tbuckley/cabot-search huggingface dataset:
A Novel Concept is Needed for Combating Alzheimer's Disease and NeuroHIV
Authors: Hu Xiu-Ti
Journal: Alzheimers Disease & Dementia (2020)

Both Alzheimer's disease (AD) and HIV-associated neurocognitive disorders (HAND) could progress to dementia, a severe consequence of neurodegenerative diseases. Cumulating evidence suggests that the β-amyloid (Aβ) theory, currently thought to be the predominant mechanism underlying AD and AD-related dementia (ADRD), needs re-evaluation, considering all treatments and new drug trials based upon this theory have been unsuccessful. Similar intention for treating HAND, including HIV-associated dementia (HAD), has also failed. Thus, novel theory, hypothesis, and therapeutic strategies are desperately needed for future study and effective treatments of AD/ADRD and HAND. There are numerous potential upstream mechanisms that may cause AD and/or HAND; but it is unrealistic to identify all of them. However, it is realistic and feasible to intervene the downstream mechanism of these two devastating neurodegenerative diseases by blocking the final common path to neurotoxicity mediated by overactivation of NMDA receptors (NMDARs) and voltage-gated calcium channels (VGCCs). Such a combined pharmacological intervention will likely ameliorate neuronal Ca2+ homeostasis by diminishing overactivated NMDAR and VGCC-mediated Ca2+ dysregulation (i.e., by reducing excessive Ca2+ influx and intracellular levels, [Ca2+]in)-induced hyperactivity, injury, and death of neurons in the critical brain regions that regulate neurocognition in the context of AD/ADRD or HAND, especially during aging. Here we present a novel theoretical concept, hypothesis, and working model for switching the battlefield from searching-and-fighting the original mechanism that may cause AD or HAND, to abolishing AD- and neuroHIV-induced neurotoxicity mediated by NMDAR and VGCC over activation, which may ultimately improve the therapeutic strategies for treating AD and HAND.
Immune-related pneumonitis associated with immune checkpoint inhibitors in lung cancer: a network meta-analysis
Authors: Xinru Chen, Zhonghan Zhang, Xue Hou, Yaxiong Zhang, Ting Zhou, Jiaqing Liu, Zhihuan Lin, Wenfeng Fang, Yunpeng Yang, Yuxiang Ma, Yan Huang, Hongyun Zhao, Li Zhang
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) have dramatically revolutionized lung cancer treatment, providing unprecedented clinical benefits. However, immune-related pneumonitis (IRP) caused by ICIs has aroused widespread concern due to its high rate of discontinuation and mortality. This network meta-analysis (NMA) aims to compare the risks of IRP among different regimens for advanced lung cancer. Methods Phase II and III randomized clinical trials (RCTs) were searched from electronic databases. The rates of grade 1–5 IRP and grade 3–5 IRP were systematically extracted. An NMA was conducted among chemotherapy, ICIs monotherapy, dual ICIs combination, and ICIs+chemotherapy. Subgroup analysis was also compared based on specific types of ICIs. Results Twenty-five RCTs involving 17,310 patients were eligible for inclusion. Compared with chemotherapy, ICI-based regimens were associated with an increased risk of grade 1–5 IRP and grade 3–5 IRP. Compared with ICIs+chemotherapy, ICIs monotherapy (grade 1–5: OR 2.14, 95% credible interval 1.12 to 4.80; grade 3–5: 3.03, 1.491 to 6.69) and dual ICIs combination (grade 1–5: 3.86, 1.69 to 9.89; grade 3–5: 5.12, 2.01 to 13.68) were associated with a higher risk of grade 1–5 IRP and grade 3–5 IRP. No significant difference was found between dual ICIs combination and ICIs monotherapy in grade 1–5 IRP (1.85, 0.91 to 3.37) or in grade 3–5 IRP (1.65, 0.81 to 3.37). Besides, compared with programmed cell death protein 1 (PD-1) inhibitors (2.56, 1.12 to 6.60), a lower risk of grade 1–5 IRP was observed in programmed cell death ligand 1 (PD-L1) inhibitors. Conclusion Compared with chemotherapy, using ICIs is associated with an increased risk of IRP. ICIs+chemotherapy is associated with a lower risk of IRP compared with dual ICIs combination and ICIs monotherapy. PD-1 inhibitors are associated with a higher risk of 1–5 grade IRP compared with PD-L1 inhibitors.
The Long and Winding Road for Breast Cancer Biomarkers to Reach Clinical Utility
Authors: Natasha B. Hunter, Mark R. Kilgore, Nancy E. Davidson
Journal: Clinical Cancer Research (2020)

Tumor data from the ABCSG 5 trial of chemotherapy versus endocrine therapy for premenopausal ER+ breast cancer supports molecular subtyping by Ki-67 IHC as a prognostic marker. But while this tissue was handled uniformly, Ki-67 testing overall is unstandardized, complicating clinical utility. Increasing potential biomarkers herald more challenges in biomarker validation.See related article by Bago-Horvath et al., p. 5682.
Antibodies Against Macrophage CD44 Protect Platelets from FcγR-Mediated Phagocytosis: A Potential Mechanism for CD44 Antibody Amelioration of Murine Immune Thrombocytopenia
Authors: Peter A A Norris, Yawen Wang, Guangheng Zhu, Lin Wang, Ming Huo, Gregory D Fairn, Heyu Ni, Alan H Lazarus
Journal: Blood (2017)
The Anatomy of Recurrent Thrombosis and Its Risk Factors in Myeloproliferative Neoplasms
Authors: Silvia Betti, Daniela Barraco, Mythri Mudireddy, Curtis A. Hanson, Rhett P. Ketterling, Animesh D. Pardanani, Naseema Gangat, Ayalew Tefferi
Journal: Blood (2017)
Abstract A43: Centrosome amplification favors survival and impairs ovarian cancer progression
Authors: Jean-Philippe Morretton, Aurelie Herbette, Camille Cosson, Bassirou Mboup, Aurelien Latouche, Pierre Gestraud, Tatiana Popova, Marc-Henri Stern, Fariba Nemati, Didier Decaudin, Guillaume Bataillon, Veronique Becette, Didier Meseure, Andre Nicolas, Odette Mariani, Claire Bonneau, Jorge Barbazan, Anne Vincent-Salomon, Fatima Mechta-Grigoriou, Sergio Roman-Roman, Roman Rouzier, Xavier Sastre-Garau, Oumou Goundiam, Renata Basto
Journal: Clinical Cancer Research (2020)

Abstract Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The most common subtype of EOC is high-grade serous (HGSOC), which responds at least initially to chemotherapy but has a worse overall prognosis. Genomic, transcriptomic, and proteogenomic profiling of HGSOC suggested a whole spectrum of molecular diversity, including homologous recombination pathway deficiencies (HRD). The centrosome is the main microtubule (MT)-organizing center of animal cells. It facilitates the accuracy of chromosome segregation during mitosis and influences cell polarity and migration. The presence of more than two centrosomes in a cell, centrosome amplification, has long been associated with tumorigenesis. However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. We screened 100 samples of primary EOCs including 88 HGSOC, using immunofluorescence and state-of-the-art microscopy, to determine the centrosome-nucleus index (CNI). We integrated these data with genomic alterations, HRD status, and patient outcome. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements, could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy, independently of HRD status. Using ovarian cancer cellular models to manipulate centrosome numbers and patient-derived xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit peritoneal cell dissemination. Citation Format: Jean-Philippe Morretton, Aurelie Herbette, Camille Cosson, Bassirou Mboup, Aurelien Latouche, Pierre Gestraud, Tatiana Popova, Marc-Henri Stern, Fariba Nemati, Didier Decaudin, Guillaume Bataillon, Veronique Becette, Didier Meseure, Andre Nicolas, Odette Mariani, Claire Bonneau, Jorge Barbazan, Anne Vincent-Salomon, Fatima Mechta-Grigoriou, Sergio Roman-Roman, Roman Rouzier, Xavier Sastre-Garau, Oumou Goundiam, Renata Basto. Centrosome amplification favors survival and impairs ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A43.
Abstract 331: Biology reconstructed: Testing immuno-oncology agents in tumor-specific 3D cell culture
Authors: Julia Kirshner, Mukti R. Parikh
Journal: Cancer Research (2020)

Abstract In recent years, immuno-oncology had emerged as a promising strategy to control tumor growth and spread. However, the advancement of immuno-oncology and development of immuno-oncology agents are hindered by the lack of in vitro models capable of supporting an intact immune compartment. Here we describe a tumor-specific 3D cell culture platform where the human tumor microenviroment is reconstructed ex vivo. Our patient-derived 3D culture approach comprehensively accounts for the major components of the cellular and extracellular tissue microenvironment preserving the critical interactions between tumors and their surroundings. Our 3D tumor-spectific models incorporate tissue-specific extracellular matrix(ces) (ECM) and tumor-specific medium supplements allowing for a true reconstruction of tumor microenvironment. The system is complete with the immune along with tumor and stromal, elements embedded within the tumor-specific ECM. Our platform retains the characteristics of the in vivo tissue demonstrating long-term viability, proliferation, and maintenance of the cellular heterogeneity appearing within the native microenvironment. Our approach is compatible with multiple classes of immuno-oncology agents from naked antibodies and antibody-drug conjugates, to bi- and tri-specific compounds, and CAR-T cells. The experimental set-up for testing immuno-oncology agents is comprized of 3 step: (1) embed tumor, stromal, and immune cells within the tissue-specific ECM and overlay with growth medium; (2) add the treatment agents to the culture medium and allow to infiltrate the ECM; and (3) evaluate the effects of the test agents either in situ, by microscopy and/or cell-based assays, or after isolation from the ECM by FACs and omics approaches. The rate of agent infiltration into the ECM was dependent on the therapeutic modality and was observed within 24-96 hours of treatment. Measurable T cell activation was detected at 48 hours post treatment and anti-tumor effects were evident within 5-9 days of exposure to therapeutic agents. Importantly, activation of the T cells in response to treatment occurred without exogenous priming. Taken together, this data position our 3D platform as a superior alternative to the currently used methods for testing of immuno-oncology agents. Citation Format: Julia Kirshner, Mukti R. Parikh. Biology reconstructed: Testing immuno-oncology agents in tumor-specific 3D cell culture [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 331.
Abstract 6367: KPG-818, a novel cereblon modulator, inhibits hematological malignancies in preclinical models
Authors: Chuansheng Ge, Baisong Liao, Lei Zhang
Journal: Cancer Research (2020)

Abstract The clinical use of lenalidomide in multiple myeloma (MM), mantle cell lymphoma (MCL) and myelodysplastic syndromes (MDS) represents a significant advance in the treatment of hematological malignancies and has altered the landscape of the blood cancer therapy. Yet, many hematological indications and refractory diseases are still without effective systemic and curative therapies. Here we present KPG-818, a small molecule compound with high affinity binding to cereblon of the E3 ubiquitin ligase (CRBN-CRL4) complex, significantly inhibits the production of the pre-inflammatory cytokines such as TNF-α and IL-6 in LPS-stimulated human PBMC cells, inhibits HUVEC tube formation, and exhibits potent anti-proliferation in multiple lymphoma and multiple myeloma cell lines in vitro. Consistent with the finding in that lenalidomide causes selective degradation of Aiolos and Ikaros, KPG-818 potently inhibits the level of the two lymphoid transcription factors in MM1.S cell line model and human PBMC cells. In in vivo pharmacology studies, KPG-818 significantly inhibits tumor growth in MM.1S multiple myeloma, WSU-DLCL-2 diffuse large B cell lymphoma, DOHH-2 follicular lymphoma, REC-1 mantle cell lymphoma xenograft models. Importantly, KPG-818 prolongs the survival of the mouse cohorts bearing systemic human H929 multiple myeloma in a dose-dependent manner. Moreover, KPG-818 shows favorable DMPK and toxicity profiles in pre-clinical IND enabling studies. In summary, these immune modulation, anti-angiogenesis and antitumor results encourage the further clinical evaluation of KPG-818 in patients with Multiple Myeloma, Diffuse Large B Cell Lymphoma, Follicular Lymphoma, Mantle Cell Lymphoma and other hematological malignancies. Citation Format: Chuansheng Ge, Baisong Liao, Lei Zhang. KPG-818, a novel cereblon modulator, inhibits hematological malignancies in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6367.
Colchicine in Patients with Chronic Coronary Disease
Authors: Stefan M. Nidorf, Aernoud T.L. Fiolet, Arend Mosterd, John W. Eikelboom, Astrid Schut, Tjerk S.J. Opstal, Salem H.K. The, Xiao-Fang Xu, Mark A. Ireland, Timo Lenderink, Donald Latchem, Pieter Hoogslag, Anastazia Jerzewski, Peter Nierop, Alan Whelan, Randall Hendriks, Henk Swart, Jeroen Schaap, Aaf F.M. Kuijper, Maarten W.J. van Hessen, Pradyot Saklani, Isabel Tan, Angus G. Thompson, Allison Morton, Chris Judkins, Willem A. Bax, Maurits Dirksen, Marco Alings, Graeme J. Hankey, Charley A. Budgeon, Jan G.P. Tijssen, Jan H. Cornel, Peter L. Thompson
Journal: New England Journal of Medicine (2020)

Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited.
Analysis of safety benefits and security concerns from the use of autonomous vehicles: A grouped random parameters bivariate probit approach with heterogeneity in means
Authors: Sheikh Shahriar Ahmed, Sarvani Sonduru Pantangi, Ugur Eker, Grigorios Fountas, Stephen E. Still, Panagiotis Ch. Anastasopoulos
Journal: Analytic Methods in Accident Research (2020)
Effect of Intraoperative Low Tidal Volume vs Conventional Tidal Volume on Postoperative Pulmonary Complications in Patients Undergoing Major Surgery
Authors: Dharshi Karalapillai, Laurence Weinberg, Philip Peyton, Louise Ellard, Raymond Hu, Brett Pearce, Chong O. Tan, David Story, Mark O’Donnell, Patrick Hamilton, Chad Oughton, Jonathan Galtieri, Anthony Wilson, Ary Serpa Neto, Glenn Eastwood, Rinaldo Bellomo, Daryl A. Jones
Journal: JAMA (2020)

<h3>Importance</h3> In patients who undergo mechanical ventilation during surgery, the ideal tidal volume is unclear. <h3>Objective</h3> To determine whether low-tidal-volume ventilation compared with conventional ventilation during major surgery decreases postoperative pulmonary complications. <h3>Design, Setting, and Participants</h3> Single-center, assessor-blinded, randomized clinical trial of 1236 patients older than 40 years undergoing major noncardiothoracic, nonintracranial surgery under general anesthesia lasting more than 2 hours in a tertiary hospital in Melbourne, Australia, from February 2015 to February 2019. The last date of follow-up was February 17, 2019. <h3>Interventions</h3> Patients were randomized to receive a tidal volume of 6 mL/kg predicted body weight (n = 614; low tidal volume group) or a tidal volume of 10 mL/kg predicted body weight (n = 592; conventional tidal volume group). All patients received positive end-expiratory pressure (PEEP) at 5 cm H<sub>2</sub>O. <h3>Main Outcomes and Measures</h3> The primary outcome was a composite of postoperative pulmonary complications within the first 7 postoperative days, including pneumonia, bronchospasm, atelectasis, pulmonary congestion, respiratory failure, pleural effusion, pneumothorax, or unplanned requirement for postoperative invasive or noninvasive ventilation. Secondary outcomes were postoperative pulmonary complications including development of pulmonary embolism, acute respiratory distress syndrome, systemic inflammatory response syndrome, sepsis, acute kidney injury, wound infection (superficial and deep), rate of intraoperative need for vasopressor, incidence of unplanned intensive care unit admission, rate of need for rapid response team call, intensive care unit length of stay, hospital length of stay, and in-hospital mortality. <h3>Results</h3> Among 1236 patients who were randomized, 1206 (98.9%) completed the trial (mean age, 63.5 years; 494 [40.9%] women; 681 [56.4%] undergoing abdominal surgery). The primary outcome occurred in 231 of 608 patients (38%) in the low tidal volume group compared with 232 of 590 patients (39%) in the conventional tidal volume group (difference, −1.3% [95% CI, −6.8% to 4.2%]; risk ratio, 0.97 [95% CI, 0.84-1.11];<i>P</i> = .64). There were no significant differences in any of the secondary outcomes. <h3>Conclusions and Relevance</h3> Among adult patients undergoing major surgery, intraoperative ventilation with low tidal volume compared with conventional tidal volume, with PEEP applied equally between groups, did not significantly reduce pulmonary complications within the first 7 postoperative days. <h3>Trial Registration</h3> ANZCTR Identifier:ACTRN12614000790640
Abstract 3765: c-Kit mediated phosphorylation of Spred1 regulates Neurofibromin-Spred1 interaction
Authors: Claire Lorenzo, Lucy C. Young, Alexandra Tannka, Anatoly Urisman, Frank McCormick
Journal: Cancer Research (2020)

Abstract Spred1 negatively regulates Ras/MAPK signaling following growth factor stimulation. Spred1 inhibits Ras by binding and localizing Neurofibromin, a RasGAP, to the plasma membrane to accelerate Ras GTPase activity. c-Kit, a receptor tyrosine kinase (RTK), is known to interact with Spred1 but the consequence of this interaction is unknown. Here we demonstrate that c-Kit signaling regulates Neurofibromin-Spred1 interaction. Stimulation with c-Kit ligand, SCF, results in a transient disruption in Neurofibromin-Spred1 binding which corresponds to increased Ras signaling, followed by restoration of Neurofibromin-Spred binding which corresponds to nearly basal levels of Ras signaling. Mass spectrometry analysis identified potential phosphorylation sites on Spred1 that correspond to the initial disruption and later restoration of Neurofibromin-Spred1 binding. Phosphomimetic and phosphodeficient mutants affect the interaction. Our findings provide a potential mechanism by which RTK signaling regulates negative feedback to allow transient activation and subsequent termination of Ras signaling. Citation Format: Claire Lorenzo, Lucy C. Young, Alexandra Tannka, Anatoly Urisman, Frank McCormick. c-Kit mediated phosphorylation of Spred1 regulates Neurofibromin-Spred1 interaction [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3765.
Abstract 4432: scMAGeCK links genotypes with multiple phenotypes in single-cell CRISPR screens
Authors: Lin Yang, Yuqing Zhu, Hua Yu, Xiaolong Cheng, Sitong Chen, Yulan Chu, He Huang, Jin Zhang, Wei Li
Journal: Cancer Research (2020)

Abstract We present scMAGeCK, a computational framework to identify genomic elements associated with multiple expression-based phenotypes in CRISPR/Cas9 functional screening that uses single-cell RNA-seq as readout. scMAGeCK outperforms existing methods, identifies genes and enhancers with known and novel functions in cell proliferation, and enables an unbiased construction of genotype-phenotype network. Single-cell CRISPR screening on mouse embryonic stem cells identifies key genes associated with different pluripotency states. Applying scMAGeCK on multiple datasets, we identify key factors that improve the power of single-cell CRISPR screening. Collectively, scMAGeCK is a novel tool to study genotype-phenotype relationships at a single-cell level. Citation Format: Lin Yang, Yuqing Zhu, Hua Yu, Xiaolong Cheng, Sitong Chen, Yulan Chu, He Huang, Jin Zhang, Wei Li. scMAGeCK links genotypes with multiple phenotypes in single-cell CRISPR screens [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4432.
Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies
Authors: Jingwen Si, Xiangjun Shi, Shuhao Sun, Bin Zou, Yaopeng Li, Dongjie An, Xingyu Lin, Yan Gao, Fei Long, Bo Pang, Xing Liu, Tian Liu, Wenna Chi, Ligong Chen, Dimiter S. Dimitrov, Yan Sun, Xinru Du, Wen Yin, Guangxun Gao, Junxia Min, Lai Wei, Xuebin Liao
Journal: Cancer Cell (2020)

Ameliorating T cell exhaustion and enhancing effector function are promising strategies for the improvement of immunotherapies. Here, we show that the HPK1-NFκB-Blimp1 axis mediates T cell dysfunction. High expression of MAP4K1 (which encodes HPK1) correlates with increased T cell exhaustion and with worse patient survival in several cancer types. In MAP4K1KO mice, tumors grow slower than in wild-type mice and infiltrating T cells are less exhausted and more active and proliferative. We further show that genetic depletion, pharmacological inhibition, or proteolysis targeting chimera (PROTAC)-mediated degradation of HPK1 improves the efficacy of CAR-T cell-based immunotherapies in diverse preclinical mouse models of hematological and solid tumors. These strategies are more effective than genetically depleting PD-1 in CAR-T cells. Thus, we demonstrate that HPK1 is a mediator of T cell dysfunction and an attractive druggable target to improve immune therapy responses.