tbuckley/cabot-search huggingface dataset:
Abstract 83: Usefulness of Serum Immunoglobulin G Levels Calculated in the Acute Phase of Kawasaki disease
Authors: Chiaki Iida, Akira Iwanaga, Katsuya Tashiro
Journal: Circulation (2015)

Background: Intravenous gamma-globulin treatment (IVGG) is an established therapy for acute phase Kawasaki disease (KD). Since a lot of studies have already testified that the efficacy of IVGG is dose-dependent, a single large dose of IVGG has been accepted as a standard treatment of KD. Some reports described the increasing rate of serum Immunoglobulin G (IgG) after IVGG would have a relationship with efficacy of IVGG. It should, therefore, be very important to compass trends of serum IgG levels in each in KD patient. However, it is unable to frequently measure values of serum IgG in KD patients from the standpoint of medical expenses. If we can estimate IgG levels in KD patients from routine biochemical data without additional costs, that is very helpful to assess inflammatory status in acute phase of KD. Aim to this study: We hypothesized that serum levels of IgG in acute phase of KD patients could be extrapolated by serum values of total protein (TP) and albumin (Alb), and, we tried to establish a simple formula to estimate serum levels of IgG. Materials and methods: We enrolled 42 KD cases (27 ± 21 month, Male 24/Female 18) that were treated in Saga University Hospital, Japan from April of 2010 to August of 2014. All cases met the diagnostic criteria of KD. They were initially treated with IVGG and aspirin or flurbiprofen. 12 patients (28.6%) needed additional treatments such as steroid and cyclosporine A. In this study, we examined relations before and after treatments of serum TP and Alb and IgG in serum of them and tried to establish a simple formula to estimate serum levels of IgG in acute phase of KD. For statistical analysis, we used paired t-test. Results: We found that values obtained by subtracting serum values of IgG and Alb from TP were almost constant through acute phase in each KD patient, regardless of differences in clinical course and therapies. Therefore, we could estimate serum IgG values, once we checked levels of TP, Alb and IgG before treatment. Calculated IgG values were lineally correlated with values of directly measured IgG (P&lt;0.0001, r=0.90). From this finding, we would assess the course of IgG levels during acute phase of KD patients correctly. Conclusion: By estimation of IgG levels, we can grasp inflammatory status of KD and make appropriate therapeutic plans.
SP0031 Genetic studies in familial ankylosing spondylitis: the north american spondylitis consortium experience
Authors: JD Reveille, J Bruckel, R Inman, M Weisman, MA Khan, DTK Yu, R Schumacher, M Mahowald, A Sawitzke, M Stone, F Vasey, J Akey, L Jin
Journal: Annals of the Rheumatic Diseases (2001)

<h3></h3> Recent genome-wide screens of English families multiplex for ankylosing spondylitis (AS) have suggested genes additional to HLA-B27 to be involved in disease susceptibility, particularly on chromosome 2q and 16q. Another recent study has suggested an association of AS with an allele of the IL-1 receptor antagonist gene (IL-1RA) on chromosome 2q. In order to confirm these findings in an independent group of families, 92 sib pairs concordant for AS by modified New York criteria from 74 North American families from the were examined with eight polymorphic microsatellite markers within the major histocompatibility complex (MHC) and HLA-DRB1, DQA1, DQB1 alleles; four markers on chromosome 2q and three on 16q near the regions previously implicated. Results for the MHC markers were as follows: No evidence of linkage was found for the markers on chromosome 2q and 16q. In addition, analysis of 29 single nucleotide polymorphisms (SNP’s) from the IL-1 RA gene in 30 AS patients and 48 controls found no evidence of disease association. These data strongly suggest the presence of a second MHC gene operative in predisposition to AS at or near the HLA-DRB1 locus. Additional families are currently being studied and fine mapping studies in progress to confirm and extend these findings.
Effect of a Family Media Use Plan on Media Rule Engagement Among Adolescents
Authors: Megan A. Moreno, Kole S. Binger, Qianqian Zhao, Jens C. Eickhoff
Journal: JAMA Pediatrics (2021)

The American Academy of Pediatrics recommends that all families use a family media use plan to select and engage with media rules. To date, the effectiveness of this tool in promoting adolescent media rule engagement is unknown.To test the effect of a family media use plan on media rule engagement in adolescents.This randomized clinical trial with parallel design used the online Qualtrics platform for recruitment, data collection, and intervention delivery. Parents and their children (aged 12 to 17 years) who spoke and read in the English language were recruited, enrolled, and randomized to either the intervention or control group. Parent-adolescent dyads in both groups completed baseline surveys individually, and the dyads in the intervention group completed the family media use plan survey. Baseline recruitment was conducted from April 8, 2019, to May 1, 2019, and follow-up surveys were completed between June 11, 2019, and July 2, 2019.The American Academy of Pediatrics family media use plan.The primary outcome was media rule engagement reported by adolescents. Media rules were extracted from the family media use plan, and adolescents rated each rule (using Likert scales) according to whether the rule was present or followed in their home. Secondary outcomes were adolescent-perceived technology importance and changes in sleep, physical activity, and depression.A total of 1520 parent-adolescent dyads were enrolled in the trial and randomized to either the intervention or control group. Adolescents had a mean (SD) age of 14.5 (1.6) years, and 789 were female (51.9%) and 1027 were White (67.6%) individuals. Parents had a mean (SD) age of 44.1 (8.5) years, and 995 were women (65.5%) and 1021 were White individuals (67.2%). For media rule engagement, the between-group difference was -0.1 (95% CI, -1.1 to 0.9).This randomized clinical trial found that completing a family media use plan did not lead to statistically significant changes in media rule engagement for adolescents in the intervention group. Future studies should consider revising the family media use plan and exploring the importance of technology as an intervention outcome.ClinicalTrials.gov Identifier: NCT03881397.
Correspondence on ‘Glucosamine and O-GlcNAcylation: a novel immunometabolic therapeutic target for OA and chronic, low-grade systemic inflammation?’
Authors: Socrates Angelides, Nicholas Manolios
Journal: Annals of the Rheumatic Diseases (2021)

Figure 1 A patient in her seventies with documented moderate osteoarthritis of the knees and, to a lesser extent, of the shoulders given intravenous 99m-technetium-labelled glucosamine.There is increased uptake involving the articular surface of the knees and shoulders, with mild uptake in the knee synovium.The irregular shape of the kidneys is due to underlying polycystic kidney disease.on July
Abstract 558: Clinical Significance of Papillary Muscle Abnormalities in Hypertrophic Cardiomyopathy Identified by Cardiovascular Magnetic Resonance
Authors: Caitlin J Harrigan, Evan Appelbaum, Barry J Maron, Jacqueline L Buros, C. Michael Gibson, John R Lesser, James E Udelson, Warren J Manning, Martin S Maron
Journal: Circulation (2007)

Background. Increased thickness of the left ventricular (LV) wall is the predominant feature of the hypertrophic cardiomyopathy (HCM) phenotype. However, the structural characteristics of the LV pa...
THU0024 METHYLATION ANALYSIS OF VITAMIN D SIGNALING PATHWAY GENES IN RHEUMATOID ARTHRITIS PATIENTS
Authors: E. Punceviciene, J. Gaizevska, R. Sabaliauskaite, L. Venceviciene, D. Vitkus, S. Jarmalaite, I. Butrimiene
Journal: Annals of the Rheumatic Diseases (2020)

Background: Vitamin D is known for its immunomodulatory and epigenome interacting effects. Vitamin D deficiency is frequently observed in rheumatoid arthritis (RA) patients compared to healthy controls, is also named as a potential risk factor in RA ethiopatogenesis and may alter DNA methylation of certain genes [1,2]. Still, causality of vitamin D deficiency in RA patients needs to be elucidated. Objectives: The aim of the study was to evaluate relationship between DNA methylation status of vitamin D related genes ( VDR , CYP24A1 , CYP2R1 ), miRNA-155 expression, vitamin D level and its association with RA. Methods: CpG islands in promoter region of the VDR , CYP24A1 , CYP2R1 genes were chosen for DNA methylation analysis by means of pyrosequencing. DNA from blood mononuclear cells of 31 RA patients and 31 age and sex matched healthy controls was assessed for methylation pattern after informed consent was obtained in Vilnius university Hospital Santaros klinikos Centre of Rheumatology. For miRNA analysis quantitative reverse transcription PCR was used. Chemiluminescent microplate immunoassay was used to asses 25(OH)D serum levels. Results: 25(OH)D concentrations varied from deficiency (&lt;50 nmol/l), insufficiency (50-75 nmol/l) to normal range (≥75-100 nmol/l) in RA (mean 47.49 nmol/l; SD ± 27.93) and healthy controls (mean 57.38 nmol/l; SD ± 29.93)). CYP24A1 methylation level was significantly higher in comparison to VDR (p&lt;0.0001) and CYP2R1 (p&lt;0.0001) genes in both groups. CYP24A1 hypermethylation was also observed in older subjects (p=0.012). The study demonstrated a significant positive correlation between vitamin D concentration and VDR , CYP2R1 genes methylation intensity (r 2 =0.31, p=0.014; r 2 =0.25, p=0.042, respectively). However, gene methylation frequency and methylation intensity showed no significant difference between RA patients and healthy controls ( VDR – 2.4 vs 2.6 %, CYP24A1 – 16.6 vs 15.3 %, CYP2R1 – 2.6 vs 2.6 %) (p&gt;0.05). To note, miRNA-155 expression negatively correlated with CYP24A1 methylation intensity (r 2 =-0.43, p=0.009). Conclusion: Our study identified significant associations between the VDR and CYP2R1 promoter methylation and vitamin D concentration. However, no significant differences in DNA methylation pattern between RA patients and healthy controls were detected. MiR-155 expression was associated with CYP24A1 methylation level, confirming its possible involvement in vitamin D metabolism. The data of our study suggests that epigenetic phenomena are significantly involved in vitamin D metabolism and may have an indirect effect on RA ethiopatogenesis. References: [1]Jeffery LE, et al. Nat Rev Rheumatol. 2016,12.4:201. [2]Fetahu IS et al. Front Physiol. 2014,5:164. Acknowledgments: This project has received funding from the Research Council of Lithuania (LMTLT), agreement No. S-MIP-17-12. Disclosure of Interests: None declared
Acute GVHD Diagnosis and Adjudication in a Multicenter Trial: A Report From the BMT CTN 1202 Biorepository Study
Authors: Ran Reshef, Wael Saber, Javier Bolaños-Meade, George Chen, Yi-Bin Chen, Vincent T. Ho, Doris M. Ponce, Ryotaro Nakamura, Michael J. Martens, John A. Hansen, John E. Levine
Journal: Journal of Clinical Oncology (2021)

PURPOSE Accurate and reproducible methods to diagnose, grade, and report acute graft-versus-host disease (GVHD) are critical for the evaluation of therapies and biomarkers. PATIENTS AND METHODS The Blood and Marrow Transplant Clinical Trials Network 1202 study is an observational study of 1,709 allogeneic hematopoietic cell transplantation recipients that implemented weekly data reporting and near real-time data adjudication by an end point review committee (ERC), assigning a confidence level (confirmed, probable, possible, or negative) to the diagnosis of acute GVHD at onset. RESULTS During the first 100 days, symptoms consistent with GVHD developed in 90% of cases but were often determined by centers to be due to causes other than GVHD. Indeed, GVHD was under consideration in only 23% of cases at symptom onset. Diagnostic biopsies were obtained in 40% of cases, but treatment often was incongruous with biopsy findings and 10.5% of biopsies were equivocal. Importantly, more than 40% of steroid courses were started for reasons other than GVHD. The ERC modified the determination of GVHD diagnosis and/or grade in 12.3% of onset cases. The cumulative incidence of acute GVHD as reported by the centers was 62%. When the ERC adjudicated GVHD onset to be present only if the confidence level was probable or confirmed, the incidence of GVHD declined to 49%. CONCLUSION This study demonstrates that the incidence of GVHD may be overestimated at symptom onset, establishes a contemporary benchmark for acute GVHD, and suggests a structured framework for reporting and adjudication of GVHD that could be used in prospective trials.
Margetuximab (M) combined with anti-PD-1 (retifanlimab) or anti-PD-1/LAG-3 (tebotelimab) +/- chemotherapy (CTX) in first-line therapy of advanced/metastatic HER2+ gastroesophageal junction (GEJ) or gastric cancer (GC).
Authors: Daniel V.T. Catenacci, Minori Koshiji Rosales, Hyun Cheol Chung, Harry H. Yoon, Lin Shen, Markus H. Moehler, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2021)

TPS264 Background: Trastuzumab (T), a monoclonal antibody (mAb) targeting HER2, is standard of care 1st-line therapy for advanced HER2+ GEJ/GC patients. M, an investigational Fc-engineered anti-HER2 mAb, targets the same HER2 epitope but with higher affinity for both 158V (high binding) and 158F (low binding) alleles of activating Fc receptor CD16A. Data suggest margetuximab coordinately enhances both innate and adaptive immunity, including antigen-specific T-cell responses to HER2. PD-1 and LAG-3 are T-cell checkpoint molecules that suppress T-cell function. Retifanlimab (also known as MGA012 or INCMGA00012) is a humanized, hinge-stabilized, IgG4 Κ anti-PD-1 mAb blocking binding of PD-L1 or PD-L2 to PD-1. Tebotelimab (also known as MGD013) is a humanized Fc-bearing bispecific tetravalent DART® protein that binds to both PD-1 and LAG-3, inhibiting their respective ligand binding. We previously reported that a CTX-free regimen of M+PD-1 blockade was well tolerated in GEJ/GC patients, and induced a 44% objective response rate (ORR) in a double-positive biomarker population. This was 2- to 3-fold greater than in historical controls with checkpoint inhibitors alone. This registration-directed trial assesses efficacy, safety, and tolerability of M+checkpoint inhibition ± CTX in metastatic/locally advanced, treatment-naïve, HER2+ GEJ/GC patients. Methods: This is a 2-cohort, adaptive open-label phase 2/3 study (NCT04082364). The first single arm, CTX-free cohort A, evaluates M+retifanlimab in HER2+ (immunohistochemistry [IHC] 3+) and PD-L1+ (excluding microsatellite instability high) patients. After 40 patients are evaluated for response/safety, additional patients will be enrolled if the threshold for continuation is met. In randomized cohort B, HER2+ (IHC 3+ or 2+/fluorescent in situ hybridization+) patients are enrolled irrespective of PD-L1 status. Part 1 of cohort B randomizes patients to 1 of 4 arms (50 patients each): control arm (T+CTX) or 1 of 3 experimental arms (M+CTX; M+CTX+retifanlimab; M+CTX+tebotelimab). CTX is investigator’s choice XELOX or mFOLFOX-6. Part 2 of cohort B consists of control (T+CTX) vs 1 experimental arm (M+CTX) + either retifanlimab or tebotelimab, depending on results from part 1; with 250 patients each. The primary efficacy endpoint for cohort A (both parts) is ORR per RECIST 1.1; for cohort B part 2 it is overall survival. Clinical trial information: NCT04082364.
Identification of a small molecule as inducer of ferroptosis and apoptosis through ubiquitination of GPX4 in triple negative breast cancer cells
Authors: Yahui Ding, Xiaoping Chen, Can Liu, Weizhi Ge, Qin Wang, Xin Hao, Mengmeng Wang, Yue Chen, Quan Zhang
Journal: Journal of Hematology & Oncology (2021)

Abstract Background TNBC is the most aggressive breast cancer with higher recurrence and mortality rate than other types of breast cancer. There is an urgent need for identification of therapeutic agents with unique mode of action for overcoming current challenges in TNBC treatment. Methods Different inhibitors were used to study the cell death manner of DMOCPTL . RNA silencing was used to evaluate the functions of GPX4 in ferroptosis and apoptosis of TNBC cells and functions of EGR1 in apoptosis. Immunohistochemical assay of tissue microarray were used for investigating correlation of GPX4 and EGR1 with TNBC. Computer-aided docking and small molecule probe were used for study the binding of DMOCPTL with GPX4. Results DMOCPTL , a derivative of natural product parthenolide, exhibited about 15-fold improvement comparing to that of the parent compound PTL for TNBC cells. The cell death manner assay showed that the anti-TNBC effect of DMOCPTL mainly by inducing ferroptosis and apoptosis through ubiquitination of GPX4. The probe of DMOCPTL assay indicated that DMOCPTL induced GPX4 ubiquitination by directly binding to GPX4 protein. To the best of our knowledge, this is the first report of inducing ferroptosis through ubiquitination of GPX4. Moreover, the mechanism of GPX4 regulation of apoptosis is still obscure. Here, we firstly reveal that GPX4 regulated mitochondria-mediated apoptosis through regulation of EGR1 in TNBC cells. Compound 13 , the prodrug of DMOCPTL , effectively inhibited the growth of breast tumor and prolonged the lifespan of mice in vivo, and no obvious toxicity was observed. Conclusions These findings firstly revealed novel manner to induce ferroptosis through ubiquitination of GPX4 and provided mechanism for GPX4 inducing mitochondria-mediated apoptosis through up-regulation of EGR1 in TNBC cells. Moreover, compound 13 deserves further studies as a lead compound with novel mode of action for ultimate discovery of effective anti-TNBC drug.
Alternative splicing landscapes in Arabidopsis thaliana across tissues and stress conditions highlight major functional differences with animals
Authors: Guiomar Martín, Yamile Márquez, Federica Mantica, Paula Duque, Manuel Irimia
Journal: Genome biology (2021)

Abstract Background Alternative splicing (AS) is a widespread regulatory mechanism in multicellular organisms. Numerous transcriptomic and single-gene studies in plants have investigated AS in response to specific conditions, especially environmental stress, unveiling substantial amounts of intron retention that modulate gene expression. However, a comprehensive study contrasting stress-response and tissue-specific AS patterns and directly comparing them with those of animal models is still missing. Results We generate a massive resource for Arabidopsis thaliana , PastDB , comprising AS and gene expression quantifications across tissues, development and environmental conditions, including abiotic and biotic stresses. Harmonized analysis of these datasets reveals that A. thaliana shows high levels of AS, similar to fruitflies, and that, compared to animals, disproportionately uses AS for stress responses. We identify core sets of genes regulated specifically by either AS or transcription upon stresses or among tissues, a regulatory specialization that is tightly mirrored by the genomic features of these genes. Unexpectedly, non-intron retention events, including exon skipping, are overrepresented across regulated AS sets in A. thaliana , being also largely involved in modulating gene expression through NMD and uORF inclusion. Conclusions Non-intron retention events have likely been functionally underrated in plants. AS constitutes a distinct regulatory layer controlling gene expression upon internal and external stimuli whose target genes and master regulators are hardwired at the genomic level to specifically undergo post-transcriptional regulation. Given the higher relevance of AS in the response to different stresses when compared to animals, this molecular hardwiring is likely required for a proper environmental response in A. thaliana .
Cost of treatment change among patients with neuroendocrine tumors (NET) treated originally with somatostatin analogs.
Authors: Bernard Tawfik, David Ray, Meghan Moynihan, Nicole Princic
Journal: Journal of Clinical Oncology (2021)

365 Background: Understanding the economic implications of changes in treatment among patients with NET will be important as treatment sequencing continues to evolve. This study describes treatment characteristics and healthcare costs prior to and following treatment change from somatostatin analog (SSA) monotherapy to another therapy among a privately-insured NET patient population in the U.S. Methods: Patients with newly diagnosed NET and treated with SSA monotherapy were extracted from IBM MarketScan claims databases in 1/1/2014-3/31/2019. NET treatment change was captured ≥30 days after SSA start date (earliest new treatment = index date). Healthcare costs (reimbursed amount in 2019 dollars) were reported for 1, 3, and 6 months pre- and post-index intervals. Results: A total of 1,122 NET patients with SSA monotherapy were identified; 305 had further treatment changes (mean age: 58 years; female: 52%; metastatic disease at NET diagnosis: 49%). The majority of patients started on octreotide (81%) vs lanreotide (19%). Common treatment changes included alternate SSA (38%), targeted therapy (everolimus or sunitinib) (30%) or chemotherapy (23%). Fewer than 10% of patients were treated with PRRT 177 Lu-dotatate or telotristat and 1% with a combination. Total healthcare cost increased from $12,376 to $25,647 (mean difference = $13,272 ±$24,189, p&lt;0.001) for 1 month before/after treatment change, from $36,395 to $59,324 ($22,929 ±$41,764, p&lt;0.001) for 3 months before/after, and from $66,786 to $109,224 ($42,438 ±$98,875, p&lt;0.001) for 6 months before/after. Patients changing to targeted therapy had the largest 1 month interval cost increase ($19,677 ±$19,023, p&lt;0.001) compared with patients changing to alternate SSA ($10,240 ±$14,112, p&lt;0.001) and to chemotherapy ($4,057 ±$20,566, p=0.155). The differences were driven by increases in outpatient services and pharmacy prescriptions. Conclusions: The setting of rising costs after treatment change from SSA indicates treatment costs as the key driver, rather than NET disease severity. Future studies should investigate the clinical effectiveness of switching from SSA relative to the economic burden imposed by treatment change.