tbuckley/cabot-search huggingface dataset:
Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists
Authors: Jialin Mo, Fang Liu, Xi Sun, Hongting Huang, Kezhe Tan, Xiaojing Zhao, Rui Li, Wenyan Jiang, Yi Sui, Xiaosong Chen, Kunwei Shen, Liye Zhang, Jie Ma, Kewen Zhao, Yujie Tang
Journal: Cancer Research (2021)

Abstract Hedgehog signaling is aberrantly activated in hematologic malignancies and solid tumors, and targeting it is a promising therapeutic strategy against these cancers. Resistance to clinically available hedgehog-targeted Smoothened inhibitor (SMOi) drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies identified inhibition of BET and CDK7 as two epigenetic/transcriptional-targeted therapeutic strategies for overcoming SMOi resistance, providing a promising direction for anti-hedgehog drug development. To uncover additional strategies for inhibiting aberrant hedgehog activity, here we performed CRISPR-Cas9 screening with an single-guide RNA library targeting epigenetic and transcriptional modulators in hedgehog-driven medulloblastoma cells, combined with tumor dataset analyses. Structure specific recognition protein 1 (SSRP1), a subunit of facilitates chromatin transcription (FACT) complex, was identified as a hedgehog-induced essential oncogene and therapeutic target in hedgehog-driven cancer. The FACT inhibitor CBL0137, which has entered clinical trials for cancer, effectively suppressed in vitro and in vivo growth of multiple SMOi-responsive and SMOi-resistant hedgehog-driven cancer models. Mechanistically, CBL0137 exerted anti-hedgehog activity by targeting transcription of GLI1 and GLI2, which are core transcription factors of the hedgehog pathway. SSRP1 bound the promoter regions of GLI1 and GLI2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 synergized with BET or CDK7 inhibitors to antagonize aberrant hedgehog pathway and growth of hedgehog-driven cancer models. Taken together, these results identify FACT inhibition as a promising epigenetic/transcriptional-targeted therapeutic strategy for treating hedgehog-driven cancers and overcoming SMOi resistance. Significance: This study identifies FACT inhibition as an anti-hedgehog therapeutic strategy for overcoming resistance to Smoothened inhibitors and provides preclinical support for initiating clinical trials of FACT-targeted drug CBL0137 against hedgehog-driven cancers.
The impact of the COVID-19 pandemic on organised cervical cancer screening: The first results of the Slovenian cervical screening programme and registry
Authors: Urška Ivanuš, Tine Jerman, Urška Gašper Oblak, Leon Meglič, Mojca Florjančič, Margareta Strojan Fležar, Tanja Premru Sršen, Špela Smrkolj, Maja Pakiž, Maja Primic Žakelj, Veronika Kloboves Prevodnik, Ana Pogačnik, Igor Josipović, Tanja Mate, Mojca Gobec
Journal: The Lancet Regional Health - Europe (2021)

The COVID-19 pandemic threatens the impact of cervical cancer screening and global cervical cancer elimination goals. As cervical cancer screening programmes were adjusting to the new situation, we evaluated the intensity, quality, and outcomes of cervical cancer screening in Slovenia in the first seven months of the pandemic.Historical observational study on data from a population-based cervical cancer screening registry. Number of cervical cytopathology (screening and follow-up), histopathology (diagnostic procedures, invasive procedures and number of newly diagnosed CIN2+ cases) and HPV test results from the entire Slovenian women population between January 1st and September 30th 2020 were compared to a three-year average of the years 2017-19.A two-month screening lock-down between March 12th and May 8th 2020 resulted in an epidemic deficit of screening (-92%), follow-up (-70%), and HPV triage tests (-68%), as well as invasive diagnostic (-47%) and treatment (-15%) of cervical lesions. Time to diagnosis and treatment did not increase; times to laboratory results fluctuated but stayed within standards. Slovenia has entered the second epidemic intending to add as little as possible to the pandemic deficit of screening smears (-23%) and yearly CIN2+ cases (-10%). Women aged 30-39 were most affected, with the highest pandemic deficit of screening smears (-26%) and yearly CIN2+ cases (-19%).The pandemic has deeply affected all levels of our lives. New vulnerable groups and inequalities have emerged that require recognition and action. To prevent long-term increases in the cervical cancer burden due to the COVID-19 pandemic, it is crucial that organised screening is maintained and monitored in settings where it can be safely and comprehensively provided.None.
Noninvasive Detection of Cardiac Amyloid With 11C-Pittsburgh Compound B PET/CT and 99mTc-PYP Scintigraphy
Authors: Xuezhu Wang, Yining Wang, Jian Li, Li Huo, Shuyang Zhang
Journal: Clinical Nuclear Medicine (2021)

Abstract We report the imaging findings of 2 cases of cardiac amyloidosis, one light chain (AL) type and another transthyretin (ATTR) type. The images showed 11 C-Pittsburgh compound B ( 11 C-PIB) uptake in the heart with AL amyloidosis, whereas the ATTR amyloidosis showed 11 C-PIB–negative and 99m Tc-PYP–positive uptake in the heart. It demonstrated that using 99m Tc-PYP scintigraphy and 11 C-PIB PET/CT might be able to differentiate these 2 major types of cardiac amyloidosis noninvasively.
大きな振動によるインペラ5.0メカニカルアシストデバイスカテーテルによって誘発された重症溶血 インペラの使用に関する新たな懸念
Authors: Nakao Yasuhisa, Aono Jun, Tasaka Tatsuro, Uetani Teruyoshi, Higashi Haruhiko, Ikeda Shuntaro, Yorozuya Toshihiro, Izutani Hironori, Yamaguchi Osamu
Journal: Circulation (2019)
Timing of<i>Mycobacterium tuberculosis</i>exposure explains variation in BCG effectiveness: a systematic review and meta-analysis
Authors: James M Trauer, Andrew Kawai, Anna K Coussens, Manjula Datta, Bridget M Williams, Emma S McBryde, Romain Ragonnet
Journal: Thorax (2021)

The heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure.
A novel approach to improve detection of glucocorticoid doping in sport with new guidance for physicians prescribing for athletes
Authors: Rosa Ventura, Peter Daley-Yates, Irene Mazzoni, Katia Collomp, Martial Saugy, Frank Buttgereit, Olivier Rabin, Mark Stuart
Journal: British Journal of Sports Medicine (2021)

The systemic effect of glucocorticoids (GCs) following injectable routes of administration presents a potential risk to both improving performance and causing harm to health in athletes. This review evaluates the current GC antidoping regulations defined by the World Anti-Doping Agency and presents a novel approach for defining permitted and prohibited use of glucocorticoids in sport based on the pharmacological potential for performance enhancement (PE) and risk of adverse effects on health. Known performance-enhancing doses of glucocorticoids are expressed in terms of cortisol-equivalent doses and thereby the dose associated with a high potential for PE for any GC and route of administration can be derived. Consequently, revised and substance-specific laboratory reporting values are presented to better distinguish between prohibited and permitted use in sport. In addition, washout periods are presented to enable clinicians to prescribe glucocorticoids safely and to avoid the risk of athletes testing positive for a doping test.
Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non–Small Cell Lung Cancer
Authors: Rui Li, Ramin Salehi-Rad, William Crosson, Milica Momcilovic, Raymond J. Lim, Stephanie L. Ong, Zi Ling Huang, Tianhao Zhang, Jensen Abascal, Camelia Dumitras, Zhe Jing, Stacy J. Park, Kostyantyn Krysan, David B. Shackelford, Linh M. Tran, Bin Liu, Steven M. Dubinett
Journal: Cancer Research (2021)

Abstract LKB1 inactivating mutations are commonly observed in patients with KRAS-mutant non–small cell lung cancer (NSCLC). Although treatment of NSCLC with immune checkpoint inhibitors (ICI) has resulted in improved overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations drive primary resistance to ICIs in NSCLC. Effective therapeutic options that overcome ICI resistance in LKB1-mutant NSCLC are limited. Here, we report that loss of LKB1 results in increased secretion of the C–X–C motif (CXC) chemokines with an NH2-terminal Glu-Leu-Arg (ELR) motif in premalignant and cancerous cells, as well as in genetically engineered murine models (GEMM) of NSCLC. Heightened levels of ELR+ CXC chemokines in LKB1-deficient murine models of NSCLC positively correlated with increased abundance of granulocytic myeloid-derived suppressor cells (G-MDSC) locally within the tumor microenvironment and systemically in peripheral blood and spleen. Depletion of G-MDSCs with antibody or functional inhibition via all-trans-retinoic acid (ATRA) led to enhanced antitumor T-cell responses and sensitized LKB1-deficent murine tumors to PD-1 blockade. Combination therapy with anti–PD-1 and ATRA improved local and systemic T-cell proliferation and generated tumor-specific immunity. Our findings implicate ELR+ CXC chemokine-mediated enrichment of G-MDSCs as a potential mediator of immunosuppression in LKB1-deficient NSCLC and provide a rationale for using ATRA in combination with anti–PD-1 therapy in patients with LKB1-deficient NSCLC refractory to ICIs. Significance: These findings show that accumulation of myeloid-derived suppressor cells in LKB1-deficient non–small cell lung cancer can be overcome via treatment with all-trans-retinoic acid, sensitizing tumors to immunotherapy.
Hypoxia and brain aging: Neurodegeneration or neuroprotection?
Authors: Johannes Burtscher, Robert T. Mallet, Martin Burtscher, Grégoire P. Millet
Journal: Ageing Research Reviews (2021)

The absolute reliance of the mammalian brain on oxygen to generate ATP renders it acutely vulnerable to hypoxia, whether at high altitude or in clinical settings of anemia or pulmonary disease. Hypoxia is pivotal to the pathogeneses of myriad neurological disorders, including Alzheimer's, Parkinson's and other age-related neurodegenerative diseases. Conversely, reduced environmental oxygen, e.g. sojourns or residing at high altitudes, may impart favorable effects on aging and mortality. Moreover, controlled hypoxia exposure may represent a treatment strategy for age-related neurological disorders. This review discusses evidence of hypoxia's beneficial vs. detrimental impacts on the aging brain and the molecular mechanisms that mediate these divergent effects. It draws upon an extensive literature search on the effects of hypoxia/altitude on brain aging, and detailed analysis of all identified studies directly comparing brain responses to hypoxia in young vs. aged humans or rodents. Special attention is directed toward the risks vs. benefits of hypoxia exposure to the elderly, and potential therapeutic applications of hypoxia for neurodegenerative diseases. Finally, important questions for future research are discussed.
365 MOVE HEALTHY-The identification of current national injury prevention programs and beliefs of coaches and youth regarding injury prevention in 6 European countries
Authors: Joske Nauta, Johan de Jong, Kristine De Martelaer, Paul Dragos, Remo Mombarg, Danielle Louise Nørager Johansen, Thomas Skovgaard, Paul Szabo-Alexi, Evert Verhagen, Anne Benjaminse
Journal: British Journal of Sports Medicine (2021)
Single-cell dual-omics reveals the transcriptomic and epigenomic diversity of cardiac non-myocytes
Authors: Li Wang, Yuchen Yang, Hong Ma, Yifang Xie, Jun Xu, David Near, Haofei Wang, Tiffany Garbutt, Yun Li, Jiandong Liu, Li Qian
Journal: Cardiovascular Research (2021)

Abstract Aims The precise cellular identity and molecular features of non-myocytes (non-CMs) in a mammalian heart at a single-cell level remain elusive. Depiction of epigenetic landscape with transcriptomic signatures using the latest single-cell multi-omics has the potential to unravel the molecular programs underlying the cellular diversity of cardiac non-myocytes. Here, we characterized the molecular and cellular features of cardiac non-CM populations in the adult murine heart at the single-cell level. Methods and results Through single-cell dual omics analysis, we mapped the epigenetic landscapes, characterized the transcriptomic profiles and delineated the molecular signatures of cardiac non-CMs in the adult murine heart. Distinct cis-regulatory elements and trans-acting factors for the individual major non-CM cell types (endothelial cells, fibroblast, pericytes, and immune cells) were identified. In particular, unbiased sub-clustering and functional annotation of cardiac fibroblasts (FBs) revealed extensive FB heterogeneity and identified FB sub-types with functional states related to the cellular response to stimuli, cytoskeleton organization, and immune regulation, respectively. We further explored the function of marker genes Hsd11b1 and Gfpt2 that label major FB subpopulations and determined the distribution of Hsd11b1+ and Gfp2+ FBs in murine healthy and diseased hearts. Conclusions In summary, we characterized the non-CM cellular identity at the transcriptome and epigenome levels using single-cell omics approaches and discovered previously unrecognized cardiac fibroblast subpopulations with unique functional states.
Thematic Analysis of Dyadic Coping in Couples With Young-Onset Dementia
Authors: Sarah M. Bannon, Victoria A. Grunberg, Mira Reichman, Paula J. Popok, Lara Traeger, Bradford C. Dickerson, Ana-Maria Vranceanu
Journal: JAMA Network Open (2021)

<h3>Importance</h3> A diagnosis of young-onset dementia (YOD) is a life-altering event for both persons with dementia and their spousal caregivers. Dyadic coping (DC) theoretical models acknowledge that dyads cope with stressors as a unit, but these models have yet to be used in YOD. <h3>Objective</h3> To explore the lived experiences of couples managing YOD using an integrated DC model. <h3>Design, Setting, and Participants</h3> This qualitative study recruited couples from a single major medical setting and through social media. Eligibility criteria included cohabitation, 1 partner diagnosed with YOD and able to participate, and both partners willing to participate. Live online video interviews were conducted from March to June 2020. <h3>Exposures</h3> One semistructured interview, which was recorded and subsequently transcribed. Recruitment was stopped once thematic saturation was reached. <h3>Main Outcomes and Measures</h3> Five themes were deductively derived based on the integrated DC framework, including stress communication, positive individual DC, positive conjoint DC, negative individual DC, and negative conjoint DC. Within each theme, subthemes were inductively identified to further characterize couples' dyadic coping experiences with YOD. <h3>Results</h3> A total of 23 couples were interviewed, comprising persons with dementia (11 women [48%]; mean [SD] age, 61.3 [4.65] years; mean [SD] time from diagnosis, 3.11 [3.85]) years; and spousal caregivers (13 women [57%]; mean [SD] age, 60.5 [5.40] years). Data supported the 5 a priori DC themes and novel subthemes describing couples' experiences with YOD. Specifically, couples enacted positive conjoint DC by approaching challenges using a teamwork approach to problem solving and relying on collaborative communication. In contrast, couples engaged in negative conjoint DC through mutual avoidance, leading to increased negative communication and conflict. Couples described initially engaging in avoidance and withdrawal to navigate YOD-related stressors. While these strategies provided short-term relief from challenging emotions, they prevented engagement in adaptive coping (eg, acceptance and collaborative problem-solving) to promote long-term adjustment. <h3>Conclusions and Relevance</h3> This study used an evidence-based integrated DC approach to identify the positive and negative coping behaviors of couples managing YOD. To our knowledge, this is the first study to use a DC framework to guide qualitative analysis, and it provides valuable insights into DC strategies used by couples navigating YOD-related stressors. Findings can inform the development of dyadic psychosocial services for couples managing YOD and have implications for other progressive illnesses.
Axillary Pathologic Complete Response After Neoadjuvant Systemic Therapy by Breast Cancer Subtype in Patients With Initially Clinically Node-Positive Disease
Authors: Sanaz Samiei, Janine M. Simons, Sanne M. E. Engelen, Regina G. H. Beets-Tan, Jean-Marc Classe, Marjolein L. Smidt
Journal: JAMA Surgery (2021)

An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically node-positive disease, is lacking.To provide pooled data of all studies in the neoadjuvant setting on axillary pCR rates for different breast cancer subtypes in patients with initially clinically node-positive disease.The electronic databases Embase and PubMed were used to conduct a systematic literature search on July 16, 2020. The references of the included studies were manually checked to identify other eligible studies.Studies in the neoadjuvant therapy setting were identified regarding axillary pCR for different breast cancer subtypes in patients with initially clinically node-positive disease (ie, defined as node-positive before the initiation of neoadjuvant systemic therapy).Two reviewers independently selected eligible studies according to the inclusion criteria and extracted all data. All discrepant results were resolved during a consensus meeting. To identify the different subtypes, the subtype definitions as reported by the included articles were used. The random-effects model was used to calculate the overall pooled estimate of axillary pCR for each breast cancer subtype.The main outcome of this study was the rate of axillary pCR and residual axillary lymph node disease after neoadjuvant systemic therapy for different breast cancer subtypes, differentiating studies with and without patients with pathologically proven clinically node-positive disease.This pooled analysis included 33 unique studies with 57 531 unique patients and showed the following axillary pCR rates for each of the 7 reported subtypes in decreasing order: 60% for hormone receptor (HR)-negative/ERBB2 (formerly HER2)-positive, 59% for ERBB2-positive (HR-negative or HR-positive), 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. No major differences were found in the axillary pCR rates per subtype by analyzing separately the studies of patients with and without pathologically proven clinically node-positive disease before neoadjuvant systemic therapy.The HR-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate. These data may help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.
Psychometrics of health-related quality of life questionnaires in bronchiectasis: a systematic review and meta-analysis
Authors: Rebecca H. McLeese, Arietta Spinou, Zina Alfahl, Michail Tsagris, J. Stuart Elborn, James D. Chalmers, Anthony De Soyza, Michael R. Loebinger, Surinder S. Birring, Konstantinos C. Fragkos, Robert Wilson, Katherine O'Neill, Judy M. Bradley
Journal: European Respiratory Journal (2021)

Understanding the psychometric properties of health-related quality of life (HRQoL) questionnaires can help inform selection in clinical trials. Our objective was to assess the psychometric properties of HRQoL questionnaires in bronchiectasis using a systematic review and meta-analysis of the literature.A literature search was conducted. HRQoL questionnaires were assessed for psychometric properties (reliability, validity, minimal clinically important difference (MCID) and floor/ceiling effects). Meta-analyses assessed the associations of HRQoL with clinical measures and responsiveness of HRQoL in clinical trials.166 studies and 12 HRQoL questionnaires were included. The Bronchiectasis Health Questionnaire (BHQ), Leicester Cough Questionnaire (LCQ), Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) had good internal consistency in all domains reported (Cronbach's α≥0.7) across all studies, and the Quality of Life-Bronchiectasis (QOL-B), St George's Respiratory Questionnaire (SGRQ), Chronic Respiratory Disease Questionnaire (CRDQ) and Seattle Obstructive Lung Disease Questionnaire (SOLQ) had good internal consistency in all domains in the majority of (but not all) studies. BHQ, SGRQ, LCQ and CAT had good test-retest reliability in all domains reported (intraclass correlation coefficient ≥0.7) across all studies, and QOL-B, CRDQ and SOLQ had good test-retest reliability in all domains in the majority of (but not all) studies. HRQoL questionnaires were able to discriminate between demographics, important markers of clinical status, disease severity, exacerbations and bacteriology. For HRQoL responsiveness, there was a difference between the treatment and placebo effect.SGRQ was the most widely used HRQoL questionnaire in bronchiectasis studies and it had good psychometric properties; however, good psychometric data are emerging on the bronchiectasis-specific HRQoL questionnaires QOL-B and BHQ. Future studies should focus on the medium- to long-term test-retest reliability, responsiveness and MCID in these HRQoL questionnaires which show potential in bronchiectasis.
Service spotlight: Dr John Best and the injury clinic for asylum seekers and refugees
Authors: Mohammad Chaker Jomaa
Journal: British Journal of Sports Medicine (2021)

Dr John Best is one of Australia’s leading sports and exercise medicine physicians. He has had a successful career for many years since being awarded his fellowship with the Australasian College of Sports and Exercise Physicians in 1992. He has worked in various elite sporting roles, including the Australian rugby (Wallabies) team between 1994 and 2000, being part of their 1999 World Cup victory. Dr Best was awarded the Australian Sports Medal for his contribution to sports medicine in 2000. He currently acts as a medical consultant to the Australian Professional Golfers’ Association tournaments and is on the Australian National Rugby League Medical Advisory Panel.

In 2017, Dr Best set up the Injury Clinic for Asylum Seekers and Refugees (ICFAR) in Western Sydney, Australia. Since its opening, the clinic has operated once every 2 weeks, serving the local disadvantaged refugee and asylum seeker communities. Patients from Sri Lanka, Syria, Afghanistan, Iran and beyond have all presented with a range of medical ailments, acute and chronic musculoskeletal injuries and sociopolitical concerns.

Dr Best volunteers his time to support …