tbuckley/cabot-search huggingface dataset:
JMJD6 Is a Druggable Oxygenase That Regulates AR-V7 Expression in Prostate Cancer
Authors: Alec Paschalis, Jonathan Welti, Antje J. Neeb, Wei Yuan, Ines Figueiredo, Rita Pereira, Ana Ferreira, Ruth Riisnaes, Daniel Nava Rodrigues, Juan M. Jiménez-Vacas, Soojin Kim, Takuma Uo, Patrizio Di Micco, Anthony Tumber, Md. Saiful Islam, Marc A. Moesser, Martine Abboud, Akane Kawamura, Bora Gurel, Rossitza Christova, Veronica S. Gil, Lorenzo Buroni, Mateus Crespo, Susana Miranda, Maryou B. Lambros, Suzanne Carreira, Nina Tunariu, Andrea Alimonti, Bissan Al-Lazikani, Christopher J. Schofield, Stephen R. Plymate, Adam Sharp, Johann S. de Bono
Journal: Cancer Research (2021)

Abstract Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P &amp;lt; 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. Significance: This study identifies JMJD6 as being critical for the generation of AR-V7 in prostate cancer, where it may serve as a tractable target for therapeutic intervention.
Abstract PS17-25: Repurposing anti-depressant imipramine for treating breast cancers
Authors: Santosh Timilsina, Subapriya Rajamanickam, Arhan Rao, Panneerdoss Subbarayalu, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia G Kaklamani, Manjeet Rao
Journal: Cancer Research (2021)

Abstract About 1 in 8 women will develop invasive breast cancer during their life time and more than 41,000 women die every year in the United States alone. Most of these deaths are attributed to relapse, distant metastasis and therapy resistance. For example, despite initial response to therapy, a significant proportion of ER+ BCs become therapy resistant and progress to incurable metastases. Similarly, TNBCs, which is highly aggressive and are more likely to occur in Hispanic and black women, have higher propensity to relapse and contribute to disproportionate number of deaths. Unfortunately, the patients who do survive, have reduced quality of life due to the chemotherapy-associated toxicity. One mechanism that helps BCs to survive and become therapy-resistant is their unique ability to keep repairing their DNA. The aim of this study was to identify and test whether any FDA-approved non-cancer drug/s can block DNA repair ability and consequently growth of BC cells. Treatment of BC cells with a set of FDA approved drugs showed that antidepressants imipramine can inhibit the BC cell growth. Imipramine treatment significantly reduced the short and long-term viability of TNBC and ER+ breast cancer cells. Further, imipramine treatment inhibited the migration and invasion of breast cancer cells. Systemic delivery of imipramine suppressed the breast cancer cells growth in orthotopic mouse xenograft model. Our results revealed that imipramine treatment induced G1/S cell cycle arrest and apoptosis in breast cancer cells. Importantly, imipramine blocked the DNA repair capacity of BC cells by inhibiting the expression of DNA repair proteins including FOXM1 and RAAD51. Notably, imipramine treatment improved the efficacy of the PARP inhibitor “olapraib” in TNBC and sensitized the tamoxifen response in tamoxifen resistant ER+ breast cancer cells. Our results suggest that imipramine can be used as a single or therapeutic adjuvant for treating therapy sensitive and therapy resistant breast cancers. Based on these results, we are currently conducting a clinical trial to test the therapeutic efficacy of imipramine for treating breast cancer patients (https://www.cancer.gov/about-cancer/treatment/clinical-trials/search/v?id=NCI-2017 01937&amp;r=1). Citation Format: Santosh Timilsina, Subapriya Rajamanickam, Arhan Rao, Panneerdoss Subbarayalu, Ismail Jatoi, Yidong Chen, Ratna Vadlamudi, Virginia G Kaklamani, Manjeet Rao. Repurposing anti-depressant imipramine for treating breast cancers [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-25.
Exercise triggers CAPN1-mediated AIF truncation, inducing myocyte cell death in arrhythmogenic cardiomyopathy
Authors: Stephen P. Chelko, Gizem Keceli, Andrea Carpi, Nunzianna Doti, Jacopo Agrimi, Angeliki Asimaki, Carlos Bueno Beti, Matthew Miyamoto, Nuria Amat-Codina, Djahida Bedja, An-Chi Wei, Brittney Murray, Crystal Tichnell, Chulan Kwon, Hugh Calkins, Cynthia A. James, Brian O’Rourke, Marc K. Halushka, Edon Melloni, Jeffrey E. Saffitz, Daniel P. Judge, Menotti Ruvo, Richard N. Kitsis, Peter Andersen, Fabio Di Lisa, Nazareno Paolocci
Journal: Science Translational Medicine (2021)

Myocyte death occurs in many inherited and acquired cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM), a genetic heart disease plagued by the prevalence of sudden cardiac death. Individuals with ACM and harboring pathogenic desmosomal variants, such as desmoglein-2 (DSG2), often show myocyte necrosis with progression to exercise-associated heart failure. Here, we showed that homozygous Dsg2 mutant mice (Dsg2 mut/mut), a model of ACM, die prematurely during swimming and display myocardial dysfunction and necrosis. We detected calcium (Ca2+) overload in Dsg2 mut/mut hearts, which induced calpain-1 (CAPN1) activation, association of CAPN1 with mitochondria, and CAPN1-induced cleavage of mitochondrial-bound apoptosis-inducing factor (AIF). Cleaved AIF translocated to the myocyte nucleus triggering large-scale DNA fragmentation and cell death, an effect potentiated by mitochondrial-driven AIF oxidation. Posttranslational oxidation of AIF cysteine residues was due, in part, to a depleted mitochondrial thioredoxin-2 redox system. Hearts from exercised Dsg2 mut/mut mice were depleted of calpastatin (CAST), an endogenous CAPN1 inhibitor, and overexpressing CAST in myocytes protected against Ca2+ overload-induced necrosis. When cardiomyocytes differentiated from Dsg2 mut/mut embryonic stem cells (ES-CMs) were challenged with β-adrenergic stimulation, CAPN1 inhibition attenuated CAPN1-induced AIF truncation. In addition, pretreatment of Dsg2 mut/mut ES-CMs with an AIF-mimetic peptide, mirroring the cyclophilin-A (PPIA) binding site of AIF, blocked PPIA-mediated AIF-nuclear translocation, and reduced both apoptosis and necrosis. Thus, preventing CAPN1-induced AIF-truncation or barring binding of AIF to the nuclear chaperone, PPIA, may avert myocyte death and, ultimately, disease progression to heart failure in ACM and likely other forms of cardiomyopathies.
Abstract 11832: Concomitant Small-Conductance Calcium-Activated Potassium Current Activation and Sodium Current Inhibition Cause J Wave Syndrome
Authors: Mu Chen, Dong-Zhu Xu, Adonis Z Wu, Shuai Guo, Juyi Wan, Dechun Yin, Shien-Fong Lin, Zhenhui Chen, Michael Rubart-von der Lohe, Thomas H Everett, Zhilin Qu, James N Weiss, Peng-Sheng Chen
Journal: Circulation (2018)

Introduction: The mechanisms of J wave syndrome are incompletely understood. Hypothesis: The concomitant activation of small-conductance calcium-activated potassium current (IKAS) and inhibition of...
Comparative Effectiveness of a Lymph Node Collection Kit Versus Heightened Awareness on Lung Cancer Surgery Quality and Outcomes
Authors: Meredith A. Ray, Carrie Fehnel, Olawale Akinbobola, Nicholas R. Faris, Meghan Taylor, Alicia Pacheco, Matthew P. Smeltzer, Raymond U. Osarogiagbon
Journal: Journal of Thoracic Oncology (2021)

IntroductionThe adverse prognostic impact of poor pathologic nodal staging has stimulated efforts to heighten awareness of the problem through guidelines, without guidance on processes to overcome it. We compared heightened awareness (HA) of nodal staging quality versus a lymph node collection kit.MethodsWe categorized curative-intent lung cancer resections from 2009 to 2020 in a population-based, nonrandomized stepped-wedge implementation study of both interventions, into preintervention baseline, HA, and kit subcohorts. We used differences in proportion and hazard ratios across the subcohorts to estimate the effect of the interventions on poor quality (nonexamination of nodes [pNX] or nonexamination of mediastinal lymph nodes) and attainment of quality recommendations of the National Comprehensive Cancer Network, the Commission on Cancer, and the proposed complete resection definition of the International Association for the Study of Lung Cancer across the three cohorts.ResultsOf 3734 resections, 39% were preintervention, 40% kit, and 21% HA cases. Cohort proportions were the following: pNX, 11% (baseline) versus 0% (kit) versus 9% (HA); nonexamination of mediastinal lymph nodes, 27% versus 1% versus 22%; Commission on Cancer benchmark attainment, 14% versus 77% versus 30%; International Association for the Study of Lung Cancer-defined complete resection, 11% versus 58% versus 24%; National Comprehensive Cancer Network attainment, 23% versus 79% versus 35% (p < 0.001 for all, except pNX rate baseline versus HA). Survival rate was significantly higher for both interventions compared with baseline (p < 0.0001).ConclusionsResections with HA or the kit significantly improved surgical quality and outcomes, but the kit was more effective. We propose to conduct a prospective, institutional cluster-randomized clinical trial comparing both interventions.
Abstract PS16-24: Mechanisms underlying obesity-induced enrichment of stem-like breast cancer cells
Authors: Shannon Mayberry, Brittany Harlow, Elizabeth Eichman, Christopher Hsu, Linda deGraffenried
Journal: Cancer Research (2021)

Abstract Background: Breast cancer represents the most common nonskin malignancy in women worldwide, and most deaths result from metastatic dissemination of the disease. At the same time, studies indicate that obesity induces a stem cell-like phenotype, required for tumor metastases and associated with cancer progression and mortality. Although the precise mechanism behind this reprogramming event remains to be elucidated, preliminary data from our lab demonstrate that the epithelial-mesenchymal transition (EMT) associated with obese conditions is linked to IL-6 mechanistically. Because IL-6 cannot be targeted clinically, it will be of the utmost importance to identify downstream effectors of this IL-6-mediated response. This said, we hypothesize that increased levels of IL-6 in obese conditions are at least partially responsible for inducing a stem cell-like phenotype in breast cancer cells through activation of the Akt-mTOR pathway.Methods: MCF-7 and T47D breast cancer cells will be exposed to sera pooled from normoweight (BMI&amp;lt;25 kg/m2) or obese (BMI≥30 kg/m2) women as an in vitro model of the systemic inflammation present in obesity. The cells will then be assessed for changes in expression of genes and proteins involved in induction of EMT using qPCR and western immunoblotting, respectively. Finally, flow cytometry will be used to confirm establishment of an EMT phenotype with measurement of the stem cell markers CD24 and CD44.Results: Our gene expression analyses confirm that obese conditions increase expression of EMT-related genes, including those encoding the transcription factors Snail and Twist. Our flow cytometric analyses also indicate an increase in the stem cell population following a 10-day IL-6 exposure. Additionally, supplementation of IL-6 to non-obese sera increased expression of Twist and Snail in breast cancer cells, while inhibition of IL-6 in obese sera reduced expression of these transcription factors. Finally, western blot analyses demonstrate mechanistic involvement of the Akt-mTOR pathway.Conclusions: These data contribute to our understanding of the means by which obesity induces a stem-like phenotype in breast cancer cells and will ultimately bring light to a therapeutic target that can be used to modulate IL-6-induced activation of the Akt-mTOR signaling pathway leading to an EMT phenotype in obese conditions. Citation Format: Shannon Mayberry, Brittany Harlow, Elizabeth Eichman, Christopher Hsu, Linda deGraffenried. Mechanisms underlying obesity-induced enrichment of stem-like breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-24.
Abstract PS15-06: The distribution of radiosensitivity index differs by PAM50 subtype in primary breast tumors
Authors: Matthew Fahey, Nicholas Russo, Casey Liveringhouse, Matthew Mills, Kamran Ahmed, Roberto Diaz
Journal: Cancer Research (2021)

Abstract Background: Prior studies identified radiosensitive and radioresistant breast tumor phenotypes and demonstrated that gene-expression signatures such as the radiosensitivity index (RSI) can be used to derive biologically rational radiation dose selection. In this study, we assessed the RSI of primary breast tumor samples and its association with PAM50 subtype.Materials/Methods: Primary breast tumor samples were identified from a multi-institutional tissue biorepository. Tumors were excluded if they were treated with neoadjuvant therapy or had distant metastatic disease at the time of sample collection. The RSI gene signature and PAM50 subtype were assessed through transcriptomic profiling performed on Affymetrix microarray chips. Distribution of RSI values across PAM50 subtypes was assessed with the Kruskal-Wallis test. Differences in proportions of radioresistant and radiosensitive tumors among PAM50 subtypes were assessed with the Chi-squared test, where radioresistant was defined as RSI&amp;gt;0.3745 based on prior studies. Clinicopathologic characteristics were obtained through clinical chart review. Results: A total of 637 primary breast tumors with available genomic profiling and clinical information were included for analysis. HIstologies were predominantly invasive ductal carcinoma (81.5%) and invasive lobular (11.6%). Most tumors were T1-T2 (91.7%) while 35.9% had pathologically positive lymph nodes. The distribution of RSI significantly differed by PAM50 classification (Kruskal-Wallis p &amp;lt; 0.001). Proportions of radioresistant vs radiosensitive tumors varied significantly according to PAM50 subtype and are included in the accompanying table (Chi-squared p &amp;lt; 0.001). Median follow-up was 89 months. Conclusion: Breast tumor PAM50 subtypes demonstrate significant variation in radiosensitivity. Further studies are needed to determine if genomic subtyping can refine the ability to predict clinical radiation response and further optimize individual therapy. PAM50TotalBasalHer2LumALumBNormalRSI PhenotypeRadioresistantn (%)50 (60.2%)32 (42.1%)146 (54.4%)82 (45.3%)24 (82.8%)334 (52.4%)Radiosensitive n (%)33 (39.8%)44 (57.9%)122 (45.6%)99 (54.7%)5 (17.2%)303 (47.5%)Total837626818129637 Citation Format: Matthew Fahey, Nicholas Russo, Casey Liveringhouse, Matthew Mills, Kamran Ahmed, Roberto Diaz. The distribution of radiosensitivity index differs by PAM50 subtype in primary breast tumors [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-06.
EFFECTS OF AUTOANTIBODY AGAINST M2-MUSCARINIC ACETYLCHOLINE RECEPTOR IN PERIPARTUM CARDIOMYOPATHY PATIENTS ON DIGOXIN ADDITIONAL TO STANDARD TREATMENT
Authors: Guiling Ma, Cheng Shi, Yin Yue, Long Chen, Yidan Wang, Xiyan Liu, Yingshih Lo, Lin Zhang
Journal: Journal of the American College of Cardiology (2021)
Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome
Authors: Takashi Taga, Shiro Tanaka, Daisuke Hasegawa, Kiminori Terui, Tsutomu Toki, Shotaro Iwamoto, Hidefumi Hiramatsu, Takako Miyamura, Yoshiko Hashii, Hiroshi Moritake, Hideki Nakayama, Hiroyuki Takahashi, Akira Shimada, Tomohiko Taki, Etsuro Ito, Asahito Hama, Masafumi Ito, Katsuyoshi Koh, Daiichiro Hasegawa, Akiko M. Saito, Souichi Adachi, Daisuke Tomizawa
Journal: Leukemia (2021)
Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine
Authors: Jean-Noel Vergnes
Journal: New England Journal of Medicine (2021)

example, the Food and Drug Administration prioritized enforcement against certain unauthorized flavored, cartridge-based e-cigarettes in January 2020 and in July 2020 sent warning letters to 10 companies to stop the sale or distribution of flavored disposable e-cigarettes and e-liquid products that appeal to youth. 5 These findings reinforce the rapidly dynamic nature of the e-cigarette landscape and the need for clinicians, public health practitioners, and the general public to keep pace with these changes.Although the 2020 NYTS data-collection period was truncated owing to the Covid-19 pandemic, this did not affect the survey design or its national representativeness. 3
Separation/connection procedures: From cleansing behavior to numerical cognition
Authors: Arianna Felisatti, Martin H. Fischer, Elena Kulkova, Katharina Kühne, Alexej Michirev
Journal: Behavioral and Brain Sciences (2021)

Lee and Schwarz (L&S) suggest that separation is the grounded procedure underlying cleansing effects in different psychological domains. Here, we interpret L&S's account from a hierarchical view of cognition that considers the influence of physical properties and sensorimotor constraints on mental representations. This approach allows theoretical integration and generalization of L&S's account to the domain of formal quantitative reasoning.
Covid-19: NHS trusts deny restricting PPE during pandemic
Authors: David Oliver
Journal: BMJ (2021)

NHS trusts have denied issuing instructions to staff to restrict their use of personal protective equipment (PPE) during the pandemic, despite hundreds of reports from doctors that trusts did so last year.

Trusts also denied that they had issued warnings to staff who had raised concerns about PPE supplies being inadequate, despite reports from doctors that this had happened, an investigation by The BMJ has found.

Many trusts said that they had reminded staff periodically of the need to adhere to locally adopted national guidelines from national organisations such as Public Health England over PPE specification and to use PPE wisely or appropriately. The UK parliamentary public spending watchdog reported this week that the government had wasted hundreds of millions of pounds on poor quality and unusable PPE that left frontline workers insufficiently protected from covid-19.1

Only one trust admitted that deaths from covid-19 among its staff were being investigated by the Health and Safety Executive (HSE). Yet over 600 NHS staff have died from covid-19, and the HSE has said that it holds data on closed or open investigations at an undisclosed number of trusts.

The BMJ sent freedom of information requests to 130 NHS trusts in England asking about their policies on covid-19 PPE in 2020 (see box). Of the 66 trusts that replied (50%), 60 denied issuing instructions to restrict PPE …
Translatomic profiling reveals novel self-restricting virus-host interactions during HBV infection
Authors: Shilin Yuan, Guanghong Liao, Menghuan Zhang, Yuanfei Zhu, Kun Wang, Weidi Xiao, Caiwei Jia, Minhui Dong, Na Sun, Axel Walch, Ping Xu, Jiming Zhang, Qiang Deng, Ronggui Hu
Journal: Journal of Hepatology (2021)
Left Atrial Mechanics in Heart Failure Before and After Decongestive Therapy: Insights From Deformation Imaging With Invasive Hemodynamics
Authors: Sebastien Deferm, Pieter Martens, Philippe B. Bertrand, Frederik H. Verbrugge, Jeroen Dauw, David Verhaert, Matthias Dupont, Pieter Vandervoort, Wilfried Mullens
Journal: Circulation (2019)
Hematopoietic stem and progenitor cells are present in healthy gingiva tissue
Authors: Siddharth Krishnan, Kelly Wemyss, Ian E. Prise, Flora A. McClure, Conor O’Boyle, Hayley M. Bridgeman, Tovah N. Shaw, John R. Grainger, Joanne E. Konkel
Journal: The Journal of Experimental Medicine (2021)

Hematopoietic stem cells reside in the bone marrow, where they generate the effector cells that drive immune responses. However, in response to inflammation, some hematopoietic stem and progenitor cells (HSPCs) are recruited to tissue sites and undergo extramedullary hematopoiesis. Contrasting with this paradigm, here we show residence and differentiation of HSPCs in healthy gingiva, a key oral barrier in the absence of overt inflammation. We initially defined a population of gingiva monocytes that could be locally maintained; we subsequently identified not only monocyte progenitors but also diverse HSPCs within the gingiva that could give rise to multiple myeloid lineages. Gingiva HSPCs possessed similar differentiation potentials, reconstitution capabilities, and heterogeneity to bone marrow HSPCs. However, gingival HSPCs responded differently to inflammatory insults, responding to oral but not systemic inflammation. Combined, we highlight a novel pathway of myeloid cell development at a healthy barrier, defining a gingiva-specific HSPC network that supports generation of a proportion of the innate immune cells that police this barrier.