tbuckley/cabot-search huggingface dataset:
PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma
Authors: Min Luo, Yuhui Xia, Fang Wang, Hong Zhang, Danting Su, Chaoyue Su, Chuan Yang, Shaocong Wu, Sainan An, Suxia Lin, Liwu Fu
Journal: Acta Pharmaceutica Sinica B (2021)

ERK pathway regulated the programmed death ligand-1 (PD-L1) expression which was linked to the response of programmed death-1 (PD-1)/PD-L1 blockade therapy. So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy. In this study, PD0325901, an oral potent ERK inhibitor, strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma (NSCLC) cells. Mechanistically, PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3+ T cells infiltration and functions in tumor tissue. There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC. And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy. Our results demonstrate that PD0325901, an ERK inhibitor, can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models. And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.
Associations of education, residence, and travel distance to oncology center on survival outcomes in patients with penile cancer: A tertiary care referral center experience.
Authors: VIKAS GARG, Mukurdipi Ray, KP Haresh, Ranjit Kumar Sahoo, Atul Sharma, Seema Kaushal, Atul Batra
Journal: Journal of Clinical Oncology (2021)

4 Background: Rural residence, educational status &amp; longer travel distance are variably associated with suboptimal cancer treatment and outcomes. There are limited data on impact of these factors on treatment patterns &amp; survival outcomes in penile cancer. Methods: Patients with a histological diagnosis of carcinoma penis during 2015 to 2019 were identified from the database of a large tertiary care center in India. Chart reviews were performed to retrieve demographic, clinicopathological and treatment details. Educational status was categorized as no formal education and any educational attainment, while travel distance was dichotomized at 500 km. Logistic regression analyses were performed to examine the associations with cancer treatments. Relapse free survival (RS) and overall survival (OS) were calculated by plotting Kaplan Meir curves and compared using log rank test. Multivariable Cox regression analysis were used to determine the associations of socioeconomic status and residence on survival outcomes. Results: A total of 100 patients were eligible for the current analysis. The median age was 56 (interquartile [IQR]range, 42-65) years. The median duration of symptoms was 6 (IQR, 4-12) months. Ulcero-proliferative growth (65%) was the most common presenting symptom followed by pain (57%) and dysuria (36%). Most patients had grade 2 tumor (60%), while stage was equally distributed from I-IV. Three-fourths of patients had clinically enlarged inguinal lymph nodes, while, 42 % were pathologically involved. Of all patients, 58% were from rural communities, 44% patient didn’t receive any formal education, and 36% had travelling distance of over 500 km from the hospital. Surgery, radiotherapy, and chemotherapy were administered in 53%, 42% and 24%, respectively. On multivariable logistic regression analysis, lower education, rural residence and longer travel distance were not associated with a lower likelihood of receiving any treatment. At a median follow-up of 50.7 months, median RFS and OS were 59.8 (95% CI, 15.8-NR) and 83.9 (95% CI, 29.2–NR) months, respectively. After adjusting for tumor stage, involvement of lymph nodes, PS, and grade, education status, primary residence (urban vs rural), and distance from the treatment center were not associated with RFS and OS. However, advanced stage was the only factor predictive of worse RFS and OS (Table). Conclusions: Rural residence, educational status and travel time were not associated with treatment administration and survival outcomes in patients with penile cancer treated in a publicly funded tertiary care center in India. [Table: see text]
High-throughput global transcriptional profiling to identify the STAT3 signaling pathway as a potential biomarker for immune checkpoint inhibitor resistance in metastatic/advanced urothelial carcinoma.
Authors: Yung Lyou, Tanya B. Dorff, Sumanta K. Pal, Yate-Ching Yuan
Journal: Journal of Clinical Oncology (2021)

474 Background: Advanced/metastatic urothelial carcinoma (UC) is a significant public health burden with median overall survival of 15 months. Although, immune checkpoint inhibitors (ICI) have provided an additional second line treatment option, only 15-40% of patients will respond. There has been much effort in determining the mechanisms of immunotherapy resistance and predictive biomarkers to further improve these treatments. Methods: Pre-treatment genomic sequencing data derived from FFPE samples from the IMVIGOR210 clinical trial (n=298) was accessed for analysis. Briefly it was a single arm phase II clinical trial where advanced/metastatic UC patients refractory to platinum chemotherapy treatment received the ICI atezolizumab. This study has been published with detailed methods (PMID: 28950298). The raw sequencing data was pre-processed using standard QC measures and aligned to the human reference genome (hg38). The resulting outputs were then normalized and processed to generate the gene level counts for differential gene expression (DGE). We did DGE analysis comparing patients who had clinical benefit (CR, PR, SD) vs non-clinical benefit (ie. PD) to atezolizumab. The list of differentially expressed genes were then analyzed using various gene ontology, pathway and systems biology tools (IPA, Enrichr, and X2Kweb). Further subset analysis was done using gene-gene correlations (ie. PD-L1 and STAT3) and clinicopathologic features (eg. gender, race, smoking history). Results: Among the 298 patients in this study, there were 25 with CR, 43 with PR, 63 with SD, and 167 with PD based on clinical response to atezolizumab. Subgroup analysis for CR vs PD patients found that approximately 847 genes were differentially expressed with statistical significance (p ≤ 0.05). IPA analysis for this list of differentially expressed genes found among the top signaling pathways were “primary immunodeficiency” and “sirtuin signaling”. Further subset analysis of 39 genes (p ≤ 0.01) enriched in PD patients using Enrichr and X2kweb found that there was an overrepresentation of STAT3 signaling genes (hypergeometric p-val 6.32x10 4 ). Conclusions: Our results found that when the transcriptional profiles of CR vs PD there was differential gene expression in STAT3, primary immunodeficiency, and sirtuin signaling pathways. Of note it has been reported that STAT3 signaling can modulate immune activity and its expression is correlated with poor prognosis in urothelial carcinoma patients. These results warrant a larger study to see if STAT3 signaling is a potential biomarker for ICI resistance. If validated this may indicate that the STAT3 pathway is a potential therapeutic target to overcome ICI resistance and improve the efficacy of these agents.
Application of immune checkpoint targets in the anti-tumor novel drugs and traditional Chinese medicine development
Authors: Yuli Wang, Xingyan Zhang, Yuyan Wang, Wenjing Zhao, Huling Li, Lixing Zhang, Xinping Li, Tiejun Zhang, Hongbing Zhang, He Huang, Changxiao Liu
Journal: Acta Pharmaceutica Sinica B (2021)

Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example, Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals, and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion. Furthermore, many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers. Therefore, it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs. In this review, we focus on research progress in the field of immune checkpoints based on three topics: (1) immune checkpoint targets and pathways, (2) development of novel immune checkpoint-based drugs, and (3) application of immune checkpoints in the development of TCMs.
A human mutation in STAT3 promotes type 1 diabetes through a defect in CD8+ T cell tolerance
Authors: Jeremy T. Warshauer, Julia A. Belk, Alice Y. Chan, Jiaxi Wang, Alexander R. Gupta, Quanming Shi, Nikolaos Skartsis, Yani Peng, Jonah D. Phipps, Dante Acenas, Jennifer A. Smith, Stanley J. Tamaki, Qizhi Tang, James M. Gardner, Ansuman T. Satpathy, Mark S. Anderson
Journal: The Journal of Experimental Medicine (2021)

Naturally occurring cases of monogenic type 1 diabetes (T1D) help establish direct mechanisms driving this complex autoimmune disease. A recently identified de novo germline gain-of-function (GOF) mutation in the transcriptional regulator STAT3 was found to cause neonatal T1D. We engineered a novel knock-in mouse incorporating this highly diabetogenic human STAT3 mutation (K392R) and found that these mice recapitulated the human autoimmune diabetes phenotype. Paired single-cell TCR and RNA sequencing revealed that STAT3-GOF drives proliferation and clonal expansion of effector CD8+ cells that resist terminal exhaustion. Single-cell ATAC-seq showed that these effector T cells are epigenetically distinct and have differential chromatin architecture induced by STAT3-GOF. Analysis of islet TCR clonotypes revealed a CD8+ cell reacting against known antigen IGRP, and STAT3-GOF in an IGRP-reactive TCR transgenic model demonstrated that STAT3-GOF intrinsic to CD8+ cells is sufficient to accelerate diabetes onset. Altogether, these findings reveal a diabetogenic CD8+ T cell response that is restrained in the presence of normal STAT3 activity and drives diabetes pathogenesis.
Abstract LT008: Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy
Authors: Pavan Bachireddy, Elham Azizi, Cassandra Burdziak, Vinhkhang Nguyen, Christina Ennis, Zi- Ning Choo, Shuqiang Li, Kenneth Livak, Donna Neuberg, Robert Soiffer, Jerome Ritz, Edwin Alyea, Dana Pe'er, Catherine Wu
Journal: Cancer Research (2021)

Abstract Immune therapies have transformed the cancer therapeutic landscape but fail to benefit most patients. To elucidate the underlying mechanisms by which T cells mediate elimination of leukemia, we generated a high-resolution map of longitudinal T cell dynamics within the same tumor microenvironment (TME; bone marrow) during response or resistance to donor lymphocyte infusion (DLI), a widely used immunotherapy for relapsed leukemia. We analyzed 87,939 bone marrow-derived single T cell transcriptomes, along with chromatin accessibility and single T cell receptor clonality profiles, by developing novel machine learning tools for integrating longitudinal and multimodal data. We found that pre-treatment enrichment and post-treatment rapid, durable expansion of ‘terminal’ (TEX) and ‘precursor’ (TPEX) exhausted subsets, respectively, defined DLI response. In contrast to the common, shared pathways marking DLI response, a heterogeneous pattern of T cell dysfunction marked DLI resistance. Unexpectedly, TPEX cells that expanded in responders did not arise from the infusion product but instead from both pre-existing and novel clonotypes recruited to the TME. Further, we introduce a Bayesian method, Symphony, to define the T cell regulatory circuitry and master regulators underlying TEX and TPEX subsets that may be broadly relevant to other exhaustion antagonists across cancers. In conclusion, our data implicate the hierarchy of both TEX and TPEX subsets for immunotherapeutic responses in leukemia, extending the scope of their relevance beyond checkpoint blockade to adoptive cellular therapy. Moreover, our results provocatively suggest that immunologic ‘help’ from DLI, rather than direct transfer of anti-leukemic T cells, drove leukemic remission. Finally, we provide a general analysis paradigm for exploiting temporal single-cell genomic profiling for deep understanding of how immune therapies differentially shape the evolutionary trajectories of the TME in accordance with clinical outcome. Citation Format: Pavan Bachireddy, Elham Azizi, Cassandra Burdziak, Vinhkhang Nguyen, Christina Ennis, Zi- Ning Choo, Shuqiang Li, Kenneth Livak, Donna Neuberg, Robert Soiffer, Jerome Ritz, Edwin Alyea, Dana Pe'er, Catherine Wu. Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr LT008.
Association of Anti–Tumor Necrosis Factor Therapy With Mortality Among Veterans With Inflammatory Bowel Disease
Authors: Shirley Cohen-Mekelburg, Beth I. Wallace, Tony Van, Wyndy L. Wiitala, Shail M. Govani, Jennifer Burns, Rachel Lipson, Huifeng Yun, Jason Hou, James D. Lewis, Jason A. Dominitz, Akbar K. Waljee
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Inflammatory bowel disease (IBD) is commonly treated with corticosteroids and anti–tumor necrosis factor (TNF) drugs; however, medications have well-described adverse effects. Prior work suggests that anti-TNF therapy may reduce all-cause mortality compared with prolonged corticosteroid use among Medicare and Medicaid beneficiaries with IBD. <h3>Objective</h3> To examine the association between use of anti-TNF or corticosteroids and all-cause mortality in a national cohort of veterans with IBD. <h3>Design, Setting, and Participants</h3> This cohort study used a well-established Veteran’s Health Administration cohort of 2997 patients with IBD treated with prolonged corticosteroids (≥3000-mg prednisone equivalent and/or ≥600 mg of budesonide within a 12-month period) and/or new anti-TNF therapy from January 1, 2006, to October 1, 2015. Data were analyzed between July 1, 2019, and December 31, 2020. <h3>Exposures</h3> Use of corticosteroids or anti-TNF. <h3>Main Outcomes and Measures</h3> The primary end point was all-cause mortality as defined by the Veterans Health Administration vital status file. Marginal structural modeling was used to compare associations between anti-TNF therapy or corticosteroid use and all-cause mortality. <h3>Results</h3> A total of 2997 patients (2725 men [90.9%]; mean [SD] age, 50.0 [17.4] years) were included in the final analysis, 1734 (57.9%) with Crohn disease (CD) and 1263 (42.1%) with ulcerative colitis (UC). All-cause mortality was 8.5% (n = 256) over a mean (SD) of 3.9 (2.3) years’ follow-up. At cohort entry, 1836 patients were new anti-TNF therapy users, and 1161 were prolonged corticosteroid users. Anti-TNF therapy use was associated with a lower likelihood of mortality for CD (odds ratio [OR], 0.54; 95% CI, 0.31-0.93) but not for UC (OR, 0.33; 95% CI, 0.10-1.10). In a sensitivity analysis adjusting prolonged corticosteroid users to include patients receiving corticosteroids within 90 to 270 days after initiation of anti-TNF therapy, the OR for UC was statistically significant, at 0.33 (95% CI, 0.13-0.84), and the OR for CD was 0.55 (95% CI, 0.33-0.92). <h3>Conclusions and Relevance</h3> This study suggests that anti-TNF therapy may be associated with reduced mortality compared with long-term corticosteroid use among veterans with CD, and potentially among those with UC.
Editing GWAS: experimental approaches to dissect and exploit disease-associated genetic variation
Authors: Shuquan Rao, Yao Yao, Daniel E. Bauer
Journal: Genome Medicine (2021)

Genome-wide association studies (GWAS) have uncovered thousands of genetic variants that influence risk for human diseases and traits. Yet understanding the mechanisms by which these genetic variants, mainly noncoding, have an impact on associated diseases and traits remains a significant hurdle. In this review, we discuss emerging experimental approaches that are being applied for functional studies of causal variants and translational advances from GWAS findings to disease prevention and treatment. We highlight the use of genome editing technologies in GWAS functional studies to modify genomic sequences, with proof-of-principle examples. We discuss the challenges in interrogating causal variants, points for consideration in experimental design and interpretation of GWAS locus mechanisms, and the potential for novel therapeutic opportunities. With the accumulation of knowledge of functional genetics, therapeutic genome editing based on GWAS discoveries will become increasingly feasible.
Abstract PO034: Hypoxia-derived extracellular vesicles promote triple-negative breast cancer invasion <i>in vitro</i>
Authors: Bianca Cruz Pachane, Wanessa Fernanda Altei, Heloisa Sobreiro Selistre-de-Araujo
Journal: Cancer Research (2021)

Abstract The increase of tumor mass and complexity triggers cell invasion, a key step of the metastatic cascade, through hypoxia-derived signalization. The decrease in oxygen levels on the inner tumor mass stimulates the secretion of extracellular vesicles (EV) to the microenvironment, whose cargo may induce an invasive behavior of breast cancer cells. In an attempt to identify key players in hypoxic EV-mediated cell invasion in breast cancer, we are investigating the molecular, cellular and biochemical changes triggered by hypoxic-EVs to triple-negative breast cancer cells (MDA-MB-231). EVs have been isolated from conditioned culture media by differential ultracentrifugation and characterized by particle analysis (NTA), transmission electron microscopy (TEM), protein quantification and western blot of EV markers according to the MISEV2018. EV-treated cells were submitted to invasion assays in i) invasion chamber with extracellular matrix-based hydrogel and ii) a fluorescent gelatin-coated surface. Cell lysate and EV samples were probed for matrix metalloproteases by western blot and zymography. Morphological analysis of cells after EV treatment have been conducted after cytoskeleton staining using fluorescent probes. EVs derived from hypoxia and normoxia-cultured MDA-MB-231 are similarly sized and enriched with CD63, FLOT-1 and ALIX, although hypoxic-EVs have displayed higher protein concentration and particle concentration. Hypoxic EVs promoted cell invasion in an extracellular matrix-based hydrogel after 6h and 16h under normal oxygen conditions. Gelatin degradation has also been observed after EV treatment in normoxia, with results akin to degradation found in cells under hypoxia. While protease activity has been detected in EVs via zymography, we have yet to confirm the role of matrix metalloproteases in EV-related cell invasion. While little morphological changes have been observed upon EV treatment in gelatin-adhered cells, they acquire an epithelial morphology in uncoated circumstances, thus indicating a key role of adhesion molecules to hypoxia-derived invasive behavior. In conclusion, hypoxia-derived EVs from breast cancer cells generate morphological and physiological changes to tumor cells in regular oxygen levels, leading to an invasive behavior in collagen-based matrixes. Citation Format: Bianca Cruz Pachane, Wanessa Fernanda Altei, Heloisa Sobreiro Selistre-de-Araujo. Hypoxia-derived extracellular vesicles promote triple-negative breast cancer invasion in vitro [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO034.
術前over systemicの肺高血圧を伴った慢性肺血栓塞栓症(CPTE)に対する肺動脈血栓内膜剥離摘出術の経験
Authors: 進藤有一郎, 市原利彦, 朝倉貞二, 酒井和好, 味岡正純, 浅井健次, 森さつき, 上田裕一, 安藤太三
Journal: Circulation (2002)
Therapeutic RNA Delivery for COVID and Other Diseases
Authors: Curtis Dobrowolski, Kalina Paunovska, Marine Z. C. Hatit, Melissa P. Lokugamage, James E. Dahlman
Journal: Advanced Healthcare Materials (2021)

Abstract RNA can alter the expression of endogenous genes and can be used to express therapeutic proteins. As a result, RNA‐based therapies have recently mitigated disease in patients. Yet most potential RNA therapies cannot currently be developed, in large part because delivering therapeutic quantities of RNA drugs to diseased cells remains difficult. Here, recent studies focused on the biological hurdles that make in vivo drug delivery challenging are described. Then RNA drugs that have overcome these challenges in humans, focusing on siRNA to treat liver disease and mRNA to vaccinate against COVID, are discussed. Finally, research centered on improving drug delivery to new tissues is highlighted, including the development of high‐throughput in vivo nanoparticle DNA barcoding assays capable of testing over 100 distinct nanoparticles in a single animal.
Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states
Authors: Xia Zhu, Hao-Di Tang, Wan-Ying Dong, Fang Kang, An Liu, Yu Mao, Wen Xie, Xulai Zhang, Peng Cao, Wenjie Zhou, Haitao Wang, Zahra Farzinpour, Wenjuan Tao, Xiaoyuan Song, Yan Zhang, Tian Xue, Yan Jin, Juan Li, Zhi Zhang
Journal: Nature Neuroscience (2021)
Ampullectomy of an unusual lesion developing 20 years after endoscopic treatment of a type III choledochocele
Authors: Guillaume Perrod, Ariane Vienne, Enrique Pérez-Cuadrado-Robles, Hedi Benosman, Chloé Broudin, Christophe Cellier, Gabriel Rahmi
Journal: Endoscopy (2021)

A type III choledochocele is a rare congenital cystic dilation of the intraduodenal portion of the main bile duct, representing 5 % of all choledochal cysts according to the Toldani classification [1]. Choledochoceles may cause biliary obstruction and carcinoma development with a reported incidence of 2.5 %. To date, endoscopic treatment remains the less invasive technique, which consists of cystic mass removal associated with sphincterotomy [2] [3]. However, the risk of carcinoma development may persist even after treatment and reports of long-term outcomes are lacking [4].