tbuckley/cabot-search huggingface dataset:
Abstract 1954: Identifying synthetic lethality with novel CDK2 small molecule inhibitors via integration of high-content microscopy and -omics level platforms
Authors: Tim Sen Wang, Jon Almaden, Chen Shen, John Lapek, Sherry Niessen, Nichol Miller, Stephen Dann, Todd VanArsdale
Journal: Cancer Research (2021)

Abstract CDK4/6 small molecule inhibitors represent a milestone in treating hormone receptor-positive breast cancer. PALOMA (Palbociclib: Ongoing Trials in the Management of Breast Cancer) studies have confirmed prolonged progression-free survival after CDK4/6 inhibitor and anti-estrogen therapy. Notably, disease progression is observed in a subset of patients receiving Palbociclib-Fulvestrant treatment (Turner et al., NEJM 2018). Circulating tumor DNA from PALOMA-3 patients revealed genetic mutations correlating with patient response (O'Leary et al., Cancer Discov, 2018). Compensations in CDK4/6i resistance include circumvention of CDK4/6 substrate regulation, CCNE1/2 amplification (Herrera-Abreu et al., Cancer Res. 2016), and compensatory CDK2 activity. The importance of compensatory CDK2 cancer re-wiring is highlighted by recently reported, highly efficacious CDK2/4/6i (Freeman-Cook et al., in review). Thus, mechanistic understanding of cancer cell and compensatory CDK2 activity is imperative to improve patient outcome. Acute, temporal phenotypes in CDK2-signaling have been observed by live single-cell tracking microscopy in human breast epithelial and ER+ breast cancer cells (Arora &amp; Moser et al., in review). In extending these studies, we utilize first-in-class small molecule inhibitors against CDK2 combined with high content imaging approaches to illuminate cancer cell CDK2 signaling and identify potential synthetic lethality. We report biomarkers parsed in cycling populations as quantifiable phenotypes and identify disengaged control of several processes including S- and G2/M licensing after CDK2i. Combined with internal -omics studies, CDK2i selective molecules support a positive regulatory role of CDK2 on CCNB1-PLK1 signaling before mitotic entry. We combine our high-content techniques with proximity labeling to quantify alternative CDK-Cyclin complex formation following pharmacologic perturbation. We hypothesize that dysregulated CDK-Cyclin complex formation elicits unintended CDK2 kinase activity, revealing potential synthetic lethality with inhibition of centrosome duplication pathways in ER+ breast cancers. Citation Format: Tim Sen Wang, Jon Almaden, Chen Shen, John Lapek, Sherry Niessen, Nichol Miller, Stephen Dann, Todd VanArsdale. Identifying synthetic lethality with novel CDK2 small molecule inhibitors via integration of high-content microscopy and -omics level platforms [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 1954.
Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials
Authors: Carsten Denkert, Fenja Seither, Andreas Schneeweiss, Theresa Link, Jens-Uwe Blohmer, Marianne Just, Pauline Wimberger, Almuth Forberger, Hans Tesch, Christian Jackisch, Sabine Schmatloch, Mattea Reinisch, Erich F Solomayer, Wolfgang D Schmitt, Claus Hanusch, Peter A Fasching, Kristina Lübbe, Christine Solbach, Jens Huober, Kerstin Rhiem, Frederik Marmé, Toralf Reimer, Marcus Schmidt, Bruno V Sinn, Wolfgang Janni, Elmar Stickeler, Laura Michel, Oliver Stötzer, Eric Hahnen, Jenny Furlanetto, Sabine Seiler, Valentina Nekljudova, Michael Untch, Sibylle Loibl
Journal: The Lancet Oncology (2021)
Discriminatory plasma biomarkers predict specific clinical phenotypes of necrotizing soft-tissue infections
Authors: Laura M. Palma Medina, Eivind Rath, Sanjeevan Jahagirdar, Trond Bruun, Martin B. Madsen, Kristoffer Strålin, Christian Unge, Marco Bo Hansen, Per Arnell, Michael Nekludov, Ole Hyldegaard, Magda Lourda, Vitor A.P. Martins dos Santos, Edoardo Saccenti, Steinar Skrede, Mattias Svensson, Anna Norrby-Teglund
Journal: Journal of Clinical Investigation (2021)

BACKGROUNDNecrotizing soft-tissue infections (NSTIs) are rapidly progressing infections frequently complicated by septic shock and associated with high mortality. Early diagnosis is critical for patient outcome, but challenging due to vague initial symptoms. Here, we identified predictive biomarkers for NSTI clinical phenotypes and outcomes using a prospective multicenter NSTI patient cohort.METHODSLuminex multiplex assays were used to assess 36 soluble factors in plasma from NSTI patients with positive microbiological cultures (n = 251 and n = 60 in the discovery and validation cohorts, respectively). Control groups for comparative analyses included surgical controls (n = 20), non-NSTI controls (i.e., suspected NSTI with no necrosis detected upon exploratory surgery, n = 20), and sepsis patients (n = 24).RESULTSThrombomodulin was identified as a unique biomarker for detection of NSTI (AUC, 0.95). A distinct profile discriminating mono- (type II) versus polymicrobial (type I) NSTI types was identified based on differential expression of IL-2, IL-10, IL-22, CXCL10, Fas-ligand, and MMP9 (AUC >0.7). While each NSTI type displayed a distinct array of biomarkers predicting septic shock, granulocyte CSF (G-CSF), S100A8, and IL-6 were shared by both types (AUC >0.78). Finally, differential connectivity analysis revealed distinctive networks associated with specific clinical phenotypes.CONCLUSIONSThis study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs.TRIAL REGISTRATIONClinicalTrials.gov NCT01790698.FUNDINGCenter for Innovative Medicine (CIMED); Region Stockholm; Swedish Research Council; European Union; Vinnova; Innovation Fund Denmark; Research Council of Norway; Netherlands Organisation for Health Research and Development; DLR Federal Ministry of Education and Research; and Swedish Children's Cancer Foundation.
Abstract 3079: The antitumoral activity of metformin in glioblastoma stem cells is mediated by tmCLIC1 protein
Authors: Ivan Verduci, Francesca Cianci, Gaetano Cannavale, Stefania Castiglione, Matteo Ranucci, Michele Mazzanti
Journal: Cancer Research (2021)

Abstract Glioblastoma (GB) is the deadliest brain tumor, representing a major clinical challenge in the field. Despite standard of care together with cutting-edge strategies, life expectancy stands invariantly poor. Tumor heterogeneity and its high-grade of invasiveness make it difficult to be surgically resected and recurrence is inevitable. There is scientific consensus that tumor relapse originates from progenitor/stem-like cells known as glioblastoma stem cells (GSCs) displaying properties of self-renewal and multi-lineage differentiation that contribute to tumor mass heterogeneity. Thus, GSCs represent the target of newly designed therapies. In recent years, it has been highlighted the anti-cancer properties of metformin, the first-line drug in Type-2 diabetes (T2D) treatment. Metformin assumption in T2D patients has been positively linked with a decrease in the risk of several cancer types and cancer-related mortality, including glioblastoma. Additionally, numerous studies demonstrated metformin's anticancer properties against GSCs. Despite metformin's mechanism of action on cancer cells has not been clarified yet, its effect has been proposed to target the oxidative phosphorylation (OXPHOS) pathway. Considering that GSCs have been reported to shuttle between glycolysis and OXPHOS energetic pathways, their metabolic plasticity should prevent the antiproliferative effect of metformin. However, metformin-treated GSCs show a phenotype superimposable to that caused by the blockage of the transmembrane form of the chloride intracellular channel 1 (tmCLIC1). tmCLIC1 involvement in the progression of GB has been assessed deeply in vitro as well as in vivo. In addition, its peculiar localization and enrichment on GSCs' membrane renders it a valuable pharmacological target for GB. The goal of the present work is to attest tmCLIC1 as the solely interactor with metformin in glioblastoma stem cells. Ivan Verduci was supported by a AIRC fellowship for Italy. Citation Format: Ivan Verduci, Francesca Cianci, Gaetano Cannavale, Stefania Castiglione, Matteo Ranucci, Michele Mazzanti. The antitumoral activity of metformin in glioblastoma stem cells is mediated by tmCLIC1 protein [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 3079.
Performance comparison between computer-software-based fusion versus cognitive fusion technique in biopsy-naïve patients: A single-center analysis
Authors: R.G. Bertolo, V. Forte, C. Cipriani, M. Vittori, A. Cavallo, V. Iacovelli, M. Antonucci, F. Petta, M. Panei, M. Sperandio, P. Bove
Journal: European Urology (2021)
Aggregating Electronic Health Record Data for COVID-19 Research—Caveat Emptor
Authors: Jeffrey S. Brown, Lisa Bastarache, Mark G. Weiner
Journal: JAMA Network Open (2021)

Tellen D. Bennett, MD; Richard A. Moffitt, PhD; Janos G. Hajagos, PhD; Benjamin Amor, PhD; Adit Anand; Mark M. Bissell; Katie Rebecca Bradwell, PhD; Carolyn Bremer, BS; James Brian Byrd, MD; Alina Denham, PhD; Peter E. DeWitt, PhD; Davera Gabriel, RN; Brian T. Garibaldi, MD; Andrew T. Girvin, PhD; Justin Guinney, PhD; Elaine L. Hill, PhD; Stephanie S. Hong, BS; Hunter Jimenez, BS; Ramakanth Kavuluru, PhD; Kristin Kostka, MPH; Harold P. Lehmann, MD; Eli Levitt, MS; Sandeep K. Mallipattu, MD; Amin Manna, MEng; Julie A. McMurry, MPH; Michele Morris, BA; John Muschelli, PhD; Andrew J. Neumann, MBA; Matvey B. Palchuk, MD; Emily R. Pfaff, PhD; Zhenglong Qian, BS; Nabeel Qureshi, BA; Seth Russell, MS; Heidi Spratt, PhD; Anita Walden, MS; Andrew E. Williams, PhD; Jacob T. Wooldridge, MD; Yun Jae Yoo; Xiaohan Tanner Zhang, MD; Richard L. Zhu, MD; Christopher P. Austin, MD; Joel H. Saltz, MD; Ken R. Gersing, MD; Melissa A. Haendel, PhD; Christopher G. Chute, MD; National COVID Cohort Collaborative (N3C) Consortium; Joel Gagnier; Siqing Hu; Kanchan Lota; Sarah Maidlow; David A. Hanauer; Kevin Weatherwax; Nikhila Gandrakota; Rishikesan Kamaleswaran; Greg Martin; Jingjing Qian; Jason E. Farley; Patricia A. Francis; Dazhi Jiao; Hadi Kharrazi; Justin T. Reese; Mariam Deacy; Usman Sheikh; Jake Chen; Michael Patton; Thomas Ramsey; Jasvinder Singh; James J. Cimino; Jing Su; William G Adams; Tim Duong; John B. Buse; Jessica Yasmine Islam; Jihad S. Obeid; Stephane Meystre; Steve Patterson; Misha Zemmel; Ron Grider; Ashley Martinez; Carlos Santos; Julian Solway; Ryan Chiu; Gerald B. Brown; Jiafeng Cui; Sharon Liang; Kamil Khanipov; Jeremy Richard Harper; Peter J. Embi; David A. Eichmann; Boyd M. Knosp; William Hillegass; Chunlei Wu; James Aaron; Darren Henderson; Muhammad Gul; Tamela Harper; Daniel Harris; Jeff Talbert; Neil Bahroos; Steven Dubinett; Jomol Mathew; Gabriel McMahan; Hongfang Liu; Claudia Lucchinetti; David L Schwartz; Ralph Sacco; Peyman Taghioff; Diane Harper; Denise Angst; Andrew Marek; Carlos E. Figueroa Castro; Bruce Blazar; Steven G. Johnson; Melissa Basford; Laura Jones; Gordon Bernard; Rosalind Wright; Joseph Finkelstein; Thomas R. Campion Jr.; Christopher E. Mason; Xiaobo Fuld; Alfred Anzalone; James C. McClay; Shyam Visweswaran; Connor Cook; Alexandra Dest; David Ellison; Rose Relevo; Andrea M. Volz; Chengda Zhang; Martha Tenzer; David S. Bowers; Francis Farrell; Qiuyuan Qin; Martin Zand; Jeanne Holden-Wiltse; Ramkiran Gouripeddi; Julio Facelli; Robert Clark; Benjamin Becerra; Yao Yan; Jimmy Phuong; Yooree Chae; Rena C. Patel; Christine Suver; Elizabeth Zampino; Ahmed S. Said; Philip R.O. Payne; Randeep Jawa; Peter L. Elkin; Farrukh M Koraishy; George Golovko; Vignesh Subbian; Daniel Weisdorf; Lawrence Sinoway; Hiroki Morizono; Keith A. Crandall; Ali Rahnavard; Nawar Shara; Alysha Taxter; Brian Ostasiewski; Qianqian Song; Uma Maheswara Reddy Vangala; Katherine Ruiz De Luzuriaga; Rasha Khatib; John Kirwan; James von Oehsen; Jason Moore; Ankit Sakhuja; Joni Rutter
統合されたscRNA-Seqは,ヒト出生後Thymus播種前駆細胞を識別し,未熟胸腺細胞分化の調節性動態を同定する【JST・京大機械翻訳】
Authors: Lavaert Marieke, Liang Kai Ling, Vandamme Niels, Park Jong-Eun, Roels Juliette, S Kowalczyk Monica, Li Bo, Ashenberg Orr, Tabaka Marcin, Dionne Danielle, L Tickle Timothy, Slyper Michal, Rozenblatt-Rosen Orit, Vandekerckhove Bart, Leclercq Georges, Regev Aviv, Van Vlierberghe Pieter, Guilliams Martin, A Teichmann Sarah, Saeys Yvan, Taghon Tom
Journal: Immunity (2020)
Identifying the most informative cut-off of psa to define biochemical recurrence after radical prostatectomy: A stage-by-stage analysis
Authors: L. Nocera, G. Gandaglia, N. Fossati, A. Stabile, V. Cucchiara, E. Mazzone, C.A. Bravi, G. Rosiello, G. Sorce, F. Pellegrino, S. Scuderi, F. Barletta, G. Cirulli, R. Colombo, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Abstract 629: Flavonoids are NR4A1 antagonists and target PAX3-FOXO1 and G9a in alveolar rhabdomyosarcoma cells
Authors: Rupesh Shrestha, Kumaravel Mohankumar, Gregory Martin, Stephen Safe
Journal: Cancer Research (2021)

Abstract Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma that is primarily observed in children and adolescent, and accounts for 50% of soft tissue sarcomas in children. There are two major forms of RMS, namely embryonal RMS (ERMS) and alveolar RMS (ARMS) and these tumors are readily distinguished by their histological and genomic characteristics. ERMS patients have a better prognosis than ARMS patients and both groups undergo radiation, surgical and chemotherapeutic regiments. Many ARMS patients express different oncogenes including the histone methyltransferase G9a and the PAX3-FOXO1 fusion gene that contribute to ARMS cell growth, survival and migration/invasion. Studies in this laboratory have demonstrated that both G9a and PAX3-FOXO1 are regulated by the orphan nuclear receptor 4A1 (NR4A1) and can be targeted by bis-indole derived (CDIMs) NR4A1 antagonists. A recent study showed that the flavonoid kaempferol decreased G9a expression in gastric cancer cells and we hypothesized that kaempferol may be an NR4A1 ligand. Kamepferol and quercetin were used as models and both compounds bound NR4A1 at low μM concentrations and decreased NR4A1-dependent transactivation in ARMS cells. Functional studies showed that like CDIM/NR4A1 ligands, kaempferol and quercetin decrease ARMS cell growth, survival and migration/invasion, consistent with their activity as antagonists and inhibitors of NR4A1 regulated pro-oncogenic functions. In addition, kaempferol and quercetin also decreased expression of G9a, PAX3-FOXO1 and downstream genes regulated by them in ARMS cells further demonstrating their activity as NR4A1 antagonists. These results suggest that NR4A1-active flavonoids could be readily incorporated into chemotherapies used for treatment of ARMS patients to improve their efficacy and decrease the toxic side-effects of currently used cytotoxic drugs. Citation Format: Rupesh Shrestha, Kumaravel Mohankumar, Gregory Martin, Stephen Safe. Flavonoids are NR4A1 antagonists and target PAX3-FOXO1 and G9a in alveolar rhabdomyosarcoma cells [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 629.
Abstract 16839: GLUT-12: A Novel Insulin-Sensitive Glucose Transporter in the Heart?
Authors: Amanda Waller, Anuradha Kalyanasundaram, Muthu Periasamy, Veronique A Lacombe
Journal: Circulation (2011)

The heart is one of the main organs to utilize glucose. Glucose uptake from the bloodstream, the rate-limiting step in whole body glucose utilization, is regulated by a family of membrane proteins called glucose transporters (GLUTs). Although GLUT4 is the predominant isoform in insulin-sensitive tissues, there is recent evidence that GLUT12 could be a novel second insulin-sensitive GLUT in skeletal muscle. However, its role in the heart is not known, as well as the regulation of insulin-stimulated myocardial GLUT12 trafficking to the cell surface. Finally, despite intensive research, the pathogenic cause of altered glucose transport observed during diabetes remains elusive, and the role of GLUT12 has never been investigated in the diabetic myocardium. Thus, we hypothesized that, as for GLUT4, insulin will regulate GLUT12 translocation to the myocardial cell surface, which will be impaired during diabetes. To test our hypothesis, mice were made diabetic (insulin deficient) by streptozotocin injection and compared to their respective healthy littermates (n=9-12/group). Active cell surface GLUT (4 &amp; 12) content was quantified by a biotinylated photolabeled assay in the intact perfused myocardium (with or without insulin stimulation). To our knowledge, we are the first to apply this technique to GLUT12. Total GLUT (4 &amp; 12) protein expression and Akt substrate of 160 kDa (AS160, the most distal signaling protein implicated in GLUT trafficking) were measured by Western blot. Insulin stimulation significantly increased translocation of GLUT-4, but not -12, in the heart of healthy mice. Active cell surface GLUT12 was significantly increased in the diabetic myocardium, potentially as a compensatory mechanism for the observed downregulation of active GLUT4. Total cardiac GLUT4 content, but not GLUT12, was decreased during diabetes. Changes in GLUT trafficking were not associated with alterations in total or phosphorylated AS160, suggesting that AS160 is not a major pathogenic factor in the heart during insulin-dependent diabetes. Overall our data suggest that, in contrast to GLUT4, the insulin-signaling pathway does not mediate myocardial translocation of GLUT12. Thus, in the heart, GLUT12 may function as a basal GLUT located primarily at the cell surface.
Abstract 684: Effects of preventive interventions on radiotherapy-induced skin toxicity in women with breast cancer: A systematic review and meta-analysis of randomized controlled trials
Authors: Claudia R. Figueroa, Rose N. Gelin, Sereen J. Khourshid, Eunkyung Lee
Journal: Cancer Research (2021)

Abstract Radiation therapy (RT)-induced skin toxicity occurs in 95% of patients undergoing RT for breast cancer. Severe cases can interrupt the original treatment regimen and affect many individuals' overall treatment efficacy and quality of life. Many interventions have been tested for the prevention of RT-induced skin toxicity; however, there are no standard recommendations yet determined. This meta-analysis aimed to evaluate the effect of different preventive interventions for RT-induced skin toxicity among breast cancer patients. We searched PubMed, Web of Science, CINAHL, and PsycINFO databases for randomized controlled trials (RCTs) meeting the inclusion criteria and published until December 2019 following the PRISMA reporting guidelines and the PICO statements. The intervention's effect on the incidence of grade ≥2 acute skin toxicity, moist desquamation, and severity score was estimated using the random-effects meta-analyses. Among 6885 publications identified, 38 studies were included in analyses. A total of 3,380 women age 42-88 years diagnosed with stage 0-III who were undergoing RT for breast cancer from all over the world were included. Identified preventive interventions included non-steroid topical agents, topical steroid agents, oral supplements, laser therapy, and films. The meta-analyses showed that interventions significantly reduced the mean severity score by 0.64 (standardized mean difference=-0.64, 95% CI=-0.85, -0.43; I2=57.6%), the incidence of grade ≥2 skin toxicity by 18% (Risk ratio [RR]=0.82, 95% CI=0.74, 0.90; I2=68.4%), and moist desquamation by 55% (RR=0.45, 95% CI=0.27-0.77, I2=48.2%). Subgroup analyses showed that oral supplements were most promising in preventing grade ≥2 skin toxicity (RR=0.32, 95% CI=0.07-1.34, I2=83.1%), suggesting further replications are needed before definitive conclusions are made. This analysis provided evidence of the effectiveness of interventions on the prevention of RT-induced skin toxicity. The effect was greater in reducing the incidence of more severe cases of moist desquamation. More replicative studies are needed to establish the standard preventive care of RT-induced skin toxicity for women with breast cancer, which can help patients comply with RT regimens and improve patients' quality of life. Citation Format: Claudia R. Figueroa, Rose N. Gelin, Sereen J. Khourshid, Eunkyung Lee. Effects of preventive interventions on radiotherapy-induced skin toxicity in women with breast cancer: A systematic review and meta-analysis of randomized controlled trials [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 684.
Open your mind without leaving your sofa
Authors: Nikki Nabavi
Journal: BMJ (2021)

As we head towards the end of term and the summer holidays, many of you will have had electives or other travel plans cancelled as a result of the ongoing pandemic (doi:10.1136/bmj.n1577). With a hotel quarantine system that is not fit for purpose (https://blogs.bmj.com/bmj/2021/06/04/the-uks-hotel-quarantine-system-is-not-fit-for-purpose/) and a traffic light system that risks letting new variants into the UK (https://blogs.bmj.com/bmj/2021/05/12/covid-19-travel-plan-will-let-new-variants-into-the-uk/), you might be better off learning about other cultures by reading our series Day in the life of a medical student, which includes this interview with Catarina Rodrigues, a sixth year …