tbuckley/cabot-search huggingface dataset:
Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC
Authors: Roy S. Herbst, Hendrik Tobias Arkenau, Johanna Bendell, Edward Arrowsmith, Martin Wermke, Andres Soriano, Nicolas Penel, Rafael Santana-Davila, Helge Bischoff, Ian Chau, Gu Mi, Hong Wang, Erik Rasmussen, David Ferry, Bo H. Chao, Luis Paz-Ares
Journal: Journal of Thoracic Oncology (2020)

IntroductionData of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)–positive NSCLC (cohort E) are reported (NCT02443324).MethodsIn this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell–inflamed, Gajewski, and effector T cells) and CD274 gene expression.ResultsCohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%–49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry.ConclusionsFirst-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.
mTORC1 hyperactivation in lymphangioleiomyomatosis leads to <i>ACE2</i> upregulation in type II pneumocytes: implications for COVID-19
Authors: Yan Tang, David J. Kwiatkowski, Elizabeth P. Henske
Journal: European Respiratory Journal (2020)

<b>Increased pneumocyte expression of the SARS-CoV-2 entry receptor ACE2 in lymphangioleiomyomatosis (LAM) is associated with upregulation of interferon pathways in natural killer cells as well as increased IL6 expression in LAM-associated fibroblasts</b>https://bit.ly/34ChSsg
Contemporary Diagnosis and Management of Rheumatic Heart Disease: Implications for Closing the Gap: A Scientific Statement From the American Heart Association
Authors: Raman Krishna Kumar, Manuel J. Antunes, Andrea Beaton, Mariana Mirabel, Vuyisile T. Nkomo, Emmy Okello, Prakash Raj Regmi, Boglarka Reményi, Karen Sliwa-Hähnle, Liesl Joanna Zühlke, Craig Sable
Journal: Circulation (2020)

The global burden of rheumatic heart disease continues to be significant although it is largely limited to poor and marginalized populations. In most endemic regions, affected patients present with heart failure. This statement will seek to examine the current state-of-the-art recommendations and to identify gaps in diagnosis and treatment globally that can inform strategies for reducing disease burden. Echocardiography screening based on World Heart Federation echocardiographic criteria holds promise to identify patients earlier, when prophylaxis is more likely to be effective; however, several important questions need to be answered before this can translate into public policy. Population-based registries effectively enable optimal care and secondary penicillin prophylaxis within available resources. Benzathine penicillin injections remain the cornerstone of secondary prevention. Challenges with penicillin procurement and concern with adverse reactions in patients with advanced disease remain important issues. Heart failure management, prevention, early diagnosis and treatment of endocarditis, oral anticoagulation for atrial fibrillation, and prosthetic valves are vital therapeutic adjuncts. Management of health of women with unoperated and operated rheumatic heart disease before, during, and after pregnancy is a significant challenge that requires a multidisciplinary team effort. Patients with isolated mitral stenosis often benefit from percutaneous balloon mitral valvuloplasty. Timely heart valve surgery can mitigate the progression to heart failure, disability, and death. Valve repair is preferable over replacement for rheumatic mitral regurgitation but is not available to the vast majority of patients in endemic regions. This body of work forms a foundation on which a companion document on advocacy for rheumatic heart disease has been developed. Ultimately, the combination of expanded treatment options, research, and advocacy built on existing knowledge and science provides the best opportunity to address the burden of rheumatic heart disease.
Transcription Factor Profiling Identifies Spatially Heterogenous Mediators of Follicular Thyroid Cancer Invasion
Authors: Norman G. Nicolson, Johan O. Paulsson, C. Christofer Juhlin, Tobias Carling, Reju Korah
Journal: Endocrine Pathology (2020)

Abstract While minimally invasive follicular thyroid cancer (miFTC) generally has low risk of recurrence or death, encapsulated angioinvasive (eaFTC) or widely invasive (wiFTC) histological subtypes display significantly worse prognosis. Drivers of invasion are incompletely understood. Therefore, tissue samples including miFTC, eaFTC, and wiFTC tumors, as well as histologically normal thyroid adjacent to benign follicular adenomas, were selected from a cohort ( n = 21) of thyroid tumor patients, and the gene expression of selected transcription factors was characterized with quantitative PCR. Invasion-relevant spatial expression patterns of selected transcription factors were subsequently characterized with immunohistochemistry. E2F1 was over-expressed in all 3 subtypes ( p &lt;0.01). SP1 was differentially expressed in eaFTC and wiFTC compared with normal ( p =0.01 and 0.04, respectively). TCF7L2 was significantly upregulated in wiFTC specifically ( p &lt;0.05). While these findings were mRNA specific, immunohistochemistry of additional cancer-associated transcription factors revealed differential expression along the tumor invasive front relative to the central tumor, and histone acetylation modulators emerged as putative invasion markers. These findings may have significant implications for the interpretation of bulk gene expression analysis of thyroid tumor samples or for the development of targeted therapeutics for this rare but aggressive thyroid cancer variant.
Full-length Dhh and N-terminal Shh act as competitive antagonists to regulate angiogenesis and vascular permeability
Authors: Pierre-Louis Hollier, Candice Chapouly, Aissata Diop, Sarah Guimbal, Lauriane Cornuault, Alain-Pierre Gadeau, Marie-Ange Renault
Journal: Cardiovascular Research (2020)

The therapeutic potential of Hedgehog (Hh) signalling agonists for vascular diseases is of growing interest. However, molecular and cellular mechanisms underlying the role of the Hh signalling in vascular biology remain poorly understood. The purpose of the present article is to clarify some conflicting literature data.
Temporal Trends in Cervical Spine Curvature of South Korean Adults Assessed by Deep Learning System Segmentation, 2006-2018
Authors: YiRang Shin, Kyunghwa Han, Young Han Lee
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The loss of the physiologic cervical lordotic curve is a common degenerative disorder known to be associated with abnormal spinal alignment. However, the changing trends among sex and age groups has not yet been well established. <h3>Objective</h3> To analyze the temporal trends in cervical curvature across sex and age groups using an automated deep learning system (DLS). <h3>Design, Setting, and Participants</h3> A retrospective cross-sectional study was conducted using lateral cervical radiographs of 13 691 individuals from January 1, 2006, to December 31, 2018. The degree of anterior vertical curvature was approximated by a DLS approach and convexity measurement method. This population-based study used the Yonsei University College of Medicine Severance Hospital, Seoul, South Korea, cohort database to identify 13 691 consecutive adults (≥18 years of age) who underwent standing lateral radiography in inpatient and outpatient settings. <h3>Main Outcomes and Measures</h3> The prevalence of kyphotic and straight cervical curve as well as the trends of degree of cervical curvature in 2006 to 2018 among sex and age groups were determined. The DLS performance was validated with quantitative metrics and compared with interobserver and intraobserver variations. <h3>Results</h3> Automatic cervical spine segmentation was identified from lateral radiographs of 13 691 individuals (mean [SD] age, 49.9 [15.3] years; 8051 women [58.8%]). From 2006 to 2018, the decrease in the lordotic curve was significant across both sexes and age groups younger than 70 years, with the decrease more pronounced in women and successively younger generations (female, −0.05; 95% CI, −0.06 to −0.04; 18-29 years of age, −0.06; 95% CI, −0.08 to −0.04; 30-39 years of age, −0.06; 95% CI, −0.08 to −0.04; and 40-49 years of age, −0.05; 95% CI, −0.06 to −0.03; all<i>P</i> &lt; .001). The prevalence of straight and kyphotic curvature had a significant increasing trend for both sexes and young generations, in which individuals 18 to 29 years of age generally had the highest prevalence rates during the study cycle (in 2018, kyphosis, 16.7%; 95% CI, 10.8%-22.5%; straight, 45.5%; 95% CI, 37.7%-53.3%). Similar trends were observed with longitudinal analysis of repeated measures of individuals, with more pronounced decreases in lordotic curvature observed among women and young adults. <h3>Conclusions and Relevance</h3> This study suggests a significant, increasing loss of normal cervical lordotic curvature for both sexes and young adults that is greater in progressively younger cohorts and women. Further research is necessary to evaluate associations between neck pain and loss of cervical curvature and address the need for active promotion and practical interventions aimed at neck posture correction.
Overcoming T-cell exhaustion in LCH: PD-1 blockade and targeted MAPK inhibition are synergistic in a mouse model of LCH
Authors: Amel Sengal, Jessica Velazquez, Meryl Hahne, Thomas M. Burke, Harshal Abhyankar, Robert Reyes, Walter Olea, Brooks Scull, Olive S. Eckstein, Camille Bigenwald, Catherine M. Bollard, Wendong Yu, Miriam Merad, Kenneth L. McClain, Carl E. Allen, Rikhia Chakraborty
Journal: Blood (2020)
Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial
Authors: Robert S. Rahimi, Rifaat Safadi, Dominique Thabut, Kalyan Ram Bhamidimarri, Nikolaos Pyrsopoulos, Amy Potthoff, Stan Bukofzer, Jasmohan S. Bajaj
Journal: Clinical Gastroenterology and Hepatology (2020)

Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and health care resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE.We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were assigned randomly to groups that received placebo or OP (10, 15, or 20 g/d, based on the severity of liver disease), plus each institution's standard of care (eg, lactulose to achieve 2-3 bowel movements with or without rifaximin, in accordance with guidelines). The primary end point was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stages 3/4 or improvement to HEST stages 0/1 from baseline stage 2, in the intent-to-treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory).Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P = .129). Analyses of central laboratory-confirmed increases in levels of ammonia at baseline (n = 201) showed clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and in 29% in the placebo group (P = .552).In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE. ClinicalTrials.gov no: NCT01966419.
Light-activatable liposomes for repetitive on-demand drug release and immunopotentiation in hypoxic tumor therapy
Authors: Yuanyuan Yang, Xin Liu, Wen Ma, Qing Xu, Gui Chen, Yufei Wang, Haihua Xiao, Nan Li, Xing-Jie Liang, Meng Yu, Zhiqiang Yu
Journal: Biomaterials (2020)
Evolution of the Epigenetic Landscape in Childhood B Acute Lymphoblastic Leukemia and Its Role in Drug Resistance
Authors: Shella Saint Fleur-Lominy, Nikki A. Evensen, Teena Bhatla, Gunjan Sethia, Sonali Narang, Jun H. Choi, Xiaotu Ma, Jun J. Yang, Stephen Kelly, Elizabeth Raetz, Richard C. Harvey, Cheryl Willman, Mignon L. Loh, Stephen P. Hunger, Patrick A. Brown, Kylie M. Getz, Cem Meydan, Christopher E. Mason, Aristotelis Tsirigos, William L. Carroll
Journal: Cancer Research (2020)

Although B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and while highly curable, it remains a leading cause of cancer-related mortality. The outgrowth of tumor subclones carrying mutations in genes responsible for resistance to therapy has led to a Darwinian model of clonal selection. Previous work has indicated that alterations in the epigenome might contribute to clonal selection, yet the extent to which the chromatin state is altered under the selective pressures of therapy is unknown. To address this, we performed chromatin immunoprecipitation, gene expression analysis, and enhanced reduced representation bisulfite sequencing on a cohort of paired diagnosis and relapse samples from individual patients who all but one relapsed within 36 months of initial diagnosis. The chromatin state at diagnosis varied widely among patients, while the majority of peaks remained stable between diagnosis and relapse. Yet a significant fraction was either lost or newly gained, with some patients showing few differences and others showing massive changes of the epigenetic state. Evolution of the epigenome was associated with pathways previously linked to therapy resistance as well as novel candidate pathways through alterations in pyrimidine biosynthesis and downregulation of polycomb repressive complex 2 targets. Three novel, relapse-specific superenhancers were shared by a majority of patients including one associated with S100A8, the top upregulated gene seen at relapse in childhood B-ALL. Overall, our results support a role of the epigenome in clonal evolution and uncover new candidate pathways associated with relapse. SIGNIFICANCE: This study suggests a major role for epigenetic mechanisms in driving clonal evolution in B-ALL and identifies novel pathways associated with drug resistance.
SP0123 Pre/post surgical interventions, post-operative care
Authors: M Jalovcová
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Aim of the study</h3> Strategies for rehabilitation following arthroplasty have been well described. However, these methods are not fully suitable for patients with rheumatologic diseases. We at the Institute of Rheumatology have worked out and practice principles of rehabilitation tailored to the special needs of these patients. <h3>Subject and methods</h3> An optimal rehabilitation plan includes pre-operative and post-operative care. We recommend that rehabilitation treatment be commenced early in post-operative care. Care should be taken to accommodate differences typical of these patients: e.g., anatomical changes in joint systems, neurophysiological changes in muscles, deformities, changes in psychological area, general weakness, less tolerance for loading, changed pain threshold, and long-term pharmacotherapy. Patients in the study ranged in age from 21 to 70 years old. Their average time of hospitalisation was 17 days. Rehabilitation therapy was administered two times per day. Patient evaluations were performed at the beginning and end of the therapy regime. The pre-therapy evaluation was essential to prescribing an effective a comprehensive rehabilitation program. The physiatricst obtained functional and vocational information (including activities typical of the patient's daily life) and evaluated the patient's range of motion, muscle strength, short muscles, weak muscles, and basic movement stereotypes. <h3>Results</h3> The knowledge of these differences leads as to specification rehabilitation technique. We changed conditions: length exercises, loading intensity, and daily time. The rehabilitation treatment in principle reduces insufficiency causes of arthroplasties. <h3>Conclusions</h3> A comparison of the pre- versus post-therapy evaluations indicates that our modified technique can be successfully employed with rheumatology patients following arthroplasty of load bearing joints. Objective confirmation of this thesis is found in two different venues: the length of acute hospital stay is materially shorter and the occurrence of admissions for re-treatment after surgery is materially less frequent.
The physiological and pathological functions of VEGFR3 in cardiac and lymphatic development and related diseases
Authors: Richard M Monaghan, Donna J Page, Pia Ostergaard, Bernard D Keavney
Journal: Cardiovascular Research (2020)

Vascular endothelial growth factor receptors (VEGFRs) are part of the evolutionarily conserved VEGF signalling pathways that regulate the development and maintenance of the body's cardiovascular and lymphovascular systems. VEGFR3, encoded by the FLT4 gene, has an indispensable and well-characterized function in development and establishment of the lymphatic system. Autosomal dominant VEGFR3 mutations, that prevent the receptor functioning as a homodimer, cause one of the major forms of hereditary primary lymphoedema; Milroy disease. Recently, we and others have shown that FLT4 variants, distinct to those observed in Milroy disease cases, predispose individuals to Tetralogy of Fallot, the most common cyanotic congenital heart disease, demonstrating a novel function for VEGFR3 in early cardiac development. Here, we examine the familiar and emerging roles of VEGFR3 in the development of both lymphovascular and cardiovascular systems, respectively, compare how distinct genetic variants in FLT4 lead to two disparate human conditions, and highlight the research still required to fully understand this multifaceted receptor.
Abstract 11285: Outcomes and Etiologies for 30-day Readmissions in Patients With Myocarditis
Authors: Bing Yue, Claire Huang Lucas, Chayakrit Krittanawong, Lingling Wu, Eyal Herzog
Journal: Circulation (2019)

Introduction: Myocarditis varies greatly in etiology, clinical presentation, and prognosis. There is limited data available on the post-discharge outcomes and healthcare resource utilization among ...
THU0063 Autoantibodies to human myc far upstream element-binding protein in patients with rheumatoid arthritis
Authors: T Nojima, A Suwa, M Hirakata, Y Ikeda, T Mimori
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> We have shown that sera from patients with rheumatoid arthritis (RA) contain a variety of autoantibodies to unknown proteins such as 60-, 45-, and 75-kDa proteins, in preliminary immunoblot studies using HeLa cell extracts.<sup>1</sup> By molecular cloning of the target antigens, we have demonstrated that calpastatin (endogenous protein inhibitor of calpain, calcium-dependent cysteine proteinase) is one of such autoantigens and the presence of anti-calpastatin antibodies may be related to pathogenic mechanisms of RA.<sup>2,3</sup> <h3>Objectives</h3> We have attempted to identify autoantigens that were recognised by newly identified autoantibodies discovered in RA patient sera. We hereby describe that human myc far upstream element binding protein (FUSEbp) is a new target of autoantibodies in RA. <h3>Methods</h3> Molecular cloning was performed using a lambda gt11 cDNA library constructed from HeLa cell mRNA and RA patient sera that contain autoantibodies to unknown 75-kDa proteins as probes. cDNA inserts of isolated clones were sequenced, and detailed homologies of nucleotide and amino acid sequences were analysed through the BLAST server at NCBI DNA databank. Immunoblot analysis was examined using bacterial lysates prepared from lysogenic E.coli Y1089 carrying the recombinant lambda phages. The partial cDNA (position 192–975 of FUSEbp mRNA, termed FUSEbp-A) was amplified by PCR and ligated into an expression vector (pMAL-C2X). The expressed FUSEbp-A-maltose binding protein fusion protein was analysed by immunoblotting for patient sera. <h3>Results</h3> The cDNA (termed RA9–2) expressing the fusion protein recognised by RA probe sera was isolated, and a 1.2 kb insert of RA9–2 was found to show a 99% homology at amino acid level with FUSEbp. The deduced molecular mass of FUSEbp was identical with the size of the 75-kDa protein in HeLa cell extracts. However, this expressed bacterial lysates containing the lambda phage were reactive with only one of 72 RA (1%) and one of 36 SLE (3%) patient sera. In contrast, the FUSEbp-A fusion protein was recognised by 7 of 72 RA sera (10%) as well as the probe serum in immunoblot analysis. <h3>Conclusion</h3> Human myc FUSEbp, regulatory factor of c-myc expression,<sup>4</sup> may be a novel autoantigen recognised by sera from patients with RA In RA, synovial fibroblasts exhibit elevated gene expression of proto-oncogenes such as c-myc. Although it remains unclear how autoantibodies to FUSEbp can be associated with etiologic and pathogenic mechanisms in RA, increased expression and release of FUSEbp may induce antoantibodies to FUSEbp in RA-specific synovial proliferation and cartilage destruction. <h3>References</h3> Nojima T, et al. Jpn J Rheumatol. 1996;6:189–200 Mimori T, Nojima T, et al. Proc Natl Acad Sci USA 1995;92:7267–71 Kanazawa Y, Nojima T, et al. Modern Rheumatol. 2000;10: 38–44 He L, et al. EMBO J. 2000;19(5):1034–44