tbuckley/cabot-search huggingface dataset:
Efficacy and safety of sodium–glucose co‐transporter <scp>2</scp> inhibition according to left ventricular ejection fraction in <scp>DAPA‐HF</scp>
Authors: Pooja Dewan, Scott D. Solomon, Pardeep S. Jhund, Silvio E. Inzucchi, Lars Køber, Mikhail N. Kosiborod, Felipe A. Martinez, Piotr Ponikowski, David L. DeMets, Marc S. Sabatine, Olof Bengtsson, Mikaela Sjöstrand, Anna Maria Langkilde, Inder S. Anand, Jan Bělohlávek, Vijay K. Chopra, Andrej Dukát, Masafumi Kitakaze, Béla Merkely, Eileen O'Meara, Morten Schou, Pham Nguyen Vinh, John J.V. McMurray
Journal: European Journal of Heart Failure (2020)

Abstract Aims The aim of this study was to examine whether left ventricular ejection fraction (LVEF) modified efficacy and safety of dapagliflozin 10 mg compared with placebo in the 4744 patients with LVEF ≤40% randomized in the Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF). Methods and results We examined whether LVEF, analysed categorically or continuously, modified the effect of dapagliflozin. The primary efficacy outcome was the composite of a worsening heart failure (HF) event (unplanned HF hospitalization/an urgent HF visit requiring intravenous therapy) or cardiovascular death. Mean LVEF was 31.1% and LVEF categories analysed were: &lt;26% ( n = 1143), 26–30% ( n = 1018), 31–35% ( n = 1187), and &gt;35% ( n = 1396). Each 5% decrease in LVEF was associated with a higher risk of the primary outcome [hazard ratio (HR) 1.18; 95% confidence interval (CI) 1.13–1.24]. The benefit of dapagliflozin was consistent across the spectrum of LVEF: the dapagliflozin vs. placebo HR was 0.75 (95% CI 0.59–0.95) for LVEF &lt;26%, 0.75 (0.57–0.98) for LVEF 26–30%, 0.67 (0.51–0.89) for LVEF 31–35%, and 0.83 (0.63–1.09) for LVEF &gt;35% ( P for interaction = 0.762). Similarly, the effect of dapagliflozin on the components of the primary endpoint was not modified by baseline LVEF ( P for interaction for cardiovascular death = 0.974, and for worsening HF = 0.161). Safety of dapagliflozin was also consistent across the range of LVEF and neither efficacy nor safety were modified by diabetes status. Conclusion Left ventricular ejection fraction was a significant predictor of hospitalization and mortality in patients with HF with reduced ejection fraction but did not modify the beneficial effect of dapagliflozin, overall or separately, in patients with and without diabetes. Clinical Trial Registration: ClinicalTrials.gov Identifier NCT03036124
COVID-19 in patients with lung cancer
Authors: J. Luo, H. Rizvi, I.R. Preeshagul, J.V. Egger, D. Hoyos, C. Bandlamudi, C.G. McCarthy, C.J. Falcon, A.J. Schoenfeld, K.C. Arbour, J.E. Chaft, R.M. Daly, A. Drilon, J. Eng, A. Iqbal, W.V. Lai, B.T. Li, P. Lito, A. Namakydoust, K. Ng, M. Offin, P.K. Paik, G.J. Riely, C.M. Rudin, H.A. Yu, M.G. Zauderer, M.T.A. Donoghue, M. Łuksza, B.D. Greenbaum, M.G. Kris, M.D. Hellmann
Journal: Annals of Oncology (2020)
Effect of Physician Notification Regarding Nonadherence to Colorectal Cancer Screening on Early Cancer Detection
Authors: Héloïse Schmeltz, Cédric Rat, Corinne Pogu, Gaëlle Bianco, Anne Cowppli-Bony, Aurélie Gaultier, Jean-Michel Nguyen
Journal: JAMA (2020)

This cluster randomized clinical trial compares the effect of physician notification for colorectal cancer screening and cancer detection on patients who were in a patient-specific reminders group in which physicians received a list of nonadherent patients, in a generic reminders group in which physicians received general information about regional screening adherence, or in a usual care group in which physicians received no reminders.
Prognostic value of minimal residual disease measured by flow-cytometry in two cohorts of infants with acute lymphoblastic leukemia treated according to either MLL-Baby or Interfant protocols
Authors: Alexander Popov, Barbara Buldini, Paola De Lorenzo, Silvia Disarò, Tatiana Verzhbitskaya, Liudmila Movchan, Emanuela Giarin, Egor Shorikov, Annamaria Di Meglio, Grigory Tsaur, Rosanna Parasole, Natalia Miakova, Elmira Boichenko, Konstantin Kondratchik, Olga Aleinikova, Alexander Karachunskiy, Alexander Roumiantsev, Franco Locatelli, Andrea Biondi, Rob Pieters, Maria Grazia Valsecchi, Larisa Fechina, Giuseppe Basso
Journal: Leukemia (2020)
Regulation of Hippo-YAP signaling by insulin-like growth factor-1 receptor in the tumorigenesis of diffuse large B-cell lymphoma
Authors: Xiangxiang Zhou, Na Chen, Hongzhi Xu, Xiaoming Zhou, Jianhong Wang, Xiaosheng Fang, Ya Zhang, Ying Li, Juan Yang, Xin Wang
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Hippo-Yes-associated protein (YAP) signaling is a key regulator of organ size and tumorigenesis, yet the underlying molecular mechanism is still poorly understood. At present, the significance of the Hippo-YAP pathway in diffuse large B-cell lymphoma (DLBCL) is ill-defined. Methods The expression of YAP in DLBCL was determined in public database and clinical specimens. The effects of YAP knockdown, CRISPR/Cas9-mediated YAP deletion, and YAP inhibitor treatment on cell proliferation and the cell cycle were evaluated both in vitro and in vivo. RNA sequencing was conducted to detect dysregulated RNAs in YAP-knockout DLBCL cells. The regulatory effects of insulin-like growth factor-1 receptor (IGF-1R) on Hippo-YAP signaling were explored by targeted inhibition and rescue experiments. Results High expression of YAP was significantly correlated with disease progression and poor prognosis. Knockdown of YAP expression suppressed cell proliferation and induced cell cycle arrest in DLBCL cells. Verteporfin (VP), a benzoporphyrin derivative, exerted an anti-tumor effect by regulating the expression of YAP and the downstream target genes, CTGF and CYR61. In vitro and in vivo studies revealed that deletion of YAP expression with a CRISPR/Cas9 genome editing system significantly restrained tumor growth. Moreover, downregulation of IGF-1R expression led to a remarkable decrease in YAP expression. In contrast, exposure to IGF-1 promoted YAP expression and reversed the inhibition of YAP expression induced by IGF-1R inhibitors. Conclusions Our study highlights the critical role of YAP in the pathogenesis of DLBCL and uncovers the regulatory effect of IGF-1R on Hippo-YAP signaling, suggesting a novel therapeutic strategy for DLBCL.
Bowman’s capsule rupture on renal biopsy improves the outcome prediction of ANCA-associated glomerulonephritis classifications
Authors: Vincenzo L'Imperio, Gisella Vischini, Fabio Pagni, Pietro Manuel Ferraro
Journal: Annals of the Rheumatic Diseases (2020)

Correspondence 0.73, respectively).This has been confirmed in the multivariate model which includes Berden's class (HR 3.61, 95% CI 1.15 to 11.34; p=0.028) and ARRS (HR 5.25, 95% CI 1.53 to 18.08; p=0.009).The present study demonstrates an improved performance of prognostic systems in predicting AAV outcome after the implementation of BCR, the additional predictive role of which can partly lie in the irreversible loss of nephrons consequent to the segmental glomerulosclerosis caused by BCR.
TAp63–miRNA–AURKA Axis as a Therapeutic Target for Cutaneous Squamous Cell Carcinoma
Authors: Alejandro Parrales, Tomoo Iwakuma
Journal: Cancer Research (2020)

Abstract Despite increasing incidence rates, prognosis of invasive cutaneous squamous cell carcinoma remains poor, mainly due to lack of reliable molecular markers that can be used for targeted therapy. Through genetic and proteogenomic analyses, Davis and colleagues in this issue of Cancer Research define TAp63 and its downstream target miRNAs, miR-30c-2*, and miR-497 as major players that can suppress progression and metastasis of mouse and human cutaneous squamous cell carcinoma. Mimics of miR-30c-2* or miR-497, as well as pharmacologic inhibition of AURKA, a miR-497 target, suppress tumor growth in xenograft mouse models, proposing the TAp63–miR-30c-2*/miR-497–AURKA axis as a potential therapeutic target. See related article by Davis et al., p. 2484
Acute Heart Failure 29 Years After Treatment for Childhood Cancer
Authors: Massimiliano Camilli, Marco Giuseppe Del Buono, Filippo Crea, Giorgio Minotti
Journal: JACC CardioOncology (2020)

Doxorubicin and other antitumor anthracyclines can cause cardiomyopathy and heart failure (HF) in a dose-related manner, with a cumulative dose of 400 mg/m2 of doxorubicin equivalent associated with 5% risk of HF in adults; however, children and the elderly may develop HF after significantly lower
Plant-based diets to manage the risks and complications of chronic kidney disease
Authors: Juan J. Carrero, Ailema González-Ortiz, Carla M. Avesani, Stephan J. L. Bakker, Vincenzo Bellizzi, Philippe Chauveau, Catherine M. Clase, Adamasco Cupisti, Angeles Espinosa-Cuevas, Pablo Molina, Karine Moreau, Giorgina B. Piccoli, Adrian Post, Siren Sezer, Denis Fouque
Journal: Nature Reviews Nephrology (2020)
Limitations in Clinical Trials Leading to Anticancer Drug Approvals by the US Food and Drug Administration
Authors: Talal Hilal, Miguel Gonzalez-Velez, Vinay Prasad
Journal: JAMA Internal Medicine (2020)

<h3>Importance</h3> While there have been multiple assessments of clinical trials leading to anticancer drug approvals by the US Food and Drug Administration (FDA), the cumulative percentage of approvals based on trials with a limitation remains uncertain. <h3>Objective</h3> To assess the percentage of clinical trials with limitations in 4 domains—lack of randomization, lack of significant overall survival advantage, inappropriate use of crossover, and use of suboptimal control arms—that led to FDA approvals from June 30, 2014, to July 31, 2019. <h3>Design, Setting, and Participants</h3> This observational analysis included all anticancer drug indications approved by the FDA from June 30, 2014, through July 31, 2019. All indications were investigated, and each clinical trial was evaluated for design, enrollment period, primary end points, and presence of a limitation in the domains of interest. The standard-of-care therapy was determined by evaluating the literature and published guidelines 1 year prior to the start of clinical trial enrollment. Crossover was examined and evaluated for optimal use. The percentage of approvals based on clinical trials with any or all limitations of interest was then calculated. <h3>Main Outcomes and Measures</h3> Estimated percentage of clinical trials with limitations of interest that led to an anticancer drug marketing authorization by the FDA. <h3>Results</h3> A total of 187 trials leading to 176 approvals for 75 distinct novel anticancer drugs by the FDA were evaluated. Sixty-four (34%) were single-arm clinical trials, and 123 (63%) were randomized clinical trials. A total of 125 (67%) had at least 1 limitation in the domains of interest; 60 of the 125 trials (48%) were randomized clinical trials. Of all 123 randomized clinical trials, 37 (30%) lacked overall survival benefit, 31 (25%) had a suboptimal control, and 17 (14%) used crossover inappropriately. <h3>Conclusions and Relevance</h3> Two-thirds of cancer drugs are approved based on clinical trials with limitations in at least 1 of 4 essential domains. Efforts to minimize these limitations at the time of clinical trial design are essential to ensure that new anticancer drugs truly improve patient outcomes over current standards.
Re: Lisa Moris, Marcus G. Cumberbatch, Thomas Van den Broeck, et al. Benefits and Risks of Primary Treatments for High-risk Localized and Locally Advanced Prostate Cancer: An International Multidisciplinary Systematic Review. Eur Urol 2020;77:614–27
Authors: Fabiana Gregucci, Roberta Carbonara, Alba Fiorentino
Journal: European Urology (2020)
Biodegradable MRI Visible Drug Eluting Stent Reinforced by Metal Organic Frameworks
Authors: Rezvani Alanagh Hamideh, Babak Akbari, Parinaz Fathi, Santosh K. Misra, Andre Sutrisno, Fan Lam, Dipanjan Pan
Journal: Advanced Healthcare Materials (2020)

Abstract Metal–organic frameworks (MOFs) have applications in numerous fields. However, the development of MOF‐based “theranostic” macroscale devices is not achieved. Here, heparin‐coated biocompatible MOF/poly( ε ‐caprolactone) (PCL) “theranostic” stents are developed, where NH 2 ‐Materials of Institute Lavoisier (MIL)‐101(Fe) encapsulates and releases rapamycin (an immunosuppressive drug). These stents also act as a remarkable source of contrast in ex vivo magnetic resonance imaging (MRI) compared to the invisible polymeric stent. The in vitro release patterns of heparin and rapamycin respectively can ensure a type of programmed model to prevent blood coagulation immediately after stent placement in the artery and stenosis over a longer term. Due to the presence of hydrolysable functionalities in MOFs, the stents are shown to be highly biodegradable in degradation tests under various conditions. Furthermore, there is no compromise of mechanical strength or flexibility with MOF compositing. The system described here promises many biomedical applications in macroscale theranostic devices. The use of MOF@PCL can render a medical device MRI‐visible while simultaneously acting as a carrier for therapeutic agents.
Descriptive study of COVID-19 outbreak among passengers and crew on Diamond Princess cruise ship, Yokohama Port, Japan, 20 January to 9 February 2020
Authors: Takuya Yamagishi, Hajime Kamiya, Kensaku Kakimoto, Motoi Suzuki, Takaji Wakita
Journal: Eurosurveillance (2020)

An outbreak of coronavirus disease (COVID-19) occurred on the Diamond Princess cruise ship making an international journey, which led to quarantine of the ship at Yokohama Port, Japan. A suspected COVID-19 case was defined as a passenger or crew member who developed a fever or respiratory symptoms, and a confirmed COVID-19 case had laboratory-confirmation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Between 3 and 9 February 2020, 490 individuals were tested for SARS-CoV-2 and 172 were positive (152 passengers (median age: 70 years; interquartile range (IQR): 64-75; males: 45%) and 20 crew (median age: 40 years; IQR: 35-48.5; males: 80%). Other than the Hong Kong-related index case, symptom onset for the earliest confirmed case was 22 January, 2 days after the cruise ship left port. Attack rates among passengers were similar across the decks, while beverage (3.3%, 2/61) and food service staff (5.7%, 14/245) were most affected. Attack rates tended to increase with age. A comprehensive outbreak response was implemented, including surveillance, provision of essential medical care, food and medicine delivery, isolation, infection prevention and control, sampling and disembarkation.
A population-based study of chronic neutrophilic leukemia in the United States
Authors: Gordon J. Ruan, Caleb J. Smith, Courtney Day, William S. Harmsen, Darci L. Zblewski, Hassan Alkhateeb, Kebede Begna, Aref Al-Kali, Mark R. Litzow, William Hogan, Natasha Szuber, Naseema Gangat, Mrinal S. Patnaik, Animesh Pardanani, Michelle A. Elliott, Ayalew Tefferi, Ronald S. Go, Mithun V. Shah
Journal: Blood Cancer Journal (2020)

Chronic neutrophilic leukemia (CNL) is a rare and aggressive BCR-ABL1 (Philadelphia chromosome) negative myeloproliferative neoplasm that carries a poor prognosis.It is defined by persistent mature neutrophilic leukocytosis, bone marrow granulocytic hyperplasia, and hepatosplenomegaly 1 .Despite the 2013 seminal discovery of the oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in CNL 2 , no standard of care exists.Chemotherapy is not able to provide durable responses, the literature on allogeneic stem cell transplantation (ASCT) is scarce, and targeted therapies such as JAK-2 inhibitors and dasatinib are still being studied for efficacy and safety 1,3,4 .There is a paucity of population-based data on CNL and contemporary clinical data are limited to institutional case series.In this study, we combined the Surveillance, Epidemiology, and End Results (SEER) program and the National Cancer Database (NCDB) to study population-based outcomes for patients with CNL.SEER is a program of the National Cancer Institute that collects and publishes cancer incidence and survival data covering ~28% of the US population 5 .The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society that is a nationwide oncology outcomes database for >1500 cancer programs in the USA and Puerto Rico, capturing 70% of all newly diagnosed cases of cancer in the USA 6 .The NCDB Participant User File and SEER 18 registries were used to identify patients with ICD-O-3 diagnosis code 9963/3 from 2004 to 2015.
An Evaluation of 17 Years of Low Dose Cytarabine As Therapy for AML Patients Not Fit for Intensive Treatment, Including Patients with Adverse Cytogenetics, Shows Improving Survival, Potential Underutilisation and Highlights the Need for New Therapy
Authors: Michael Dennis, Robert K. Hills, Nigel H. Russell, Mhairi Copland, Ian Thomas, Mary Frances Frances McMullin, Sahra Ali, Alan K. Burnett
Journal: Blood (2017)
Type 2 Diabetes, Change in Depressive Symptoms Over Time, and Cerebral Small Vessel Disease: Longitudinal Data of the AGES-Reykjavik Study
Authors: Sytze P. Rensma, Thomas T. van Sloten, Jennifer Ding, Sigurdur Sigurdsson, Coen D.A. Stehouwer, Vilmundur Gudnason, Lenore J. Launer
Journal: Diabetes Care (2020)

OBJECTIVE Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms. RESEARCH DESIGN AND METHODS We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose–lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up. RESULTS Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (β = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association. CONCLUSIONS Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association.
THU0010 GENES ASSOCIATED WITH NUCLEOTIDE OLIGOMERIZATION DOMAIN-LIKE RECEPTOR SIGNALING PATHWAY ARE UPREGULATED IN CUTANEOUS LUPUS ERYTHEMATOSUS
Authors: I. Calderon, R. Mina
Journal: Annals of the Rheumatic Diseases (2020)

Background: Cutaneous Lupus Erythematosus (CLE) is a disfiguring autoimmune skin disorder with several subtypes: discoid lupus, subacute cutaneous lupus, and acute cutaneous lupus. CLE is associated with defects in the adaptive immune system, and, at times, systemic involvement. The innate immune system is likely involved as seen in the presence of interface dermatitis, which is observed in viral exanthems, and improvement of CLE using inhibitors to membrane-bound Pattern Recognition Receptors. Objectives: Compare the expression of genes associated with the innate immune system in active CLE skin lesions of different subtypes compared to normal skin controls. Methods: Five datasets selected from the Gene Expression Omnibus (GEO) were analyzed using GEO2R to compare the gene expressions between different subtypes of CLE. Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database, Gene Card, and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analysis were used to identify the interaction and function of specific genes. Results: There were a total of 147 CLE skin samples and 52 normal controls. Genes associated with the Nucleotide-Binding Oligomerization Domain-Like Receptor (NLR) signaling pathway were upregulated in CLE skin samples (adjusted p-value &lt; 0.001). Five genes associated with the NLR signaling pathway, STAT1, OAS1, OAS2, OAS3, and AIM2, were found to be upregulated in skin samples of CLE patients in all datasets, regardless of type, compared to normal controls in all datasets. These five genes are associated with transcription activation, regulation of viral infection, and interferon response. Conclusion: Genes associated with the NLR signaling pathway are upregulated in the skin lesions of CLE patients compared to normal controls, supporting the role of the innate immune system in CLE. Further validation studies using experimental methods are needed. References: [1]Enhanced inflammasome activity in systemic lupus erythematosus is mediated via type I interferon upregulation of interferon regulatory factor 1. Liu J, et al. Arth Rheum. 2017; 69(9): 1840-1849. Disclosure of Interests: None declared
Functional Categorization of <i>BRCA1</i> Variants of Uncertain Clinical Significance in Homologous Recombination Repair Complementation Assays
Authors: Peter Bouwman, Ingrid van der Heijden, Hanneke van der Gulden, Roebi de Bruijn, Merel E. Braspenning, Setareh Moghadasi, Lodewyk F.A. Wessels, Maaike P.G. Vreeswijk, Jos Jonkers
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Because BRCA1 is a high-risk breast/ovarian cancer susceptibility gene, BRCA1 sequence variants of uncertain clinical significance (VUS) complicate genetic counseling. As most VUS are rare, reliable classification based on clinical and genetic data is often impossible. However, all pathogenic BRCA1 variants analyzed result in defective homologous recombination DNA repair (HRR). Thus, BRCA1 VUS may be categorized based on their functional impact on this pathway. Experimental Design: Two hundred thirty-eight BRCA1 VUS—comprising most BRCA1 VUS known in the Netherlands and Belgium—were tested for their ability to complement Brca1-deficient mouse embryonic stem cells in HRR, using cisplatin and olaparib sensitivity assays and a direct repeat GFP (DR-GFP) HRR assay. Assays were validated using 25 known benign and 25 known pathogenic BRCA1 variants. For assessment of pathogenicity by a multifactorial likelihood analysis method, we collected clinical and genetic data for functionally deleterious VUS and VUS occurring in three or more families. Results: All three assays showed 100% sensitivity and specificity (95% confidence interval, 83%–100%). Out of 238 VUS, 45 showed functional defects, 26 of which were deleterious in all three assays. For 12 of these 26 variants, we could calculate the probability of pathogenicity using clinical and genetic data, resulting in the identification of 7 (likely) pathogenic variants. Conclusions: We have functionally categorized 238 BRCA1 VUS using three different HRR-related assays. Classification based on clinical and genetic data alone for a subset of these variants confirmed the high sensitivity and specificity of our functional assays.