tbuckley/cabot-search huggingface dataset:
Towards Precision Medicine With Human iPSCs for Cardiac Channelopathies
Authors: Joseph C. Wu, Priyanka Garg, Yoshinori Yoshida, Shinya Yamanaka, Lior Gepstein, Jean-Sébastien Hulot, Björn C. Knollmann, Peter J. Schwartz
Journal: Circulation Research (2019)

Long-QT syndrome, a frequently fatal inherited arrhythmia syndrome caused by genetic variants (congenital) or drugs (acquired), affects 1 in 2000 people worldwide. Its sentinel event is often sudden cardiac death, which makes preclinical diagnosis by genetic testing potentially life-saving. Unfortunately, clinical experience with genetic testing has shown that it is difficult to correctly identify genetic variants as disease causing. These current deficiencies in accurately assigning pathogenicity led to the discovery of increasing numbers of rare variants classified as variant of uncertain significance. To overcome these challenges, new technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) genome editing can be combined with human induced pluripotent stem cell-derived cardiomyocytes to provide a new approach to decipher pathogenicity of variants of uncertain significance and to better predict arrhythmia risk. To that end, the overarching goal of our network is to establish the utility of induced pluripotent stem cell-based platforms to solve major clinical problems associated with long-QT syndrome by determining how to (1) differentiate pathogenic mutations from background genetic noise, (2) assess existing and novel variants associated with congenital and acquired long-QT syndrome, and (3) provide genotype- and phenotype- guided risk stratification and pharmacological management of long-QT syndrome. To achieve these goals and to further advance the use of induced pluripotent stem cells in disease modeling and drug discovery, our team of investigators for this Leducq Foundation Transatlantic Networks of Excellence proposal will work together to (1) improve differentiation efficiency, cellular maturation, and lineage specificity, (2) develop new assays for high throughput cellular phenotyping, and (3) train young investigators to clinically implement patient-specific genetic modeling.
Cetuximab with irinotecan or oxaliplatin for first-line metastatic colorectal cancer: Effectiveness in the EREBUS cohort compared to pivotal trials.
Authors: Annie Fourrier-Réglat, Magali Rouyer, Pernelle Noize, Emmanuelle Bignon, Alise Le Monies, Jeremy Jove, Alain Monnereau, Antonio Sa Cunha, Eric Francois, Emmanuel Mitry, Denis Michel Smith
Journal: Journal of Clinical Oncology (2013)

e14542 Background: Cetuximab (CTX) has demonstrated improved survival outcomes in metastatic colorectal cancer (mCRC) but information from real-life use is sparse. Here, CTX survival and safety outcomes in real-life are compared to those observed in OPUS and CRYSTAL trials. Methods: EREBUS is a French multicenter cohort study that included over two years (2009-2010) patients with unresectable mCRC and wild-type KRAS initiating CTX as 1st-line therapy in 65 centres and followed for 12 months from treatment initiation. Results: We included 389 patients treated with a combination of CTX with irinotecan-based (56.0%) or CTX with oxaliplatin-based (37.8%) chemotherapy. The main characteristics, safety, response rate, and one year survival of this cohort are presented in the Table below in parallel with results obtained in pivotal trials. Conclusions: Despite differences in baseline characteristics between real-life and pivotal trials (such as ECOG status), the response rate and PFS were comparable in mCRC patients with wt KRAS treated with 1st-line CTX. The nature of adverse events was in-line with the trials but the frequency was lower probably owing to under-notification in real-life. [Table: see text]
P065 Regulation of joint destruction by activin a in rheumatoid arthritis
Authors: V Kracke, M Fennen, J Intemann, E Werbenko, D de Gorter, P Paruzel, T Pap, B Dankbar
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> Activins and inhibins belong to the transforming growth factor β family. Activins are disulphide-linked homo- or heterodimers consisting of two inhibin β chains (βA, βB) that are expressed in many cell types. However, activin A (βA βA) is the only activin that is expressed in bone and cartilage. Moreover, activin A has been demonstrated not only to stimulate receptor activator of NF-κB ligand (RANKL)-induced osteoclast (OC) differentiation but also to inhibit osteoblast differentiation. <h3>Objectives</h3> Here we investigate the impact of activin A on joint destruction in rheumatoid arthritis. <h3>Methods</h3> Synovial tissue samples from rheumatoid arthritis (RA) and osteoarthritis (OA) patients were analysed by immunohistochemical staining. For <i>in vitro</i> experiments, synovial fibroblasts (FLS) were isolated from hind paws of WT mice. Effects of cytokines on the secretion of activin A by mouse FLS were evaluated by ELISA. Bone marrow-derived macrophages (BMM) were isolated from femurs and tibias of WT mice and differentiated into osteoclasts in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL with or without activin A. OC differentiation was characterised by TRAP staining. Resorption activity was determined by quantification of osteoclast-mediated pit formation on a calcium phosphate-coated plate. Furthermore, osteoclast-specific gene expression as well as the activation of SMAD2 in BMMs, OCs and FLS were analysed by immunoblotting. The interaction of phospho-SMAD2 with NFATc1 was evaluated by co-immunoprecipitation using Dynabeads. <h3>Results</h3> We demonstrate that activin A is highly abundant in the synovium of RA but not of OA patients. <i>In vitro</i>, activin A secretion by FLS was strongly enhanced by pro-inflammatory cytokines. Furthermore, activin A strongly enhanced the RANKL-mediated differentiation of BMMs into mature OCs, reflected by a significantly increased OC number and OC size. Moreover, concomitant administration of activin A led to a significant increase of the total resorption area as well as resorption area per pit, indicating an increased activity of individual OCs. Furthermore, activin A enhanced the RANKL-induced expression OC differentiation markers, but alone was not able to induce OC differentiation. Analyses of signaling pathways revealed that activin A induce the activation of SMAD2 in BMMs and OCs. Finally, upon co-stimulation with RANKL, activin A resulted in an increased interaction between activated SMAD2 and NFATc1. <h3>Conclusions</h3> The data strongly suggest that increased expression of activin A in the arthritic joint is associated with enhanced osteoclast formation, promoting joint destruction in rheumatoid arthritis. <h3>Disclosure of Interest</h3> None declared.
Circulating dipeptidyl peptidase 3 and alteration in haemodynamics in cardiogenic shock: results from the OptimaCC trial
Authors: Koji Takagi, Alice Blet, Bruno Levy, Benjamin Deniau, Feriel Azibani, Elodie Feliot, Andreas Bergmann, Karine Santos, Oliver Hartmann, Etienne Gayat, Alexandre Mebazaa, Antoine Kimmoun
Journal: European Journal of Heart Failure (2019)
Preoperative chemoradiation and cetuximab for resectable, locally advanced esophageal cancer: Preliminary results of a prospective phase Ib/II trial.
Authors: Baruch Brenner, Yulia Kundel, Ofer Purim, Gal Medalia, Liran Olshinka, Hanoch Kashtan, Nikolai Menasherov, Eyal Fenig, Aaron Sulkes, Efraim Idelevich
Journal: Journal of Clinical Oncology (2012)

e14571 Background: This prospective phase IB/II study evaluated the safety and efficacy of the addition of cetuximab to standard preoperative chemoradiation (CRT) in locally advanced esophageal cancer (LAEC). We hereby report its preliminary results. Methods: Patients (pts) with potentially resectable LAEC, defined as T2-4N0-1M0, T1-4N1M0 or T1-4N0-1M1A tumors, received an induction cycle of cisplatin 100 mg/m 2 , day 1, and 5-FU 1000 mg/m 2 /day as a continuous infusion (CI), days 1–5, followed 4 weeks later by 50.4 Gy radiotherapy (RT) given concurrently with 2 cycles of cisplatin 75 mg/m 2 and escalating doses of CI 5-FU, days 1–4 and 29-32. Pts received also 10 weekly infusions of cetuximab, 250 mg/m 2 , with a loading dose of 400 mg/m 2 , starting from the induction. The phase II part of the study started when the 5-FU dose during CRT was defined. Surgery was planned 6-8 weeks after CRT. Results: Thirty-six pts have been enrolled to date and 32 completed CRT. The median age was 65 years and 60% were males. The ratio of squamous/adeno histologies was 53%/47%. Pts had very advanced tumors: 95% T3-T4, 63% N1 and 28% M1A. In the absence of dose limiting toxicity, 31 pts received the phase II dose of 5-FU, defined as 1000 mg/m 2 /day. The most common grade &gt;3 toxicities were leucopenia (51% of pts) and neutropenia (48%). There was one toxic death, due to neutropenic sepsis. Among the 27 operated pts, R0 resection was achieved in 24 (89%). There were 4 cases (15%) of postoperative mortality, due to infection (3 pts) or respiratory failure (1). Downstaging was noted in 83% of pts and pathological complete response (pCR) in 32%. Pts with squamous histology had a higher pCR rate (53% vs 7%, p=0.007). At the time of the analysis, 14 pts (40%) remain free of disease and the local control rate is 92%. Updated results will be presented at the meeting. Conclusions: Preliminary results from this prospective study suggest that the addition of cetuximab to standard CRT is safe. The R0, pCR and local control rates are encouraging. Squamous cell tumors may gain more benefit from the addition of cetuximab.
Hygiene of the Voice.
Journal: JAMA (1924)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer
Authors: Marian L. Burr, Christina E. Sparbier, Kah Lok Chan, Yih-Chih Chan, Ariena Kersbergen, Enid Y.N. Lam, Elizabeth Azidis-Yates, Dane Vassiliadis, Charles C. Bell, Omer Gilan, Susan Jackson, Lavinia Tan, Stephen Q. Wong, Sebastian Hollizeck, Ewa M. Michalak, Hannah V. Siddle, Michael T. McCabe, Rab K. Prinjha, Glen R. Guerra, Benjamin J. Solomon, Shahneen Sandhu, Sarah-Jane Dawson, Paul A. Beavis, Richard W. Tothill, Carleen Cullinane, Paul J. Lehner, Kate D. Sutherland, Mark A. Dawson
Journal: Cancer Cell (2019)

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
Phase II trial of huKS-IL2 with cyclophosphamide (CTX) in patients with extensive disease small-cell lung cancer (ED-SCLC).
Authors: Oleg Gladkov, Mikhail Biakhov, Rodryg Ramlau, Piotr Serwatowski, Janusz Milanowski, Janusz Tomeczko, Philip B Komarnitsky, Laurence Bernard, Daniel Kramer, Maciej Jerzy Krzakowski
Journal: Journal of Clinical Oncology (2012)

7090 Background: huKS-IL2 immunocytokine is a humanized antibody specific for EpCAM, fused at its Fc end to two molecules of IL2. Results of a phase 1b study of huKS-IL2 plus low-dose CTX, and preclinical data, provided a rationale to evaluate this combination in SCLC, which is often EpCAM-positive. Methods: Patients (pts) with ED-SCLC responding (PR/CR) to 4 cycles of first-line Pt-based chemotherapy were randomized 1,5:1 to receive huKS-IL2/CTX or best supportive care (BSC). Pts in the huKS-IL2/CTX arm received six 21-day cycles of CTX 300 mg/m 2 on day (d) 1, and 1.5 mg/m 2 /d huKS-IL2 on d2–4, followed by 21-d cycles of CTX on d1 and huKS-IL2 on d2 until progression. Pts were stratified for prophylactic cranial irradiation (PCI) and response to chemotherapy. Primary endpoint was PFS rate at 6 months (mo). Secondary endpoints included OS rates at 12 and 18 mo from start of Pt-based chemotherapy, median PFS and OS, safety, and immunogenicity. Results: 108 pts (64 huKS-IL2/CTX arm, 44 BSC arm) were randomized and treated. Baseline characteristics were balanced between arms; however, higher % of males (75 vs 61.4%) and of ECOG PS 0 (45.3 vs 38.6%) were observed in the active arm. Median age was 61.7 (32; 81) and 59.2 (45; 74) years in the active and BSC arm, respectively. Most pts were in PR at randomization (2 pts – 1 in each arm – had CR). PCI was used in 15 (23.4%) and 11 (25%) pts in the active and BSC arm, respectively. No significant differences in PFS or OS were observed in the active vs BSC arm: PFS rate was 6.4 vs 12.2%; median PFS was 1.5 vs 1.4 mo; OS rates at 12 and 18 mo were 52 vs 61% and 24 vs 29%, respectively; median OS was 12.3 vs 14.1 mo. One PR (45% reduction vs randomization baseline) was observed in the active arm. In a subset of pts who received PCI, median PFS was 1.7 vs 1.5 mo, median OS 21.5 vs 14.3 mo in the active vs BSC arm, respectively. AEs observed more frequently in the active arm were flu-like symptoms, rash, hypotension, lymphopenia, LFT and creatinine elevations; all Grade 3/4 AEs related to huKS-IL2 were reversible/manageable. Conclusions: HuKS-IL2/CTX was well tolerated, but showed no benefit in pts with ED-SCLC in PR/CR after chemotherapy. A trend for improved PFS and OS was observed in pts who received prior PCI.
Exon Skipping of AIMP2 and Lymphomagenesis
Authors: Doyeun Kim, Seulki Song, Dae-Yoon Kim, Dongchan Kim, Nam Hoon Kwon, Byung-Su Kim, Hyun Jung Lee, Hyo Jung Kim, Jung Lim Lee, Sung-Soo Yoon, Yoon Kyung Jeon, Sunghoon Kim, Youngil Koh
Journal: Blood (2018)
P033/O31 CD38-expressing memory T cells are expanded in peripheral blood, contained in inflamed tissue and represent a potential treatment target in systemic lupus erythematosus
Authors: L Ostendorf, P Enghard, F Hiepe, T Alexander
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> The unresponsiveness of long-lived plasma cells (PC) to immunosuppressive and B cell depleting therapies represents a therapeutic challenge in systemic lupus erythematosus (SLE) and other immune-mediated diseases. Novel potential targets such as CD38 have emerged.<sup>1</sup> <h3>Objectives</h3> Here, we aimed to analyze expression levels of CD38 on circulating plasmablast and peripheral blood and tissue residing lymphocyte subsets in SLE to estimate the therapeutic potential of CD38-targeting therapies. <h3>Methods</h3> Multicolor flow cytometry was performed to investigate the CD38 expression on peripheral blood mononuclear cells (PBMCs) of SLE patients (n=36), healthy controls (HC, n=20) and multiple myeloma (MM, n=10) patients. In addition, kidney-infiltrating T cells isolated from urine were analyzed in patients with lupus nephritis (LN). To investigate the cytokine secreting potential, cytokines were analyzed intracellularly in CD38-expressing T cells after polyclonal stimulation <i>in vitro</i> with PMA/Ionomycin. <h3>Results</h3> Circulating CD19<sup>+</sup>CD24<sup>neg</sup>CD27<sup>high</sup> plasmablasts are more frequent in SLE and MM patients and display higher mean fluorescence intensity for CD38 compared to HC. In SLE, CD38 is significantly higher expressed in both CCR7<sup>+</sup> central and CCR7<sup>neg</sup> effector memory CD4 and CD8 T cells compared to HC. Such cells co-express other markers of T cell activation and recent proliferative history such as HLA-DR and Ki-67, and are preferentially negative for FoxP3 and Helios. CD38 is most exclusively expressed on CXCR3<sup>+</sup> memory T cells isolated from urine of patients with LN in contrast to their CXCR3<sup>neg</sup> counterparts. Upon polyclonal stimulation, cytokine (IFN-g, IL-17, TNFa, IL-2) secreting cells were confined to memory T cells lacking CD38 expression. <h3>Conclusions</h3> Expression levels of CD38 are significantly higher in peripheral blood memory B- and T-cell subsets from patients with SLE compared to HC. CD38<sup>pos</sup> T cells co-express markers of recent activation and proliferative history, are confined to conventional memory T cells and contained in inflamed tissue, suggesting a pathogenic role of a chronically activated memory T cell compartment in SLE. The lack of effector cytokine secretion of such cells is unexpected and merits further investigation. PC depleting therapies targeting CD38 may represent a promising treatment option in SLE given their potential therapeutic effect on activated memory T cells in inflamed tissue. <h3>Reference</h3> Hiepe F, Radbruch A. <i>Nat Rev Nephrol</i> 2016. <h3>Acknowledgements</h3> We thank all study participants and blood donors. <h3>Disclosure of Interest</h3> None declared.
Effect of change of body position in spontaneous sleeping healthy infants on SF<sub>6</sub>-based multiple breath washout
Authors: Paul D. Robinson, Laszlo Kadar, Anders Lindblad, Per M. Gustafsson
Journal: European Respiratory Journal (2019)

<b>Change of body position from supine to sitting had no effect on FRC and only a minimal effect on MBW indices of ventilation inhomogeneity. Change of body position contributes minimally to the difference observed between infant and preschool LCI values.</b>http://bit.ly/2MjbYFv
Solitary fibrous tumor: A Brazilian cohort analysis.
Authors: Marcelle Goldner Cesca, Celso Lopes Mello, Tiago Felismino, Maria Nirvana Formiga, Ulisses Ribaldo Nicolau, Samuel Aguiar, Joyce Maria L. Maia
Journal: Journal of Clinical Oncology (2019)

11068 Background: Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that account for less than 2% of all soft tissue sarcomas. SFT has been identified in multiple anatomic locations and can arise anywhere in the body. Surgical management is the mainstay of treatment for localized disease. However, about 20% will develop locoregional recurrences or distant metastasis with a role for systemic treatment. Methods: A retrospective analysis was carried out in a large cancer center in Brazil. Our primary objective was to evaluate clinical and treatment aspects of metastatic/ locally advanced (Mtx/LA) SFT cohort and secondary to describe clinical characteristics of entire population diagnosed with SFT. Descriptive statistics was used for main results. Survival curves were estimated using Kaplan-Meier. Data were retrieved from electronic patient medical records. Results: From April, 1971 to October, 2017, 82 patients with SFT were treated. Median follow-up was 45.5 months. 67 (81.7%) were alive on the cut-off date. Median age at diagnosis was 51 (14-78). 40.2% men. Most common primary sites (PS) were pleura (19.8%), central nervous system (CNS - 11%) and pelvis (11%). 18 (21.9%) underwent chemotherapy for Mtx/LA disease. In this subgroup, 61.1% were men; PS retroperitoneal (22.2%), extremities (16.7%), CNS (16.7%). 66.7% had pulmonary, 44.4% hepatic, 27.8% bone metastasis and one (5.5%) local recurrence. All patients had at least one adverse prognostic factor (tumor size ≥ 10cm, positive margins, necrosis, ≥ 4/10 mitosis). One (5,5%) had Doege-Potter syndrome. 7 (38.9%) did one, 5 (27.8%) two and 6 (33.3%) ≥ 3 lines of treatment. First line was temozolomide/bevacizumab (TMZ/Bev) in 55.6%, followed by chemotherapy (Ch) in 27.8% and tyrosine kinase inhibitors (TKI) in 16.7%. Median progression-free survival was 3.5 months (95% IC: 0.0-7.4) and overall survival 27.3 months (95% IC: 18.7-36.0). Response rate using RECIST criteria was 12.5% for TMZ/Bev and 62.5% had stable disease. TKI and Ch had no response. Conclusions: SFT is rare and with heterogeneous clinical presentation. In our analysis, patients received a wide range of therapy, reflecting the lack of well-established systemic treatment option. TMZ/Bev showed consistent activity in Mtx/LA scenario.