tbuckley/cabot-search huggingface dataset:
Gene expression profiling (GEP) to identify metabolic gene signature predictive of recurrence after surgery in stage III clear-cell renal cell carcinoma (ccRCC).
Authors: Shuchi Gulati, Vemuri Bhargav, Tom Cunningham, David Plas, Julio Alberto Landero, Jarek Meller, Maria Czyzyk-Krzeska
Journal: Journal of Clinical Oncology (2021)

355 Background: Management of patients with localized or locally advanced renal cell cancer (RCC) involves surgical resection. However, 20-40% of all localized kidney cancer patients experience a recurrence. Adjuvant treatment in high-risk kidney cancer has not proven to successfully improve overall survival (OS) and the only drug approved so far in this setting is vascular endothelial growth factor (VEGF) inhibitor, sunitinib. As multiple trials are evaluating drugs including immune checkpoint inhibitors in patients with high risk localized clear cell RCC, there is an urgent need to identify biomarkers to help with therapeutic decisions as well as for risk stratification. Here we present analysis pertaining to genes involved in metabolic reprogramming in kidney cancer. Methods: A deep transcriptomic analysis of patients with stage III ccRCC in the TCGA KIRC Firehose Legacy cohort was undertaken. Caucasian males with stage III ccRCC in the TCGA cohort for whom recurrence data was available with a minimum follow-up of 2 years were identified for the analysis. Expression profiles of differentially expressed genes were clustered using the Bayesian infinite mixture model and samples clustered using average linkage hierarchical clustering based on pairwise Pearson’s correlations as the measure of similarity. Enrichment analysis of up- and down-regulated genes was performed using logistic regression. R package was used to generate Kaplan-Meier curves and assess statistical significance of differences in overall and disease-free survival using log-rank test. Results: The cohort evaluated for this study included Caucasian male patients that remained disease free for at least 24 months after surgery (n = 22) and patients whose cancer recurred within 24 months (n = 20). We identified metabolic genes, encoding subunits of mitochondrial electron transport chain as well as malate aspartate shuttle (MAS), where loss of coordinated co-expression between these genes identified patients at risk of recurrence after surgery. The gene signature stratified the 42 patients into three subtypes: significantly enriched for a) recurrence (subtype 1), for b) disease free status (subtype 2) and b) intermediate (subtype 3). Work is underway to combine the use of individual gene expression and ratios of gene expression within the signature to optimize prognostic biomarkers for localized ccRCC. Conclusions: In this analysis, we have identified a novel metabolic gene signature which can help identify patients with localized ccRCC at high risk of recurrence after surgery to guide aggressive therapy. These findings require further validation in tumors collected from patients with stage III ccRCC.
Molecular Signatures of Kidney Antibody–Secreting Cells in Lupus Patients With Active Nephritis Upon Immunosuppressive Therapy
Authors: Etienne Crickx, Farah Tamirou, Tessa Huscenot, Nathalie Costedoat‐Chalumeau, Marion Rabant, Alexandre Karras, Ailsa Robbins, Tatiana Fadeev, Véronique Le Guern, Philippe Remy, Aurélie Hummel, Selda Aydin, Bernard Lauwerys, Jean‐Claude Weill, Claude‐Agnès Reynaud, Frédéric Houssiau, Matthieu Mahévas
Journal: Arthritis & Rheumatology (2021)

This study was undertaken to characterize kidney and urine antibody-secreting cells (ASCs) from patients with active lupus nephritis, before and after induction therapy. We included patients with biopsy-proven active lupus nephritis and performed anti-CD138 staining of kidney biopsy samples to visualize ASCs. We performed single-cell gene expression profiling on sorted ASCs from fresh biopsy samples using multiplex reverse transcriptase-polymerase chain reaction. We used a gene set that allowed for the study of ASC maturation from plasmablasts to long-lived plasma cells. We quantified urine ASCs from untreated patients with lupus nephritis at diagnosis and after 6 months of prospective follow-up during induction therapy. The number of kidney CD138+ ASCs in 46 untreated patients with lupus nephritis was correlated with a low estimated glomerular filtration rate and with tubulointerstitial damage. Most kidney ASCs from 3 untreated patients had a plasmablast molecular signature; in contrast, in 4 patients with refractory lupus nephritis, the kidney ASCs were mainly long-lived plasma cells, representing an ASC transcriptional profile similar to that in the bone marrow of 2 healthy donors. Some urine ASCs with a plasmablast signature were detected in patients with untreated active lupus nephritis. The presence of urine ASCs at 6 months was associated with treatment failure. Our results suggest potential for ASC-directed therapy in refractory lupus nephritis.
Identification of prognostic and predictive biomarkers of overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel, prednisone (DP) +/- bevacizumab (B) in CALGB 90401 (Alliance).
Authors: Susan Halabi, Qian Yang, Mark D. Starr, John C. Brady, Andrew J. Armstrong, Daniel J. George, William Kevin Kelly, Himisha Beltran, Michael J. Morris, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2021)

154 Background: CALGB 90401 was a phase III trial of 1050 pts with mCRPC comparing DP+B versus DP alone. While this trial did not show an improvement in OS in the overall population, there were improved PSA response, objective responses and delays in progression suggesting that subsets of men may derive benefit from this combination The purpose of this analysis was to identify and validate plasma angiokines (PAs) that are prognostic or predictive of OS and PFS benefit from bevacizumab in men with mCRPC. Methods: Baseline EDTA plasma samples from 679 consenting pts were analyzed using an optimized multiplex ELISA platform for 25 PAs related to tumor growth, angiogenesis, and inflammation. The data were randomly split into training (n = 462) and testing (n = 217) sets. The proportional hazards model was utilized to test for the prognostic and predictive importance of the PAs in predicting OS and PFS, with and without adjustment for clinical risk score. Analyses were adjusted for multiplicity using false discovery rate (FDR). Results: For the prognostic analysis, 14 PAs (angiopoeitin-2, BMP9, Chromogranin A, HER3, HGF, ICAM-1, IL6, OPN, PIGF, TIMP, TSP2, VEGFA, VEGFR1, and VEGF-R3) were prognostic of OS and 8 PAs (angiopoietin-2, HER3, ICAM-1, IL6, OPN, TIMP, VEGFA and VEGF-R3) were prognostic of PFS in the training set (FDR &lt; 0.05). None of the PAs were statistically significant for OS or PFS when adjusting by the clinical risk score, suggesting that angiokine levels associate with clinical prognostic factors. OPN was predictive of OS in the training set but no other PAs were found to be predictive of PFS improvement with DP+B. Using the testing set, we were unable to validate that OPN is predictive of OS/PFS or any of the PAs are predictive biomarkers of the OS or PFS benefits of DP+B over DP alone in men with mCRPC. Conclusions: While PAs are prognostic for OS and PFS in univariate analysis, we were unable to validate the results in the testing set. Furthermore, we did not identify any PAs that are predictive of benefit from the addition of bevacizumab to docetaxel/prednisone with ADT in this setting. Nevertheless, these remain worthy of further evaluation as potential therapeutic targets.
Venetoclax treatment of patients with relapsed T-cell prolymphocytic leukemia
Authors: Paul J. Hampel, Sameer A. Parikh, Timothy G. Call, Mithun V. Shah, N. Nora Bennani, Aref Al-Kali, Kari G. Rabe, Yucai Wang, Eli Muchtar, Jose F. Leis, Saad S. Kenderian, Amber B. Koehler, Susan M. Schwager, Susan L. Slager, Neil E. Kay, Curtis A. Hanson, Daniel L. Van Dyke, Min Shi, Wei Ding
Journal: Blood Cancer Journal (2021)
Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer
Authors: Incheol Seo, Hye Won Lee, Sang Jun Byun, Jee Young Park, Hyeonji Min, Sung Hwan Lee, Ju-Seog Lee, Shin Kim, Sung Uk Bae
Journal: Journal for ImmunoTherapy of Cancer (2021)

Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC.We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets.Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature.Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.
Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery
Authors: Shin-Heng Chiou, Diane Tseng, Alexandre Reuben, Vamsee Mallajosyula, Irene S. Molina, Stephanie Conley, Julie Wilhelmy, Alana M. McSween, Xinbo Yang, Daisuke Nishimiya, Rahul Sinha, Barzin Y. Nabet, Chunlin Wang, Joseph B. Shrager, Mark F. Berry, Leah Backhus, Natalie S. Lui, Heather A. Wakelee, Joel W. Neal, Sukhmani K. Padda, Gerald J. Berry, Alberto Delaidelli, Poul H. Sorensen, Elena Sotillo, Patrick Tran, Jalen A. Benson, Rebecca Richards, Louai Labanieh, Dorota D. Klysz, David M. Louis, Steven A. Feldman, Maximilian Diehn, Irving L. Weissman, Jianjun Zhang, Ignacio I. Wistuba, P. Andrew Futreal, John V. Heymach, K. Christopher Garcia, Crystal L. Mackall, Mark M. Davis
Journal: Immunity (2021)

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
Abstract IA-12: Functional analysis of BRCA regulatory variants with deep learning models
Authors: Olga Troyanskaya
Journal: Clinical Cancer Research (2021)

Abstract Precision medicine in oncology depends on identifying variants that are functional and interpreting them in terms of cancer disease risk, treatment guidance, and prognosis. This is especially challenging for regulatory variants, which constitute the majority of the genome and control transcription and RNA processing. We use state-of-the-art deep learning models that predict the molecular impact of variants to systematically analyze genomes and SNPs and discover BRCA-associated SNPs that impact transcriptional and post-transcriptional regulation of gene expression, identify genes and biological processes implicated across tissues of impact, and reconcile these findings with prior genomic annotation-based analysis. Citation Format: Olga Troyanskaya. Functional analysis of BRCA regulatory variants with deep learning models [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-12.
Fibroblastic reticular cell lineage convergence in Peyer’s patches governs intestinal immunity
Authors: Alejandro Prados, Lucas Onder, Hung-Wei Cheng, Urs Mörbe, Mechthild Lütge, Cristina Gil-Cruz, Christian Perez-Shibayama, Vasiliki Koliaraki, Burkhard Ludewig, George Kollias
Journal: Nature Immunology (2021)
Cost-effectiveness analysis of neoadjuvant immune checkpoint inhibition (ICI) versus cisplatin-based chemotherapy (CBC) in muscle-invasive bladder cancer (MIBC).
Authors: Ali Raza Khaki, Yong Shan, Richard Nelson, Sapna Kaul, John L. Gore, Petros Grivas, Stephen B. Williams
Journal: Journal of Clinical Oncology (2021)

419 Background: Multiple single-arm clinical trials have shown promising pathologic complete response (pCR) rates with neoadjuvant ICIs in MIBC. However, ICIs remain costly. We conducted a cost-effectiveness analysis comparing neoadjuvant ICIs with CBC. Methods: We applied a decision analytic simulation model with a health care payer perspective and two-year time horizon to compare neoadjuvant ICIs vs CBC. For the primary analysis we compared pembrolizumab with dose dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC). We performed a secondary analysis with gemcitabine/cisplatin (GC) as CBC and exploratory analyses with atezolizumab or nivolumab/ipilimumab as ICIs (vs both ddMVAC and GC). We input pCR rates from trials (ICIs) or a weighted average of prior studies (CBC) and costs from average sales price. Outcomes of interest included costs, 2-year recurrence-free survival (RFS), and incremental cost-effectiveness ratio (ICER) of cost per 2-year RFS. A threshold analysis estimated a pCR rate or price reduction for ICI to be cost-effective and one-way and probabilistic sensitivity analyses were performed. Results: Results of the cost effectiveness analysis are shown in the table. The incremental cost of pembrolizumab compared with ddMVAC was $8,042 resulting in an incremental improvement of 0.66% in 2-year RFS for an ICER of $1,218,485 per 2-year RFS. A pCR of 71% or a 26% reduction in cost of pembrolizumab would render it more cost-effective with an ICER of $100,000 per 2-year RFS. GC required a 96% pembrolizumab cost reduction to achieve an ICER of $100,000 per 2-year RFS. Atezolizumab appeared to be more cost-effective than ddMVAC, even though the 2yr RFS was 0.66% worse. Conclusions: ICIs were not cost-effective as neoadjuvant therapies, except when atezolizumab was compared with ddMVAC. Pembrolizumab would approach cost-effective thresholds with 26% or 96% reduction in cost when compared to ddMVAC and GC, respectively. Randomized clinical trials, larger sample sizes and longer follow-up are required to better understand the value of ICIs as neoadjuvant treatments. [Table: see text]
Incidence of Hepatitis C Virus Infections Among Users of Human Immunodeficiency Virus Pre-exposure Prophylaxis
Authors: Sahar Tabatabavakili, Wesam Aleyadeh, Orlando Cerrocchi, Harry L.A. Janssen, Bettina E. Hansen, Isaac I. Bogoch, Jordan J. Feld
Journal: Clinical Gastroenterology and Hepatology (2021)
Acute onset supraclavicular lymphadenopathy coinciding with intramuscular mRNA vaccination against COVID-19 may be related to vaccine injection technique, Spain, January and February 2021
Authors: María Fernández-Prada, Irene Rivero-Calle, Ana Calvache-González, Federico Martinón-Torres
Journal: Eurosurveillance (2021)

Monitoring adverse reactions following immunisation is essential, particularly for new vaccines such as those against COVID-19. We describe 20 cases of acute onset of a single supraclavicular lymphadenopathy manifesting between 24 h and 9 days after ipsilateral intramuscular administration of an mRNA-based COVID-19 vaccine, referred to our WHO Collaborating Centre for Vaccine Safety. Our results indicate that the swelling of supraclavicular lymph nodes following immunisation may constitute a benign and self-limited condition, related to a higher than recommended injection site.
PD1 blockade potentiates the therapeutic efficacy of photothermally-activated and MRI-guided low temperature-sensitive magnetoliposomes
Authors: Guanglong Ma, Nina Kostevšek, Ilaria Monaco, Amalia Ruiz, Boštjan Markelc, Calvin C.L. Cheung, Samo Hudoklin, Mateja E. Kreft, Hatem A.F.M. Hassan, Matthew Barker, Jamie Conyard, Christopher Hall, Stephen Meech, Andrew G. Mayes, Igor Serša, Maja Čemažar, Katarina Marković, Janez Ščančar, Mauro Comes Franchini, Wafa T. Al-Jamal
Journal: Journal of Controlled Release (2021)
Transcription factor competition at the γ-globin promoters controls hemoglobin switching
Authors: Nan Liu, Shuqian Xu, Qiuming Yao, Qian Zhu, Yan Kai, Jonathan Y. Hsu, Phraew Sakon, Luca Pinello, Guo-Cheng Yuan, Daniel E. Bauer, Stuart H. Orkin
Journal: Nature Genetics (2021)
Anastacia Awad: Women in STEM outside the lab
Authors: Stephanie Houston
Journal: The Journal of Experimental Medicine (2021)

Anastacia Awad is the Head of Diversity and Inclusion (D&I) globally for the Novartis Institutes for BioMedical Research, which is the research engine of Novartis. She completed her PhD in genetics and molecular biology at the University of North Carolina at Chapel Hill, followed by a postdoc with Alan Hall at Memorial Sloan Kettering Cancer Center. I chatted with Anastacia about her career in science and her journey from the bench to industry.
Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease
Authors: Xiaojiaoyang Li, Junde Ge, Yajing Li, Yajie Cai, Qi Zheng, Nana Huang, Yiqing Gu, Qi Han, Yunqian Li, Rong Sun, Runping Liu
Journal: Acta Pharmaceutica Sinica B (2021)

Nonalcoholic fatty liver disease (NAFLD) has become one of the most prominent causes of chronic liver diseases and malignancies. However, few therapy has been approved. Radix Bupleuri (RB) is the most frequently used herbal medicine for the treatment of liver diseases. In the current study, we aim to systemically evaluate the therapeutic effects of saikosaponin A (SSa) and saikosaponin D (SSd), the major bioactive monomers in RB, against NAFLD and to investigate the underlying mechanisms. Our results demonstrated that both SSa and SSd improved diet-induced NAFLD. Integrative lipidomic and transcriptomic analysis revealed that SSa and SSd modulated glycerolipid metabolism by regulating related genes, like Lipe and Lipg. SSd profoundly suppressed the fatty acid biosynthesis by downregulating Fasn and Acaca expression and promoted fatty acid degradation by inducing Acox1 and Cpt1a expression. Bioinformatic analysis further predicted the implication of master transcription factors, including peroxisome proliferator-activated receptor alpha (PPARα), in the protective effects of SSa and SSd. These results were further confirmed in vitro in mouse primary hepatocytes. In summary, our study uncoded the complicated mechanisms underlying the promising anti-steatosis activities of saikosaponins (SSs), and provided critical evidence inspiring the discovery of innovative therapies based on SSa and SSd for the treatment of NAFLD and related complications.
The Management of Gout
Authors: Bryan T. Emmerson
Journal: New England Journal of Medicine (1996)

Gout is a clinical syndrome resulting from the deposition of urate (monosodium urate monohydrate) crystals. The crystals may be deposited in a joint, leading to an acute inflammatory response, or in soft tissues, such as cartilage, causing no inflammation. Most cases of gout are characterized by the sudden onset of severe acute monarticular arthritis in a peripheral joint in the leg. The arthritis remits completely and then recurs with increasing frequency. After approximately 10 years of recurrent gouty arthritis, tophi develop in cartilage, tendons, and bursae in some patients.Established criteria for the diagnosis of gout include the presence of . . .
Simultaneous Inhibition of LSD1 and TGFβ Enables Eradication of Poorly Immunogenic Tumors with Anti–PD-1 Treatment
Authors: Wanqiang Sheng, Yi Liu, Damayanti Chakraborty, Brian Debo, Yang Shi
Journal: Cancer Discovery (2021)

Abstract Epigenetic regulators are a class of promising targets in combination with immune checkpoint inhibitors for cancer treatment, but the impact of the broad effects of perturbing epigenetic regulators on tumor immunotherapy remains to be fully explored. Here we show that ablation of the histone demethylase LSD1 in multiple tumor cells induces TGFβ expression, which exerts an inhibitory effect on T-cell immunity through suppressing the cytotoxicity of intratumoral CD8+ T cells and consequently dampens the antitumor effect of LSD1 ablation–induced T-cell infiltration. Importantly, concurrent depletion of LSD1 and TGFβ in combination with PD-1 blockade significantly increases both CD8+ T-cell infiltration and cytotoxicity, leading to eradication of poorly immunogenic tumors and a long-term protection from tumor rechallenge. Thus, combining LSD1 inhibition with blockade of TGFβ and PD-1 may represent a promising triple combination therapy for treating certain refractory tumors. SignIficance: Cotargeting LSD1 and TGFβ cooperatively elevates intratumoral CD8+ T-cell infiltration and unleashes their cytotoxicity, leading to tumor eradication upon anti–PD-1 treatment. Our findings illustrate a duality of epigenetic perturbations in immunotherapy and implicate the combination of LSD1 inhibition with dual PD-1/TGFβ blockade in treating certain poorly immunogenic tumors. This article is highlighted in the In This Issue feature, p. 1861
Access to Cancer Surgery in a Universal Health Care System During the COVID-19 Pandemic
Authors: Antoine Eskander, Qing Li, Julie Hallet, Natalie Coburn, Timothy P. Hanna, Jonathan Irish, Rinku Sutradhar
Journal: JAMA Network Open (2021)

This cohort study quantifies the cancer surgical backlog and determines whether there were differences in sociodemographic and hospital characteristics among patients undergoing cancer surgery in the pre– and peri–coronavirus disease 2019 (COVID-19) periods.