tbuckley/cabot-search huggingface dataset:
Abstract 2457: NANOG bindsPRC2 to reprogram metabolismandpromotelabel-retaining populationin experimental mouse and clinical carcinoma
Authors: Da-Wei Yeh, Juan Carlos Hernandez, Keigo Machida
Journal: Cancer Research (2021)

Abstract Background: Alcohol and HCV synergistically promote hepatocarcinogenesis. Our previous studies indicated that this synergistic effect of HCV and alcohol was mediated by TLR4, which increases the expression of NANOG, a transcription factor important for the stemness of TICs. Our recent studies further indicated that NANOG could repress mitochondrial oxidative phosphorylation (OXPHOS) genes to support the self-renewal and drug resistance of tumor-initiating stem cell-like cells (TICs), leading to relapse and metastasis (Chen et al., Cell Metabolism). In addition, approximately 39% of HCV-alcohol-associated HCCs have mutations in ARID1A, a component of the chromatin remodeling complex SWI/SNF. Hypothesis: The efficacy of the combined FAOi and PRC2 inhibition (PRC2i) therapy relies on activation of cell death signaling. Aims: We (1) tested if NANOG together with the PRC2 complex inhibits OXPHOS and generates TICs in the presence of ARID1A mutations; (2) tested if specific genetic alterations and NANOG cooperate to generate different classes of TICs for the development of HCC; (3) tested if ARID1A mutations with NANOG induction generate TICs. Methods: We transduced LPCs with a lentiviral vector that expresses mCherry and used the CRISPR/Cas9 system to target Arid1a or Ctnnb1. EZH2, SUZ12 and EED were silenced in patient-derived TICs (with or without ARID1A mutations). Surviving cells are subjected to the spheroid formation assay on ultra-low attachment plates for analysis of their self-renewal ability. Results: Mutant Arid1a HCCs with Nanog overexpression caused HCC metastasis to the lung. The humanized FRG mice subjected to alcohol feeding and/or HCV infection developed HCCs, especially in the CTNNB1 or ARID1A mutant hepatoblast groups, six months post-HCV infection and/or alcohol feeding. HCV-infected humanized livers in these mice contained HCV RNA, but not in the UV-irradiated HCV infected group. Conclusion: ARID1A gene loss promotes sorafenib-resistance phenotype and self-renewal through PRC2 complex genes. We demonstrated that sorafenib induced cytochrome c release from mitochondria to cause apoptosis of TICs, that restoration of OXPHOS was overexpressed in TICs. The studies established a novel therapy to overcome the chemoresistance of TICs for HCC treatment. Citation Format: Da-Wei Yeh, Juan Carlos Hernandez, Keigo Machida. NANOG bindsPRC2 to reprogram metabolismandpromotelabel-retaining populationin experimental mouse and clinical carcinoma [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 2457.
Abstract CT134: A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC)
Authors: Kathryn A. Gold, Assuntina Sacco, Julie Bykowski, Gregory Daniels, Emily Pittman, Karen Messer, Ruifeng Chen, Ezra Cohen
Journal: Cancer Research (2021)

Abstract Background: Checkpoint inhibitors have activity in RM HNSCC, but response rates to single agent therapy are low. Combination therapy may improve outcomes. We aimed to study a novel combination of palbociclib (P) and cetuximab (C) with the PD-L1 inhibitor avelumab (A) in RM HNSCC. Methods: Eligible patients (pts) with RM HNSCC received P in combination with A 10 mg/kg IV every 2 wks and C 400 mg/m2 IV x 1, then 250 mg/m2 weekly. The starting dose of P was 75 mg PO daily on days 1 to 21 of a 28 day cycle. The 3+3 dose escalation design included planned doses of P 100 mg and P 125 mg, with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included response rate and progression free survival (PFS). Results: As of 10/15/20, 12 pts have been treated in 3 cohorts: P 75 mg PO daily (3 pts), 100 mg PO daily (3 pts), and 125 mg PO daily (6 pts). Median age was 56 yo, 92% were male, with 58% p16+, 25% p16-, 17% p16 unknown. One DLT was observed in cohort 3: a grade 3 infusion reaction related to C. The RP2D was P 125 mg, with A and C at standard doses. Other grade 3 AEs were leukopenia (4 pts), neutropenia (4 pts), acneiform rash (2 pts), cellulitis (1pt), increased WBC (1pt). One pt had grade 4 leukopenia. There were no grade 5 AEs. Tx related AEs occurring in &amp;gt; 30% of pts were: acneiform rash (11pts), fatigue (10pts), mucositis (7pts), dry skin (6 pts), decreased WBCs (5 pts), paronychia (5 pts), nausea (5pts), hypomagnesemia (4pts). Response rate by RECIST 1.1 was 42% (3 CRs, 2PRs); median duration of response has not been reached. Median PFS was 6.5 m. Reasons for discontinuation were disease progression (8 pts), pt choice (1 pt). 3 patients remain on therapy (after 20, 15, and 9 months). Conclusions: The combination of APC was well tolerated in patients with RM HNSCC; no unexpected toxicities were seen. The RP2D is A 10 mg/kg every 2 wks, C 400 mg/m2 x 1 then 250 mg/m2 wkly, and P 125 mg daily, 3 wks on, one wk off. Promising response rates were seen, and several pts have had durable responses. These data support further development of this combination. Biomarker analyses on tissue and blood are ongoing. NCT03498378. Citation Format: Kathryn A. Gold, Assuntina Sacco, Julie Bykowski, Gregory Daniels, Emily Pittman, Karen Messer, Ruifeng Chen, Ezra Cohen. A phase I study of avelumab, palbociclib, and cetuximab (APC) in recurrent or metastatic head and neck squamous cell carcinoma (RM HNSCC) [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 CT134.
Stone clearance using the EMS Swiss LithoClast® Trilogy: Results of the European multicentre prospective study in comparison to the BAUS national PCNL outcomes on behalf of European Society of UroTechnology
Authors: N. Thakare, F. Tanase, K. Saeb-Parsy, N. Atassi, R. Endriss, G. Kamphuis, D. Pérez-Fentes, M. Hasan, M. Brehmer, P.J. Osther, H. Jung, B. Turney, W. Finch, N. Burgess, S. Irving, L. Dragos, E. Liatsikos, T. Knoll, V. Cauni, O. Wiseman
Journal: European Urology (2021)
Covid-19: Billions spent on private contracts should have gone to public services, says people’s inquiry
Authors: Richard Hurley
Journal: BMJ (2021)

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<i>APOE</i> ε4 Association With Cognition and Alzheimer Disease Biomarkers in Down Syndrome—Implications for Clinical Trials and Treatments for All
Authors: Cynthia A. Lemere, Elizabeth Head, David M. Holtzman
Journal: JAMA Neurology (2021)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Partial versus radical nephrectomy for the treatment of T1 renal tumors: A large contemporary matched-cohort study (RECORd2 Project)
Authors: R. Tellini, A. Mari, D. Amparore, A. Antonelli, M. Allasia, P. Bove, E. Brunocilla, U. Capitanio, F. Di Maida, A. Gallioli, A.A. Grosso, P. Gontero, N. Longo, F. Montorsi, F. Porpiglia, A. Porreca, B. Rocco, R. Schiavina, V. Li Marzi, C. Trombetta, V. Ficarra, M. Carini, A. Minervini
Journal: European Urology (2021)
An Independent Evolutionary Origin for Insect Deterrent Cucurbitacins in<i>Iberis amara</i>
Authors: Lemeng Dong, Aldo Almeida, Jacob Pollier, Bekzod Khakimov, Jean-Etienne Bassard, Karel Miettinen, Dan Stærk, Rahimi Mehran, Carl Erik Olsen, Mohammed Saddik Motawia, Alain Goossens, Søren Bak
Journal: Molecular Biology and Evolution (2021)

Abstract Pieris rapae and Phyllotreta nemorum are Brassicaceae specialists, but do not feed on Iberis amara spp. that contain cucurbitacins. The cucurbitacins are highly oxygenated triterpenoid, occurring widespread in cucurbitaceous species and in a few other plant families. Using de novo assembled transcriptomics from I. amara, gene co-expression analysis and comparative genomics, we unraveled the evolutionary origin of the insect deterrent cucurbitacins in I. amara. Phylogenetic analysis of five oxidosqualene cyclases and heterologous expression allowed us to identify the first committed enzyme in cucurbitacin biosynthesis in I. amara, cucurbitadienol synthase (IaCPQ). In addition, two species-specific cytochrome P450s (CYP708A16 and CYP708A15) were identified that catalyze the unique C16 and C22 hydroxylation of the cucurbitadienol backbone, enzymatic steps that have not been reported before. Furthermore, the draft genome assembly of I. amara showed that the IaCPQ was localized to the same scaffold together with CYP708A15 but spanning over 100 kb, this contrasts with the highly organized cucurbitacin gene cluster in the cucurbits. These results reveal that cucurbitacin biosynthesis has evolved convergently via different biosynthetic routes in different families rather than through divergence from an ancestral pathway. This study thus provides new insight into the mechanism of recurrent evolution and diversification of a plant defensive chemical.
Abstract 2480: RE1-silencing transcription factor (REST) controls neuroendocrine gene programs in pancreatic ductal adenocarcinoma
Authors: Kevin Alexander MacPherson, Meghan M. Joly, Brittany Allen-Petersen, Carl Pelz, Mary C. Thoma, Kristof Torkenczy, Andrew Adey, Daniel Liefwalker, Patrick J. Worth, Rosalie C. Sears
Journal: Cancer Research (2021)

Abstract Neuroendocrine (NE) differentiation features contribute to intratumoral heterogeneity and aggressive biology in a subset of pancreatic ductal adenocarcinoma (PDAC) tumors associated with poor disease outcome. We recently showed that treating pancreatic cancer cells with gemcitabine, a standard-of-care chemotherapy for PDAC, increases expression of NE markers, suggesting that ductal to neuroendocrine lineage plasticity could play a role in drug resistance. NE features in prostate cancer have been previously associated with loss of the neuronal gene repressor RE1-Silencing Transcription Factor (REST); in the present study, we explore a potential role of REST in regulating NE differentiation in PDAC. Our experiments show that loss of REST in PDAC cells increases NE gene expression, gemcitabine resistance, and colony formation. RNA sequencing data from gemcitabine-treated PDAC cells were enriched for REST target genes, suggesting gemcitabine relieves REST-mediated repression. Chromatin immunoprecipitation experiments corroborated this by demonstrating that gemcitabine reduces REST binding to the NE genes SYP and SNAP25. In addition, single cell ATAC sequencing also uncovered a heterogeneous response to gemcitabine treatment, revealing two gemcitabine-driven cell states with differing REST motif accessibility. Our study indicates that REST controls NE gene programs in PDAC and that loss of REST promotes gemcitabine resistance and oncogenic growth. Mirroring the heterogeneity of PDAC tumors, a subset of PDAC cells treated with gemcitabine have reduced REST motif accessibility, which may reflect a therapy resistant NE-like subpopulation. Citation Format: Kevin Alexander MacPherson, Meghan M. Joly, Brittany Allen-Petersen, Carl Pelz, Mary C. Thoma, Kristof Torkenczy, Andrew Adey, Daniel Liefwalker, Patrick J. Worth, Rosalie C. Sears. RE1-silencing transcription factor (REST) controls neuroendocrine gene programs in pancreatic ductal adenocarcinoma [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 2480.
Abstract 1021: Investigating the mechanism of PARP7 inhibition in type I interferon signaling by arrayed CRISPR screening
Authors: Bin Gui, Ryan Abo, Patrick Flynn, Alvin Z. Lu, Jan-Rung Mo, Joseph M. Gozgit, Melissa M. Vasbinder, Zacharenia A. Varsamis, Andrew Santospago, Victoria M. Richon, Kevin W. Kuntz, Heike Keilhack, Timothy J. Mitchison, Mario Niepel
Journal: Cancer Research (2021)

Abstract Genomic instability in cancer cells leads to cellular stress through the accumulation of aberrant nucleic acid species in the cytosol. We have shown that PARP7, a monoPARP, is a negative regulator of cytosolic nucleic acid sensing in cancer cells. RBN-2397 is a potent and selective PARP7 inhibitor that induces antitumor immunity in preclinical models and is currently being evaluated in a Phase I clinical trial. In our preclinical investigations, we found that in a subset of cancer cell lines, such as NCI-H1373, inhibition of PARP7 triggers Type I IFN release, STAT1 phosphorylation, and growth arrest. In contrast, other cell lines, for example, HARA, do not mount an IFN-response upon PARP7 inhibition, even though they are responsive to transfection of exogenous nucleic acids and PARP7 is expressed and enzymatically active. To investigate the underlying mechanism of PARP7 inhibition and to determine the drivers of the differential sensitivity across cell lines we performed arrayed CRISPR knockout screens, targeting approximately 240 genes in the nucleic acid sensing and IFN signaling pathways, in the presence and absence of PARP7 inhibition. Our arrayed screens confirmed multiple hits from a previous genome-wide pooled synthetic/lethal CRISPR dropout screen. For example, targeting genes in the cGAS/STING pathway conferred resistance to PARP7 inhibition in the NCI-H1373 responder cells, suggesting a critical dependence on this sensing pathway. In the PARP7 inhibitor-resistant HARA cells, deletion of components of innate immune-signaling (such as AIM2 and ADAR1), the NF-κB pathway, and genes involved in autophagy sensitized the cells to PARP7 inhibition. We further delineated the function of PARP7 by comparing the effects of the CRISPR perturbation across different cellular readouts such as STAT1 phosphorylation, IFN release, and proliferation. With our work, we shed light on the mechanism by which PARP7 acts as a critical suppressor of the innate immune response. Our findings demonstrate both redundancy and crosstalk between different nucleic acid-sensing pathways and may explain why some cell lines are resistant to PARP7 inhibition. Citation Format: Bin Gui, Ryan Abo, Patrick Flynn, Alvin Z. Lu, Jan-Rung Mo, Joseph M. Gozgit, Melissa M. Vasbinder, Zacharenia A. Varsamis, Andrew Santospago, Victoria M. Richon, Kevin W. Kuntz, Heike Keilhack, Timothy J. Mitchison, Mario Niepel. Investigating the mechanism of PARP7 inhibition in type I interferon signaling by arrayed CRISPR screening [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 1021.
A Conformable, Gas‐Permeable, and Transparent Skin‐Like Micromesh Architecture for Glucose Monitoring
Authors: Ya‐Lei Li, Yan‐Hua Liu, Lin‐Sen Chen, Jian‐Long Xu
Journal: Advanced Healthcare Materials (2021)

Monitoring the concentration of useful biomarkers via electronic skins (e-skins) is highly important for the development of wearable health management systems. While some biosensor e-skins with high flexibility, sensitivity, and stability have been developed, little attention has been paid to their long-term comfortability and optical transparency. Here, a conformable, gas permeable, and transparent skin-like Cu2 O@Ni micromesh structural glucose monitoring patch is reported. With its self-supporting micromesh structure, the skin-like glucose monitoring patch exhibits excellent shape conformability, high gas permeability, and high optical transmittance. The skin-like glucose biosensor achieves real-time monitoring of glucose concentrations with high sensitivity (15 420 µA cm-2 mM-1 ), low detection limit (50 nM), fast response time (＜2 s), high selectivity, and long-term stability. These desirable performance properties arise from the synergistic effects of the self-supporting micromesh configuration, high conductivity of the metallic Ni micromesh, and high electrocatalytic activities of the Cu2 O toward glucose. This work presents a versatile and efficient strategy for constructing conformable, gas permeable, and transparent biosensor e-skins with excellent practicability towards wearable electronics.
Analysis of clinical characteristics, treatment patterns, and outcome of patients with bilateral testicular germ cell tumors
Authors: R. Noy, M. Haifler, S. Golan, R. Mano, Y. Freifeld, B. Rosenzweig, B. Shalom, Y. Stabholz, R. Ben David, G.E. Amiel, A. Hoffman
Journal: European Urology (2021)
Nanoengineered biomimetic Cu-based nanoparticles for multifunational and efficient tumor treatment
Authors: Zengzhen Chen, Qiong Wu, Wenna Guo, Meng Niu, Longfei Tan, Ning Wen, Lisheng Zhao, Changhui Fu, Jie Yu, Xiangling Ren, Ping Liang, Xianwei Meng
Journal: Biomaterials (2021)
miRNA expression characterizes histological subtypes and metastasis in penile squamous cell carcinoma
Authors: A. Hiresh, J. Heinzelmann, S. Hölters, O. Khalmurzaev, A. Pryalukhin, P. Loertzer, J. Heinzelbecker, S. Lohse, C. Geppert, H. Loertzer, H. Wunderlich, R.M. Bohle, M. Stöckle, V. Matveev, A. Hartmann, K. Junker
Journal: European Urology (2021)
Covid-19: Looking back at the experiences of graduates and educators during the interim Foundation Year 1
Authors: Viktorija Kaminskaite
Journal: BMJ (2021)

In March 2020, thousands of final year medical students in the UK graduated early to join the medical workforce as "interim Foundation Year 1" (FiY1) doctors. <b>Viktorija Kaminskaite</b>, BMJ Clegg Scholar, spoke to the administrators, educators, and junior doctors involved in this graduating year.
Abstract 2398: Disruption of mitochondrial metabolism by ClpP activation in triple negative breast cancer
Authors: Emily M. Fennell, Lucas J. Aponte-Collazo, Blake R. Rushing, Yuan-Yuan Li, Wimal Pathmasiri, Joshua D. Wynn, Paul R. Graves, Ekhson L. Holmuhamedov, Laura E. Herring, Edwin J. Iwanowicz, Lee M. Graves
Journal: Cancer Research (2021)

Abstract ONC201 is a novel anticancer compound currently in over 20 clinical trials for multiple different cancers, including triple negative breast cancer (TNBC). We recently demonstrated that ONC201 and the more potent TR compounds selectively activate the mitochondrial protease ClpP. While previous studies demonstrated substantial effects on mitochondrial metabolism, the consequences of ClpP activation on cancer cell metabolism are yet to be defined. To investigate this, we performed an unbiased metabolomics and proteomics analysis comparing the effects of ONC201 and TR-57 on the TNBC metabolome and proteome. Consistent with these compounds targeting the mitochondria, our studies identified multiple mitochondrial metabolites and enzymes that were impacted by ClpP activation, such as TCA cycle intermediates and enzymes, heat shock proteins and mitochondrial ribosomal proteins. In addition to previously reported elements of the integrated stress response (ATF4, CHOP), we identified several proteins that were upregulated as part of the mitochondrial-nuclear signaling process. qRT-PCR was used to determine the impact of ONC201 or TR-57 treatment on transcript levels of proteomic hits. Importantly, the effects of ONC201 and the TR compounds on these proteins and cell growth were abolished in ClpP null cells. In summary, our studies further demonstrate that loss of metabolic function in mitochondria contributes to the anticancer activity of these ClpP activator compounds. Citation Format: Emily M. Fennell, Lucas J. Aponte-Collazo, Blake R. Rushing, Yuan-Yuan Li, Wimal Pathmasiri, Joshua D. Wynn, Paul R. Graves, Ekhson L. Holmuhamedov, Laura E. Herring, Edwin J. Iwanowicz, Lee M. Graves. Disruption of mitochondrial metabolism by ClpP activation in triple negative breast 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 2398.
Abstract 3189: Integrated analysis for tumor-immune interaction and its application to ENKTCL immunotyping
Authors: Yanbin Liu, Yan Gao, Yun Shao, Fang Meng, Huiqiang Huang, Frank Xiaofeng Qin
Journal: Cancer Research (2021)

Abstract Immunotherapy represents a major breakthrough for multiple cancer types, yet it remains necessary to expand disease indications and improve treatment efficiency based on better understanding of tumor-immune interaction. Three currently validated biomarkers (PD-L1, MSI/dMMR and TMB) are not sufficient to predict the efficacy and patient selection for immune checkpoint therapy. We hereby propose a comprehensive tumor-immune interaction typing strategy by integrating WES, RNA-seq and TCR-seq omic technologies for the detection of gene mutations, copy number variation, fusion genes, clone variation, HLA typing, tumor antigen prediction, tumor microenvironment immune repertoire analysis and tumor lymphocyte infiltration composition under the condition of one-time sampling. Thus enabling the systematic analysis of the tumor microenvironment characteristics. Applied to a cohort of ENKTCL patients, we studied the interactions between the tumor cells and the immune system tumor microenvironment. We discovered changes of tumor immunogenicity caused by DNA variation, e.g. abnormalities in immune regulatory region 6q21, DNA repair region, cases of fusion, CNV and LOH events. These mutational events summarizes the tumor intrinsic factors in NKTL. To study the TME and “extrinsic” factors, we investigated mRNA signature enrichment patterns in patient samples and found upregulation of various immune signatures such as macrophages, T helper cells in NKT tissue samples. As examples, CD274 and PDCD1 are significantly upregulated in NKTL tissue. We also found lower TCR diversity in NKTL patients. These discoveries suggest the association of tumor microenvironment with tumor intrinsic factors to elucidate the NKTL disease etiology. Taking together, our multi-omics datasets may also provide useful resources for further interrogating with treatment and clinical outcomes. Citation Format: Yanbin Liu, Yan Gao, Yun Shao, Fang Meng, Huiqiang Huang, Frank Xiaofeng Qin. Integrated analysis for tumor-immune interaction and its application to ENKTCL immunotyping [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 3189.