which remove technical effects and systematic biases to unmask biological signals of interest. Although a number of computational methods have been developed, there is no guidance for choosing appropriate procedures in different scenarios. In this study, we assessed the performance of 28 scRNA-seq noise reduction procedures in 55 scenarios using simulated and real datasets. The scenarios accounted for multiple biological and technical factors that greatly affect the denoising performance, including relative magnitude of batch effects, the extent of cell population imbalance, the complexity of cell group structures, the proportion and the similarity of nonoverlapping cell populations, dropout rates and variable library sizes. We used multiple quantitative metrics and visualization of low-dimensional cell embeddings to evaluate the performance on batch mixing while preserving the original cell group and gene structures. Based on our results, we specified technical or biological factors affecting the performance of each method and recommended proper methods in different scenarios. In addition, we highlighted one challenging scenario where most methods failed and resulted in overcorrection. Our studies not only provided a comprehensive guideline for selecting suitable noise reduction procedures but also pointed out unsolved issues in the field, especially the urgent need of developing metrics for assessing batch correction on imperceptible cell-type mixing.
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http://dx.doi.org/10.1093/bib/bbab565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8921632PMC
March 2022

Preoperative and Postoperative Systemic Therapy for Operable Non-Small-Cell Lung Cancer.

J Clin Oncol 2022 02 5;40(6):546-555. Epub 2022 Jan 5.

Department of Medicine, Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD.

Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected stage II or III non-small-cell lung cancer. However, biomarker-informed clinical trials are starting to push the management of early-stage lung cancer beyond cytotoxic chemotherapy. This review explores recent and ongoing studies focused on improving cytotoxic chemotherapy and incorporating targeted and immunotherapies in the management of early-stage, resectable lung cancer. Adjuvant osimertinib for patients with -mutant tumors, preoperative chemoimmunotherapy, and adjuvant immunotherapy could improve outcomes for selected patients with resectable lung cancer, and ongoing or planned studies leveraging biomarkers, immunotherapy, and targeted therapy may further improve survival. We also discuss the unique barriers associated with clinical trials of early-stage lung cancer and the need for innovative trial designs to overcome these challenges.
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http://dx.doi.org/10.1200/JCO.21.01589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8853628PMC
February 2022

COVID-19 vaccination and breakthrough infections in patients with cancer.

Ann Oncol 2022 03 24;33(3):340-346. Epub 2021 Dec 24.

Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, USA; Department of Medicine, Division of Hematology/Oncology, Vanderbilt University, Nashville, USA; Department of Biomedical Informatics, Vanderbilt University, Nashville, USA. Electronic address:

Background: Vaccination is an important preventive health measure to protect against symptomatic and severe COVID-19. Impaired immunity secondary to an underlying malignancy or recent receipt of antineoplastic systemic therapies can result in less robust antibody titers following vaccination and possible risk of breakthrough infection. As clinical trials evaluating COVID-19 vaccines largely excluded patients with a history of cancer and those on active immunosuppression (including chemotherapy), limited evidence is available to inform the clinical efficacy of COVID-19 vaccination across the spectrum of patients with cancer.

Patients And Methods: We describe the clinical features of patients with cancer who developed symptomatic COVID-19 following vaccination and compare weighted outcomes with those of contemporary unvaccinated patients, after adjustment for confounders, using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19).

Results: Patients with cancer who develop COVID-19 following vaccination have substantial comorbidities and can present with severe and even lethal infection. Patients harboring hematologic malignancies are over-represented among vaccinated patients with cancer who develop symptomatic COVID-19.

Conclusions: Vaccination against COVID-19 remains an essential strategy in protecting vulnerable populations, including patients with cancer. Patients with cancer who develop breakthrough infection despite full vaccination, however, remain at risk of severe outcomes. A multilayered public health mitigation approach that includes vaccination of close contacts, boosters, social distancing, and mask-wearing should be continued for the foreseeable future.
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http://dx.doi.org/10.1016/j.annonc.2021.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704021PMC
March 2022

A pan-cancer immunogenomic atlas for immune checkpoint blockade immunotherapy.

Cancer Res 2021 Dec 13. Epub 2021 Dec 13.

Biostatistics, Vanderbilt University Medical Center.

The ability to identify robust genomic signatures that predict response to immune checkpoint blockade is restricted by limited sample sizes and ungeneralizable performance across cohorts. To address these challenges, we established Cancer-Immu (http://bioinfo.vanderbilt.edu/database/Cancer-Immu/) a comprehensive platform that integrates large-scale multidimensional omics data, including genetic, bulk, and single-cell transcriptomic, proteomic, and dynamic genomic profiles, with clinical phenotypes to explore consistent and rare immunogenomic connections. Currently Cancer-Immu has incorporated data for 3,652 samples for 16 cancer types. It provides easy access to immunogenomic data and empowers researchers to translate omics datasets into biological insights and clinical applications.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-2335DOI Listing
December 2021

Lung Cancer and Severe Acute Respiratory Syndrome Coronavirus 2 Infection: Identifying Important Knowledge Gaps for Investigation.

J Thorac Oncol 2022 02 10;17(2):214-227. Epub 2021 Nov 10.

Center of Excellence for Thoracic Oncology, The Tisch Cancer Institute, Icahn School of Medicine, at Mount Sinai, New York, New York. Electronic address:

Patients with lung cancer are especially vulnerable to coronavirus disease 2019 (COVID-19) with a greater than sevenfold higher rate of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19, a greater than threefold higher hospitalization rate with high complication rates, and an estimated case fatality rate of more than 30%. The reasons for the increased vulnerability are not known. In addition, beyond the direct impact of the pandemic on morbidity and mortality among patients with lung cancer, COVID-19, with its disruption of patient care, has also resulted in substantial impact on lung cancer screening and treatment/management.COVID-19 vaccines are safe and effective in people with lung cancer. On the basis of the available data, patients with lung cancer should continue their course of cancer treatment and get vaccinated against the SARS-CoV-2 virus. For unknown reasons, some patients with lung cancer mount poor antibody responses to vaccination. Thus, boosting vaccination seems urgently indicated in this subgroup of vulnerable patients with lung cancer. Nevertheless, many unanswered questions regarding vaccination in this population remain, including the magnitude, quality, and duration of antibody response and the role of innate and acquired cellular immunities for clinical protection. Additional important knowledge gaps also remain, including the following: how can we best protect patients with lung cancer from developing COVID-19, including managing care in patient with lung cancer and the home environment of patients with lung cancer; are there clinical/treatment demographics and tumor molecular demographics that affect severity of COVID-19 disease in patients with lung cancer; does anticancer treatment affect antibody production and protection; does SARS-CoV-2 infection affect the development/progression of lung cancer; and are special measures and vaccine strategies needed for patients with lung cancer as viral variants of concern emerge.
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http://dx.doi.org/10.1016/j.jtho.2021.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8579698PMC
February 2022

Association Between Androgen Deprivation Therapy and Mortality Among Patients With Prostate Cancer and COVID-19.

JAMA Netw Open 2021 11 1;4(11):e2134330. Epub 2021 Nov 1.

Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Importance: Androgen deprivation therapy (ADT) has been theorized to decrease the severity of SARS-CoV-2 infection in patients with prostate cancer owing to a potential decrease in the tissue-based expression of the SARS-CoV-2 coreceptor transmembrane protease, serine 2 (TMPRSS2).

Objective: To examine whether ADT is associated with a decreased rate of 30-day mortality from SARS-CoV-2 infection among patients with prostate cancer.

Design, Setting, And Participants: This cohort study analyzed patient data recorded in the COVID-19 and Cancer Consortium registry between March 17, 2020, and February 11, 2021. The consortium maintains a centralized multi-institution registry of patients with a current or past diagnosis of cancer who developed COVID-19. Data were collected and managed using REDCap software hosted at Vanderbilt University Medical Center in Nashville, Tennessee. Initially, 1228 patients aged 18 years or older with prostate cancer listed as their primary malignant neoplasm were included; 122 patients with a second malignant neoplasm, insufficient follow-up, or low-quality data were excluded. Propensity matching was performed using the nearest-neighbor method with a 1:3 ratio of treated units to control units, adjusted for age, body mass index, race and ethnicity, Eastern Cooperative Oncology Group performance status score, smoking status, comorbidities (cardiovascular, pulmonary, kidney disease, and diabetes), cancer status, baseline steroid use, COVID-19 treatment, and presence of metastatic disease.

Exposures: Androgen deprivation therapy use was defined as prior bilateral orchiectomy or pharmacologic ADT administered within the prior 3 months of presentation with COVID-19.

Main Outcomes And Measures: The primary outcome was the rate of all-cause 30-day mortality after COVID-19 diagnosis for patients receiving ADT compared with patients not receiving ADT after propensity matching.

Results: After exclusions, 1106 patients with prostate cancer (before propensity score matching: median age, 73 years [IQR, 65-79 years]; 561 (51%) self-identified as non-Hispanic White) were included for analysis. Of these patients, 477 were included for propensity score matching (169 who received ADT and 308 who did not receive ADT). After propensity matching, there was no significant difference in the primary end point of the rate of all-cause 30-day mortality (OR, 0.77; 95% CI, 0.42-1.42).

Conclusions And Relevance: Findings from this cohort study suggest that ADT use was not associated with decreased mortality from SARS-CoV-2 infection. However, large ongoing clinical trials will provide further evidence on the role of ADT or other androgen-targeted therapies in reducing COVID-19 infection severity.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.34330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8590166PMC
November 2021

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women.

Am J Clin Nutr 2022 Mar;115(3):643-651

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Background: Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development.

Objective: The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women.

Methods: We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models.

Results: After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall < 0.001 and P-nonlinearity = 0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall = 0.04 and P-nonlinearity = 0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk.

Conclusions: This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.
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http://dx.doi.org/10.1093/ajcn/nqab358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895217PMC
March 2022

scMRMA: single cell multiresolution marker-based annotation.

Nucleic Acids Res 2022 01;50(2):e7

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN 37203, USA.

Single-cell RNA sequencing has become a powerful tool for identifying and characterizing cellular heterogeneity. One essential step to understanding cellular heterogeneity is determining cell identities. The widely used strategy predicts identities by projecting cells or cell clusters unidirectionally against a reference to find the best match. Here, we develop a bidirectional method, scMRMA, where a hierarchical reference guides iterative clustering and deep annotation with enhanced resolutions. Taking full advantage of the reference, scMRMA greatly improves the annotation accuracy. scMRMA achieved better performance than existing methods in four benchmark datasets and successfully revealed the expansion of CD8 T cell populations in squamous cell carcinoma after anti-PD-1 treatment.
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http://dx.doi.org/10.1093/nar/gkab931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8789072PMC
January 2022

Pan-Cancer Analysis Reveals Common and Specific Relationships between Intragenic miRNAs and Their Host Genes.

Biomedicines 2021 Sep 18;9(9). Epub 2021 Sep 18.

Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

MicroRNAs (miRNAs) are small endogenous non-coding RNAs that play important roles in regulating gene expression. Most miRNAs are located within or close to genes (host). miRNAs and their host genes have either coordinated or independent transcription. We performed a comprehensive investigation on co-transcriptional patterns of miRNAs and host genes based on 4707 patients across 21 cancer types. We found that only 11.6% of miRNA-host pairs were co-transcribed consistently and strongly across cancer types. Most miRNA-host pairs showed a strong coexpression only in some specific cancer types, demonstrating a high heterogenous pattern. For two particular types of intergenic miRNAs, readthrough and divergent miRNAs, readthrough miRNAs showed higher coexpression with their host genes than divergent ones. miRNAs located within non-coding genes had tighter co-transcription with their hosts than those located within protein-coding genes, especially exonic and junction miRNAs. A few precursor miRNAs changed their dominate form between 5' and 3' strands in different cancer types, including miR-486, miR-99b, let-7e, miR-125a, let-7g, miR-339, miR-26a, miR-16, and miR-218, whereas only two miRNAs with multiple host genes switched their co-transcriptional partner in different cancer types (miR-219a-1 with and miR-3615 with ). miRNAs generated from distinct precursors (such as miR-125b from miR-125b-1 or miR-125b-2) were more likely to have cancer-dependent main contributors. miRNAs and hosts were less co-expressed in KIRC than other cancer types, possibly due to its frequent VHL mutations. Our findings shed new light on miRNA biogenesis and cancer diagnosis and treatments.
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http://dx.doi.org/10.3390/biomedicines9091263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471046PMC
September 2021

A domain damage index to prioritizing the pathogenicity of missense variants.

Hum Mutat 2021 11 15;42(11):1503-1517. Epub 2021 Aug 15.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Prioritizing causal variants is one major challenge for the clinical application of sequencing data. Prompted by the observation that 74.3% of missense pathogenic variants locate in protein domains, we developed an approach named domain damage index (DDI). DDI identifies protein domains depleted of rare missense variations in the general population, which can be further used as a metric to prioritize variants. DDI is significantly correlated with phylogenetic conservation, variant-level metrics, and reported pathogenicity. DDI achieved great performance for distinguishing pathogenic variants from benign ones in three benchmark datasets. The combination of DDI with the other two best approaches improved the performance of each individual method considerably, suggesting DDI provides a powerful and complementary way of variant prioritization.
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http://dx.doi.org/10.1002/humu.24269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511099PMC
November 2021

A Grant-Based Experiment to Train Clinical Investigators: The AACR/ASCO Methods in Clinical Cancer Research Workshop.

Clin Cancer Res 2021 10 26;27(20):5472-5481. Epub 2021 Jul 26.

University of Geneva Faculty of Medicine, Geneva, Switzerland.

To address the need for clinical investigators in oncology, American Association for Cancer Research (AACR) and American Society for Clinical Oncology (ASCO) established the Methods in Clinical Cancer Research Workshop (MCCRW). The workshop's objectives were to: (i) provide training in the methods, design, and conduct of clinical trials; (ii) ensure that clinical trials met federal and international ethical guidelines; (iii) evaluate the effectiveness of the workshop; and (iv) create networking opportunities for young investigators with mentoring senior faculty. Educational methods included: (i) didactic lectures, (ii) Small Group Discussion Sessions, (iii) Protocol Development Groups, and (iv) one-on-one mentoring. Learning focused on the development of an Institutional Review Board (IRB)-ready protocol, which was submitted on the last day of the workshop. Evaluation methods included: (i) pre- and postworkshop tests, (ii) students' workshop evaluations, (iii) faculty's ratings of protocol development, (iv) students' productivity in clinical research after the workshop, and (v) an independent assessment of the workshop. From 1996 to 2014, 1,932 students from diverse backgrounds attended the workshop. There was a significant improvement in the students' level of knowledge from the pre- to the postworkshop exams ( < 0.001). Across the classes, student evaluations were very favorable. At the end of the workshop, faculty rated 92% to 100% of the students' protocols as ready for IRB submission. Intermediate and long-term follow-ups indicated that more than 92% of students were actively involved in patient-related research, and 66% had implemented five or more protocols. This NCI-sponsored MCCRW has had a major impact on the training of clinicians in their ability to design and implement clinical trials in cancer research.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530870PMC
October 2021

The CoVID-TE risk assessment model for venous thromboembolism in hospitalized patients with cancer and COVID-19.

J Thromb Haemost 2021 10 13;19(10):2522-2532. Epub 2021 Aug 13.

Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.

Background: Hospitalized patients with COVID-19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well-known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID-19 is lacking.

Objectives: To assess the incidence of and risk factors for thrombosis in hospitalized patients with cancer and COVID-19.

Methods: Among patients with cancer in the COVID-19 and Cancer Consortium registry (CCC19) cohort study, we assessed the incidence of VTE and ATE within 90 days of COVID-19-associated hospitalization. A multivariable logistic regression model specifically for VTE was built using a priori determined clinical risk factors. A simplified RAM was derived and internally validated using bootstrap.

Results: From March 17, 2020 to November 30, 2020, 2804 hospitalized patients were analyzed. The incidence of VTE and ATE was 7.6% and 3.9%, respectively. The incidence of VTE, but not ATE, was higher in patients receiving recent anti-cancer therapy. A simplified RAM for VTE was derived and named CoVID-TE (Cancer subtype high to very-high risk by original Khorana score +1, VTE history +2, ICU admission +2, D-dimer elevation +1, recent systemic anti-cancer Therapy +1, and non-Hispanic Ethnicity +1). The RAM stratified patients into two cohorts (low-risk, 0-2 points, n = 1423 vs. high-risk, 3+ points, n = 1034) where VTE occurred in 4.1% low-risk and 11.3% high-risk patients (c statistic 0.67, 95% confidence interval 0.63-0.71). The RAM performed similarly well in subgroups of patients not on anticoagulant prior to admission and moderately ill patients not requiring direct ICU admission.

Conclusions: Hospitalized patients with cancer and COVID-19 have elevated thrombotic risks. The CoVID-TE RAM for VTE prediction may help real-time data-driven decisions in this vulnerable population.
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http://dx.doi.org/10.1111/jth.15463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8420489PMC
October 2021

Severity of illness scores at presentation predict ICU admission and mortality in COVID-19.

J Emerg Crit Care Med 2021 Jan 25;5. Epub 2021 Jan 25.

Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: The COVID-19 pandemic has overwhelmed hospital systems in multiple countries and necessitated caring for patients in atypical healthcare settings. The goal of this study was to ascertain if the conventional critical care severity scores qSOFA, SOFA, APACHE-II, and SAPS-II could predict which patients admitted to the hospital from an emergency department would eventually require intensive care.

Methods: This single-center, retrospective cohort study enrolled patients admitted to Vanderbilt University Hospital from the emergency room with symptomatic, confirmed COVID-19 infection between March 8, 2020 through May 15, 2020. Clinical phenotyping was performed by chart abstraction, and the correlation of the qSOFA, SOFA, APACHE-II, and SAPS-II scores for the primary endpoint of ICU admission and secondary endpoint of in-hospital mortality was evaluated.

Results: During the study period, 128 patients were admitted to Vanderbilt University Hospital from the emergency room with COVID-19. Of these, 39 patients eventually required intensive care; the remaining 89 were discharged from the medical ward. All severity of illness scores demonstrated at least moderate ability to identify patients who would die or require ICU admission. Of the three severity of illness scores assessed, the APACHE-II score performed best with an AUC of 0.851 (95% CI: 0.786 to 0.917) for identifying patient that would require ICU admission. No patient with an APACHE-II score at the time of presentation less than 8 or qSOFA of 0 required intensive care unit (ICU) admission. All patients with an APACHE-II score less than 10 or qSOFA score of 0 survived to hospital discharge.

Conclusions: The APACHE-II score accurately predicts the eventual need for ICU admission. This may allow for risk-stratification of patients safe to treat in alternative health care settings and prognostic enrichment to accelerate clinical trials of COVID-19 therapies.
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http://dx.doi.org/10.21037/jeccm-20-92DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232354PMC
January 2021

Immu-Mela: An open resource for exploring immunotherapy-related multidimensional genomic profiles in melanoma.

J Genet Genomics 2021 05 14;48(5):361-368. Epub 2021 May 14.

Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville TN 37203, USA; Department of Biostatistics, Vanderbilt University Medical Center, Nashville TN 37203, USA. Electronic address:

There are increasing studies aimed to reveal genomic hallmarks predictive of immune checkpoint blockade (ICB) treatment response, which generated a large number of data and provided an unprecedented opportunity to identify response-related features and evaluate their robustness across cohorts. However, those valuable data sets are not easily accessible to the research community. To take full advantage of existing large-scale immuno-genomic profiles, we developed Immu-Mela (http://bioinfo.vanderbilt.edu/database/Immu-Mela/), a multidimensional immuno-genomic portal that provides interactive exploration of associations between ICB responsiveness and multi-omics features in melanoma, including genetic, transcriptomics, immune cells, and single-cell populations. Immu-Mela also enables integrative analysis of any two genomic features. We demonstrated the value of Immu-Mela by identifying known and novel genomic features associated with ICB response. In addition, Immu-Mela allows users to upload their data sets (unrestricted to any cancer types) and co-analyze with existing data to identify and validate signatures of interest. Immu-Mela reduces barriers between researchers and complex genomic data, facilitating discoveries in cancer immunotherapy.
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http://dx.doi.org/10.1016/j.jgg.2021.03.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349898PMC
May 2021

MetaGSCA: A tool for meta-analysis of gene set differential coexpression.

PLoS Comput Biol 2021 05 4;17(5):e1008976. Epub 2021 May 4.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Analyses of gene set differential coexpression may shed light on molecular mechanisms underlying phenotypes and diseases. However, differential coexpression analyses of conceptually similar individual studies are often inconsistent and underpowered to provide definitive results. Researchers can greatly benefit from an open-source application facilitating the aggregation of evidence of differential coexpression across studies and the estimation of more robust common effects. We developed Meta Gene Set Coexpression Analysis (MetaGSCA), an analytical tool to systematically assess differential coexpression of an a priori defined gene set by aggregating evidence across studies to provide a definitive result. In the kernel, a nonparametric approach that accounts for the gene-gene correlation structure is used to test whether the gene set is differentially coexpressed between two comparative conditions, from which a permutation test p-statistic is computed for each individual study. A meta-analysis is then performed to combine individual study results with one of two options: a random-intercept logistic regression model or the inverse variance method. We demonstrated MetaGSCA in case studies investigating two human diseases and identified pathways highly relevant to each disease across studies. We further applied MetaGSCA in a pan-cancer analysis with hundreds of major cellular pathways in 11 cancer types. The results indicated that a majority of the pathways identified were dysregulated in the pan-cancer scenario, many of which have been previously reported in the cancer literature. Our analysis with randomly generated gene sets showed excellent specificity, indicating that the significant pathways/gene sets identified by MetaGSCA are unlikely false positives. MetaGSCA is a user-friendly tool implemented in both forms of a Web-based application and an R package "MetaGSCA". It enables comprehensive meta-analyses of gene set differential coexpression data, with an optional module of post hoc pathway crosstalk network analysis to identify and visualize pathways having similar coexpression profiles.
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http://dx.doi.org/10.1371/journal.pcbi.1008976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121311PMC
May 2021

Expression of CCL2/CCR2 signaling proteins in breast carcinoma cells is associated with invasive progression.

Sci Rep 2021 04 22;11(1):8708. Epub 2021 Apr 22.

Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.

Ductal carcinoma in situ (DCIS) is the most common type of pre-invasive breast cancer diagnosed in women. Because the majority of DCIS cases are unlikely to progress to invasive breast cancer, many women are over-treated for DCIS. By understanding the molecular basis of early stage breast cancer progression, we may identify better prognostic factors and design treatments tailored specifically to the predicted outcome of DCIS. Chemokines are small soluble molecules with complex roles in inflammation and cancer progression. Previously, we demonstrated that CCL2/CCR2 chemokine signaling in breast cancer cell lines regulated growth and invasion through p42/44MAPK and SMAD3 dependent mechanisms. Here, we sought to determine the clinical and functional relevance of CCL2/CCR2 signaling proteins to DCIS progression. Through immunostaining analysis of DCIS and IDC tissues, we show that expression of CCL2, CCR2, phospho-SMAD3 and phospho-p42/44MAPK correlate with IDC. Using PDX models and an immortalized hDCIS.01 breast epithelial cell line, we show that breast epithelial cells with high CCR2 and high CCL2 levels form invasive breast lesions that express phospho-SMAD3 and phospho-p42/44MAPK. These studies demonstrate that increased CCL2/CCR2 signaling in breast tissues is associated with DCIS progression, and could be a signature to predict the likelihood of DCIS progression to IDC.
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http://dx.doi.org/10.1038/s41598-021-88229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062684PMC
April 2021

Development and Evaluation of a Method to Correct Misinterpretation of Clinical Trial Results With Long-term Survival.

JAMA Oncol 2021 Jul;7(7):1041-1044

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

Importance: In immune checkpoint inhibitor (ICI) trials, long tails and crossovers in survival curves-which violate the proportional hazards (PH) assumption-are commonly observed, making cure or restricted mean survival time models preferable for analysis of ICI survival data. Cox PH analysis, however, still appears in major medical journals, leading to potential misinterpretation of clinical significance.

Objective: To convert inappropriate Cox hazard ratios (HRs) to appropriate PH cure model treatment-effect estimates (HR for short-term survivors and difference in proportions [DP] for long-term survivors) for more accurate interpretation of published ICI trials.

Design And Setting: This study uses the Taylor expansion technique to demonstrate the mathematical relationship between Cox PH and PH cure models for data with long-term survival, and based on this relationship, proposes the Cox-TEL (Cox PH-Taylor expansion adjustment for long-term survival data) adjustment method. The proposed Cox-TEL method requires only 2 inputs: the reported Cox HRs and Kaplan-Meier-estimated survival probabilities.

Results: Comprehensive simulations show the strength of the proposed method in terms of power, bias, and type I error rate; these results, which are close to PH cure model estimates, were further verified in a melanoma data set (N = 285; Cox HR = 0.71; 95% CI, 0.51-0.91; Cox-TEL HR = 0.83; 95% CI, 0.60-1.07; PH cure HR = 0.86; 95% CI, 0.61-1.11; Cox-TEL DP = 0.10; 95% CI, 0.01-0.23; PH cure DP = 0.10; 95% CI, 0.00-0.21). The magnitude of potential difference between reported and adjusted HRs using real-world ICI trial results is demonstrated. For example, in the CheckMate 067 trial (nivolumab/ipilimumab combination therapy vs ipilimumab), the Cox HR was 0.54 (95% CI, 0.44-0.67), and the Cox-TEL HR was 0.90 (95% CI, 0.73-1.11).

Conclusions And Relevance: The findings of this study suggest the need to revisit published ICI survival data analysis to address potential misinterpretation. The Cox-TEL method not only is designed for this purpose, but also is user friendly and easy to implement using published clinical trial data and a freely available R software package.
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http://dx.doi.org/10.1001/jamaoncol.2021.0289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050786PMC
July 2021

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation.

Oncologist 2021 07 5;26(7):e1104-e1109. Epub 2021 May 5.

Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA.

Lessons Learned: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation.

Background: Cediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib, resulting in an objective response in patients with mPDAC.

Methods: Patients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30 mg daily and olaparib 200 mg twice daily, orally. The primary endpoint was objective response (OR) rate.

Results: Nineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six because of clinical progression and one because of an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment-related adverse events were fatigue, hypertension, and diarrhea.

Conclusion: Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.
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http://dx.doi.org/10.1002/onco.13758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265343PMC
July 2021

Prediction models for breast cancer prognosis among Asian women.

Cancer 2021 06 11;127(11):1758-1769. Epub 2021 Mar 11.

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Robust and reliable prognosis prediction models have not been developed and validated for Asian patients with breast cancer, a rapidly growing yet understudied population in the United States.

Methods: We used longitudinal data from the Shanghai Breast Cancer Survival Study, a population-based prospective cohort study (n = 5042), to develop prediction models for 5- and 10-year disease-free survival (DFS) and overall survival (OS). The initial models considered age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. We then evaluated whether the addition of modifiable lifestyle factors (physical activity, soy isoflavones intake, and postdiagnostic weight change) improved the models. All final models have been validated internally and externally in the National Cancer Database when applicable.

Results: Our final models included age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, ER status, PR status, 6-month postdiagnostic weight change, interaction between ER status and tamoxifen therapy, and interaction between age and TNM stage. The internal validation yielded C-statistics of 0.76, 0.74, 0.78, and 0.75 for 5-year DFS, 10-year DFS, 5-year OS, and 10-year OS, respectively. The external validation yielded C-statistics of 5- and 10-year OS both at 0.78 for Chinese ethnicity, 0.79 for East Asian ethnicity, and 0.75 and 0.76 for all ethnic groups combined.

Conclusion: We developed prediction models for breast cancer prognosis from a large prospective study. Our prognostic models performed very well in women from the United States-particularly in Asian American women-and demonstrated high prediction accuracy and generalizability.
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http://dx.doi.org/10.1002/cncr.33425DOI Listing
June 2021

Association of Social Determinants of Health with Time to Diagnosis and Treatment Outcomes in Idiopathic Subglottic Stenosis.

Ann Otol Rhinol Laryngol 2021 Oct 25;130(10):1116-1124. Epub 2021 Feb 25.

Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA, USA.

Objectives: To examine whether social determinants of health (SDH) factors are associated with time to diagnosis, treatment selection, and time to recurrent surgical intervention in idiopathic subglottic stenosis (iSGS) patients.

Methods: Adult patients with diagnosed iSGS were recruited prospectively (2015-2017) via clinical providers as part of the North American Airway Collaborative (NoAAC) and via an online iSGS support community on Facebook. Patient-specific SDH factors included highest educational attainment (self-reported), median household income (matched from home zip code via U.S. Census data), and number of close friends (self-reported) as a measure of social support. Main outcomes of interest were time to disease diagnosis (years from symptom onset), treatment selection (endoscopic dilation [ED] vs cricotracheal resection [CTR] vs endoscopic resection with adjuvant medical therapy [ERMT]), and time to recurrent surgical intervention (number of days from initial surgical procedure) as a surrogate for disease recurrence.

Results: The total 810 participants were 98.5% female, 97.2% Caucasian, and had a median age of 50 years (IQR, 43-58). The cohort had a median household income of $62 307 (IQR, $50 345-$79 773), a median of 7 close friends (IQR, 4-10), and 64.7% of patients completed college or graduate school. Education, income, and number of friends were not associated with time to diagnosis via multivariable linear regression modeling. Univariable multinominal logistic regression demonstrated an association between education and income for selecting ED versus ERMT, but no associations were noted for CTR. No associations were noted for time to recurrent surgical procedure via Kaplan Meier modeling and Cox proportional hazards regression.

Conclusions: Patient education, income, and social support were not associated with time to diagnosis or time to disease recurrence. This suggests additional patient, procedure, or disease-specific factors contribute to the observed variations in iSGS surgical outcomes.
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http://dx.doi.org/10.1177/0003489421995283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762607PMC
October 2021

Outcomes After Use of a Lymph Node Collection Kit for Lung Cancer Surgery: A Pragmatic, Population-Based, Multi-Institutional, Staggered Implementation Study.

J Thorac Oncol 2021 04 16;16(4):630-642. Epub 2021 Feb 16.

Department of Surgery, Washington University, St. Louis, Missouri.

Introduction: Suboptimal pathologic nodal staging prevails after curative-intent resection of lung cancer. We evaluated the impact of a lymph node specimen collection kit on lung cancer surgery outcomes in a prospective, population-based, staggered implementation study.

Methods: From January 1, 2014, to August 28, 2018, we implemented the kit in three homogeneous institutional cohorts involving 11 eligible hospitals from four contiguous hospital referral regions. Our primary outcome was pathologic nodal staging quality, defined by the following evidence-based measures: the number of lymph nodes or stations examined, proportions with poor-quality markers such as nonexamination of lymph nodes, and aggregate quality benchmarks including the National Comprehensive Cancer Network criteria. Additional outcomes included perioperative complications, health care utilization, and overall survival.

Results: Of 1492 participants, 56% had resection with the kit and 44% without. Pathologic nodal staging quality was significantly higher in the kit cases: 0.2% of kit cases versus 9.8% of nonkit cases had no lymph nodes examined; 3.2% versus 25.3% had no mediastinal lymph nodes; 75% versus 26% attained the National Comprehensive Cancer Network criteria (p < 0.0001 for all comparisons). Kit cases revealed no difference in perioperative complications or health care utilization except for significantly shorter duration of surgery, lower proportions with atelectasis, and slightly higher use of blood transfusion. Resection with the kit was associated with a lower hazard of death (crude, 0.78 [95% confidence interval: 0.61-0.99]; adjusted 0.85 [0.71-1.02]).

Conclusions: Lung cancer surgery with a lymph node collection kit significantly improved pathologic nodal staging quality, with a trend toward survival improvement, without excessive perioperative morbidity or mortality.
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http://dx.doi.org/10.1016/j.jtho.2020.12.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012255PMC
April 2021

Biomarker Discovery and Validation: Statistical Considerations.

J Thorac Oncol 2021 04 2;16(4):537-545. Epub 2021 Feb 2.

Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.

Biomarkers have various applications including disease detection, diagnosis, prognosis, prediction of response to intervention, and disease monitoring. In this era of precision medicine, having validated biomarkers to inform clinical decision making is more important than ever. In this article, we discuss best the practices and potential issues in biomarker discovery and validation. We encourage team science partnerships to bring cutting-edge discovery from bench to bedside, leading to improved patient care and outcomes.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012218PMC
April 2021

The design and analysis of non-randomized studies: a case study of off-label use of hydroxychloroquine in the COVID-19 pandemic.

Authors:
Derek Shyr Yu Shyr

Expert Opin Investig Drugs 2021 Feb 29;30(2):111-117. Epub 2020 Dec 29.

Department of Biostatistics, Vanderbilt University School of Medicine , Nashville, TN, USA.

: The COVID-19 pandemic has prompted researchers to conduct non-randomized studies in an effort to find an off-label drug that can effectively combat the virus and its effects. While these studies can expedite the drug approval process, researchers must carefully design and analyze such studies in order to perform rigorous science that is reproducible and credible. This article focuses on several key design and analysis considerations that can improve the scientific rigor of non-randomized studies of off-label drugs. : The aim of this article is to provide an overview of best approaches that should be considered for non-randomized studies on off-label drugs. We discuss these approaches in detail and use a non-randomized study by Rivera et al. in as an example of methods that have been undertaken for COVID-19. : While non-randomized studies are inherently biased, they may be unavoidable in situations such as the COVID-19 pandemic, where researchers need to find an effective treatment quickly. We believe that a well-formed experimental design, high-quality data collection, and a well-thought-out statistical and data analysis plan are sufficient to produce rigorous and credible results for making an optimal decision.
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http://dx.doi.org/10.1080/13543784.2021.1868435DOI Listing
February 2021

Scientific Rigor in the Age of COVID-19.

JAMA Oncol 2021 Feb;7(2):171-172

Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.

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http://dx.doi.org/10.1001/jamaoncol.2020.6639DOI Listing
February 2021

Differential immunomodulatory effect of PARP inhibition in BRCA1 deficient and competent tumor cells.

Biochem Pharmacol 2021 02 4;184:114359. Epub 2020 Dec 4.

Department of Cellular and Molecular Medicine, University of Arizona Cancer Center College, Tucson, AZ, USA. Electronic address:

Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP inhibitors (PARPi) have been suggested to act by either catalytic inhibition or by PARP localization in chromatin. In this study, we treat BRCA1 mutant cells derived from a patient with triple negative breast cancer and control cells for three weeks with veliparib, a PARPi, to determine if treatment with this drug induces increased levels of mutations and/or an inflammatory response. We show that long-term treatment with PARPi induces an inflammatory response in HCC1937 BRCA1 mutant cells. The levels of chromatin-bound PARP1 in the BRCA1 mutant cells correlate with significant upregulation of inflammatory genes and activation of the cyclic GMP-AMP synthase (cGAS)/signaling effector stimulator of interferon genes (STING pathway). In contrast, an increased mutational load is induced in BRCA1-complemented cells treated with a PARPi. Our results suggest that long-term PARP inhibitor treatment may prime both BRCA1 mutant and wild-type tumors for positive responses to immune checkpoint blockade, but by different underlying mechanisms.
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http://dx.doi.org/10.1016/j.bcp.2020.114359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8668236PMC
February 2021
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