tbuckley/cabot-search huggingface dataset:
PBRM1 Deficiency Confers Synthetic Lethality to DNA Repair Inhibitors in Cancer
Authors: Roman M. Chabanon, Daphné Morel, Thomas Eychenne, Léo Colmet-Daage, Ilirjana Bajrami, Nicolas Dorvault, Marlène Garrido, Cornelia Meisenberg, Andrew Lamb, Carine Ngo, Suzanna R. Hopkins, Theodoros I. Roumeliotis, Samuel Jouny, Clémence Hénon, Asuka Kawai-Kawachi, Clémence Astier, Asha Konde, Elaine Del Nery, Christophe Massard, Stephen J. Pettitt, Raphaël Margueron, Jyoti S. Choudhary, Geneviève Almouzni, Jean-Charles Soria, Eric Deutsch, Jessica A. Downs, Christopher J. Lord, Sophie Postel-Vinay
Journal: Cancer Research (2021)

Abstract Inactivation of Polybromo 1 (PBRM1), a specific subunit of the PBAF chromatin remodeling complex, occurs frequently in cancer, including 40% of clear cell renal cell carcinomas (ccRCC). To identify novel therapeutic approaches to targeting PBRM1-defective cancers, we used a series of orthogonal functional genomic screens that identified PARP and ATR inhibitors as being synthetic lethal with PBRM1 deficiency. The PBRM1/PARP inhibitor synthetic lethality was recapitulated using several clinical PARP inhibitors in a series of in vitro model systems and in vivo in a xenograft model of ccRCC. In the absence of exogenous DNA damage, PBRM1-defective cells exhibited elevated levels of replication stress, micronuclei, and R-loops. PARP inhibitor exposure exacerbated these phenotypes. Quantitative mass spectrometry revealed that multiple R-loop processing factors were downregulated in PBRM1-defective tumor cells. Exogenous expression of the R-loop resolution enzyme RNase H1 reversed the sensitivity of PBRM1-deficient cells to PARP inhibitors, suggesting that excessive levels of R-loops could be a cause of this synthetic lethality. PARP and ATR inhibitors also induced cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) innate immune signaling in PBRM1-defective tumor cells. Overall, these findings provide the preclinical basis for using PARP inhibitors in PBRM1-defective cancers. Significance: This study demonstrates that PARP and ATR inhibitors are synthetic lethal with the loss of PBRM1, a PBAF-specific subunit, thus providing the rationale for assessing these inhibitors in patients with PBRM1-defective cancer.
Abstract PO-035: Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression
Authors: Alexandru Suvac, Richard Rebello, Stephen Lyons, Robert G. Bristow
Journal: Clinical Cancer Research (2021)

Abstract Prostate cancer is the most commonly diagnosed cancer in the UK. Increased levels of prostate hypoxia have been shown to drive tumor aggression as an adverse prognostic factor following surgery or radiotherapy, especially when combined with tumor genetic instability. Our recent collaborative bioinformatic studies (Bhandari et al, Nat. Genetics 2019; Nat. Communications 2020) have shown various copy number changes to be enriched in hypoxic tumors, with mono- or bi-allelic loss of the PTEN being the most significant. To delineate a direct relationship between hypoxia and PTEN loss, we interrogated the impact of chronic hypoxia (1% O2, 0.2% O2; 72 h) on PTEN oncogenic signaling and asked whether this translates to improved fitness and survival in non-transformed and transformed PTEN isogenic cell lines. Despite increased oncogenic signaling (increased phospho-AKT) of PTEN-null 22Rv1 cells and hTERT-immortalized prostate epithelial cells (GHM) under chronic hypoxic gassing conditions, this did not lead to increased adaption and tumor clone survival. Differential survival for the PTEN isogenic cell lines following prostate cancer therapies (i.e. IR, PARPi, cDDP, taxols) under oxia and hypoxia are underway to further this work and determine a potential translational importance to clinical treatment. Independent evidence also points to hypoxia/PTEN loss in deregulating centrosome biology as a potential mechanism for genetic instability under hypoxia. Hence, we also hypothesized that the relationship between PTEN and hypoxia might be unearthed if aberrant unstable mitoses following deregulation of spindle poles under hypoxia selectively adapt and have a survival advantage. Quantitative immunofluorescence of centrosome aberrations, using antibodies to phospho-Histone H3 and Centrin-1, show significant increases in centriole numbers (p &amp;lt; 0.05) in mitotic cells under chronic hypoxic conditions and an increase in the incidence of micronuclei (p &amp;lt; 0.005), specifically in chronic hypoxic cells with PTEN loss, supporting our hypothesis. Current studies are investigating in situ staining of centrosomes as a readout of chromosomal instability (CIN) in primary prostate cancer tissues with variable PTEN status as a new biomarker for aggressiveness to link hypoxia-associated genetic instability with novel clinical trial development. (Funded by Cancer Research UK as a core grant to RGB). Citation Format: Alexandru Suvac, Richard Rebello, Stephen Lyons, Robert G. Bristow. Understanding the role of hypoxia and PTEN loss in driving prostate cancer progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-035.
IGFBP-2 partly mediates the early metabolic improvements caused by bariatric surgery
Authors: Justine Faramia, Zheng Hao, Michael B. Mumphrey, R. Leigh Townsend, Stéphanie Miard, Anne-Marie Carreau, Mélanie Nadeau, Frédérique Frisch, Elena-Dana Baraboi, Thomas Grenier-Larouche, Christophe Noll, Meng Li, Laurent Biertho, Simon Marceau, Frédéric-Simon Hould, Stéfane Lebel, Christopher D. Morrison, Heike Münzberg, Denis Richard, André C. Carpentier, André Tchernof, Hans-Rudolf Berthoud, Frédéric Picard
Journal: Cell Reports Medicine (2021)

Insulin-like growth factor-binding protein (IGFBP)-2 is a circulating biomarker of cardiometabolic health. Here, we report that circulating IGFBP-2 concentrations robustly increase after different bariatric procedures in humans, reaching higher levels after biliopancreatic diversion with duodenal switch (BPD-DS) than after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). This increase is closely associated with insulin sensitization. In mice and rats, BPD-DS and RYGB operations also increase circulating IGFBP-2 levels, which are not affected by SG or caloric restriction. In mice, Igfbp2 deficiency significantly impairs surgery-induced loss in adiposity and early improvement in insulin sensitivity but does not affect long-term enhancement in glucose homeostasis. This study demonstrates that the modulation of circulating IGFBP-2 may play a role in the early improvement of insulin sensitivity and loss of adiposity brought about by bariatric surgery.
AIF3 splicing switch triggers neurodegeneration
Authors: Shuiqiao Liu, Mi Zhou, Zhi Ruan, Yanan Wang, Calvin Chang, Masayuki Sasaki, Veena Rajaram, Andrew Lemoff, Kalyani Nambiar, Jennifer E. Wang, Kimmo J. Hatanpaa, Weibo Luo, Ted M. Dawson, Valina L. Dawson, Yingfei Wang
Journal: Molecular Neurodegeneration (2021)

Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain.
Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer
Authors: Anthony M. Musolf, Claire L. Simpson, Bilal A. Moiz, Claudio W. Pikielny, Candace D. Middlebrooks, Diptasri Mandal, Mariza de Andrade, Michael D. Cole, Colette Gaba, Ping Yang, Ming You, Yafang Li, Elena Y. Kupert, Marshall W. Anderson, Ann G. Schwartz, Susan M. Pinney, Christopher I. Amos, Joan E. Bailey-Wilson
Journal: Cancer Research (2021)

Abstract Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: ARID1B at 6q25.3, MAP3K4 at 6q26, and UTRN (6q24.1) and PHACTR2 (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. Significance: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
Abstract 16218: Fibulin-3 Plays a Key Role in Cardiac Fibrosis Following Myocardial Infarction in Mice
Authors: Lucy A Murtha, Nishani S Mabotuwana, Sean A Hardy, Andrew J Boyle
Journal: Circulation (2017)

Introduction: Cardiac fibrosis is the final common pathway of cardiac disease. The consequence is a stiff, dysfunctional heart, and the long-term outcome is inevitable progression to heart failure....
Vaccine Breakthrough Infections with SARS-CoV-2 Variants
Authors: Ezgi Hacisuleyman, Caryn Hale, Yuhki Saito, Nathalie E Blachere, Marissa Bergh, Erin G Conlon, Dennis J Schaefer-Babajew, Justin DaSilva, Frauke Muecksch, Christian Gaebler, Richard Lifton, Michel C Nussenzweig, Theodora Hatziioannou, Paul D Bieniasz, Robert B Darnell
Journal: New England Journal of Medicine (2021)

SummaryEmerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of clinical concern. In a cohort of 417 persons who had received the second dose of BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) vaccine at least 2 weeks previously, we identified 2 women with vaccine breakthrough infection. Despite evidence of vaccine efficacy in both women, symptoms of coronavirus disease 2019 developed, and they tested positive for SARS-CoV-2 by polymerase-chain-reaction testing. Viral sequencing revealed variants of likely clinical importance, including E484K in 1 woman and three mutations (T95I, del142–144, and D614G) in both. These observations indicate a potential risk of illness after successful vaccination and subsequent infection with variant virus, and they provide support for continued efforts to prevent and diagnose infection and to characterize variants in vaccinated persons. (Funded by the National Institutes of Health and others.)
Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome
Authors: Luke Y.C. Chen, Catherine M. Biggs, Shahin Jamal, Sophie Stukas, Cheryl L. Wellington, Mypinder S. Sekhon
Journal: Cell Reports Medicine (2021)

Data suggest that interleukin (IL)-6 blockade could reduce mortality in severe COVID-19, yet IL-6 is only modestly elevated in most patients. Chen et al. describe the role of soluble interleukin-6 receptor (sIL-6R) in IL-6
Abstract 20900: Exercise Training Fails to Improve Cardiac Dysfunction in DNA Repair-Deficient Xpg Mice
Authors: Martine de Boer, Maaike te Lintel Hekkert, Marion G de Kleijnen, Daphne Merkus, Jan H Hoeijmakers, Dirk J Duncker
Journal: Circulation (2017)

Background &amp; Hypothesis: The exact molecular mechanisms underlying the pathogenesis of heart failure (HF) remain incompletely understood hampering a more mechanism-based approach to effective treatment and prevention. Every cell contains DNA repair systems to protect against DNA damage-induced cancer and aging-related diseases. Evidence indicates that DNA damage is associated with heart failure. Physical activity is beneficial for maintaining and improving cardiac function. Therefore we hypothesized that voluntary wheel running (EX) would ameliorate cardiac function in cardiomyocyte-specific DNA repair-deficient Xpg mice. Methods: αMHC-Xpg c/- and wildtype (WT) mice were exposed to 11 wks of sedentary housing (SED) or EX, resulting in 4 groups; αMHC-Xpg c/- SED (n=12), WT SED (n=10), αMHC-Xpg c/- EX (n=16) and WT EX (n=13). At age 16 wks, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements. Results: Cardiomyocyte-specific inactivation of Xpg resulted in systolic as well as diastolic dysfunction, demonstrated by decreases in fractional shortening (23±2 vs. 39±2 %), LV systolic pressure (82±4 vs. 91±3 mmHg), LV dP/dt at 30 mmHg (5240±350 vs. 7480±440 mmHg/s) and LV dP/dtmin (-6740±830 vs. -10890±780 mmHg/s; all p&lt;0.05). In addition, LV end-diastolic lumen diameter (LVEDD) was markedly increased (3.9±0.1 vs. 3.0±0.1 mm; p&lt;0.05). Total running distance was indistinguishable between αMHC-Xpg c/- EX and WT EX (881±61 vs. 856±39 km resp.). Global LV function was unaffected by EX in WT mice. Contrary to our hypothesis, LV remodeling and dysfunction tended to aggravate by EX in αMHC-Xpg c/- mice, as evidenced by further increases in LVEDD (4.2±0.1 vs. 3.9±0.1 mm; p&lt;0.05) and relaxation time constant tau (19.2±2.6 vs. 13.6±2.9 ms; p&lt;0.06). Conclusion: Although, αMHC-Xpg c/- mice display a cardiac phenotype which is largely similar to mice subjected to MI and we have previously shown exercise improves LV remodeling and dysfunction after MI, exercise failed to ameliorate LV remodeling and dysfunction associated with cardiomyocyte-restricted loss of DNA-repair protein Xpg.
Re: Vuthy Ea, Anne Bergougnoux, Pascal Philibert, et al. How Far Should We Explore Hypospadias? Next-generation Sequencing Applied to a Large Cohort of Hypospadiac Patients. Eur Urol 2021;79:507-515
Authors: Zhongzhong Chen, Hua Xie, Fang Chen
Journal: European Urology (2021)
Complex interplay between greenness and air pollution in respiratory health
Authors: Elaine Fuertes, Debbie Jarvis
Journal: Thorax (2021)

For many, it seems self-evident that a greener city improves the quality of life and health for its citizens. Epidemiological studies are providing increasing evidence that the presence and amount of vegetation around locations where one spends a lot of time (home, work and school) have numerous beneficial effects on physical and mental health, including increased longevity.1 Interestingly, the evidence supporting a positive role of vegetation on allergic and respiratory health is much weaker, possibly because of the complex role played by air pollution. Beneficial effects attributed to vegetation may be due to less air pollution, as levels tend to be lower in vegetated areas. Some vegetation types may also actively reduce air pollution levels, although the scientific consensus is that this occurs only to a limited extent.2 Air pollutants may also interact with vegetation, such as pollen,3 to influence associations with health. These mechanisms are relevant in urban settings where air pollution levels can be high.

Various metrics are used to estimate ‘vegetation exposure’ in epidemiological studies. The Normalised Difference Vegetation Index (NDVI) is common and assesses surrounding levels of green vegetation, often termed ‘greenness’. The NDVI is calculated from satellite data giving the ratio of visible and near-infrared light reflection and ranges from −1 (water), 0 (barren rock) to +1 (dense green vegetation). It provides a measure …
Novel recessive locus for body mass index in childhood asthma
Authors: Sanghun Lee, Jessica Lasky-Su, Sungho Won, Cecelia Laurie, Juan Carlos Celedón, Christoph Lange, Scott Weiss, Julian Hecker
Journal: Thorax (2021)

Most genome-wide association studies of obesity and body mass index (BMI) have so far assumed an additive mode of inheritance in their analysis, although association testing supports a recessive effect for some of the established loci, for example, rs1421085 in FTO . In two whole-genome sequencing (WGS) studies of children with asthma and their parents (892 Costa Rican trios and 286 North American trios), we discovered an association between a locus (rs9292139) in LOC102724122 and BMI that reaches genome-wide significance under a recessive model in the combined analysis. As the association does not achieve significance under an additive model, our finding illustrates the benefits of the recessive model in WGS analyses.
Algorithmovigilance—Advancing Methods to Analyze and Monitor Artificial Intelligence–Driven Health Care for Effectiveness and Equity
Authors: Peter J. Embi
Journal: JAMA Network Open (2021)

Yoonyoung Park, ScD; Jianying Hu, PhD; Moninder Singh, PhD; Issa Sylla, BA; Irene Dankwa-Mullan, MD, MPH; Eileen Koski, MPhil; Amar K. Das, MD, PhD
MYBL2 disrupts the Hippo-YAP pathway and confers castration resistance and metastatic potential in prostate cancer
Authors: Qiji Li, Min Wang, Yanqing Hu, Ensi Zhao, Jun Li, Liangliang Ren, Meng Wang, Yuandong Xu, Qian Liang, Di Zhang, Yingrong Lai, Shaoyu Liu, Xinsheng Peng, Chengming Zhu, Liping Ye
Journal: Theranostics (2021)

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.
Abstract 15990: Incidence and Outcomes of Elevated Troponins in Patients With Rhabdomyolysis
Authors: Nitheesha Ganta, Hilda Gonzalez, Olubode Olufajo, Prafulla P Mehrotra
Journal: Circulation (2020)

Introduction: The relationship between rhabdomyolysis and elevated troponins has not been clearly established. Literature has been limited to case reports and small single center studies. However, there are no studies that evaluated the incidence and outcomes of troponin elevation in patients with rhabdomyolysis. Methods: Patients of 18 years and older with rhabdomyolysis were selected from the Healthcare Cost and Utilization Project National Inpatient Sample, 2005 to 2014. Patients with elevated troponins were identified. Information on demographics, co-morbidities and interventions (percutaneous coronary intervention (PCI) vs. no PCI) were extracted. The two main outcomes were mortality and hospital cost. Differences in characteristics and outcomes of patients with elevated troponins and those without elevated troponins were evaluated using descriptive analyses and multivariate regression models. Results: A total of 404,369 rhabdomyolysis participants were identified with 24,986 (6.18%) having elevated troponins. Of these, only 133 (0.03%) patients underwent PCI. Compared to the patients without elevated troponins, patients with elevated troponins were older (69y vs. 61y; P &lt;0.001), and the majority were white (73.9% vs. 66.0%; P &lt;0.001). In-hospital mortality in patients with elevated troponins was 20.5% compared to 5.4% in patients without elevated troponins ( P &lt;0.001) resulting in an adjusted odds ratio of 4.05 (95% CI: 3.90 - 4.20). Compared to the patients without elevated troponins, the median hospital cost in patients with elevated troponins was $17,308 vs. $8,434 ( P &lt;0.001) resulting in an adjusted mean difference of $9,547 (95% CI: $9,189 - $9,904). Conclusions: Our analysis showed that 6.1% of rhabdomyolysis patients have elevated troponins. Of these, very few patients underwent PCI, suggesting myocardial injury in these patients. Patients with elevated troponins had higher in-hospital mortality and increased cost of hospitalization. Due to the bad prognosis associated with elevated troponins, there is need for further evaluation for underlying coronary artery disease in patients with myocardial injury.
Response to first vaccination against SARS-CoV-2 in patients with multiple myeloma
Authors: Sarah Bird, Aikaterini Panopoulou, Robyn L Shea, Micky Tsui, Radovan Saso, Amit Sud, Sharon West, Katy Smith, John Barwood, Ewa Kaczmarek, Carmela Panlaqui, Martin Kaiser, Simon Stern, Charlotte Pawlyn, Kevin Boyd
Journal: The Lancet Haematology (2021)
Prehospital management of exertional heat stroke at sports competitions: International Olympic Committee Adverse Weather Impact Expert Working Group for the Olympic Games Tokyo 2020
Authors: Yuri Hosokawa, Sebastien Racinais, Takao Akama, David Zideman, Richard Budgett, Douglas J Casa, Stéphane Bermon, Andrew J Grundstein, Yannis P Pitsiladis, Wolfgang Schobersberger, Fumihiro Yamasawa
Journal: British Journal of Sports Medicine (2021)

This document aimed to summarise the key components of exertional heat stroke (EHS) prehospital management.Members of the International Olympic Committee Adverse Weather Impact Expert Working Group for the Olympic Games Tokyo 2020 summarised the current best practice regarding the EHS prehospital management.Sports competitions that are scheduled under high environmental heat stress or those that include events with high metabolic demands should implement and adopt policy and procedures for EHS prehospital management. The basic principles of EHS prehospital care are: early recognition, early diagnosis, rapid, on-site cooling and advanced clinical care. In order to achieve these principles, medical organisers must establish an area called the heat deck within or adjacent to the main medical tent that is optimised for EHS diagnosis, treatment and monitoring. Once admitted to the heat deck, the rectal temperature of the athlete with suspected EHS is assessed to confirm an elevated core body temperature. After EHS is diagnosed, the athlete must be cooled on-site until the rectal temperature is below 39°C. While cooling the athlete, medical providers are recommended to conduct a blood analysis to rule out exercise-associated hyponatraemia or hypoglycaemia, provided that this can be safely performed without interrupting cooling. The athlete is transported to advanced care for a full medical evaluation only after the treatment has been provided on-site.A coordination of care among all medical stakeholders at the sports venue, during transport, and at the hospital is warranted to ensure effective management is provided to the EHS athlete.