tbuckley/cabot-search huggingface dataset:
The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells
Authors: Junxia Wang, Minghua Chen, Mengyan Wang, Wenxia Zhao, Conghui Zhang, Xiujun Liu, Meilian Cai, Yuhan Qiu, Tianshu Zhang, Huimin Zhou, Wuli Zhao, Shuyi Si, Rongguang Shao
Journal: Acta Pharmaceutica Sinica B (2021)

Pancreatic adenocarcinoma (PAAD) is one of the most lethal malignancies. Although gemcitabine (GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C (Sec C) is a natural compound from the endophytic fungus
The Search for New 2-18F-FDG PET/CT Imaging Biomarkers in Advanced Ovarian Cancer Patients
Authors: Roberto C. Delgado Bolton, Adriana K. Calapaquí Terán, Olivier Pellet, Annamaria Ferrero, Francesco Giammarile
Journal: Clinical Nuclear Medicine (2021)

Delgado Bolton, Roberto C. MD, PhD; Calapaquí Terán, Adriana K. MD; Pellet, Olivier MD; Ferrero, Annamaria MD, PhD; Giammarile, Francesco MD, PhDAuthor Information
Abstract 2089: Epigenetic regulation of sprouty2 in colorectal cancer
Authors: Alexei Stuckel, Sharad Khare
Journal: Cancer Research (2021)

Abstract Background: The specific role of Sprouty-2 in colorectal cancer (CRC) as either a tumor suppressor or an oncogene is unclear. This is further obscured by the fact that no known driver mutations of Sprouty-2 have been reported. Therefore, for the first time, alterations of DNA 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were investigated to better understand the regulation of Sprouty-2 in CRC. Methods: Sprouty-2 transcript expression was evaluated in CRC patient samples and Sprouty-2 protein expression was evaluated in CRC cells. The DNA methylation status spanning Sprouty-2 gene was evaluated using combined bisulfite restriction analysis (COBRA). The 5hmC status in the Sprouty-2 gene body and promoter was analyzed using previously performed nano-hmC-seal data from colon cancers and adjacent normal colonic mucosa. Publicly available RNA-seq and methylation data from The Cancer Genome Atlas (TCGA) were extracted from tumors from CRC patients. Results: Variable Sprouty-2 mRNA expression was observed among CRC patient tumors compared to adjacent normal appearing colonocytes. For the first time, differential methylation between adjacent normal colon and CRC samples was identified in 2 CTCF binding sites and in the promoter near the Transcriptional Start Site (TSS) of Sprouty-2, where the 5mC status in 1 of the CTCF binding sites correlated with transcript abundance. In CRC, this is the first study to reveal increases of 5hmC deposition in the gene body and promoter region of Sprouty-2 compared to normal colon. In metastatic CRC, an inverse correlation of increased Sprouty-2 promoter 5mC and decreased mRNA expression was found in patients registered in TCGA. Conclusions: In terms of tumor growth, epigenetic aberrations including Sprouty-2 promoter hypomethylation and increased 5hmC may play a prominent role in positive regulation of Sprouty-2 in CRC. In metastatic stages of CRC, increases in Sprouty-2 promoter 5mC may downregulate Sprouty-2 expression, which may ultimately label Sprouty-2 as a tumor suppressor in CRC. Citation Format: Alexei Stuckel, Sharad Khare. Epigenetic regulation of sprouty2 in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2089.
K-ATP ニコランジルへのチャネンネル開口薬:ウィスター京都ラットにおける腎臓血液動力学に対する効果と自発性高血圧症
Authors: Kawata T, Mimuro T, Onuki T, Tsuchiya K, Nihei H, Koike T
Journal: Kidney International (1998)
Prospective study on fdg-pet/ct for on-treatment assessment of response to neoadjuvant or induction chemotherapy in invasive bladder cancer
Authors: S. Einerhand, C.S. Voskuilen, E.E. Fransen Van De Putte, M.L. Donswijk, A. Bruining, M.S. Van Der Heijden, L.S. Mertens, K. Hendricksen, E. Vegt, B.W.G. Van Rhijn
Journal: European Urology (2021)
Testicular salvage: Using machine learning algorithm to develop a more predictive model in testicular torsion
Authors: M. Ekşi, A.H. Yavuzsan, İ. Evren, A. Ayten, A.E. Fakir, F. Akkaş, K. Bursalı, A. Akdağ, S. Şahin, A.İ. Taşçı
Journal: European Urology (2021)
Single centre retrospective analysis of endocrine stimulation therapy prior to microsurgical Testicular Sperm retrieval (mTESE) in men with hypogonadism and Non-Obstructive Azoospermia (NOA)
Authors: G. Chiriacò, K. Naylor, V. Talaulikar, E. Williamson, D. Ralph, G. Conway, P. Sangster
Journal: European Urology (2021)
Electrochemically derived nanographene oxide activates endothelial tip cells and promotes angiogenesis by binding endogenous lysophosphatidic acid
Authors: Wenjing Liu, Haiyun Luo, Qinwei Wei, Jia Liu, Junrong Wu, Yanli Zhang, Lili Chen, Wencai Ren, Longquan Shao
Journal: Bioactive Materials (2021)

Graphene oxide (GO) exhibits good mechanical and physicochemical characteristics and has extensive application prospects in bone tissue engineering. However, its effect on angiogenesis is unclear, and its potential toxic effects are heavily disputed. Herein, we found that nanographene oxide (NGO) synthesized by one-step water electrolytic oxidation is smaller and shows superior biocompatibility. Moreover, NGO significantly enhanced angiogenesis in calvarial bone defect areas in vivo, providing a good microenvironment for bone regeneration. Endothelial tip cell differentiation is an important step in the initiation of angiogenesis. We verified that NGO activates endothelial tip cells by coupling with lysophosphatidic acid (LPA) in serum via strong hydrogen bonding interactions, which has not been reported. In addition, the mechanism by which NGO promotes angiogenesis was systematically studied. NGO-coupled LPA activates LPAR6 and facilitates the formation of migratory tip cells via Hippo/Yes-associated protein (YAP) independent of reactive oxygen species (ROS) stimulation or additional complex modifications. These results provide an effective strategy for the application of electrochemically derived NGO and more insight into NGO-mediated angiogenesis.
Abstract 1055: Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress and enhances the chemotherapeutic activity of widely used DNA damaging agents
Authors: Ukhyun Jo, Ilya Senatorov, Astrid Zimmermann, Liton Kumar Saha, Yasuhisa Murai, Se Hyun Kim, Vinodh N Rajapakse, Fathi Elloumi, Nobuyuki Takahashi, Christopher Schultz, Anish Thomas, Frank Zenke, Yves Pommier
Journal: Cancer Research (2021)

Abstract Purpose: Although several ATR inhibitors are in development, there are unresolved questions regarding their differential potency, molecular signatures of cancer patients for predicting activity and most effective therapeutic combinations. Here, we elucidate how to improve ATR-based chemotherapy with the newly developed ATR inhibitor, M4344 using in vitro and in vivo models. Experimental design: The potency of M4344 was compared with the clinically developed ATR inhibitors BAY1895344, berzosertib, and ceralasertib. The anticancer activity of M4344 was investigated as monotherapy and combination with clinical DNA damaging agents in multiple cancer cell lines, patient-derived tumor organoids and mouse xenograft models. We also elucidated the anticancer mechanisms and potential biomarkers for M4344. Results: M4344 is highly potent among the clinically developed ATR inhibitors. Replication stress (RepStress) and neuroendocrine (NE) gene expression signatures are significantly associated with a response to M4344 treatment. M4344 kills cancer cells by inducing cellular catastrophe and DNA damage. M4344 is highly synergistic with a broad range of DNA-targeting anticancer agents. It significantly synergizes with topotecan and irinotecan in patient-derived tumor organoids and xenograft models. Conclusions: M4344 is a promising and highly potent ATR inhibitor. It enhances the activity of clinical DNA damaging agents commonly used in cancer treatment including topoisomerase inhibitors, gemcitabine, cisplatin and talazoparib. RepStress and NE gene expression signatures can be exploited as predictive markers for M4344. Citation Format: Ukhyun Jo, Ilya Senatorov, Astrid Zimmermann, Liton Kumar Saha, Yasuhisa Murai, Se Hyun Kim, Vinodh N Rajapakse, Fathi Elloumi, Nobuyuki Takahashi, Christopher Schultz, Anish Thomas, Frank Zenke, Yves Pommier. Novel and highly potent ATR inhibitor M4344 kills cancer cells with replication stress and enhances the chemotherapeutic activity of widely used DNA damaging agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1055.
Novel Evidence That the Mannan-Binding Lectin (MBL) Pathway of Complement Activation Plays a Pivotal Role in Triggering Mobilization of Hematopoietic Stem/Progenitor Cells By Activation of Both the Complement and Coagulation Cascades
Authors: Mateusz Adamiak, Malwina Suszynska, Ahmed Abdel-Latif, Ahmed Abdelbaset-Ismail, Janina Ratajczak, Magdalena Kucia, Mariusz Z Ratajczak
Journal: Blood (2016)
Application of Artificial Intelligence-based classifiers to predict the outcome measures and stone-free status following percutaneous nephrolithotomy for staghorn calculi: Cross-validation of data and estimation of accuracy
Authors: B.M. Zeeshan Hameed, B. Somani, R. T P, S.Z. Raza, R. Paul, N. Naik, H. Singh, M. Shah, S. Reddy
Journal: European Urology (2021)
Measurement of hypoxia in the lung in idiopathic pulmonary fibrosis: an F-MISO PET/CT study
Authors: Joanna C. Porter, Thida Win, Kjell Erlandsson, Francesco Fraioli, Alaleh Rashidnasab, Beverley Holman, Balaji Ganeshan, Nicholas J. Screaton, Toby M. Maher, Raymond Endozo, John Hoath, Robert I. Shortman, Elise Emond, Kris Thielemans, Brian F. Hutton, Pauline T. Lukey, Franklin Aigbirhio, Saif Khan, Manuel Rodriguez-Justo, Ashley M. Groves
Journal: European Respiratory Journal (2021)

<b>This study found no detectable <sup>18</sup>F-MISO signal in fibrotic lung despite some histological expression of hypoxic markers, and concludes that in these IPF patients, the degree of hypoxia is too low to be detectable with <sup>18</sup>F-MISO-PET/CT</b>https://bit.ly/3wLJwja
Trainee Sex and Accreditation Council for Graduate Medical Education Milestone Assessments During General Surgery Residency
Authors: Sarah I. Landau, Solomiya Syvyk, Chris Wirtalla, Cary B. Aarons, Samantha Butts, Eric Holmboe, Rachel R. Kelz
Journal: JAMA Surgery (2021)

In evaluating the effectiveness of general surgery (GS) training, an unbiased assessment of the progression of residents with attention to individual learner factors is imperative.To evaluate the role of trainee sex in milestone achievement over the course of GS residency using national data from the Accreditation Council for Graduate Medical Education (ACGME).This cross-sectional study evaluated female and male GS residents enrolled in ACGME-accredited programs in the US from 2014 to 2018 with reported variation in milestones performance across years in training and representation. Data were analyzed from November 2019 to June 2021.Mean reported milestone score at initial and final assessment, and predicted time-to-attainment of equivalent performance by sex.Among 4476 GS residents from 250 programs who had milestone assessments at any point in their clinical training, 1735 were female (38.8%). Initially, female and male residents received similar mean (SD) milestone scores (1.95 [0.50] vs 1.94 [0.50]; P = .69). At the final assessment, female trainees received overall lower mean milestone scores than male trainees (4.25 vs 4.31; P < .001). Significantly lower mean milestone scores were reported for female residents at the final assessment for several subcompetencies in both univariate and multivariate analyses, with only medical knowledge 1 (pathophysiology, diagnosis, and initial management) common to both. Multilevel mixed-effects linear modeling demonstrated that female trainees had significantly lower rates of monthly milestone attainment in the subcompetency of medical knowledge 1, which was associated with a significant difference in training time of approximately 1.8 months.Both female and male GS trainees achieved the competency scores necessary to transition to independence after residency as measured by the milestones assessment system. Initially, there were no sex differences in milestone score. By graduation, there were differences in the measured assessment of female and male trainees across several subcompetencies. Careful monitoring for sex bias in the evaluation of trainees and scrutiny of the training process is needed to ensure that surgical residency programs support the educational needs of both female and male trainees.
Abstract 1487: Cytotoxic CD4+ T cells contribute to anti-tumor immune responses in NSCLC
Authors: Denise Lau, Sonal Khare, Derek Reiman, Tim Rand, Ameen A. Salahudeen, Aly Khan
Journal: Cancer Research (2021)

Abstract Immune checkpoint blockade (ICB) is widely used to treat non-small cell lung cancer (NSCLC) patients and works by inhibiting the PD-1/PDL1 axis to reinvigorate exhausted T cells. In the prevailing model, the primary mechanism for direct tumor cell killing occurs through cytotoxic CD8+ T cells. Here, we use single-cell multi-omic profiling (a combination of single-cell RNA sequencing, TCR sequencing, and surface protein profiling) in 10 NSCLC patients to identify a population of CD4+ T cells that are tumor-infiltrating, clonally expanded, and express a cytotoxic gene program. Concordantly, we found in the same patients a subpopulation of tumor cells with elevated HLA class II expression, suggesting a mechanism for tumor-mediated antigen presentation to CD4+ T cells. Finally, we show that a cytotoxic CD4 gene signature is associated with improved progression-free survival in a cohort of 180 NSCLC patients treated with ICB regimens, including those with loss of heterozygosity at the HLA class I locus. Overall, these results suggest a model where cytotoxic CD4+ T cells can perform direct tumor cell killing in a class II restricted manner and that their presence is associated with favorable ICB outcomes in NSCLC. Citation Format: Denise Lau, Sonal Khare, Derek Reiman, Tim Rand, Ameen A. Salahudeen, Aly Khan. Cytotoxic CD4+ T cells contribute to anti-tumor immune responses in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1487.
Abstract 1736: Antigen-specific targeting of tissue-resident gamma delta T cells with recombinant butyrophilin heterodimeric fusion proteins
Authors: Suresh de Silva, George Fromm, Anne Lai, Louis Gonzalez, Arpita Patel, Kyung Jin Yoo, Kellsey Johannes, Kinsley Evans, Keith Wilson, Taylor H. Schreiber
Journal: Cancer Research (2021)

Abstract A major mechanism of acquired resistance to immune checkpoint inhibition involves downregulation of antigen presentation, including the MHC I complex itself. Downregulation of antigen presentation on MHC I can render tumor cells invisible to any α/β T cell directed therapy. γδ T cells (γδT) are a small subset of the overall T cell compartment, but are characterized by increased cytolytic capacity relative to α/β T cells. Rather than MHC I, γδT recognize target cells via a complex of heterodimerized butyrophilin (BTN) proteins. Thus, display of BTN heterodimers on the surface of tumor cells may enhance immunity to tumors that have downregulated MHC I, or which express low abundance or low affinity antigens. We have previously reported the generation of a heterodimeric BTN protein targeting the CD19 antigen, referred to as BTN2A1/3A1-Fc-CD19scFv. While the BTN2A1/3A1 complex is a potent activator of γδT expressing the Vγ9δ2 T cell receptor (TCR), which is the major γδT population in human peripheral blood, Vγ9δ2 T cells are not the predominant γδT in many tissues. The murine equivalent of BTN2A1/3A1-Fc-CD19scFv, BTNL1/6-Fc-CD19scFv, stimulated specific proliferation and increased the cytolytic capacity of peripheral blood γδT in mice, but not other tissue-restricted GDT populations. These data suggested that distinct BTN heterodimers may preferentially activate tissue-restricted subsets of GDT. To characterize potential differences between peripheral blood and tissue-restricted γδT , we performed a multi-layered analysis, including single-cell sequencing of γδ TCR from paired peripheral blood and tumor tissues from human cancer patients such as melanoma, prostate and colon cancer. These data identified tissue-specific preferences for individual γδ TCRs, with corresponding tissue-specific preferences for individual BTN proteins. Based on this information, we generated a panel of distinct heterodimeric BTN proteins, and show that specific γδT populations are preferentially activated by specific BTN heterodimers in a lock-and-key fashion. These data are a necessary pre-requisite for designing γδT specific therapeutics that may target both immune neglected and acquired resistant tumors that have limited visibility to α/β T cell directed approaches. Citation Format: Suresh de Silva, George Fromm, Anne Lai, Louis Gonzalez, Arpita Patel, Kyung Jin Yoo, Kellsey Johannes, Kinsley Evans, Keith Wilson, Taylor H. Schreiber. Antigen-specific targeting of tissue-resident gamma delta T cells with recombinant butyrophilin heterodimeric fusion proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1736.
Effect of Oral Azithromycin vs Placebo on COVID-19 Symptoms in Outpatients With SARS-CoV-2 Infection
Authors: Catherine E. Oldenburg, Benjamin A. Pinsky, Jessica Brogdon, Cindi Chen, Kevin Ruder, Lina Zhong, Fanice Nyatigo, Catherine A. Cook, Armin Hinterwirth, Elodie Lebas, Travis Redd, Travis C. Porco, Thomas M. Lietman, Benjamin F. Arnold, Thuy Doan
Journal: JAMA (2021)

Azithromycin has been hypothesized to have activity against SARS-CoV-2.To determine whether oral azithromycin in outpatients with SARS-CoV-2 infection leads to absence of self-reported COVID-19 symptoms at day 14.Randomized clinical trial of azithromycin vs matching placebo conducted from May 2020 through March 2021. Outpatients from the US were enrolled remotely via internet-based surveys and followed up for 21 days. Eligible participants had a positive SARS-CoV-2 diagnostic test result (nucleic acid amplification or antigen) within 7 days prior to enrollment, were aged 18 years or older, and were not hospitalized at the time of enrollment. Among 604 individuals screened, 297 were ineligible, 44 refused participation, and 263 were enrolled. Participants, investigators, and study staff were masked to treatment randomization.Participants were randomized in a 2:1 fashion to a single oral 1.2-g dose of azithromycin (n = 171) or matching placebo (n = 92).The primary outcome was absence of self-reported COVID-19 symptoms at day 14. There were 23 secondary clinical end points, including all-cause hospitalization at day 21.Among 263 participants who were randomized (median age, 43 years; 174 [66%] women; 57% non-Hispanic White and 29% Latinx/Hispanic), 76% completed the trial. The trial was terminated by the data and safety monitoring committee for futility after the interim analysis. At day 14, there was no significant difference in proportion of participants who were symptom free (azithromycin: 50%; placebo: 50%; prevalence difference, 0%; 95% CI, -14% to 15%; P > .99). Of 23 prespecified secondary clinical end points, 18 showed no significant difference. By day 21, 5 participants in the azithromycin group had been hospitalized compared with 0 in the placebo group (prevalence difference, 4%; 95% CI, -1% to 9%; P = .16).Among outpatients with SARS-CoV-2 infection, treatment with a single dose of azithromycin compared with placebo did not result in greater likelihood of being symptom free at day 14. These findings do not support the routine use of azithromycin for outpatient SARS-CoV-2 infection.ClinicalTrials.gov Identifier: NCT04332107.
Fulfilling the Mandate of the US Food and Drug Administration’s Accelerated Approval Pathway
Authors: Bishal Gyawali, Joseph S. Ross, Aaron S. Kesselheim
Journal: JAMA Internal Medicine (2021)

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Ten-year oncological outcomes of diagnostic ureteroscopy prior to nephroureterectomy for upper tract urothelial carcinoma
Authors: R. Veeratterapillay, R. Geraghty, R.M. Pandian, C. Roy, G. Stenhouse, N. Soomro, E. Paez, A. Rogers, T. Page, D. Rix, D. Thomas, B.P. Rai
Journal: European Urology (2021)
Abstract 578: Comparative analysis of cell free DNA with whole-exome sequencing (cfWES) and application to personalized minimal residual disease (MRD) monitoring
Authors: Amy Xiaohong Wang, Zhixin Zhao, Chao Dai, Kemin Zhou, Shidong Jia, Pan Du, Shujun Luo
Journal: Cancer Research (2021)

Abstract Liquid biopsy has become increasingly important in cancer diagnosis, personalized medicine, and disease progression monitoring. Conventional liquid biopsy relies on cancer gene panels which often contain fewer than 500 genes. Despite the revolutionary impact it has brought to the cancer research and cancer patient care, gene panels often miss many key mutations involved in cancer development and drug response. To fully capture the genetic variations embedded in cfDNA, we have developed Predicine-cfWES assay, which expands the features of our existing 152-gene PredicineCARE and 600-gene PredicineATLAS NGS panel with additional coverage of coding regions of the entire human genome. With 2500 x sequencing depth, Predicine-cfWES assay detects common cancer variants at sensitivity of 1% allele frequency and precisely measures copy number variations, such as loss of tumor suppressor genes (PTEN, BRCA2, p53) and gain of oncogenic driver genes (AR, Myc, ERBB2). Variants detected by Predicine-cfWES assay was confirmed by PredicineCARE panel based NGS assay and further used in tumor-agnostic personalized MRD assay. In conclusion, we have developed a comprehensive liquid biopsy solution to profile cfDNA with broad coverage of ~20,000 genes in the whole exome and higher sensitivity in a focused set of clinically actionable cancer variants for more personalized MRD monitoring in cancer patients. Citation Format: Amy Xiaohong Wang, Zhixin Zhao, Chao Dai, Kemin Zhou, Shidong Jia, Pan Du, Shujun Luo. Comparative analysis of cell free DNA with whole-exome sequencing (cfWES) and application to personalized minimal residual disease (MRD) monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 578.