tbuckley/cabot-search huggingface dataset:
Consequences of covid-19 on the childhood obesity epidemic
Authors: Rosemarie R Patterson, Sangeetha Sornalingam, Max Cooper
Journal: BMJ (2021)

rosemarie.patterson1@nhs.net Senthilingam describes the growing obesity epidemic and rightly identifies that the covid-19 pandemic presents opportunities for change.1 But she does little to explore the pandemic’s effect on the longstanding childhood obesity epidemic.1 The consequences of childhood obesity on physical and mental health, self-esteem, and social wellbeing are endangering the health of children and will increase future demand on NHS resources.2 The most recent UK National Child Measurement Programme (data collected pre-pandemic) shows that 21% of children aged 10-11 are already obese, increasing to 27.5% in more deprived areas.3 This is likely to worsen after covid-19 lockdowns, which have affected 75% of schoolchildren globally—weight gain is correlated with time spent out of school during holiday closures and is greater among those of lower socioeconomic status.45 Combined with food insecurity (over 20% of UK households are worse off financially now than before the pandemic), families are more likely to buy cheaper and more calorie-dense foods.6 Physical activity has also decreased. Before the pandemic, over 50% of children were not achieving physical activity guidelines.7 Despite restrictions allowing 60 minutes of exercise in a local area, nearly 30% of children report not leaving the house on a typical lockdown day.8 With parks, recreational areas, and sports clubs closed and screen time increased, there has been further reduction in physical activity in young people;this is more pronounced among ethnic minority communities.89 Like previous policy documents, the July 2020 UK Obesity Strategy does not go far enough to tackle underlying health inequalities linked with childhood obesity.10 It contains many previously proposed (but never implemented) strategies, and these measures are weak in comparison with other countries.101112 Convergence of the childhood obesity epidemic and the covid-19 pandemic means that now is the time for urgent and decisive action by government to protect the wellbeing of children and future health of the UK population. National child measurement programme, England 2019-20 school year. 2020. https://digital.nhs.uk/data-and-information/publications/statistical/national-child-measurement-programme/2019-20-school-year#summary. 4 Franckle R Adler R Davison K. Accelerated weight gain among children during summer versus school year and related racial/ethnic disparities: a systematic review.
Age-related changes in muscle architecture and metabolism in humans: The likely contribution of physical inactivity to age-related functional decline
Authors: N.F. Shur, L. Creedon, S. Skirrow, P.J. Atherton, I.A. MacDonald, J. Lund, P.L. Greenhaff
Journal: Ageing Research Reviews (2021)

In the United Kingdom (UK), it is projected that by 2035 people aged >65 years will make up 23 % of the population, with those aged >85 years accounting for 5% of the total population. Ageing is associated with progressive changes in muscle metabolism and a decline in functional capacity, leading to a loss of independence. Muscle metabolic changes associated with ageing have been linked to alterations in muscle architecture and declines in muscle mass and insulin sensitivity. However, the biological features often attributed to muscle ageing are also seen in controlled studies of physical inactivity (e.g. reduced step-count and bed-rest), and it is currently unclear how many of these ageing features are due to ageing per se or sedentarism. This is particularly relevant at a time of home confinements reducing physical activity levels during the Covid-19 pandemic. Current knowledge gaps include the relative contribution that physical inactivity plays in the development of many of the negative features associated with muscle decline in older age. Similarly, data demonstrating positive effects of government recommended physical activity guidelines on muscle health are largely non-existent. It is imperative therefore that research examining interactions between ageing, physical activity and muscle mass and metabolic health is prioritised so that it can inform on the "normal" muscle ageing process and on strategies for improving health span and well-being. This review will focus on important changes in muscle architecture and metabolism that accompany ageing and highlight the likely contribution of physical inactivity to these changes.
Metformin improves diabetic endothelial barrier integrity by increasing ACE-2 receptor expression
Authors: E. Fick, M. Leo
Journal: Circulation Research (2020)

Background: The COVID-19 virus gains entry into cells through the Angiotensinconverting enzyme 2 (ACE-2) receptor present on the cell surface  The ACE-2 receptor is present in many cell types including endothelial cells, where it helps protect against oxidative damage  Recent reports suggest that some patients who test positive for COVID-19 also showed symptoms related to endothelial damage  We investigated this effect in vitro using endothelial cell culture and commercially procured recombinant COVID-19 spike protein S1 Receptor-Binding Domain (S1RBD)  Materials and Methods: Mouse brain microvascular endothelial cells from normal (C57BL/6) and diabetic (db/db) mice were used  ACE-2 receptor expression was studied using real time-PCR (RT-PCR) and Western blot  A commercial endothelial transwell permeability assay kit was used to assess endothelial barrier integrity in vitro  Results: ACE-2 mRNA and total protein expression decreased by ∼50% in diabetic endothelial cells  Endothelial permeability increased ∼3-fold in diabetic cells compared to normal cells which indicated impaired barrier integrity  Incubation of normal cells for 18h with PD123319, a specific ACE-2 receptor blocker, or recombinant S1RBD, decreased ACE-2 total protein by ∼50% and ∼60% respectively, and also increased endothelial permeability by ∼2 5-fold each, compared to untreated controls  Addition of PD123319 and S1RBD to diabetic cells caused a further reduction in ACE-2 total protein to ∼55% and ∼63% respectively, and ∼3-fold increase in endothelial permeability compared to normal untreated controls  Metformin alone had no significant effect on ACE-2 receptor expression in normal cells but increased expression almost 3-fold and decreased permeability by ∼40% in diabetic cells compared to untreated diabetic controls  Pre-treatment of diabetic cells for 12h with metformin and then co-incubating with the S1RBD for 18h, not only prevented loss of ACE-2 protein but also increased expression ∼2-fold and decreased endothelial permeability ∼2 5-fold compared to S1RBD treatment alone  Conclusion: Metformin protects endothelial barrier integrity against recombinant S1RBD challenge by stabilizing ACE-2 receptor expression in diabetic cells
Genetic Architecture Underlying Nascent Speciation—The Evolution of Eurasian Pigs under Domestication
Authors: Hai-Bing Xie, Li-Gang Wang, Chen-Yu Fan, Long-Chao Zhang, Adeniyi C Adeola, Xue Yin, Zhao-Bang Zeng, Li-Xian Wang, Ya-Ping Zhang
Journal: Molecular Biology and Evolution (2021)

Speciation is a process whereby the evolution of reproductive barriers leads to isolated species. Although many studies have addressed large-effect genetic footprints in the advanced stages of speciation, the genetics of reproductive isolation in nascent stage of speciation remains unclear. Here, we show that pig domestication offers an interesting model for studying the early stages of speciation in great details. Pig breeds have not evolved the large X-effect of hybrid incompatibility commonly observed between "good species." Instead, deleterious epistatic interactions among multiple autosomal loci are common. These weak Dobzhansky-Muller incompatibilities confer partial hybrid inviability with sex biases in crosses between European and East Asian domestic pigs. The genomic incompatibility is enriched in pathways for angiogenesis, androgen receptor signaling and immunity, with an observation of many highly differentiated cis-regulatory variants. Our study suggests that partial hybrid inviability caused by pervasive but weak interactions among autosomal loci may be a hallmark of nascent speciation in mammals.
Government and medical educators must act to reduce deaths from air pollution, says coroner
Authors: Clare Dyer
Journal: BMJ (2021)

The coroner who made the first UK ruling giving toxic air as a cause of death has called on the government and doctors’ training bodies to take urgent action to cut the risk of deaths from air pollution.1

Philip Barlow, assistant coroner for inner south London, concluded last December that air pollution made a significant contribution to the 2013 death of nine year old Ella Adoo-Kissi-Debrah, who had severe asthma and lived near the busy South Circular Road in Lewisham, south London.2

In his regulation 28 report to prevent future deaths, published on 21 April, he called for government action to reduce air pollution, wide …
Abstract PO-077: Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress
Authors: Kim N. Chi, Ur Metser, Johannes Czernin, Jeremie Calais, Vikas Prasad, Matthias Eiber, Neal Shore, Jessica Jensen, Neil Fleshner, Scott Tagawa, Oliver Sartor
Journal: Clinical Cancer Research (2021)

Abstract Background: Treatment options with minimal toxicity and novel mechanisms of action are urgently needed to improve clinical outcomes from mCRPC. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) represents a new treatment for patients with PSMA-avid mCRPC. 177Lu-PNT2002 (also known as [Lu-177]-PSMA-I&amp;T) is a PSMA-targeting agent and studies have shown demonstrable promising initial data. This trial seeks to prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive mCRPC after androgen receptor axis-targeted (ARAT) therapy. Methods: This is a multi-center, open-label, phase III study. All patients must be at least 18 years of age, have documented progressive mCRPC at time of screening, high PSMA expression by PSMA PET/CT per blinded independent central review (BICR), chemotherapy naïve for CRPC and unfit or unwilling to receive chemotherapy. The study will commence with a 25-patient dosimetry lead-in. In the dosimetry phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. In the randomization phase, approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Patients randomized to Arm B have an option to crossover to 177Lu-PNT2002 treatment after BICR-assessed radiologic progression. The primary endpoint is Radiological progression-free survival (rPFS) assessed by BICR using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (soft tissue) and Prostate Cancer Working Group 3 (PCWG3) (bone) criteria. Key secondary endpoints include objective response rate, duration of response, PSA response, and overall survival. The study is powered at 90% to test the alternative hypothesis of a hazard ratio (HR) ≤ 0.66 at an α of 0.025. ClinicalTrials.gov identifier: NCT04647526. Citation Format: Kim N. Chi, Ur Metser, Johannes Czernin, Jeremie Calais, Vikas Prasad, Matthias Eiber, Neal Shore, Jessica Jensen, Neil Fleshner, Scott Tagawa, Oliver Sartor. Study evaluating metastatic castrate resistant prostate cancer (mCRPC) treatment using 177Lu-PNT2002 PSMA therapy after second-line hormonal treatment (SPLASH) - Trial in progress [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-077.
Association between ambient PM2·5 and under-5, infant, and child mortality in Latin America, 2010–15: a longitudinal analysis
Authors: Ana Ortigoza, Nelson Gouveia, Josiah Kephart, Francisco Prado-Galbarro, Amelia A Friche, Brisa N Sanchez, Ana V Diez-Roux
Journal: The Lancet Planetary Health (2021)

BackgroundHighly urbanised and rapidly urbanising countries are facing critical air pollution problems. In Latin American cities, the effect of ambient PM2·5 on child health has not been extensively explored. We examined associations between ambient PM2·5 and under-5 mortality (deaths in those younger than 5 years per 1000 livebirths) infant mortality (deaths in those younger than 1 year per 1000 livebirths), and child mortality (deaths in those aged 1–4 years per 10 000 children) in Latin American cities.MethodsIn this longitudinal analysis, we estimated under-5 mortality, infant mortality, and child mortality for the period Jan 1, 2010, to dec 12, 2015, for 1152 subcity units clustered in 337 cities in Argentina, Brazil, Chile, Colombia, Costa Rica, Guatemala, and Mexico. We retrieved mean annual PM2·5 for each subcity unit. Using linear mixed-effects models, we estimated the percentage change in under-5 mortality, infant mortality, and child mortality associated with a 1 μg/m3 increase in annual PM2·5, adjusted for city-level and subcity-level predictors (population growth, gross domestic product, living conditions, water and sanitation provision, population education, and mass transit availability).FindingsOver the study period, mean annual PM2·5 was 12·7 μg/m3 (SD 6·3), under-5 mortality was 14·2 deaths per 1000 livebirths, infant mortality was 12·1 deaths per 1000 livebirths, and child mortality was 4·8 deaths per 10 000 children. A 1 μg/m3 annual increase in PM2·5 was associated with 0·4% (95% CI 0·1 to 0·7) increase in under-5 mortality and 0·5% (95% CI 0·2 to 0·9) increase in infant mortality We found no significant association between PM2·5 increases and changes in child mortality (–0·1% [95% CI −0·8 to 0·6]).InterpretationOur findings support the need for environmental protection in the Latin American region for improving both planetary and population health. Transdisciplinary strategies at local levels, including public health practitioners and policy stakeholders involved in urban development, are key for implementing these changes.FundingThe Wellcome Trust initiative Our Planet, Our Health.
Determinants of hepatic insulin clearance – Results from a Mendelian Randomization study
Authors: Apostolia Lamprinou, Caroline Willmann, Jürgen Machann, Fritz Schick, Sabine S. Eckstein, Chiara Dalla Man, Roberto Visentin, Andreas L. Birkenfeld, Andreas Peter, Norbert Stefan, Hans-Ulrich Häring, Andreas Fritsche, Martin Heni, Robert Wagner
Journal: Metabolism (2021)
Homeobox B5 promotes metastasis and poor prognosis in Hepatocellular Carcinoma, via FGFR4 and CXCL1 upregulation
Authors: Qin He, Wenjie Huang, Danfei Liu, Tongyue Zhang, Yijun Wang, Xiaoyu Ji, Meng Xie, Mengyu Sun, Dean Tian, Mei Liu, Limin Xia
Journal: Theranostics (2021)

Background: Since metastasis remains the main reason for HCC-associated death, a better understanding of molecular mechanism underlying HCC metastasis is urgently needed. Here, we elucidated the role of Homeobox B5 (HOXB5), a member of the HOX transcriptional factor family, in promoting HCC metastasis. Method: The expression of HOXB5 and its functional targets fibroblast growth factor receptor 4 (FGFR4) and C-X-C motif chemokine ligand 1 (CXCL1) were detected by immunohistochemistry. Luciferase reporter and chromatin immunoprecipitation assays were performed to measure the transcriptional regulation of target genes by HOXB5. The effects of FGFR4 and CXCL1 on HOXB5-mediated metastasis were analyzed by an orthotopic metastasis model. Results: Elevated expression of HOXB5 had a positive correlation with poor tumour differentiation, higher TNM stage, and indicated unfavorable prognosis. Overexpression of HOXB5 promoted HCC metastasis through transactivating FGFR4 and CXCL1 expression, whereas knockdown of FGFR4 and CXCL1 decreased HOXB5-enhanced HCC metastasis. Moreover, HOXB5 overexpression in HCC cells promoted myeloid derived suppressor cells (MDSCs) infiltration through CXCL1/CXCR2 axis. Either depletion of MDSCs by anti-Gr1 or blocking CXCL1-CXCR2 axis by CXCR2 inhibitor impaired HOXB5-mediated HCC metastasis. In addition, fibroblast growth factor 19 (FGF19) contributed to the HOXB5 upregulation through PI3K/AKT/HIF1α pathway. Overexpression of FGF15 (an analog of FGF19 in mouse) promoted HCC metastasis, whereas knockdown of HOXB5 significantly inhibited FGF15-enhanced HCC metastasis in immunocompetent mice. HOXB5 expression was positively associated with CXCL1 expression and intratumoral MDSCs accumulation in human HCC tissues. Patients who co-expressed HOXB5/CXCL1 or HOXB5/CD11b exhibited the worst prognosis. Furthermore, the combination of FGFR4 inhibitor BLU-554 and CXCR2 inhibitor SB265610 dramatically decreased HOXB5-mediated HCC metastasis. Conclusion: HOXB5 was a potential prognostic biomarker in HCC patients and targeting this loop may provide a promising treatment strategy for the inhibition of HOXB5-mediated HCC metastasis.
Mastectomy or Breast-Conserving Therapy for <i>BRCA1/2</i> Variant Carriers
Authors: Marissa Howard-McNatt
Journal: JAMA Network Open (2021)

Qiting Wan, MD; Liming Su, MD; Tao Ouyang, MD; Jinfeng Li, MD; Tianfeng Wang, MD; Zhaoqing Fan, MD; Tie Fan, MD; Benyao Lin, MD; Yuntao Xie, MD, PhD
Abstract PO-033: Papaverine derivative smv-32 alleviates tumor hypoxia and radiosensitizes tumors by inhibiting mitochondrial metabolism
Authors: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko
Journal: Clinical Cancer Research (2021)

Abstract Radiation therapy is a standard type of treatment modality used to achieve local control in more than 50% of all cancer patients. However, tumor hypoxia reduces the effectiveness of radiation therapy by limiting the biologically effective dose. We identified that FDA-approved phosphodiesterase 10A (PDE10A) inhibitor papaverine (PPV) has an off-target effect inhibiting mitochondrial oxygen consumption (OCR) leading to acute reduction of tumor hypoxia and significant radiosensitization of model tumors. Our data suggests that PDE10A does not contribute to the radiosensitizing effect. Based on PPV’s structure, we used biomedicinal chemistry approach to engineer its novel derivative SMV-32 with reduced PDE10A inhibition. We used Seahorse metabolic flux analyzer to determine the effect of PPV and SMV-32 on mitochondrial OCR in vitro. Near-infrared optical spectroscopy and pODD-luciferase in vivo reporter system was used for pharmacodynamics analyses and dose response evaluation. Local radiation therapy was delivered using Small Animal Radiation Research Platform (SARRP). We compared intraperitoneal (IP) and intravenous (IV) delivery and optimized dosing using pODD luciferase reporter system. SMV-32 showed superior OCR inhibition in vitro and enhanced hypoxia reduction in vivo compared to PPV. A single clinically relevant dose of PPV or SMV-32 significantly reduced the hypoxic fractions of heterotopic and orthotopic tumors in mice and sensitized the tumors to radiation therapy. PPV and SMV-32 appear to be ideal candidates for clinical radiosensitization. PPV is already in phase I clinical trial for treatment of non-small cell lung cancer combined with stereotactic body radiation therapy. Citation Format: Martin Benej, Jinghai Wu, McKenzie Kreamer, Sandip Vibhute, Ioanna Papandreou, Nicholas C. Denko. Papaverine derivative smv-32 alleviates tumor hypoxia and radiosensitizes tumors by inhibiting mitochondrial metabolism [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-033.
COVID-19 Lessons From the National Basketball Association Bubble—Can Persistently SARS-CoV-2–Positive Individuals Transmit Infection to Others?
Authors: James W. Salazar, Mitchell H. Katz
Journal: JAMA Internal Medicine (2021)

Christina D. Mack, PhD, MSPH; John DiFiori, MD; Caroline G. Tai, PhD; Kristin Y. Shiue, MPH; Yonatan H. Grad, MD; Deverick J. Anderson, MD; David D. Ho, MD; Leroy Sims, MD; Christopher LeMay, DO; Jimmie Mancell, MD; Lisa L Maragakis, MD, MPH
Profound dysregulation of T cell homeostasis and function in patients with severe COVID‐19
Authors: Sarah Adamo, Stéphane Chevrier, Carlo Cervia, Yves Zurbuchen, Miro E. Raeber, Liliane Yang, Sujana Sivapatham, Andrea Jacobs, Esther Baechli, Alain Rudiger, Melina Stüssi‐Helbling, Lars C. Huber, Dominik J. Schaer, Bernd Bodenmiller, Onur Boyman, Jakob Nilsson
Journal: Allergy (2021)

Abstract Background Coronavirus disease 2019 (COVID‐19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and shows a broad clinical presentation ranging from asymptomatic infection to fatal disease. A very prominent feature associated with severe COVID‐19 is T cell lymphopenia. However, homeostatic and functional properties of T cells are ill‐defined in COVID‐19. Methods We prospectively enrolled individuals with mild and severe COVID‐19 into our multicenter cohort and performed a cross‐sectional analysis of phenotypic and functional characteristics of T cells using 40‐parameter mass cytometry, flow cytometry, targeted proteomics, and functional assays. Results Compared with mild disease, we observed strong perturbations of peripheral T cell homeostasis and function in severe COVID‐19. Individuals with severe COVID‐19 showed T cell lymphopenia and redistribution of T cell populations, including loss of naïve T cells, skewing toward CD4 + T follicular helper cells and cytotoxic CD4 + T cells, and expansion of activated and exhausted T cells. Extensive T cell apoptosis was particularly evident with severe disease and T cell lymphopenia, which in turn was accompanied by impaired T cell responses to several common viral antigens. Patients with severe disease showed elevated interleukin‐7 and increased T cell proliferation. Furthermore, patients sampled at late time points after symptom onset had higher T cell counts and improved antiviral T cell responses. Conclusion Our study suggests that severe COVID‐19 is characterized by extensive T cell dysfunction and T cell apoptosis, which is associated with signs of homeostatic T cell proliferation and T cell recovery.