tbuckley/cabot-search huggingface dataset:
Genome‐Wide Occupancy Profiling Reveals Critical Roles of FoxO1 in Regulating Extracellular Matrix and Circadian Rhythm Genes in Human Chondrocytes
Authors: Tomas Duffy, Hirofumi Bekki, Martin K. Lotz
Journal: Arthritis & Rheumatology (2020)

Objective Osteoarthritis ( OA ) is the most common age‐related joint disease. With aging and in OA , the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome‐wide occupancy profile of FoxO1. Methods We performed FoxO1 chromatin immunoprecipitation followed by high‐throughput sequencing (Ch IP ‐Seq) on human primary chondrocytes. Ch IP ‐Seq data were integrated with RNA sequencing ( RNA ‐Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor. Results Analysis of FoxO1 Ch IP ‐Seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FoxO1 binding to tissue‐specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with RNA ‐Seq data comparing OA and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in OA . Pathway analysis showed enrichment for genes belonging to the senescence pathway (log P = −6.73), extracellular matrix ( ECM ) pathway (log P = −12.97), and circadian clock pathway (log P = −6.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in OA . Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes. Conclusion FoxO1 regulates ubiquitous and cartilage‐specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, ECM , and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis.
Light-activated gold nanorod vesicles with NIR-II fluorescence and photoacoustic imaging performances for cancer theranostics
Authors: Xiaoguang Ge, Qinrui Fu, Lichao Su, Zhi Li, Wenmin Zhang, Tao Chen, Huanghao Yang, Jibin Song
Journal: Theranostics (2020)

Fluorescence (FL) and photoacoustic (PA) imaging in the second near infrared window (NIR-II FL and NIR-II PA) hold great promise for biomedical applications because of their non-invasive nature and excellent spatial resolution properties.
Nuclear translocation of PLSCR1 activates STAT1 signaling in basal-like breast cancer
Authors: Panpan Huang, Ruocen Liao, Xingyu Chen, Xuebiao Wu, Xiaoli Li, Yifan Wang, Qianhua Cao, Chenfang Dong
Journal: Theranostics (2020)

Rationale: Basal-like breast cancer (BLBC) is associated with high grade, distant metastasis, and poor prognosis; however, the mechanism underlying aggressiveness of BLBC is still unclear.Emerging evidence has suggested that phospholipid scramblase 1 (PLSCR1) is involved in tumor progression.Here, we aimed to study the possible involvement and molecular mechanisms of PLSCR1 contributing to the aggressive behavior of BLBC.Methods: The potential functions of PLSCR1 in breast cancer cells were assessed by Western blotting, colony formation, migration and invasion, Cell Counting Kit-8 assay, mammosphere formation and flow cytometry.The relationship between nuclear translocation of PLSCR1 and transactivation of STAT1 was examined by immunostaining, co-IP, ChIP, and quantitative reverse transcription PCR.The effect of PLSCR1 expression on BLBC cells was determined by in vitro and in vivo tumorigenesis and a lung metastasis mouse model.Results: Compared to other subtypes, PLSCR1 was considerably increased in BLBC.Phosphorylation of PLSCR1 at Tyr 69/74 contributed to the nuclear translocation of this protein.PLSCR1 was enriched in the promoter region of STAT1 and enhanced STAT3 binding to the STAT1 promoter, resulting in transactivation of STAT1; STAT1 then enhanced cancer stem cell (CSC)-like properties that promoted BLBC progression.The knockdown of PLSCR1 led to significant inhibitory effects on proliferation, migration, invasion, tumor growth and lung metastasis of BLBC cells.Clinically, high PLSCR1 expression was strongly correlated with large tumor size, high grade, metastasis, chemotherapy resistance, and poor survival, indicating poor prognosis in breast cancer patients.Conclusions: Our data show that overexpression and nuclear translocation of PLSCR1 provide tumorigenic and metastatic advantages by activating STAT1 signaling in BLBC.This study not only reveals a critical mechanism of how PLSCR1 contributes to BLBC progression, but also suggests potential prognostic indicators and therapeutic targets for this challenging disease.
Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D™ Pilot Trial
Authors: Annie Young, Andrea Marshall, Jennifer Thirlwall, Catherine Hill, Danielle Hale, Janet Dunn, Anand Lokare, Ajay K. Kakkar, Mark N. Levine, Oliver Chapman
Journal: Blood (2017)
Urgent considerations for the neuro-oncologic treatment of patients with gliomas during the COVID-19 pandemic
Authors: Nimish A Mohile, Jaishri O Blakeley, Na Tosha N Gatson, Andreas F Hottinger, Andrew B Lassman, Douglas E Ney, Adriana Olar, David Schiff, Helen A Shih, Roy Strowd, Martin J van den Bent, Mateo Ziu
Journal: Neuro-Oncology (2020)

The COVID-19 outbreak is posing unprecedented risks and challenges for all communities and healthcare systems, worldwide. There are unique considerations for many adult patients with gliomas who are vulnerable to the novel coronavirus due to older age and immunosuppression. As patients with terminal illnesses, they present ethical challenges for centers that may need to ration access to ventilator care due to insufficient critical care capacity. It is urgent for the neuro-oncology community to develop a pro-active and coordinated approach to the care of adults with gliomas in order to provide them with the best possible oncologic care while also reducing their risk of viral infection during times of potential healthcare system failure. In this article, we present an approach developed by an international multi-disciplinary group to optimize the care of adults with gliomas during this pandemic. We recommend measures to promote strict social distancing and minimize exposures for patients, address risk and benefit of all therapeutic interventions, pro-actively develop end of life plans, educate patients and caregivers and ensure the health of the multi-disciplinary neuro-oncology workforce. This pandemic is already changing neuro-oncologic care delivery around the globe. It is important to highlight opportunities to maximize the benefit and minimize the risk of glioma management during this pandemic and potentially, in the future.
Effects of sedentary behaviour interventions on biomarkers of cardiometabolic risk in adults: systematic review with meta-analyses
Authors: Nyssa T Hadgraft, Elisabeth Winkler, Rachel E Climie, Megan S Grace, Lorena Romero, Neville Owen, David Dunstan, Genevieve Healy, Paddy C Dempsey
Journal: British Journal of Sports Medicine (2020)

Context/purpose Observational and acute laboratory intervention research has shown that excessive sedentary time is associated adversely with cardiometabolic biomarkers. This systematic review with meta-analyses synthesises results from free living interventions targeting reductions in sedentary behaviour alone or combined with increases in physical activity. Methods Six electronic databases were searched up to August 2019 for sedentary behaviour interventions in adults lasting for ≥7 days publishing cardiometabolic biomarker outcomes covering body anthropometry, blood pressure, glucose and lipid metabolism, and inflammation (54 studies). The pooled effectiveness of intervention net of control on 15 biomarker outcomes was evaluated using random effects meta-analyses in the studies with control groups not providing other relevant interventions (33 studies; 6–25 interventions analysed). Results Interventions between 2 weeks and &lt;6 months in non-clinical populations from North America, Europe and Australia comprised much of the evidence base. Pooled effects revealed small, significant (p&lt;0.05) beneficial effects on weight (≈ −0.6 kg), waist circumference (≈ −0.7 cm), percentage body fat (≈ −0.3 %), systolic blood pressure (≈ −1.1 mm Hg), insulin (≈ −1.4 pM) and high-density lipoprotein cholesterol (≈ 0.04 mM). Pooled effects on the other biomarkers (p&gt;0.05) were also small, and beneficial in direction except for fat-free mass (≈ 0.0 kg). Heterogeneity ranged widely (I 2 =0.0–72.9). Conclusions Our review of interventions targeting sedentary behaviour reductions alone, or combined with increases in physical activity, found evidence of effectiveness for improving some cardiometabolic risk biomarkers to a small degree. There was insufficient evidence to evaluate inflammation or vascular function. Key limitations to the underlying evidence base include a paucity of high-quality studies, interventions lasting for ≥12 months, sensitive biomarkers and clinical study populations (eg, type 2 diabetes). PROSPERO trial registration number CRD42016041742
Irene Marion Desmet: pioneering neonatal surgeon
Authors: John Illman
Journal: BMJ (2020)

desmet010420.f1 



The eminent paediatric and neonatal surgeon Irene Marion Desmet (nee Irving) wrote with classic understatement: “I feel that my real claim to fame is that of having managed to combine the careers of motherhood and surgery.”

This was much harder for her generation than for today’s. A former senior consultant surgeon at Alder Hey Children’s Hospital in Liverpool, and a prolific author, Desmet was among the first women to go to medical school immediately after the second world war—at the age of just 17. As a surgeon, mother of three children, and a hotelier wife who often cooked for guests, she was pulled in many different directions.

The challenge may have overwhelmed lesser women, but Desmet was—to use a word not then fashionable—“feisty.” She qualified as a pilot at the age of 20 and, rare for a woman then, had a passion for cars. As a woman she was viewed with …
Efficacy of psychological therapies for irritable bowel syndrome: systematic review and network meta-analysis
Authors: Christopher J Black, Elyse R Thakur, Lesley A Houghton, Eamonn M M Quigley, Paul Moayyedi, Alexander C Ford
Journal: Gut (2020)

Objectives National guidelines for the management of irritable bowel syndrome (IBS) recommend that psychological therapies should be considered, but their relative efficacy is unknown, because there have been few head-to-head trials. We performed a systematic review and network meta-analysis to try to resolve this uncertainty. Design We searched the medical literature through January 2020 for randomised controlled trials (RCTs) assessing efficacy of psychological therapies for adults with IBS, compared with each other, or a control intervention. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic, with a 95% CI to summarise efficacy of each comparison tested, and ranked by therapy according to P score. Results We identified 41 eligible RCTs, containing 4072 participants. After completion of therapy, the psychological interventions with the largest numbers of trials, and patients recruited, demonstrating efficacy included self-administered or minimal contact cognitive behavioural therapy (CBT) (RR 0.61; 95% CI 0.45 to 0.83, P score 0.66), face-to-face CBT (RR 0.62; 95% CI 0.48 to 0.80, P score 0.65) and gut-directed hypnotherapy (RR 0.67; 95% CI 0.49 to 0.91, P score 0.57). After completion of therapy, among trials recruiting only patients with refractory symptoms, group CBT and gut-directed hypnotherapy were more efficacious than either education and/or support or routine care, and CBT via the telephone, contingency management, CBT via the internet and dynamic psychotherapy were all superior to routine care. Risk of bias of trials was high, with evidence of funnel plot asymmetry; the efficacy of psychological therapies is therefore likely to have been overestimated. Conclusions Several psychological therapies are efficacious for IBS, although none were superior to another. CBT-based interventions and gut-directed hypnotherapy had the largest evidence base and were the most efficacious long term. Trial registration number The study protocol was published on the PROSPERO international prospective register of systematic reviews (registration number CRD 42020163246).
Letter by Consuegra-Sánchez et al Regarding Article, “Magnesium-Based Resorbable Scaffold Versus Permanent Metallic Sirolimus-Eluting Stent in Patients With ST-Segment Elevation Myocardial Infarction: The MAGSTEMI Randomized Clinical Trial”
Authors: Luciano Consuegra-Sánchez, Peter Ong, Juan Carlos Kaski
Journal: Circulation (2020)
Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan
Authors: Xiaochen Li, Shuyun Xu, Muqing Yu, Ke Wang, Yu Tao, Ying Zhou, Jing Shi, Min Zhou, Bo Wu, Zhenyu Yang, Cong Zhang, Junqing Yue, Zhiguo Zhang, Harald Renz, Xiansheng Liu, Jungang Xie, Min Xie, Jianping Zhao
Journal: Journal of Allergy and Clinical Immunology (2020)

In December 2019, the coronavirus disease 2019 (COVID-19) outbreak occurred in Wuhan. Data on the clinical characteristics and outcomes of patients with severe COVID-19 are limited.We sought to evaluate the severity on admission, complications, treatment, and outcomes of patients with COVID-19.Patients with COVID-19 admitted to Tongji Hospital from January 26, 2020, to February 5, 2020, were retrospectively enrolled and followed-up until March 3, 2020. Potential risk factors for severe COVID-19 were analyzed by a multivariable binary logistic model. Cox proportional hazard regression model was used for survival analysis in severe patients.We identified 269 (49.1%) of 548 patients as severe cases on admission. Older age, underlying hypertension, high cytokine levels (IL-2R, IL-6, IL-10, and TNF-α), and high lactate dehydrogenase level were significantly associated with severe COVID-19 on admission. The prevalence of asthma in patients with COVID-19 was 0.9%, markedly lower than that in the adult population of Wuhan. The estimated mortality was 1.1% in nonsevere patients and 32.5% in severe cases during the average 32 days of follow-up period. Survival analysis revealed that male sex, older age, leukocytosis, high lactate dehydrogenase level, cardiac injury, hyperglycemia, and high-dose corticosteroid use were associated with death in patients with severe COVID-19.Patients with older age, hypertension, and high lactate dehydrogenase level need careful observation and early intervention to prevent the potential development of severe COVID-19. Severe male patients with heart injury, hyperglycemia, and high-dose corticosteroid use may have a high risk of death.
Impact of Asparaginase Discontinuation on Outcome in Childhood Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group
Authors: Sumit Gupta, Cindy Wang, Elizabeth A. Raetz, Reuven Schore, Wanda L. Salzer, Eric C. Larsen, Kelly W. Maloney, Len A. Mattano, William L. Carroll, Naomi J. Winick, Stephen P. Hunger, Mignon L. Loh, Meenakshi Devidas
Journal: Journal of Clinical Oncology (2020)

Asparaginase (ASNase) is an important component of acute lymphoblastic leukemia (ALL) treatment, but is often discontinued because of toxicity. Erwiniachrysanthemi ASNase (Erwinia) substitution was approved in 2011 for allergic reactions. Erwinia has, however, been intermittently unavailable because of drug supply issues. The impact of Erwinia substitution or complete ASNase discontinuation is unknown.Patients aged 1-30.99 years in frontline Children's Oncology Group trials for B-cell acute lymphoblastic leukemia between 2004 and 2011 (National Cancer Institute [NCI] standard risk [SR]: AALL0331; NCI high risk: AALL0232) were included. The number of prescribed pegaspargase (PEG-ASNase) doses varied by trial and strata. Maintenance therapy did not contain ASNase. Landmark analyses at maintenance compared disease-free survival (DFS) among those receiving all prescribed PEG-ASNase doses versus switching to Erwinia but receiving all doses versus not receiving all ASNase doses.We included 5,195 AALL0331 and 3,001 AALL0232 patients. The cumulative incidence of PEG-ASNase discontinuation was 12.2% ± 4.6% in AALL0331 and 25.4% ± 0.8% in AALL0232. In multivariable analyses, NCI high-risk patients not receiving all prescribed ASNase doses had inferior DFS (hazard ratio [HR], 1.5; 95% CI, 1.2 to 1.9; P = .002) compared with those receiving all prescribed PEG-ASNase doses. Patients with Erwinia substitution who completed subsequent courses were not at increased risk (HR, 1.1; 95% CI, 0.7 to 1.6; P = .69). NCI SR patients who discontinued ASNase were not at elevated risk (HR, 1.2; 95% CI, 0.9 to 1.6; P = .23), except when restricted to those with slow early response, who were prescribed more ASNase because of therapy intensification (HR, 1.7; 95% CI, 1.1 to 2.7; P = .03).Discontinuation of ASNase doses is associated with inferior DFS in higher-risk patients. Our results illustrate the severe consequences of Erwinia shortages.
Incidence of and Factors Associated With Leprosy Among Household Contacts of Patients With Leprosy in Brazil
Authors: Camila Silveira Silva Teixeira, Júlia Moreira Pescarini, Flávia Jôse Oliveira Alves, Joilda Silva Nery, Mauro Niskier Sanchez, Carlos Teles, Maria Yury Travassos Ichihara, Anna Ramond, Liam Smeeth, Maria Lucia Fernandes Penna, Laura Cunha Rodrigues, Elizabeth B. Brickley, Gerson Oliveira Penna, Maurício Lima Barreto, Rita de Cássia Ribeiro Silva
Journal: JAMA Dermatology (2020)

Despite progress toward reducing global incidence, leprosy control remains a challenge in low- and middle-income countries.To estimate new case detection rates of leprosy among household contacts of patients with previously diagnosed leprosy and to investigate its associated risk factors.This population-based cohort study included families registered in the 100 Million Brazilian Cohort linked with nationwide registries of leprosy; data were collected from January 1, 2007, through December 31, 2014. Household contacts of patients with a previous diagnosis of leprosy from each household unit were followed up from the time of detection of the primary case to the time of detection of a subsequent case or until December 31, 2014. Data analysis was performed from May to December 2018.Clinical characteristics of the primary case and sociodemographic factors of the household contact.Incidence of leprosy, estimated as the new case detection rate of leprosy per 100 000 household contacts at risk (person-years at risk). The association between occurrence of a subsequent leprosy case and the exposure risk factors was assessed using multilevel mixed-effects logistic regressions allowing for state- and household-specific random effects.Among 42 725 household contacts (22 449 [52.5%] female; mean [SD] age, 22.4 [18.5] years) of 17 876 patients detected with leprosy, the new case detection rate of leprosy was 636.3 (95% CI, 594.4-681.1) per 100 000 person-years at risk overall and 521.9 (95% CI, 466.3-584.1) per 100 000 person-years at risk among children younger than 15 years. Household contacts of patients with multibacillary leprosy had higher odds of developing leprosy (adjusted odds ratio [OR], 1.48; 95% CI, 1.17-1.88), and the odds increased among contacts aged 50 years or older (adjusted OR, 3.11; 95% CI, 2.03-4.76). Leprosy detection was negatively associated with illiterate or preschool educational level (adjusted OR, 0.59; 95% CI, 0.38-0.92). For children, the odds were increased among boys (adjusted OR, 1.70; 95% CI, 1.20-2.42).The findings in this Brazilian population-based cohort study suggest that the household contacts of patients with leprosy may have increased risk of leprosy, especially in households with existing multibacillary cases and older contacts. Public health interventions, such as contact screening, that specifically target this population appear to be needed.
Emicizumab Subcutaneous Dosing Every 4 Weeks for the Management of Hemophilia A: Preliminary Data from the Pharmacokinetic Run-in Cohort of a Multicenter, Open-Label, Phase 3 Study (HAVEN 4)
Authors: Victor Jimenez-Yuste, Midori Shima, Katsuyuki Fukutake, Michaela Lehle, Sammy Chebon, Sylvie Retout, Agnès Portron, Gallia G. Levy
Journal: Blood (2017)
ACC/AHA Clinical Competence Statement on Electrocardiography and Ambulatory Electrocardiography
Authors: Alan H. Kadish, Alfred E. Buxton, Harold L. Kennedy, Bradley P. Knight, Jay W. Mason, Claudio D. Schuger, Cynthia M. Tracy, William L. Winters, Alan W. Boone, Michael Elnicki, John W. Hirshfeld, Beverly H. Lorell, George P. Rodgers, Cynthia M. Tracy, Howard H. Weitz
Journal: Circulation (2001)
Endpoints in Heart Failure Drug Development
Authors: Mona Fiuzat, Naomi Lowy, Norman Stockbridge, Marco Sbolli, Federica Latta, JoAnn Lindenfeld, Eldrin F. Lewis, William T. Abraham, John Teerlink, Mary Walsh, Paul Heidenreich, Biykem Bozkurt, Randall C. Starling, Scott Solomon, G. Michael Felker, Javed Butler, Clyde Yancy, Lynne W. Stevenson, Christopher O'Connor, Ellis Unger, Robert Temple, John McMurray
Journal: JACC Heart Failure (2020)
A CRISPR-based assay for the detection of opportunistic infections post-transplantation and for the monitoring of transplant rejection
Authors: Michael M. Kaminski, Miguel A. Alcantar, Isadora T. Lape, Robert Greensmith, Allison C. Huske, Jacqueline A. Valeri, Francisco M. Marty, Verena Klämbt, Jamil Azzi, Enver Akalin, Leonardo V. Riella, James J. Collins
Journal: Nature Biomedical Engineering (2020)