tbuckley/cabot-search huggingface dataset:
Abstract PR-003: Radiosensitization by targeting the NPM1/RAD51 axis
Authors: Michael L. Freeman, Geri Traver, Konjeti R. Sekhar, Peter A. Crooks
Journal: Clinical Cancer Research (2021)

Abstract NPM1 is a chaperone involved in base excision, translesion synthesis and homologous recombination (HR). In the presence of DNA DSBs pT199 NPM1 co-localizes with H2AX foci, a consequence of binding to K63-linked ubiquitinated histones that surround DSBs via its pT199 domain comprised of an acidic tract and adjacent ubiquitin interacting motif-like domain (1-3). SUMOlyated K263 NPM1 binds to and promotes Rad51 loading onto resected 3-prime DNA at the DSB. Failure to SUMOlyate K263NPM or inhibition of NPM1 reduces Rad51 filament formation, thus inhibiting HR (4). A major effort is underway to develop DNA damage response inhibitors. The novel chemical entity YTR107 is a 5-((N-benzyl-1H-indol-3-yl) methylene) pyrimidine-2, 4,6(1H,3H,5H) trione developed using forward chemical genetics and structure/function screening (5). Colony formation assays revealed that YTR107 radiosensitized 7 NSCLC lines (dose modifying factors of 1.5). Radiosensitization was NPM1-dependent as YTR107 did not radiosensitize an NPM1 null mouse embryo fibroblast cell line (3). Here we show that YTR107 inhibits radiation-induced NPM1 binding to Rad51, Rad 51 foci formation and repair of DNA DSBs.Tumor initiating cells (TICs) were radiosensitized by YTR107. YTR107 inhibited tumor growth (P = 0.027, 2-way ANOVA) and increased the survival of A549 tumor-bearing mice, determined 70 days after the last treatment. Survival of tumor-bearing mice was 60% for mice treated with YTR107and 2.2 Gy(q.d. x 7) vs 20% for mice treated with 2.2 Gy alone (q.d.x 7). Cox Proportional log rank hazard ratio for irradiated vs unirradiated tumor-bearing mice was 0.24 (P = 0.0034) while the log rank hazard ratio for YTR107 plus irradiation vs unirradiated (± YTR107) tumor-bearing mice was 0.17 (P = 0.0023). Thus, these data provide support for development of YTR107 as a therapeutic radiation sensitizer. Supported in part by R44CA228756. 1.Koike A, Nishikawa H, Wu W, Okada Y, Venkitaraman AR, Ohta T.Cancer Res 2010;70:6746-56 2. Sekhar KR, Benamar M, Venkateswaran A, Sasi S, Penthala NR, Crooks PA, et al. Int J Radiat Oncol Biol Phys 2014;89:1106-14 3. Sekhar KR, Reddy YT, Reddy PN, Crooks PA, Venkateswaran A, McDonald WH, et al. Clin Cancer Res 2011;17:6490-9 4. Xu R, Yu S, Zhu D, Huang X, Xu Y, Lao Y, et al. Nat Commun 2019;10:3812 5. Reddy YT, Sekhar KR, Sasi N, Reddy PN, Freeman ML, Crooks PA. Bioorg Med Chem Lett 2010;20:600-2 Citation Format: Michael L. Freeman, Geri Traver, Konjeti R. Sekhar, Peter A. Crooks. Radiosensitization by targeting the NPM1/RAD51 axis [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 PR-003.
Abstract PO-053: Targeting focal adhesions to limit radiation-induced glioblastoma cell invasion
Authors: Lisa R. Decotret, Rocky Shi, Kevin L. Bennewith
Journal: Clinical Cancer Research (2021)

Abstract Introduction: Glioblastoma multiforme (GBM) is a grade IV brain tumor that is considered incurable with a median overall survival of 15 months. This low survival rate is partially attributed to the highly infiltrative nature of GBM cells. A key component of GBM cell invasion is the degradation of extracellular matrix (ECM), which is facilitated by the formation of invadosomes: focal adhesions (FAs) and invadopodia. The majority of GBM patients will receive a conventional radiation schedule of 2 Gy in 30 fractions, while a subset of patients will receive a hypofractioned radiation schedule of ~3 Gy in 15 fractions. Recent pre-clinical reports indicate the population of GBM cells that survive ionizing radiation (IR) exhibit increased invasiveness, suggesting IR may regulate FA and invadopodia function. Understanding how IR affects invadosome biology may lead to new therapeutic strategies to halt the invasion of GBM cells and increase overall survival of patients treated with radiation. Results: We found that irradiated GBM cells were significantly more invasive in vitro. GBM cells irradiated with 0-4 Gy and plated onto fluorescently-tagged gelatin to analyze ECM degradation. Cells exposed to 0-2 Gy IR produced small dot-like patterns of degradation resembling active invadopodia. However, cells exposed to 3-4 Gy IR produced oblong-shaped patterns of degradation at the periphery of the cell resembling active FAs. Using immunofluorescent markers of invadopodia (TKS5/actin) and FAs (vinculin), we found total focal adhesion and invadopodia formation remained unchanged. Rather, we found that exposing cells to 3 Gy IR increased pFAK-397 in FA structures suggesting IR increases ECM degradation by promoting FA activity. Conclusions: These data suggest higher IR doses promote FA-mediated ECM degradation and GBM cell invasion. We are currently investigating the impact of IR on FAs, ECM degradation, and GBM cell invasion in murine brain slices ex vivo. Citation Format: Lisa R. Decotret, Rocky Shi, Kevin L. Bennewith. Targeting focal adhesions to limit radiation-induced glioblastoma cell invasion [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-053.
Abstract 16717: Cardiovascular Risk Profile of a Young Adult Population Assisted on a Primary Family Health Care Unit Located in Rio De Janeiro - A Pilot Project of LapARC Cohort Study
Authors: Rafael B Azevedo, Letícia Z Andrade, Marcelle G Oliveira, Thiago O Campos, Isadora S Miguel, Juliana B Assunção, Jaquline A Carvalho, Raquel M Costa, Yan B Barbosa, Gustavo d Ganem, Lais A Carvalho, Maria Eduarda A Ramos, Rafaela d Ramalho, Lucas L Pereira, Humberto M Crivellari, Bruna Pedrosa, Aline S Pereira, Abraão I Angelim, Ana Luisa B Franco, Carolina S Silva, Elizabeth S Muxfeldt
Journal: Circulation (2018)

Methods: This cross-sectional population study enrolled young adults between 20-50 years old, registered in a primary family healthcare unit located in the center of Rio de Janeiro, Brazil. The pilot study has already evaluated 23% of the local population. A database is being developed at the entrance of each participant into the cohort including sociodemographic characteristics, anthropometric measurements, and traditional cardiovascular (CV) risk factors. Furthermore, Office Blood Pressure (BP) was measured in 2 different occasions and the mean value was registered. Also, all subjects were submitted to a standard protocol, including a thorough clinical examination, a laboratory evaluation (lipid and glycemic profile and renal function) and electrocardiogram (EKG). Results: A total of 411 subjects were evaluated [162 (40%) males, mean age: 38 ± 8 years]. The most common CV risk factor was physical inactivity (45%), followed by obesity (25%) and dyslipidemia (19%). The prevalence of hypertension was 23%. Hypertensives were more frequently male, with a high prevalence of obesity and diabetes, and increased Sokolow’s index in the EKG. Moreover, a total of 23 (5%) subjects were diagnosed with impaired glucose tolerance and 18 (4%) with Diabetes Mellitus (DM), considering those with a previous diagnosis and the ones with serum glucose higher than 126mg/dL. The diabetic patients were older, with a higher prevalence of obesity, hypertension and dyslipidemia. A total of 147 (32%) presented dyslipidemia and only 15 (3%) are undergoing pharmacological intervention. The prevalence of metabolic syndrome was 21%. In relation to renal function, there are only 2 patients with Chronic Kidney Disease (CKD) stage 3 and no patients presented moderately increased albuminuria. Median UAER was 4.01 [IQL 2.75-5.92] and there is no difference between genders. Additionally, only 29% of participants did not present CV risk factors while 31% presented 2 to 5 CV risk factors. Conclusions: This young and apparently healthy population presented a high prevalence of modifiable (obesity and physical inactivity) and controllable (hypertension and dyslipidemia) CV risk factors, pointing to the importance of early CV risk stratification. Thus, effective prevention measures can be planned and implemented to decrease the probability of this population to develop a CV disease in the future.
Modeling Immunity In Vitro: Slices, Chips, and Engineered Tissues
Authors: Jennifer H. Hammel, Sophie R. Cook, Maura C. Belanger, Jennifer M. Munson, Rebecca R. Pompano
Journal: Annual Review of Biomedical Engineering (2021)

Modeling immunity in vitro has the potential to be a powerful tool for investigating fundamental biological questions, informing therapeutics and vaccines, and providing new insight into disease progression. There are two major elements to immunity that are necessary to model: primary immune tissues and peripheral tissues with immune components. Here, we systematically review progress made along three strategies to modeling immunity: ex vivo cultures, which preserve native tissue structure; microfluidic devices, which constitute a versatile approach to providing physiologically relevant fluid flow and environmental control; and engineered tissues, which provide precise control of the 3D microenvironment and biophysical cues. While many models focus on disease modeling, more primary immune tissue models are necessary to advance the field. Moving forward, we anticipate that the expansion of patient-specific models may inform why immunity varies from patient to patient and allow for the rapid comprehension and treatment of emerging diseases, such as coronavirus disease 2019.
Diffuse White Adipose Tissue 18F-FDG Uptake—An Unusual Finding on 18F-FDG PET/CT
Authors: Himanshu Bansal, Mudalsha Ravina, Siddhartha Nanda, Tinu Thadiyananickal Lukose, Sarin Krishna
Journal: Clinical Nuclear Medicine (2021)

Brown adipose tissue of cervical, supraclavicular, and paravertebral regions can show increased FDG uptake. But human white adipose tissue (WAT) shows negligible FDG uptake on 18F-FDG PET/CT scan. We present a case of carcinoma cervix treated with concurrent chemoradiation. 18F-FDG PET/CT shows altered biodistribution of FDG with intense FDG uptake throughout the WAT. Later on, patient confirmed taking herbal medication for herpes zoster infection, which could contain corticosteroids, resulting in enhanced WAT uptake of 18F-FDG.
Coaggregation of urogenital bacteria in vitro and in vivo
Authors: Gregor Reid, Estelle Gaudier, Francisco Guarner, Gary B. Huffnagle, Jean M. Macklaim, Alicia Murcia Munoz, Margaret Martini, Tamar Ringel-Kulka, Balfor R. Sartor, Robert R. Unal, Kristin Verbeke, Jens Walter
Journal: Gut Microbes (2010)
GRANADA consensus on analytical approaches to assess associations with accelerometer-determined physical behaviours (physical activity, sedentary behaviour and sleep) in epidemiological studies
Authors: Jairo H Migueles, Eivind Aadland, Lars Bo Andersen, Jan Christian Brønd, Sebastien F Chastin, Bjørge H Hansen, Kenn Konstabel, Olav Martin Kvalheim, Duncan E McGregor, Alex V Rowlands, Séverine Sabia, Vincent T van Hees, Rosemary Walmsley, Francisco B Ortega
Journal: British Journal of Sports Medicine (2021)

The inter-relationship between physical activity, sedentary behaviour and sleep (collectively defined as physical behaviours) is of interest to researchers from different fields. Each of these physical behaviours has been investigated in epidemiological studies, yet their codependency and interactions need to be further explored and accounted for in data analysis. Modern accelerometers capture continuous movement through the day, which presents the challenge of how to best use the richness of these data. In recent years, analytical approaches first applied in other scientific fields have been applied to physical behaviour epidemiology (eg, isotemporal substitution models, compositional data analysis, multivariate pattern analysis, functional data analysis and machine learning). A comprehensive description, discussion, and consensus on the strengths and limitations of these analytical approaches will help researchers decide which approach to use in different situations. In this context, a scientific workshop and meeting were held in Granada to discuss: (1) analytical approaches currently used in the scientific literature on physical behaviour, highlighting strengths and limitations, providing practical recommendations on their use and including a decision tree for assisting researchers' decision-making; and (2) current gaps and future research directions around the analysis and use of accelerometer data. Advances in analytical approaches to accelerometer-determined physical behaviours in epidemiological studies are expected to influence the interpretation of current and future evidence, and ultimately impact on future physical behaviour guidelines.
Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency
Authors: Stefano Vavassori, Janet Chou, Laura Eva Faletti, Veronika Haunerdinger, Lennart Opitz, Pascal Joset, Christopher J. Fraser, Seraina Prader, Xianfei Gao, Luise A. Schuch, Matias Wagner, Julia Hoefele, Maria Elena Maccari, Ying Zhu, George Elakis, Michael T. Gabbett, Maria Forstner, Heymut Omran, Thomas Kaiser, Christina Kessler, Heike Olbrich, Patrick Frosk, Abduarahman Almutairi, Craig D. Platt, Megan Elkins, Sabrina Weeks, Tamar Rubin, Raquel Planas, Tommaso Marchetti, Danil Koovely, Verena Klämbt, Neveen A. Soliman, Sandra von Hardenberg, Christian Klemann, Ulrich Baumann, Dominic Lenz, Andreas Klein-Franke, Martin Schwemmle, Michael Huber, Ekkehard Sturm, Steffen Hartleif, Karsten Häffner, Charlotte Gimpel, Barbara Brotschi, Guido Laube, Tayfun Güngör, Michael F. Buckley, Raimund Kottke, Christian Staufner, Friedhelm Hildebrandt, Simone Reu-Hofer, Solange Moll, Achim Weber, Hundeep Kaur, Stephan Ehl, Sebastian Hiller, Raif Geha, Tony Roscioli, Matthias Griese, Jana Pachlopnik Schmid
Journal: Journal of Allergy and Clinical Immunology (2021)
Screening for Vitamin D Deficiency in Adults
Authors: Leila C. Kahwati, Erin LeBlanc, Rachel Palmieri Weber, Kayla Giger, Rachel Clark, Kara Suvada, Amy Guisinger, Meera Viswanathan
Journal: JAMA (2021)

<h3>Importance</h3> Low serum vitamin D levels have been associated with adverse clinical outcomes; identifying and treating deficiency may improve outcomes. <h3>Objective</h3> To review the evidence about screening for vitamin D deficiency in adults. <h3>Data Sources</h3> PubMed, EMBASE, the Cochrane Library, and trial registries through March 12, 2020; bibliographies from retrieved articles, outside experts, and surveillance of the literature through November 30, 2020. <h3>Study Selection</h3> Fair- or good-quality, English-language randomized clinical trials (RCTs) of screening with serum 25-hydroxyvitamin D (25[OH]D) compared with no screening, or treatment with vitamin D (with or without calcium) compared with placebo or no treatment conducted in nonpregnant adults; nonrandomized controlled intervention studies for harms only. Treatment was limited to studies enrolling or analyzing participants with low serum vitamin D levels. <h3>Data Extraction and Synthesis</h3> Two reviewers assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; when at least 3 similar studies were available, meta-analyses were conducted. <h3>Main Outcomes and Measures</h3> Mortality, incident fractures, falls, diabetes, cardiovascular events, cancer, depression, physical functioning, and infection. <h3>Results</h3> Forty-six studies (N = 16 205) (77 publications) were included. No studies directly evaluated the health benefits or harms of screening. Among community-dwelling populations, treatment was not significantly associated with mortality (pooled absolute risk difference [ARD], 0.3% [95% CI, −0.6% to 1.1%]; 8 RCTs, n = 2006), any fractures (pooled ARD, −0.3% [95% CI, −2.1% to 1.6%]; 6 RCTs, n = 2186), incidence of diabetes (pooled ARD, 0.1% [95% CI, −1.3% to 1.6%]; 5 RCTs, n = 3356), incidence of cardiovascular disease (2 RCTs; hazard ratio, 1.00 [95% CI, 0.74 to 1.35] and 1.09 [95% CI, 0.68 to 1.76]), incidence of cancer (2 RCTs; hazard ratio, 0.97 [95% CI, 0.68 to 1.39] and 1.01 [95% CI, 0.65 to 1.58], or depression (3 RCTs, various measures reported). The pooled ARD for incidence of participants with 1 or more falls was −4.3% (95% CI, −11.6% to 2.9%; 6 RCTs). The evidence was mixed for the effect of treatment on physical functioning (2 RCTs) and limited for the effect on infection (1 RCT). The incidence of adverse events and kidney stones was similar between treatment and control groups. <h3>Conclusions and Relevance</h3> No studies evaluated the direct benefits or harms of screening for vitamin D deficiency. Among asymptomatic, community-dwelling populations with low vitamin D levels, the evidence suggests that treatment with vitamin D has no effect on mortality or the incidence of fractures, falls, depression, diabetes, cardiovascular disease, cancer, or adverse events. The evidence is inconclusive about the effect of treatment on physical functioning and infection.
Indoor Air Changes and Potential Implications for SARS-CoV-2 Transmission
Authors: Joseph G. Allen, Andrew M. Ibrahim
Journal: JAMA (2021)

This JAMA Insights review summarizes basic measures of indoor air ventilation as a means to explain how increases in frequency of air exchange and filtration capture efficiency could mitigate far-field airborne transmission of SARS-CoV-2 inside rooms and buildings.
Abstract 13803: A Short Connexin43 Carboxyl Terminal-Based Peptide Permeates Hemichannels and Provides Post-Infarction Cardioprotection in vivo
Authors: Stefano Toldo, Jingbo Jiang, Antonio Abbate, Jane L Jourdan, Robert G Gourdie
Journal: Circulation (2019)

Introduction: We have reported that αCT1, a therapeutic peptide incorporating the ZO-1 binding domain of Cx43 reduces arrhythmias and improves function following cardiac injury in a mouse model. αC...
ZNF410 represses fetal globin by singular control of CHD4
Authors: Divya S. Vinjamur, Qiuming Yao, Mitchel A. Cole, Connor McGuckin, Chunyan Ren, Jing Zeng, Mir Hossain, Kevin Luk, Scot A. Wolfe, Luca Pinello, Daniel E. Bauer
Journal: Nature Genetics (2021)
Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment
Authors: Valerie A Flores, Lubna Pal, JoAnn E Manson
Journal: Endocrine Reviews (2021)

Abstract Hormone therapy (HT) is an effective treatment for menopausal symptoms, including vasomotor symptoms and genitourinary syndrome of menopause. Randomized trials also demonstrate positive effects on bone health, and age-stratified analyses indicate more favorable effects on coronary heart disease and all-cause mortality in younger women (close proximity to menopause) than in women more than a decade past menopause. In the absence of contraindications or other major comorbidities, recently menopausal women with moderate or severe symptoms are appropriate candidates for HT. The Women’s Health Initiative (WHI) hormone therapy trials—estrogen and progestin trial and the estrogen-alone trial—clarified the benefits and risks of HT, including how the results differed by age. A key lesson from the WHI trials, which was unfortunately lost in the posttrial cacophony, was that the risk:benefit ratio and safety profile of HT differed markedly by clinical characteristics of the participants, especially age, time since menopause, and comorbidity status. In the present review of the WHI and other recent HT trials, we aim to provide readers with an improved understanding of the importance of the timing of HT initiation, type and route of administration, and of patient-specific considerations that should be weighed when prescribing HT.
Modeling vaccination rollouts, SARS-CoV-2 variants and the requirement for non-pharmaceutical interventions in Italy
Authors: Giulia Giordano, Marta Colaneri, Alessandro Di Filippo, Franco Blanchini, Paolo Bolzern, Giuseppe De Nicolao, Paolo Sacchi, Patrizio Colaneri, Raffaele Bruno
Journal: Nature Medicine (2021)

Despite the progress in medical care, combined population-wide interventions (such as physical distancing, testing and contact tracing) are still crucial to manage the SARS-CoV-2 pandemic, aggravated by the emergence of new highly transmissible variants. We combine the compartmental SIDARTHE model, predicting the course of COVID-19 infections, with a new data-based model that projects new cases onto casualties and healthcare system costs. Based on the Italian case study, we outline several scenarios: mass vaccination campaigns with different paces, different transmission rates due to new variants, and different enforced countermeasures, including the alternation of opening and closure phases. Our results demonstrate that non-pharmaceutical interventions (NPIs) have a higher impact on the epidemic evolution than vaccination, which advocates for the need to keep containment measures in place throughout the vaccination campaign. We also show that, if intermittent open-close strategies are adopted, deaths and healthcare system costs can be drastically reduced, without any aggravation of socioeconomic losses, as long as one has the foresight to start with a closing phase rather than an opening one.
Advances in Type 1 Diabetes Prediction Using Islet Autoantibodies: Beyond a Simple Count
Authors: Michelle So, Cate Speake, Andrea K Steck, Markus Lundgren, Peter G Colman, Jerry P Palmer, Kevan C Herold, Carla J Greenbaum
Journal: Endocrine Reviews (2021)

Islet autoantibodies are key markers for the diagnosis of type 1 diabetes. Since their discovery, they have also been recognized for their potential to identify at-risk individuals prior to symptoms. To date, risk prediction using autoantibodies has been based on autoantibody number; it has been robustly shown that nearly all multiple-autoantibody-positive individuals will progress to clinical disease. However, longitudinal studies have demonstrated that the rate of progression among multiple-autoantibody-positive individuals is highly heterogenous. Accurate prediction of the most rapidly progressing individuals is crucial for efficient and informative clinical trials and for identification of candidates most likely to benefit from disease modification. This is increasingly relevant with the recent success in delaying clinical disease in presymptomatic subjects using immunotherapy, and as the field moves toward population-based screening. There have been many studies investigating islet autoantibody characteristics for their predictive potential, beyond a simple categorical count. Predictive features that have emerged include molecular specifics, such as epitope targets and affinity; longitudinal patterns, such as changes in titer and autoantibody reversion; and sequence-dependent risk profiles specific to the autoantibody and the subject's age. These insights are the outworking of decades of prospective cohort studies and international assay standardization efforts and will contribute to the granularity needed for more sensitive and specific preclinical staging. The aim of this review is to identify the dynamic and nuanced manifestations of autoantibodies in type 1 diabetes, and to highlight how these autoantibody features have the potential to improve study design of trials aiming to predict and prevent disease.