tbuckley/cabot-search huggingface dataset:
Intravenous supplementation type and volume are associated with 1-year outcome and major complications in patients with chronic intestinal failure
Authors: Loris Pironi, Ezra Steiger, Francisca Joly, Geert J A Wanten, Cecile Chambrier, Umberto Aimasso, Anna Simona Sasdelli, Kinga Szczepanek, Amelia Jukes, Miriam Theilla, Marek Kunecki, Joanne Daniels, Mireille J Serlie, Sheldon C Cooper, Florian Poullenot, Henrik Højgaard Rasmussen, Charlene W Compher, Adriana Crivelli, Sarah-Jane Hughes, Lidia Santarpia, Francesco William Guglielmi, Nada Rotovnik Kozjek, Lars Ellegard, Stéphane M Schneider, Przemysław Matras, Alastair Forbes, Nicola Wyer, Anna Zmarzly, Marina Taus, Margie O'Callaghan, Emma Osland, Ronan Thibault, Cristina Cuerda, Lynn Jones, Brooke Chapman, Peter Sahin, Núria M Virgili, Andre Dong Won Lee, Paolo Orlandoni, Konrad Matysiak, Simona Di Caro, Maryana Doitchinova-Simeonova, Luisa Masconale, Corrado Spaggiari, Carmen Garde, Aurora E Serralde-Zúñiga, Gabriel Olveira, Zeljko Krznaric, Estrella Petrina Jáuregui, Ana Zugasti Murillo, José P Suárez-Llanos, Elena Nardi, André Van Gossum, Simon Lal
Journal: Gut (2020)

Background and aim No marker to categorise the severity of chronic intestinal failure (CIF) has been developed. A 1-year international survey was carried out to investigate whether the European Society for Clinical Nutrition and Metabolism clinical classification of CIF, based on the type and volume of the intravenous supplementation (IVS), could be an indicator of CIF severity. Methods At baseline, participating home parenteral nutrition (HPN) centres enrolled all adults with ongoing CIF due to non-malignant disease; demographic data, body mass index, CIF mechanism, underlying disease, HPN duration and IVS category were recorded for each patient. The type of IVS was classified as fluid and electrolyte alone (FE) or parenteral nutrition admixture (PN). The mean daily IVS volume, calculated on a weekly basis, was categorised as &lt;1, 1–2, 2–3 and &gt;3 L/day. The severity of CIF was determined by patient outcome (still on HPN, weaned from HPN, deceased) and the occurrence of major HPN/CIF-related complications: intestinal failure-associated liver disease (IFALD), catheter-related venous thrombosis and catheter-related bloodstream infection (CRBSI). Results Fifty-one HPN centres included 2194 patients. The analysis showed that both IVS type and volume were independently associated with the odds of weaning from HPN (significantly higher for PN &lt;1 L/day than for FE and all PN &gt;1 L/day), patients’ death (lower for FE, p=0.079), presence of IFALD cholestasis/liver failure and occurrence of CRBSI (significantly higher for PN 2–3 and PN &gt;3 L/day). Conclusions The type and volume of IVS required by patients with CIF could be indicators to categorise the severity of CIF in both clinical practice and research protocols.
A05 ART1, a Mono-ADP-Ribosyltransferase, Regulates Tumor-Infiltrating CD8+ T Cells and Is Highly Expressed in EGFR Mutated Lung Cancers
Authors: S. Mukherjee, E. Wennerberg, C. Hung, N. Saadallah, S. Kariyawasam, M.K. Hussein, N. Narula, P. Adusumilli, A. Borczuk, N. Altorki, T. McGraw, B.M. Stiles
Journal: Journal of Thoracic Oncology (2020)
GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein
Authors: Jing Cheng, Linda R. Klei, Nathaniel E. Hubel, Ming Zhang, Rebekka Schairer, Lisa M. Maurer, Hanna B. Klei, Heejae Kang, Vincent J. Concel, Phillip C. Delekta, Eric V. Dang, Michelle A. Mintz, Mathijs Baens, Jason G. Cyster, Narayanan Parameswaran, Margot Thome, Peter C. Lucas, Linda M. McAllister-Lucas
Journal: Journal of Clinical Investigation (2020)

Antigen receptor-dependent (AgR-dependent) stimulation of the NF-κB transcription factor in lymphocytes is a required event during adaptive immune response, but dysregulated activation of this signaling pathway can lead to lymphoma. AgR stimulation promotes assembly of the CARMA1-BCL10-MALT1 complex, wherein MALT1 acts as (a) a scaffold to recruit components of the canonical NF-κB machinery and (b) a protease to cleave and inactivate specific substrates, including negative regulators of NF-κB. In multiple lymphoma subtypes, malignant B cells hijack AgR signaling pathways to promote their own growth and survival, and inhibiting MALT1 reduces the viability and growth of these tumors. As such, MALT1 has emerged as a potential pharmaceutical target. Here, we identified G protein-coupled receptor kinase 2 (GRK2) as a new MALT1-interacting protein. We demonstrated that GRK2 binds the death domain of MALT1 and inhibits MALT1 scaffolding and proteolytic activities. We found that lower GRK2 levels in activated B cell-type diffuse large B cell lymphoma (ABC-DLBCL) are associated with reduced survival, and that GRK2 knockdown enhances ABC-DLBCL tumor growth in vitro and in vivo. Together, our findings suggest that GRK2 can function as a tumor suppressor by inhibiting MALT1 and provide a roadmap for developing new strategies to inhibit MALT1-dependent lymphomagenesis.
Cystic fibrosis transmembrane conductance regulator dysfunction in platelets drives lung hyperinflammation
Authors: Guadalupe Ortiz-Muñoz, Michelle A. Yu, Emma Lefrançais, Beñat Mallavia, Colin Valet, Jennifer J. Tian, Serena Ranucci, Kristin M. Wang, Zhe Liu, Nicholas Kwaan, Diana Dawson, Mary Ellen Kleinhenz, Fadi T. Khasawneh, Peter M. Haggie, Alan S. Verkman, Mark R. Looney
Journal: Journal of Clinical Investigation (2020)

Cystic fibrosis (CF) lung disease is characterized by an inflammatory response that can lead to terminal respiratory failure. The cystic fibrosis transmembrane conductance regulator (CFTR) is mutated in CF, and we hypothesized that dysfunctional CFTR in platelets, which are key participants in immune responses, is a central determinant of CF inflammation. We found that deletion of CFTR in platelets produced exaggerated acute lung inflammation and platelet activation after intratracheal LPS or Pseudomonas aeruginosa challenge. CFTR loss of function in mouse or human platelets resulted in agonist-induced hyperactivation and increased calcium entry into platelets. Inhibition of the transient receptor potential cation channel 6 (TRPC6) reduced platelet activation and calcium flux, and reduced lung injury in CF mice after intratracheal LPS or Pseudomonas aeruginosa challenge. CF subjects receiving CFTR modulator therapy showed partial restoration of CFTR function in platelets, which may be a convenient approach to monitoring biological responses to CFTR modulators. We conclude that CFTR dysfunction in platelets produces aberrant TRPC6-dependent platelet activation, which is a major driver of CF lung inflammation and impaired bacterial clearance. Platelets and TRPC6 are what we believe to be novel therapeutic targets in the treatment of CF lung disease.
Prolidase deficiency: a new genetic cause of combined pulmonary fibrosis and emphysema syndrome in the adult
Authors: Vincent Cottin, Mouhamad Nasser, Julie Traclet, Lara Chalabreysse, Anne-Sophie Lèbre, Salim Si-Mohamed, François Philit, Françoise Thivolet-Béjui
Journal: European Respiratory Journal (2020)

Pulmonary fibrosis is considered to result from recurrent alveolar epithelial injury coupled with dysfunctional alveolar wound healing mechanisms, some of which have a genetic background. Pulmonary fibrosis in the adult has not been previously associated with prolidase deficiency, an innate deficiency of amino acid metabolism. Prolidase deficiency is a new genetic cause of combined pulmonary fibrosis and emphysema syndrome in the adult <http://bit.ly/2QRgqMH> We thank Sylvie Boyer (Lyon) for aminoacids measurement, and Kais Ahmad, Jade Cuilleron, Sylvie Ernesto, Laure Folliet, Nathalie Guffon, Lize Kiakouama, Jacques-Olivier Maillard, Pascale Nesme-Meyer and Judith Proovost and for clinical care of the patient.
Infantile Systemic Hyalinosis
Authors: Li Liu, Faliang Ren, Qi Tan
Journal: JAMA Dermatology (2019)

This case report describes a 19-month-old boy pearly papules in the perianal area and on the thighs, clawhand, contracture of the large joints, and gingival hyperplasia who was diagnosed with infantile systemic hyalinosis.
Junior doctor who was convicted of downloading child pornography is struck off
Authors: Clare Dyer
Journal: BMJ (2020)

A junior doctor who worked in paediatrics before his arrest and conviction for downloading child pornography has been struck off the UK medical register.

Ralph Harper, 32, pleaded guilty last March to multiple charges of making indecent photographs. He admitted downloading 36 videos involving children, of which 21 were in the most serious “A” category, which specifies penetrative sex, bestiality, or sadism.

He was sentenced last April at Snaresbrook Crown Court, northeast London, to eight months imprisonment, suspended for 16 months.1 He was also placed on the sex …
CD19-Directed Fast CART Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia: From Bench to Bedside
Authors: Cheng Zhang, Jiaping He, Li Liu, Jishi Wang, Sanbin Wang, Ligen Liu, Lei Gao, Li Gao, Yao Liu, Peiyan Kong, Jia Liu, Yu Han, Yongliang Zhang, Zhe Sun, Xun Ye, Yan He, Lianjun Shen, Wei Cao, Xi Zhang
Journal: Blood (2019)
Reduction in Global Myocardial Glucose Metabolism in Subjects With 1-Hour Postload Hyperglycemia and Impaired Glucose Tolerance
Authors: Elena Succurro, Elisabetta Pedace, Francesco Andreozzi, Annalisa Papa, Patrizia Vizza, Teresa Vanessa Fiorentino, Francesco Perticone, Pierangelo Veltri, Giuseppe Lucio Cascini, Giorgio Sesti
Journal: Diabetes Care (2020)

Impaired insulin-stimulated myocardial glucose uptake has occurred in patients with type 2 diabetes with or without coronary artery disease. Whether cardiac insulin resistance is present remains uncertain in subjects at risk for type 2 diabetes, such as individuals with impaired glucose tolerance (IGT) or those with normal glucose tolerance (NGT) and 1-h postload glucose ≥155 mg/dL during an oral glucose tolerance test (NGT 1-h high). This issue was examined in this study.The myocardial metabolic rate of glucose (MRGlu) was measured by using dynamic 18F-fluorodeoxyglucose positron emission tomography combined with a euglycemic-hyperinsulinemic clamp in 30 volunteers without coronary artery disease. Three groups were studied: 1) those with 1-h postload glucose <155 mg/dL (NGT 1-h low) (n = 10), 2) those with NGT 1-h high (n = 10), 3) and those with IGT (n = 10).After adjusting for age, sex, and BMI, both subjects with NGT 1-h high (23.7 ± 6.4 mmol/min/100 mg; P = 0.024) and those with IGT (16.4 ± 6.0 mmol/min/100 mg; P < 0.0001) exhibited a significant reduction in global myocardial MRGlu; this value was 32.8 ± 9.7 mmol/min/100 mg in subjects with NGT 1-h low. Univariate correlations showed that MRGlu was positively correlated with insulin-stimulated whole-body glucose disposal (r = 0.441; P = 0.019) and negatively correlated with 1-h (r = -0.422; P = 0.025) and 2-h (r = -0.374; P = 0.05) postload glucose levels, but not with fasting glucose.This study shows that myocardial insulin resistance is an early defect that is already detectable in individuals with dysglycemic conditions associated with an increased risk of type 2 diabetes, such as IGT and NGT 1-h high.
Surrogate tumor antigen (STA) surface expression may be required for cross-priming and induction of systemic tumor immunity following STA-based vaccination
Authors: Jennifer D. Lewis, Robert K. Bright
Journal: Cancer Research (2004)

4696  Vaccination against cancer has been difficult to exploit for poorly immunogenic tumors for which no tumor antigens have been identified, a scenario that reflects most human malignancies. To begin addressing this we employed the 4T1 murine mammary carcinoma model. Since 4T1 tumor cells are relatively non-immunogenic we engineered them to express either simian virus 40 large tumor antigen (SV40 Tag) or ovalbumin (OVA) as surrogate tumor associated antigens (STA). Immunization of mice with recombinant SV40 Tag (rTag) in alum had no effect on parental 4T1 tumor formation. However, if 4T1 tumor challenge was preceded by rejection of s.c. 4T1.Tag challenge, the formation of parental 4T1 tumors was completely prevented and mice were protected from spontaneous lung metastases. Previously we reported that both CD4+ T cells and anti-Tag IgG antibodies were required for the rejection of Tag positive tumors, and that ADCC may be involved. To further address this, mice were immunized with purified OVA in alum using a dosage, route and schedule similar to that used for Tag. Sera were collected and analyzed by ELISA for the presence of anti-OVA IgG antibodies. Two weeks following the final immunization mice were challenged with 4T1.OVA and monitored for tumor growth. Within 2 weeks of challenge tumors were palpable in spite of the presence of anti-OVA IgG antibodies. Thus unlike the Tag experiments, mice immunized with OVA and challenged with 4T1.OVA did not reject the challenge. This lack of rejection may be due to the lack of surface expression of OVA on 4T1.OVA cells, unlike 4T1.Tag cells. OVA expression on the surface of 4T1 may enable the immune system to reject challenge with OVA expressing 4T1 cells and result in cross-priming and systemic tumor immunity against parental 4T1 tumor cells. To address the necessity of STA surface expression, full length OVA cDNA was sub-cloned into a surface expression vector and parental 4T1 cells transfected to yield the cell line 4T1.OVAsur. Expression of OVA protein in 4T1.OVAsur was confirmed by Western Blot analysis, and surface expression confirmed by flow-cytometry using OVA-specific antibodies. Mice immunized with OVA protein in alum will be challenged with 4T1.OVAsur and tumor growth monitored. Following rejection of 4T1.OVAsur, mice will be challenged with parental 4T1 cells in the opposite flank, and tumor growth and lung metastasis measured. These results should provide pre-clinical insight into whether surface expression of an STA is necessary for the rejection of STA expressing tumor cells and subsequent cross priming against parental (indigenous) tumor cells.
IA16 A New Generation of Anti-Myc Mini-Proteins as Potential Therapy for NSCLC
Authors: M.-E. Beaulieu, T. Jauset, D. Massó-Vallés, S. Martínez-Martín, M.F. Zacarias-Fluck, S. Casacuberta-Serra, E.S. del Pozo, L. Foradada, V.C. Cano, G. Martín, J. Kaur, M. Ángel Morcillo Alonso, J.R. Whitfield, P. Lavigne, L. Soucek
Journal: Journal of Thoracic Oncology (2020)
A10 A Novel Inhibitor for KRASG12C Mutant Lung Carcinoma
Authors: H.Y. Khan, Y. Li, A. Aboukameel, G. Mpilla, R. Sexton, T. Kanbur, H. Cetinkaya, A. Cagir, M.N. Al-Hallak, A. Sukari, A.S. Azmi, M. Nagasaka
Journal: Journal of Thoracic Oncology (2020)
Efficacy, immunogenicity, and safety of an oral influenza vaccine: a placebo-controlled and active-controlled phase 2 human challenge study
Authors: David Liebowitz, Keith Gottlieb, Nikita S Kolhatkar, Shaily J Garg, Jason M Asher, Jonathan Nazareno, Kenneth Kim, David R McIlwain, Sean N Tucker
Journal: The Lancet Infectious Diseases (2020)
Evolutionary Dynamics of Abundant 7-bp Satellites in the Genome of<i>Drosophila virilis</i>
Authors: Jullien M Flynn, Manyuan Long, Rod A Wing, Andrew G Clark
Journal: Molecular Biology and Evolution (2020)

The factors that drive the rapid changes in abundance of tandem arrays of highly repetitive sequences, known as satellite DNA, are not well understood. Drosophila virilis has one of the highest relative amounts of simple satellites of any organism that has been studied, with an estimated >40% of its genome composed of a few related 7-bp satellites. Here, we use D. virilis as a model to understand technical biases affecting satellite sequencing and the evolutionary processes that drive satellite composition. By analyzing sequencing data from Illumina, PacBio, and Nanopore platforms, we identify platform-specific biases and suggest best practices for accurate characterization of satellites by sequencing. We use comparative genomics and cytogenetics to demonstrate that the highly abundant AAACTAC satellite family arose from a related satellite in the branch leading to the virilis phylad 4.5-11 Ma before exploding in abundance in some species of the clade. The most abundant satellite is conserved in sequence and location in the pericentromeric region but has diverged widely in abundance among species, whereas the satellites nearest the centromere are rapidly turning over in sequence composition. By analyzing multiple strains of D. virilis, we saw that the abundances of two centromere-proximal satellites are anticorrelated along a geographical gradient, which we suggest could be caused by ongoing conflicts at the centromere. In conclusion, we illuminate several key attributes of satellite evolutionary dynamics that we hypothesize to be driven by processes including selection, meiotic drive, and constraints on satellite sequence and abundance.
A35 Dendritic Cell in Situ Vaccination Potentiates Anti-PD-1 Efficacy and Induces Immunoediting in a Murine Model of NSCLC
Authors: R. Salehi-Rad, R. Li, R. Lim, L. Tran, J. Abascal, S. Ong, B. Liu, S. Dubinett
Journal: Journal of Thoracic Oncology (2020)
Identification of cases and estimate of direct costs of unresectable and advanced cutaneous squamous cell carcinoma: real‐world data from a large Italian database
Authors: G. Ronconi, C. Piccinni, L. Dondi, S. Calabria, A. Pedrini, I. Esposito, P.A. Ascierto, L. Naldi, N. Martini
Journal: British Journal of Dermatology (2020)
Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study
Authors: Nanshan Chen, Min Zhou, Xuan Dong, Jieming Qu, Fengyun Gong, Yang Han, Yang Qiu, Jingli Wang, Ying Liu, Yuan Wei, Jia'an Xia, Ting Yu, Xinxin Zhang, Li Zhang
Journal: The Lancet (2020)
Trends in Pediatric Primary Care Visits Among Commercially Insured US Children, 2008-2016
Authors: Kristin N. Ray, Zhuo Shi, Ishani Ganguli, Aarti Rao, E. John Orav, Ateev Mehrotra
Journal: JAMA Pediatrics (2020)

Primary care is the foundation of pediatric care. While policy interventions have focused on improving access and quality of primary care, trends in overall use of primary care among children have not been described.To assess trends in primary care visit rates and out-of-pocket costs, to examine variation in these trends by patient and visit characteristics, and to assess shifts to alternative care options (eg, retail clinics, urgent care, and telemedicine).Observational cohort study of claims data from 2008 to 2016 for children 17 years and younger covered by a large national commercial health plan. Visit rate per 100 child-years was determined for each year overall, by child and geographic characteristics, and by visit type (eg, primary diagnosis), and trends were assessed with a series of child-year Poisson models. Data were analyzed from November 2017 to September 2019.Visits to primary care and other settings.This cohort study included more than 71 million pediatric primary care visits over 29 million pediatric child-years (51% male in 2008 and 2016; 37% between 12-17 years in 2008 and 38% between 12-17 years in 2016). Unadjusted results for primary care visit rates per 100 child-years decreased from 259.6 in 2008 to 227.2 in 2016, yielding a regression-estimated change in primary care visits across the 9 years of -14.4% (95% CI, -15.0% to -13.9%; absolute change: -32.4 visits per 100 child-years). After controlling for shifts in demographics, the relative decrease was -12.8% (95% CI, -13.3% to -12.2%). Preventive care visits per 100 child-years increased from 74.9 in 2008 to 83.2 visits in 2016 (9.9% change in visit rate; 95% CI, 9.0%-10.9%; absolute change: 8.3 visits per 100 child-years), while problem-based visits per 100 child-years decreased from 184.7 in 2008 to 144.1 in 2016 (-24.1%; 95% CI, -24.6% to -23.5%; absolute change: -40.6 visits per 100 child-years). Visit rates decreased for all diagnostic groups except for the behavioral and psychiatric category. Out-of-pocket costs for problem-based primary care visits increased by 42% during the same period. Per 100 child-years, visits to other acute care venues increased from 21.3 to 27.6 (30.3%; 95% CI, 28.5% to 32.1%; absolute change: 6.3 visits per 100 child-years) and visits to specialists from 45.2 to 53.5 (16.4%; 95% CI, 14.8% to 18.0%, absolute change: 8.3 visits per 100 child-years).Primary care visit rates among commercially insured children decreased over the last decade. Increases in out-of-pocket costs and shifts to other venues appear to explain some of this decrease.
Type I Interferon Regulates a Coordinated Gene Network to Enhance Cytotoxic T Cell–Mediated Tumor Killing
Authors: Jun-Bao Fan, Sayuri Miyauchi, Hui-Zhong Xu, Dan Liu, Leo J.Y. Kim, Christoph Burkart, Hua Cheng, Kei-ichiro Arimoto, Ming Yan, Yu Zhou, Balázs Győrffy, Klaus-Peter Knobeloch, Jeremy N. Rich, Hu Cang, Xiang-Dong Fu, Dong-Er Zhang
Journal: Cancer Discovery (2020)

Abstract Type I interferons (IFN), which activate many IFN-stimulated genes (ISG), are known to regulate tumorigenesis. However, little is known regarding how various ISGs coordinate with one another in developing antitumor effects. Here, we report that the ISG UBA7 is a tumor suppressor in breast cancer. UBA7 encodes an enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of another ISG (ISG15) to cellular proteins in a process known as “ISGylation.” ISGylation of other ISGs, including STAT1 and STAT2, synergistically facilitates production of chemokine-receptor ligands to attract cytotoxic T cells. These gene-activation events are further linked to clustering and nuclear relocalization of STAT1/2 within IFN-induced promyelocytic leukemia (PML) bodies. Importantly, this coordinated ISG–ISGylation network plays a central role in suppressing murine breast cancer growth and metastasis, which parallels improved survival in patients with breast cancer. These findings reveal a cooperative IFN-inducible gene network in orchestrating a tumor-suppressive microenvironment. Significance: We report a highly cooperative ISG network, in which UBA7-mediated ISGylation facilitates clustering of transcription factors and activates an antitumor gene-expression program. These findings provide mechanistic insights into immune evasion in breast cancer associated with UBA7 loss, emphasizing the importance of a functional ISG–ISGylation network in tumor suppression. This article is highlighted in the In This Issue feature, p. 327
B19 New Potential Targets of Antibody-Drug Conjugates for Small-Cell Lung Carcinoma
Authors: T. Yotsumoto, Y. Matsumoto, K. Zokumasu, T. Ando, K. Maemura, Y. Amano, K. Watanabe, H. Kage, K. Kakimi, J. Nakajima, D. Takai
Journal: Journal of Thoracic Oncology (2020)
CQC to reinspect dozens of care homes after uncovering “duplicate material” in reports
Authors: Gareth Iacobucci
Journal: BMJ (2020)

The Care Quality Commission (CQC) is to carry out dozens of reinspections of care and nursing homes after an internal audit revealed that inspection reports contained “duplicate material.”

The regulator found evidence of duplication in 108 reports. Some 68 care homes will now be reinspected. The remaining 40 reports will …