tbuckley/cabot-search huggingface dataset:
Abstract B54: Enhancer reprogramming by ASPSCR1-TFE3 in alveolar soft part sarcoma
Authors: Miwa Tanaka, Takuro Nakamura
Journal: Cancer Research (2020)

Abstract Alveolar soft part sarcoma (ASPS) predominantly affects adolescents and young adults, with lower legs and buttocks as frequent primary sites. ASPS is characterized by alveolar structure of tumor cells, abundant vascularization, and frequent hematogenous metastasis. As for gene abnormality, the ASPSCR1-TFE3 (AT3) fusion is invariably observed in all ASPS cases with low genetic mutational burdens. To understand the functional roles of AT3 in ASPS development, we have generated an ex vivo mouse model for ASPS that well recapitulates its phenotypes. TFE3 belongs to the MiT/TFE (TFE3/TFEB/TFEC/MITF) gene family encoding bHLH/leucine zipper transcription factors, all of which share common DNA-binding domains and consensus DNA-binding motifs. Mutations or overexpression of MiT/TFE family genes trigger human malignancies including ASPS, renal cell carcinoma (RCC), and malignant melanoma (MM). To address whether AT3 possesses a specific potency to induce ASPS, we have generated artificial chimeras between ASPSCR1 and MiT/TFE family genes and have revealed that only TFE3 and TFEB could induce ASPS in vivo whereas the others could not. To get insights into the role of AT3 in enhancer reprogramming that affects tumor phenotypes, we investigated the epigenetic landscape of ASPS. ChIP-seq analyses of human and mouse ASPS showed frequent overlapping of AT3 DNA-binding with histone H3K27ac and H3K4me3 at target loci, indicating that AT3 frequently binds to active enhancers. Among them, canonical MiT/TFE target genes involved in the autophagy, lysosome/endosome and vesicle/protein transport, and mTOR signaling pathways were significantly enriched. Analysis of dataset from GEO revealed that these loci were common targets of MiT/TFE transcription factors activated in human ASPS, RCC, and MM. To identify the AT3-specific and/or AT3-dependent enhancer reprograming mechanism, we focused on super-enhancers (SEs) that determine the cell identity and characteristic phenotypes of ASPS, and examined its modification by AT3. Frequent association of SEs with genes for vasculogenesis and apoptosis were observed in ASPS but not in MM, and AT3 depletion in ASPS resulted in disappearance of these SEs, suggesting that AT3 contributes to chromatin remodeling to promote vasculogenesis required for its alveolar structure and growth expansion. Taken together, our study provides novel aspects on common oncogenic pathways regulated by MiT/TFE family tumor in ASPS, RCC, and MM as well as AT3-specific regulatory mechanism in ASPS, which will offer potential therapeutic targets and biomarkers. Citation Format: Miwa Tanaka, Takuro Nakamura. Enhancer reprogramming by ASPSCR1-TFE3 in alveolar soft part sarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B54.
Abstract 18769: Is Conservative Treatment Justified in Marfan Syndrome Patients with Non-Complicated Acute Type B Aortic Dissection? Insights from the International Registry of Acute Aortic Dissection
Authors: Dan Gilon, Reed E Pyeritz, Arturo Evangelista, Patrick O'Gara, Kevin M Harris, Alan C Braverman, Mark D Peterson, Matthias Voehringer, Toru Suzuki, Lori D Conklin, Daniel G Montgomery, Eric M Isselbacher, Christoph A Nienaber, Kim A Eagle, Amit Korach
Journal: Circulation (2012)

Introduction: Conservative treatment is the treatment of choice in patients (pts) with non- complicated acute type B aortic dissection (TBAAD). This strategy has not been validated in patients with Marfan Syndrome (MFS) presenting with non-complicated TBAAD. Methods: Our study evaluated 586 medically managed patients with non-complicated TBAAD enrolled in IRAD between 1996 and 2011. The patients were divided into groups based on the presence (N=15, 2.6%) or absence (N=571, 97.4%) of MFS. Categorical variables were analyzed using chi-square test and Fischer’s exact test where applicable. Continuous variables were analyzed using student’s t-test for normally distributed data, and test of medians for non-normally distributed data. Results: The mean age was significantly lower for MFS patients (41.3±9.4 years vs 65±13.5 years [p&lt;0.001]). Significantly more patients without MFS had history of hypertension (61.5% vs 40% [p&lt;0.001]). Additionally, those with MFS had significantly higher incidence of prior aortic dissection (64.3% vs 5.8% [p&lt;0.001]), and family history of aortic disease (75% vs 9.5% [p&lt;0.001]). Significantly more non-MFS patients presented with hypertension (70% vs 33.3% [p&lt;0.008]). Abdominal vessels involvement was more frequent in patients with MFS (53.3% vs 22.8% [p=0.011]). During the hospitalization, more patients with MFS had extension of their dissection (20% vs 4% [p=0.024]). None of the patients with MFS died during the index hospitalization, nor did they have new neurological or visceral ischemia. Kaplan-Meyer survival curve showed no significant difference in survival between the two groups from admission to five years follow-up. Conclusion: The presence of dissection extension in patients with MFS warrants special in-hospital attention. However, our results indicate that, similar to patients without MFS, conservative treatment may be safe in Marfan Syndrome patients presenting with non-complicated acute type B aortic dissection. Given the limited study population, more research is needed to definitively analyze whether non-complicated TBAAD MFS patients would benefit from conservative versus more aggressive dissection management.
Abstract A44: Comparative gene expression analysis for identification and prioritization of therapeutic targets in a cohort of childhood cancers
Authors: Lauren M. Sanders, A. Geoffrey Lyle, Holly C. Beale, Ellen Towle Kephart, Katrina Learned, Jennifer Peralez, Norman Lacayo, Arun Rangaswami, Sheri L. Spunt, Isabel Bjork, David Haussler, Sofie R. Salama, Olena M. Vaske
Journal: Cancer Research (2020)

Abstract Here we describe the utility of comparative RNA sequencing (RNA-seq) analysis in identifying cancer driver pathways and relevant therapeutics in childhood cancer, and we introduce a novel system for prioritizing gene targets based on analytical and published evidence. The purpose of our study was to evaluate the clinical utility of comparative N-of-1 gene expression analysis in identifying therapeutic options for pediatric patients with relapsed or recurrent cancers. The comparative analysis framework and large cancer background cohorts were developed at the Treehouse Childhood Cancer Initiative at UC Santa Cruz. We employed this analysis in a pilot study of 26 patients at the Lucile Packard Children’s Hospital. We analyzed RNA-seq data from 30 biopsied samples from 26 patient donors, including 16 sarcomas, 5 CNS tumors, 3 hematopoietic cancers, 1 liver, and 1 colon cancer. We compared gene expression from each child’s tumor biopsy to a background cohort of RNA-seq data from over 11,000 cancer patients, and also to a smaller cohort defined by molecular and histopathologic similarity to the child’s tumor biopsy. This comparison yielded outlier gene activations in the child’s biopsy compared to those in the background cohorts, reflecting cancer driver pathways in the child’s tumor that are actionable. We stratified each of the resulting therapeutic leads into 5 baskets: RTK activation, JAK/STAT signaling, PI3K/AKT/mTOR signaling, Cell Cycle activation, or Other. Because 27 of the 30 samples had more than one lead, we developed a novel scoring system to prioritize each sample’s therapeutic gene targets based on the analytical strength of the gene expression analysis result, and on published literature evidence for each gene as a biomarker indicative of drug response. We presented the results of our analysis in genomic consensus meetings at Stanford and surveyed the responses of clinicians and families on the utility of our analysis for treatment decisions. Here we report our experience with the method and highlight case studies in which this analysis informed treatment decisions. Citation Format: Lauren M. Sanders, A. Geoffrey Lyle, Holly C. Beale, Ellen Towle Kephart, Katrina Learned, Jennifer Peralez, Norman Lacayo, Arun Rangaswami, Sheri L. Spunt, Isabel Bjork, David Haussler, Sofie R. Salama, Olena M. Vaske. Comparative gene expression analysis for identification and prioritization of therapeutic targets in a cohort of childhood cancers [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A44.
Sleep-related breathing disorders and pulmonary hypertension
Authors: Yochai Adir, Marc Humbert, Ari Chaouat
Journal: European Respiratory Journal (2020)

Sleep-related breathing disorders (SBDs) include obstructive apnoea, central apnoea and sleep-related hypoventilation. These nocturnal events have the potential to increase pulmonary arterial pressure (PAP) during sleep but also in the waking state. "Pure" obstructive sleep apnoea syndrome (OSAS) is responsible for a small increase in PAP whose clinical impact has not been demonstrated. By contrast, in obesity hypoventilation syndrome (OHS) or overlap syndrome (the association of chronic obstructive pulmonary disease (COPD) with obstructive sleep apnoea (OSA)), nocturnal respiratory events contribute to the development of pulmonary hypertension (PH), which is often severe. In the latter circumstances, treatment of SBDs is essential in order to improve pulmonary haemodynamics.Patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are at risk of developing SBDs. Obstructive and central apnoea, as well as a worsening of ventilation-perfusion mismatch, can be observed during sleep. There should be a strong suspicion of SBDs in such a patient population; however, the precise indications for sleep studies and the type of recording remain to be specified. The diagnosis of OSAS in patients with PAH or CTEPH should encourage treatment with continuous positive airway pressure (CPAP). The presence of isolated nocturnal hypoxaemia should also prompt the initiation of long-term oxygen therapy. These treatments are likely to avoid worsening of PH; however, it is prudent not to treat central apnoea and Cheyne-Stokes respiration (CSR) with adaptive servo-ventilation in patients with chronic right-heart failure because of a potential risk of serious adverse effects from such treatment.In this review we will consider the current knowledge of the consequences of SBDs on pulmonary haemodynamics in patients with and without chronic respiratory disease (group 3 of the clinical classification of PH) and the effect of treatments of respiratory events during sleep on PH. The prevalence and consequences of SBDs in PAH and CTEPH (groups 1 and 4 of the clinical classification of PH, respectively), as well as therapeutic options, will also be discussed.
Abstract IA01: Pediatric neuro-oncology: What’s next?
Authors: Stefan M. Pfister
Journal: Cancer Research (2020)

Abstract Based on recent discoveries and data integration in genomics and epigenomics, a lot more is known about the biology of childhood brain tumors today when compared to a decade ago. This has vastly benefitted brain tumor diagnostics, including classification and some predictive and prognostic biomarkers. Yet the gap between this newly defined diagnostic gold standard and routine clinical implementation largely remains to be bridged. Additionally, the cell of origin for a majority of brain tumor entities remains elusive. The increased granularity of understanding intertumor heterogeneity also comes with the challenge of accounting for this heterogeneity in our therapeutic approaches. Ever-smaller patient groups and, on the other hand, an ever-increasing portfolio of potentially available drugs, require a paradigm shift in how we run and evaluate preclinical and clinical trials. Academically rewarding proof-of-concept studies that are typically well published, which certainly have a different purpose and thus lack the rigor of thorough preclinical filtering (because they typically embark on one or two “representative” models, which certainly does not cover the heterogeneity of a disease by any means), should no longer be regarded “sufficient preclinical evidence” to justify a clinical trial. Thus, novel incentives and funding models for this “less academically attractive,” but highly patient-relevant studies need to be explored. Phase I trials just with the purpose of dose finding should not be carried without a path forward into efficacy testing. Drugs with no evidence for brain penetration should not “just” be tried in patients with brain tumors without even making the best effort to understand brain and tumor penetrance. Academic work-up of biologic material from every single patient being enrolled on a trial should be mandatory rather than “nice to have.” Hereditary cancer predisposition should no longer be ignored when it comes to treatment stratification. Reimbursement models for “next-generation diagnostics,” preclinical phase I and phase II studies, and academic clinical trials (focusing on combinations rather than monotherapies in end-stage disease) have to shift from traditional third-party funding to alternative funding models. If we do not manage to address this paradigm shift, high-risk brain tumor patients may still mostly die from their disease 10 years from now. Citation Format: Stefan M. Pfister. Pediatric neuro-oncology: What’s next? [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA01.
Dual Targeting with CAR T Cells to Limit Antigen Escape in Multiple Myeloma
Authors: Sylvain Simon, Stanley R. Riddell
Journal: Blood Cancer Discovery (2020)

Summary: Adoptive T-cell therapy targeting a single tumor antigen can induce remissions of hematologic cancers but relapses often occur due to the outgrowth of tumor cells with absent or low expression of the antigen. Strategies to simultaneousy target multiple antigens are needed to fully capitalize on the promise of this therapeutic strategy. In this issue of Blood Cancer Discovery, Fernández de Larrea and colleagues demonstrate in preclinical models of multiple myeloma that targeting BCMA and GPRC5D simultaneously with T cells engineered to express chimeric antigen receptors specific for these antigens may prevent tumor cell escape. See related article by Fernández de Larrea et al., p. 146.
AB0351 EFFICACY OF IGURATIMOD FOR RHEUMATOID ARTHRITIS IN ELDERLY PATIENTS
Authors: Y. Mochida, K. Harigane, T. Shimazaki, Y. Inaba, A. Nagaoka
Journal: Annals of the Rheumatic Diseases (2020)

Background: Iguratimod (IGU) was started development as new non-steroidal anti-inflammatory drugs (NSAIDs), but it was changed for development as disease modifying antirheumatic drugs (DMARDs) because it showed suppression of inflammatory cytokine and inflammatory parameter which was not to be found in existing NSAIDs in the early stage of pharmacological study of drug efficacy. Although the clinical efficacy and the safety of IGU were already reported, the efficacy for elderly cases was not sufficiently analyzed. Objectives: In this study, we compared the efficacy of IGU in elderly group with the non-elderly group. Methods: 190 patients who were able to continuously administer IGU more than three months was included. Cases were divided into two groups. Group A (75 years or older) includes 57 patients, and Group B (younger than 75 years) includes 133 patients. The patients background, the use of methotrexate (MTX) and glucocorticoid, the change of serum CRP, and the DAS28-ESR (before, 6, 12, and 24 months) as an evaluation of the disease activity were compared between two groups. The study protocol was approved by our institutional review board. All the patients were required to give written informed consent. Results: The average age at the beginning of IGU was 79.9±4.1 years old in Group A, and 59.9±10.6 years old in Group B. The average disease duration was 14.8±16.5 year in Group A and 8.5±10.6 year in Group B (p&lt;0.01). Although the rate of concomitant use of MTX was significantly lower in Group A (Group A; 28.1%, Group B; 56.4%), the averaged dose of MTX did not show difference between groups (7.0 and 8.4 mg/week, respectively). Group A showed significantly higher rate of concomitant use of glucocorticoid (56.1%, and 36.1%, respectively), but the averaged dose of glucocorticoid did not show a difference between groups (4.3 and 3.6mg/day, respectively). Similarly, the rate of concomitant use of NSAIDs did not have a difference in two groups. Group A showed significantly higher serum CRP at the beginning of the IGU (Group A; 2.0 mg/dl, Group B; 1.2 mg/dl), but there was no difference after six months. In both groups, serum CRP was significantly decreased when compared at the beginning of IGU. After six months of IGU administration, both groups showed good clinical performance with DAS28-ESR, more than 60% of the cases showed remission or low disease activity. No difference of DAS28-ESR scores between two groups was observed after six months. Conclusion: From the results of this study, the efficacy of IGU for elderly patients was confirmed and did not show differences with non-elderly people. IGU is an inexpensive drug with enough efficacy and thought to be possible substitute for cases with insufficient reaction with other DMARDs. References: [1]Nozaki Y, et al. Modern Rheumatology 1439-7595, 2019. [2]Yoshikawa A, et al. Mod Rheumatol 28: 227-234, 2018. Disclosure of Interests: None declared
Response to: ‘Correspondence on ‘Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort’ by Ventura<i>et al’</i>
Authors: Juliette Chommeloux, Marie Pouletty, Naim Ouldali, Mathieu Kerneis, Alexis Mathian, Raphaele Mestiri, Julien Rohmer, Guillaume Hekimian, Isabelle Melki
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background</h3> There is evidence of increasing use of the synthetic cathinone mephedrone (4-methylmethcathinone), particularly amongst clubbers. However, there have only two single case reports of mephedrone toxicity. The aim of this study is to report the pattern of clinical toxicity seen with mephedrone use. <h3>Case Series</h3> We describe 15 patients who presented to our Emergency Department following self-reported mephedrone use. Significant clinical features seen included agitation in 53.3%, tachycardia in 40%, systolic hypertension in 20% and seizures in 20%. Twenty per cent required treatment with benzodiazepines, predominantly for management of agitation. All patients were discharged with no sequelae. Previous user reports have suggested that mephedrone use is associated with cool/blue peripheries; this was not seen in any of the patients in our series. <h3>Conclusion</h3> The pattern of toxicity seen with mephedrone in this series is similar to that seen with 1-benzylpiperazine which has recently been classified under UK and EU misuse of drugs legislation. On the basis of this, together with a recent confirmed mephedrone related death in Sweden, we feel that appropriate assessments should be undertaken to determine the legal status of mephedrone.
Multi‐Tissue Epigenetic and Gene Expression Analysis Combined With Epigenome Modulation Identifies <i>RWDD2B</i> as a Target of Osteoarthritis Susceptibility
Authors: Eleanor Parker, Ines M. J. Hofer, Sarah J. Rice, Lucy Earl, Sami A. Anjum, David J. Deehan, John Loughlin
Journal: Arthritis & Rheumatology (2020)

Osteoarthritis (OA) is polygenic, with more than 90 risk loci currently mapped, including at the single-nucleotide polymorphism rs6516886. Previous analysis of OA cartilage DNA identified 6 CpG dinucleotides whose methylation levels correlated with the rs6516886 genotype, forming methylation quantitative trait loci (mQTLs). We undertook this study to investigate these mQTLs and to map expression quantitative trait loci (eQTLs) across joint tissues in order to prioritize a particular gene as a target of the rs6516886 association effect.Nucleic acids were extracted from the cartilage, fat pad, synovium, and peripheral blood from OA patients. Methylation of CpGs and allelic expression imbalance of potential target genes were assessed by pyrosequencing. A chondrocyte cell line expressing deactivated Cas9 (dCas9)-TET1 was used to directly alter CpG methylation levels, with effects on gene expression quantified by polymerase chain reaction.Multiple mQTLs were detected, with effects strongest in joint tissues and with methylation at CpG cg20220242 correlating most significantly with the rs6516886 genotype. CpG cg20220242 is located upstream of RWDD2B. Significant rs6516886 eQTLs were observed for this gene, with the OA risk-conferring allele of rs6516886 correlating with reduced expression CpG methylation also correlated with allelic expression of RWDD2B, forming methylation-expression QTLs (meQTLs). Deactivated Cas9-TET1 reduction in the methylation of cg20220242 increased expression of RWDD2B.The rs6516886 association signal is a multi-tissue meQTL involving cg20220242 and acting on RWDD2B. Modulating CpG methylation reverses the impact of the risk allele. RWDD2B codes for a protein about which little is currently known. Its further analysis as a target of OA genetic risk will provide novel insight into this complex disease.
Women’s journey in Mexican rheumatology. Comment on ‘Gender gap in rheumatology: speaker representation at annual conferences’ by Monga<i>et al</i>
Authors: Iris J Colunga-Pedraza, Rosa I Arvizu-Rivera, Griselda Serna-Peña, Ana Laura De-Leon-Ibarra, Deshire Alpizar Rodriguez, Alejandra Pérez-Villar, Mayra Alejandra Reyes Soto, Dionicio Angel Galarza-Delgado
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the letter written by Monga et al addressing the narrowing of the gender gap in the annual meetings of the American College of Rheumatology, in which they reported an increase in female speakers from 42.8% in 2017 to 47.0% in 2018.1 However, women under-representation goes beyond annual meetings as Adami et al found that of 366 guidelines and recommendations in Rheumatology published from 2004 to 2019, only 32% of first authors were women, a proportion which has been increasing in the last 15 years.2 Their findings propelled us to evaluate women’s participation as first authors of oral presentations in the …