tbuckley/cabot-search huggingface dataset:
Augmentation of NK Cell Proliferation and Anti-tumor Immunity by Transgenic Expression of Receptors for EPO or TPO
Authors: Chantiya Chanswangphuwana, David S.J. Allan, Mala Chakraborty, Robert N. Reger, Richard W. Childs
Journal: Molecular Therapy (2020)

Many investigational adoptive immunotherapy regimens utilizing natural killer (NK) cells require the administration of interleukin-2 (IL-2) or IL-15, but these cytokines cause serious dose-dependent toxicities. To reduce or preclude the necessity for IL-2 use, we investigated whether genetic engineering of NK cells to express the erythropoietin (EPO) receptor (EPOR) or thrombopoietin (TPO) receptor (c-MPL) could be used as a method to improve NK cell survival and function. Viral transduction of NK-92 cells to express EPOR or c-MPL receptors conveyed signaling via appropriate pathways, protected cells from apoptosis, augmented cellular proliferation, and increased cell cytotoxic function in response to EPO or TPO ligands in vitro. In the presence of TPO, viral transduction of primary human NK cells to express c-MPL enhanced cellular proliferation and increased degranulation and cytokine production toward target cells in vitro. In contrast, transgenic expression of EPOR did not augment the proliferation of primary NK cells. In immunodeficient mice receiving TPO, in vivo persistence of primary human NK cells genetically modified to express c-MPL was higher compared with control NK cells. These data support the concept that genetic manipulation of NK cells to express hematopoietic growth factor receptors could be used as a strategy to augment NK cell proliferation and antitumor immunity.
Author Correction: Complex genetic signatures in immune cells underlie autoimmunity and inform therapy
Authors: Valeria Orrù, Maristella Steri, Carlo Sidore, Michele Marongiu, Valentina Serra, Stefania Olla, Gabriella Sole, Sandra Lai, Mariano Dei, Antonella Mulas, Francesca Virdis, Maria Grazia Piras, Monia Lobina, Mara Marongiu, Maristella Pitzalis, Francesca Deidda, Annalisa Loizedda, Stefano Onano, Magdalena Zoledziewska, Stephen Sawcer, Marcella Devoto, Myriam Gorospe, Gonçalo R. Abecasis, Matteo Floris, Mauro Pala, David Schlessinger, Edoardo Fiorillo, Francesco Cucca
Journal: Nature Genetics (2020)
Intratumoral Immunotherapy: From Trial Design to Clinical Practice
Authors: Stéphane Champiat, Lambros Tselikas, Siham Farhane, Thibault Raoult, Matthieu Texier, Emilie Lanoy, Christophe Massard, Caroline Robert, Samy Ammari, Thierry De Baère, Aurélien Marabelle
Journal: Clinical Cancer Research (2020)

Abstract Systemic immunotherapies such as immune checkpoint blockade targeted at PD(L)1 and CTLA4 have demonstrated their ability to provide durable tumor responses and long-term overall survival benefits for some patients in several solid tumor types. However, a majority of patients remain resistant to these treatments and a significant proportion of them develop severe autoimmune and inflammatory adverse events. Preclinical studies have demonstrated that intratumoral injections of immunostimulatory products (oncolytics, pattern recognition receptor agonists,…) that are able to trigger type I IFN release and enhance tumor antigen presentation on immune cells could generate a strong antitumor immunity and overcome the resistance to systemic immune checkpoint blockade therapies. The intratumoral immunotherapy strategies that are currently in clinical development offer a unique therapeutic and exploratory setting to better understand the immune contexture across tumor lesions of patients with metastatic cancer. Also these local therapeutic products could turn cold tumors into hot and improve the response rates to cancer immunotherapies while diminishing their systemic exposure and toxicities. Intratumoral immunotherapies could prime or boost the immunity against tumors and therefore radically change the combinatorial therapeutic strategies currently pursued for metastatic and local cancers to improve their long-term survival. We aimed to review and discuss the scientific rationale for intratumoral immunotherapy, the challenges raised by this strategy in terms of drug development within clinical trials and the current state-of-the-art regarding the clinical practice of this innovative approach.
Switching From Insulin Bolus Treatment to GLP-1 RAs Added to Continued Basal Insulin in People With Type 2 Diabetes on Basal-Bolus Insulin
Authors: Geremia B. Bolli, Francesca Porcellati, Juris J. Meier
Journal: Diabetes Care (2020)

In this issue of Diabetes Care , Rosenstock et al. (1) present successful substitution of prandial insulin with the long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA) albiglutide in the majority of a large group of people with type 2 diabetes (T2D) previously on basal-bolus (BB) insulin. The authors demonstrate that discontinuation of prandial insulin, either in total or in part, with add-on of albiglutide once per week while continuing titrated basal insulin (BI) improves glycemic control similarly to optimization of BB, reduces the risk for hypoglycemia, lowers body weight, and simplifies the insulin regimen, with improved patient-related outcomes. Before this study, the possibility of successful add-on of a GLP-1 RA, either short- (2,3) or long-acting (4,5), as alternative to prandial insulin was demonstrated in people on BI who needed treatment for prandial control. Two relatively small studies reported some advantages with addition of a long-acting GLP-1 RA to maintained BB (6,7), but it was only the FLAT-SUGAR (FLuctuATion Reduction With inSULin and Glp-1 Added togetheR) trial that demonstrated in 102 people with T2D and high cardiovascular risk on BB that the short-acting GLP-1 RA exenatide could fully substitute for prandial insulin (8). However, it was not known whether people already on BB could switch from three daily prandial insulin injections to a weekly GLP-1 RA while continuing BI before the study by Rosenstock et al. (1). If confirmed, these new findings will lead to a change in the treatment paradigm of the presently insulin-treated T2D population, estimated worldwide to be more than 60 million patients (9), at least one-third of whom are likely on BB insulin.

T2D is characterized by variable combinations of impaired insulin secretion and insulin resistance, primarily hepatic. While insulin resistance remains relatively stable over time, the progressive deterioration of …
Comparative Effectiveness of SGLT2 Inhibitors, GLP-1 Receptor Agonists, DPP-4 Inhibitors, and Sulfonylureas on Risk of Kidney Outcomes: Emulation of a Target Trial Using Health Care Databases
Authors: Yan Xie, Benjamin Bowe, Andrew K. Gibson, Janet B. McGill, Geetha Maddukuri, Yan Yan, Ziyad Al-Aly
Journal: Diabetes Care (2020)

OBJECTIVE To examine the comparative effectiveness of sodium–glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1), dipeptidyl peptidase 4 inhibitors (DPP-4), and sulfonylureas on risk of kidney outcomes among people with type 2 diabetes. RESEARCH DESIGN AND METHODS U.S. veterans initiated on SGLT2i (n = 18,544), GLP-1 (n = 23,711), DPP-4 (n = 39,399), or sulfonylureas (n = 134,904) were followed for up to 3 years to evaluate the risk of the composite outcome of estimated glomerular filtration rate (eGFR) decline &amp;gt;50%, end-stage kidney disease (ESKD), or all-cause mortality. Risks were estimated using survival models adjusted for predefined covariates as well as covariates identified by a high-dimensional variable selection algorithm through application of generalized propensity scores. RESULTS Compared with those treated with sulfonylureas, treatment with SGLT2i, GLP-1, and DPP-4 was associated with a lower risk of the composite outcome (hazard ratio 0.68 [95% CI 0.63, 0.74], 0.72 [0.67, 0.77], and 0.90 [0.86, 0.95], respectively). While we did not observe a statistically significant difference in risk between the SGLT2i and GLP-1 arms (0.95 [0.87, 1.04]), both SGLT2i and GLP-1 had a lower risk of the composite outcome than DPP-4 (0.76 [0.70, 0.82] and 0.79 [0.74, 0.85], respectively). Analyses by eGFR category suggested that compared with the sulfonylurea arm, those in the SGLT2i and GLP-1 arms exhibited a lower risk of the composite outcome in all eGFR categories, including eGFR &amp;lt;45 mL/min/1.73 m2. Compared with DPP-4, both SGLT2i and GLP-1 exhibited a reduced risk of the composite outcome in eGFR &amp;lt;90 to ≥60, &amp;lt;60 to ≥45, and &amp;lt;45 mL/min/1.73 m2. CONCLUSIONS In type 2 diabetes, treatment with SGLT2i or GLP-1 compared with DPP-4 or sulfonylureas was associated with a lower risk of adverse kidney outcomes.
What are network meta-analyses (NMAs)? A primer with four tips for clinicians who read NMAs and who perform them (methods matter series)
Authors: Amin Doosti-Irani, Maryam Nazemipour, Mohammad Ali Mansournia
Journal: British Journal of Sports Medicine (2020)

One randomised controlled trial (RCT) of a treatment does not revolutionise clinical practice. Clinician readers of BJSM will have noticed the increasing frequency of meta-analysis of treatment studies—valuable synthesis from many RCTs. The classic pairwise meta-analysis compares two treatments—most commonly one treatment over a control. The meta-analysis reports that exercise treatment reduces pain in osteoarthritis versus an education programme (control). Boom! Done.

But what about when there are many treatment options? We can immediately think of at least eight treatments for Achilles tendinopathy. Some of those treatments have not been compared against each other in RCTs (eg, heel raise inserts vs plasma-rich protein). This is where it is time for the clinician to call 1-800 Network Meta-Analysis. Network meta-analysis (NMA) is a clever and popular statistical method to compare numerous treatments for a condition. An NMA allows two treatments to be compared statistically, even if they have not been compared directly in any previous randomised controlled trial, via a common comparator. NMA methods also allow researchers to rank a series of treatments by their effectiveness.1

The Enhancing the Quality and Transparency of health Research reporting guidelines such as the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklists are extremely helpful for conducting NMAs1 and reporting the results,2 but …
Growth concerns in the early weeks of life
Authors: Russell J Peek, Nicky Wilson, Emma Cronin-Preece
Journal: BMJ (2020)

### What you need to know 

Amelia is four weeks old. At the request of her health visitor, Amelia’s mother comes to see you with concerns about growth. Amelia is Lucy's first baby, is breastfed, and has just regained her birth weight. The growth chart in her parent-held child health record shows Amelia is currently on the 25th centile, having been on the 75th centile at birth. Lucy is worried about whether she is able to meet Amelia’s nutritional needs. 

This article explores how to approach concerns about infant growth in the early weeks after birth, how to manage common problems, and when to seek additional support.

The aims of the consultation are to understand and explore parental concerns, look for evidence of illness in mother or baby, assess feeding, and provide advice, guiding families to additional support if required. Conversations about infant growth can be emotive and highly influential, making it essential to recognise and respond to parental concerns with sensitivity and provide evidence-informed guidance.

Anxiety about infant weight gain is common and can lead to early cessation of breastfeeding.12 In a UK-wide survey on infant feeding, the most common reasons to discontinue breastfeeding were concerns about milk supply, latch, or painful feeding.3 Slow weight gain in infants is usually related to suboptimal nutritional intake. Glandular breast tissue hypoplasia, which limits a woman’s ability to produce milk, is uncommon, with a reported incidence of 1 in 1000.45 Therefore, the consultation should consider maternal concerns and …
Hypertension and SARS-CoV-2 infection: is inflammation the missing link?
Authors: Elena Bartoloni, Carlo Perricone, Giacomo Cafaro, Roberto Gerli
Journal: Cardiovascular Research (2020)

receptor The dramatic emergence of the pandemic coronavirus disease COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) raised significant medical and public health concerns for the high disease mortality rate ranging from 1% to more than 5%.In this setting, patients with severe disease exhibit high serum levels of proinflammatory cytokines, including interleukin (IL)-1b and IL-6, and their elevated concentrations closely relate to worse outcome. 1 In addition to respiratory failure, cardiovascular system involvement and myocardial Figure 1 Alveolar epithelial cell internalize SARS-CoV-2 by ACE2.Viral PAMPs bind to TLR4 located on alveolar macrophage and activate adaptor protein MyD88-TNF receptor-associated factor (TRAF) 6 pathway, nuclear factor kappa B (NF-jB) translocation into the nucleus and pro-inflammatory cytokine release.TLR4-associated activation of TIR-domain-containing adapter-inducing interferon-b (TRIF) signalling results in a cascade similar to MyD88 pathway.Moreover, the NLRP3 inflammasome complex may be directly activated by NF-jB with IL-1b secretion and cytokine storm.The same mechanism may occur on endothelial cells inducing endothelial damage and subsequent hypertension.
Clinical and Striatal Dopamine Transporter Predictors of Mild Behavioral Impairment in Drug-Naive Parkinson Disease
Authors: Han Soo Yoo, Sangwon Lee, Seok Jong Chung, Byoung Seok Ye, Young H. Sohn, Mijin Yun, Phil Hyu Lee
Journal: Clinical Nuclear Medicine (2020)

Purpose Neuropsychiatric symptoms are important and frequent nonmotor features in Parkinson disease (PD). We explored mild behavioral impairment (MBI) in drug-naive patients with PD and its clinical and dopamine transporter (DAT) correlates. Methods We recruited 275 drug-naive patients with PD who had undergone Unified Parkinson’s Disease Rating Scale, a neuropsychological battery, Neuropsychiatric Inventory, and N -(3-[ 18 F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) PET within 6 months. Patients with PD were divided into groups without MBI (PD-MBI−, n = 186) and with MBI (PD-MBI+, n = 89) according to the Neuropsychiatric Inventory. We performed comparative analysis of DAT availability, cognitive function, and motor deficits between the groups. Results Mild behavioral impairment was found in 32.4% of PD patients at the time of diagnosis, and affective dysregulation and decreased motivation were the 2 most common neuropsychiatric domains. Dopamine transporter availability in the anterior caudate (odds ratio, 0.60; P = 0.016) and anterior putamen (odds ratio, 0.58; P = 0.008) was associated with the development of MBI in PD. PD-MBI+ group had a lower z -score in memory-related tests and Stroop color reading test than PD-MBI− group. PD-MBI+ group had a higher Unified Parkinson’s Disease Rating Scale motor score after controlling for DAT availability in the posterior putamen than PD-MBI− group ( P = 0.007). Conclusions This study suggests that early behavioral impairment is associated with more pathological involvement in the anterior striatum, memory and frontal dysfunction, and motor deficits, which could be regarded as a different phenotype in PD.
Serum Concentrations of Per- and Polyfluoroalkyl Substances and Risk of Renal Cell Carcinoma
Authors: Joseph J Shearer, Catherine L Callahan, Antonia M Calafat, Wen-Yi Huang, Rena R Jones, Venkata S Sabbisetti, Neal D Freedman, Joshua N Sampson, Debra T Silverman, Mark P Purdue, Jonathan N Hofmann
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Background Per- and polyfluoroalkyl substances (PFAS) are highly persistent chemicals that have been detected in the serum of over 98% of the US population. Studies among highly exposed individuals suggest an association with perfluorooctanoic acid (PFOA) exposure and kidney cancer. It remains unclear whether PFOA or other PFAS are renal carcinogens or if they influence risk of renal cell carcinoma (RCC) at concentrations observed in the general population. Methods We measured prediagnostic serum concentrations of PFOA and 7 additional PFAS in 324 RCC cases and 324 individually matched controls within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Multivariable conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs) relating serum PFAS concentrations and RCC risk. Individual PFAS were modeled continuously (log2-transformed) and categorically, with adjustment for kidney function and additional potential confounders. All statistical tests were 2-sided. Results We observed a positive association with RCC risk for PFOA (doubling in serum concentration, ORcontinuous = 1.71, 95% CI = 1.23 to 2.37, P = .002) and a greater than twofold increased risk among those in the highest quartile vs the lowest (OR = 2.63, 95% CI = 1.33 to 5.20, Ptrend = .007). The association with PFOA was similar after adjustment for other PFAS (ORcontinuous = 1.68, 95% CI = 1.07 to 2.63, P = .02) and remained apparent in analyses restricted to individuals without evidence of diminished kidney function and in cases diagnosed 8 or more years after phlebotomy. Conclusions Our findings add substantially to the weight of evidence that PFOA is a renal carcinogen and may have important public health implications for the many individuals exposed to this ubiquitous and highly persistent chemical.
Cognitive behavioural therapy for chronic fatigue and chronic fatigue syndrome: outcomes from a specialist clinic in the UK
Authors: James Adamson, Sheila Ali, Alastair Santhouse, Simon Wessely, Trudie Chalder
Journal: Journal of the Royal Society of Medicine (2020)

Objectives Cognitive behavioural therapy is commonly used to treat chronic fatigue syndrome and has been shown to be effective for reducing fatigue and improving physical functioning. Most of the evidence on the effectiveness of cognitive behavioural therapy for chronic fatigue syndrome is from randomised control trials, but there are only a few studies in naturalistic treatment settings. Our aim was to examine the effectiveness of cognitive behavioural therapy for chronic fatigue syndrome in a naturalistic setting and examine what factors, if any, predicted outcome. Design Using linear mixed effects analysis, we analysed patients' self-reported symptomology over the course of treatment and at three-month follow-up. Furthermore, we explored what baseline factors were associated with improvement at follow-up. Setting Data were available for 995 patients receiving cognitive behavioural therapy for chronic fatigue syndrome at an outpatient clinic in the UK. Participants Participants were referred consecutively to a specialist unit for chronic fatigue or chronic fatigue syndrome. Main outcome measures Patients were assessed throughout their treatment using self-report measures including the Chalder Fatigue Scale, 36-item Short Form Health Survey, Hospital Anxiety and Depression Scale and Global Improvement and Satisfaction. Results Patients’ fatigue, physical functioning and social adjustment scores significantly improved over the duration of treatment with medium to large effect sizes (|d| = 0.45–0.91). Furthermore, 85% of patients self-reported that they felt an improvement in their fatigue at follow-up and 90% were satisfied with their treatment. None of the regression models convincingly predicted improvement in outcomes with the best model being (R 2 = 0.137). Conclusions Patients’ fatigue, physical functioning and social adjustment all significantly improved following cognitive behavioural therapy for chronic fatigue syndrome in a naturalistic outpatient setting. These findings support the growing evidence from previous randomised control trials and suggest that cognitive behavioural therapy could be an effective treatment in routine treatment settings.
Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma
Authors: Thomas Powles, Se Hoon Park, Eric Voog, Claudia Caserta, Begoña P. Valderrama, Howard Gurney, Haralabos Kalofonos, Siniša Radulović, Wim Demey, Anders Ullén, Yohann Loriot, Srikala S. Sridhar, Norihiko Tsuchiya, Evgeny Kopyltsov, Cora N. Sternberg, Joaquim Bellmunt, Jeanny B. Aragon-Ching, Daniel P. Petrylak, Robert Laliberte, Jing Wang, Bo Huang, Craig Davis, Camilla Fowst, Nuno Costa, John A. Blake-Haskins, Alessandra di Pietro, Petros Grivas
Journal: New England Journal of Medicine (2020)

Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance.
Extensive germline genome engineering in pigs
Authors: Yanan Yue, Weihong Xu, Yinan Kan, Hong-Ye Zhao, Yixuan Zhou, Xiaobin Song, Jiajia Wu, Juan Xiong, Dharmendra Goswami, Meng Yang, Lydia Lamriben, Mengyuan Xu, Qi Zhang, Yu Luo, Jianxiong Guo, Shengyi Mao, Deling Jiao, Tien Dat Nguyen, Zhuo Li, Jacob V. Layer, Mailin Li, Violette Paragas, Michele E. Youd, Zhongquan Sun, Yuan Ding, Weilin Wang, Hongwei Dou, Lingling Song, Xueqiong Wang, Lei Le, Xin Fang, Haydy George, Ranjith Anand, Shi Yun Wang, William F. Westlin, Marc Güell, James Markmann, Wenning Qin, Yangbin Gao, Hong-Jiang Wei, George M. Church, Luhan Yang
Journal: Nature Biomedical Engineering (2020)
International Olympic Committee (IOC) Sport Mental Health Assessment Tool 1 (SMHAT-1) and Sport Mental Health Recognition Tool 1 (SMHRT-1): towards better support of athletes’ mental health
Authors: Vincent Gouttebarge, Abhinav Bindra, Cheri Blauwet, Niccolo Campriani, Alan Currie, Lars Engebretsen, Brian Hainline, Emily Kroshus, David McDuff, Margo Mountjoy, Rosemary Purcell, Margot Putukian, Claudia L Reardon, Simon M Rice, Richard Budgett
Journal: British Journal of Sports Medicine (2020)

Objectives To develop an assessment and recognition tool to identify elite athletes at risk for mental health symptoms and disorders. Methods We conducted narrative and systematic reviews about mental health symptoms and disorders in active and former elite athletes. The views of active and former elite athletes (N=360) on mental health symptoms in elite sports were retrieved through an electronic questionnaire. Our group identified the objective(s), target group(s) and approach of the mental health tools. For the assessment tool, we undertook a modified Delphi consensus process and used existing validated screening instruments. Both tools were compiled during two 2-day meeting. We also explored the appropriateness and preliminary reliability and validity of the assessment tool. Sport Mental Health Assessment Tool 1 and Sport Mental Health Recognition Tool 1 The International Olympic Committee Sport Mental Health Assessment Tool 1 (SMHAT-1) was developed for sports medicine physicians and other licensed/registered health professionals to assess elite athletes (defined as professional, Olympic, Paralympic or collegiate level; aged 16 years and older) potentially at risk for or already experiencing mental health symptoms and disorders. The SMHAT-1 consists of: (i) triage with an athlete-specific screening tool, (ii) six subsequent disorder-specific screening tools and (iii) a clinical assessment (and related management) by a sports medicine physician or licensed/registered mental health professional (eg, psychiatrist and psychologist). The International Olympic Committee Sport Mental Health Recognition Tool 1 (SMHRT-1) was developed for athletes and their entourage (eg, friends, fellow athletes, family and coaches). Conclusion The SMHAT-1 and SMHRT-1 enable that mental health symptoms and disorders in elite athletes are recognised earlier than they otherwise would. These tools should facilitate the timely referral of those athletes in need for appropriate support and treatment.