tbuckley/cabot-search huggingface dataset:
Commercial <scp>anti‐CD19 CAR</scp> T cell therapy for patients with relapsed/refractory aggressive B cell lymphoma in a European center
Authors: Pierre Sesques, Emmanuelle Ferrant, Violaine Safar, Florent Wallet, Jérémie Tordo, Anthony Dhomps, Lionel Karlin, Gabriel Brisou, Marlène Vercasson, Carole Hospital‐Gustem, Vérane Schwiertz, Florence Ranchon, Catherine Rioufol, Marion Choquet, Pierre Sujobert, Dana Ghergus, Fadhela Bouafia, Camille Golfier, Helène Lequeu, Anne Lazareth, Silvana Novelli, Perrine Devic, Alexandra Traverse Glehen, Sébastien Viel, Fabienne Venet, Valérie Mialou, Olivier Hequet, Adrien Chauchet, Yazid Arkam, Emmanuelle Nicolas‐Virelizier, Frederic Peyrade, Doriane Cavalieri, Florence Ader, Hervé Ghesquières, Gilles Salles, Emmanuel Bachy
Journal: American Journal of Hematology (2020)

Two autologous anti-CD19 chimeric antigen receptors (CAR) T cells (axicabtagene ciloleucel [axi-cel] and tisagenlecleucel [tisa-cel]) are commercially approved in Europe for relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). We performed a retrospective study to evaluate patterns of use, efficacy and safety for axi-cel and tisa-cel. Data from 70 patients who underwent apheresis for commercial CAR T cells between January 2018 and November 2019 in our institution were retrospectively collected. Sixty-one patients were infused. The median age at infusion was 59 years old (range 27-75 years). The median number of prior therapies was 3 (range, 2-6). The overall response rates (ORRs) at 1 month and 3 months were 63% and 45%, respectively, with 48% and 39% achieving a complete response (CR), respectively. After a median follow-up after infusion of 5.7 months, the median progression-free survival (PFS) was 3.0 months (95% CI, 2.8-8.8 months), and the median overall survival (OS) was 11.8 months (95% CI, 6.0-12.6 months). In multivariate analysis, factors associated with poor PFS were the number of previous lines of treatment before CAR T cells (≥4) (P = .010) and a C reactive protein (CRP) value >30 mg/L at the time of lymphodepletion (P < .001). Likewise, the only factor associated with a shorter OS was CRP >30 mg/L (P = .009). Cytokine release syndrome (CRS) of any grade occurred in 85% of patients, including 8% of patients with CRS of grade 3 or higher. Immune cell-associated neurotoxicity syndrome (ICANS) of any grade occurred in 28% of patients, including 10% of patients with ICANS of grade 3 or higher. Regarding efficacy and safety, no significant difference was found between axi-cel and tisa-cel. This analysis describes one of the largest real-life cohorts of patients treated with axi-cel and tisa-cel for R/R aggressive B cell lymphoma in Europe.
Insulator-based loops mediate the spreading of H3K27me3 over distant micro-domains repressing euchromatin genes
Authors: Alexandre Heurteau, Charlène Perrois, David Depierre, Olivier Fosseprez, Jonathan Humbert, Stéphane Schaak, Olivier Cuvier
Journal: Genome biology (2020)

Abstract Background Chromosomes are subdivided spatially to delimit long-range interactions into topologically associating domains (TADs). TADs are often flanked by chromatin insulators and transcription units that may participate in such demarcation. Remarkably, single-cell Drosophila TAD units correspond to dynamic heterochromatin nano-compartments that can self-assemble. The influence of insulators on such dynamic compartmentalization remains unclear. Moreover, to what extent heterochromatin domains are fully compartmentalized away from active genes remains unclear from Drosophila to human. Results Here, we identify H3K27me3 micro-domains genome-wide in Drosophila, which are attributed to the three-dimensional spreading of heterochromatin marks into euchromatin. Whereas depletion of insulator proteins increases H3K27me3 spreading locally, across heterochromatin borders, it concomitantly decreases H3K27me3 levels at distant micro-domains discrete sites. Quantifying long-range interactions suggests that random interactions between heterochromatin TADs and neighbor euchromatin cannot predict the presence of micro-domains, arguing against the hypothesis that they reflect defects in self-folding or in insulating repressive TADs. Rather, micro-domains are predicted by specific long-range interactions with the TAD borders bound by insulator proteins and co-factors required for looping. Accordingly, H3K27me3 spreading to distant sites is impaired by insulator mutants that compromise recruitment of looping co-factors. Both depletions and insulator mutants significantly reduce H3K27me3 micro-domains, deregulating the flanking genes. Conclusions Our data highlight a new regulatory mode of H3K27me3 by insulator-based long-range interactions controlling distant euchromatic genes.
Effect of COVID-19 lockdown on alcohol consumption in patients with pre-existing alcohol use disorder
Authors: Jin Un Kim, Amir Majid, Rebekah Judge, Peter Crook, Rooshi Nathwani, Nowlan Selvapatt, James Lovendoski, Pinelopi Manousou, Mark Thursz, Ameet Dhar, Heather Lewis, Nikhil Vergis, Maud Lemoine
Journal: The Lancet. Gastroenterology & hepatology (2020)
Management Options for an Older Adult With Advanced Chronic Kidney Disease and Dementia
Authors: Risa B. Burns, Sushrut S. Waikar, Melissa W. Wachterman, Zahir Kanjee
Journal: Annals of Internal Medicine (2020)

About 15% of adults in the United States—37 million persons—have chronic kidney disease (CKD). Chronic kidney disease is divided into 5 groups, ranging from stage 1 to stage 5 CKD, whereas end-stage kidney disease (ESKD) is defined as permanent kidney failure. The treatment options for ESKD are kidney replacement therapy (KRT) and conservative management. The options for KRT include hemodialysis (either in-center or at home), peritoneal dialysis, and kidney transplant. Conservative management, a multidisciplinary model of care for patients with stage 5 CKD who want to avoid dialysis, is guided by patient values, preferences, and goals, with a focus on quality of life and symptom management. In 2015, the Kidney Disease Outcomes Quality Initiative recommended that patients with an estimated glomerular filtration rate below 30 mL/min/1.73 m2 be educated about options for both KRT and conservative management. In 2018, the National Institute for Health and Care Excellence recommended that assessment for KRT or conservative management start at least 1 year before the need for therapy. It also recommended that in choosing a management approach, predicted quality of life, predicted life expectancy, patient preferences, and other patient factors be considered, because little difference in outcomes has been found among options. Here, 2 experts—a nephrologist and a general internist–palliative care physician—reflect on the care of a patient with advanced CKD and mild to moderate dementia. They discuss the management options for patients with advanced CKD, the pros and cons of each method, and how to help a patient choose among the options.
Extracorporeal CO<sub>2</sub> removal (ECCO<sub>2</sub>R) in patients with stable COPD with chronic hypercapnia: a proof-of-concept study
Authors: Lara Pisani, Stefano Nava, Emilia Desiderio, Mario Polverino, Tommaso Tonetti, V Marco Ranieri
Journal: Thorax (2020)

Abstract Domiciliary non-invasive ventilation (NIV) effectively reduces arterial carbon dioxide pressure (PaCO 2 ) in patients with stable hypercapnic chronic obstructive pulmonary disease, but a consistent percentage of them may remain hypercapnic. We hypothesised that extracorporeal CO 2 removal (ECCO 2 R) may lower their PaCO 2 . Ten patients hypercapnic despite ≥6 months of NIV underwent a 24-hour trial of ECCO 2 R. Six patients completed the ECCO 2 R-trial with a PaCO 2 drop ranging between 23% and 47%. Time to return to baseline after interruption ranged 48–96 hours. In four patients, mechanical events led to ECCO 2 R premature interruption, despite a decreased in PaCO 2 . This time window ‘free’ from hypercapnia might allow to propose the concept of ‘CO 2 dialysis’.
66 Oesophageal granular cell tumours-a local case series
Authors: EA Gormand Ea, D McManus, Jbm Doyle, D McKernan, L Mainie
Journal: Gut (2017)

Background  Granular cell tumours (GCT) are soft tissue tumours that present in the skin/oral cavity, with 5% presenting in the gastrointestinal tract.  We present a local case series, illustrating endoscopic, ultrasonograpic and histological appearances of GCT in the oesophagus and subsequent management.  Aim  Describing clinicopathological characteristics of oesophageal GCT with follow up.  Method  Retrospective case notes review.  Results  Case 1-A 51 year old female presented with dysphagia. OGD showed two small oesophageal lesions (  Case 2-A 55 year old female presented with lethargy. OGD showed a small oesophageal lesion (0.6 cm) at 34 cm. EUS revealed a mucosal lesion with minimal submucosal involvement. MDT discussion for both patients recommended a conservative approach, follow up for >3 years has shown no ultrasonographic change.  Case 3-A 31 year old male presented with dyspepsia. OGD showed a small oesophageal lesion (  Case 4-A 67 year old female presented with dyspepsia. OGD revealed a small oesophageal lesion (  Conclusions  GCT’s are rare, with low malignant potential. They are usually asymptomatic, and have a classical endoscopic appearance of a firm, yellow, submucosal lesion. EUS is critical in staging, with MDT discussion. A conservative approach appears justified, with yearly endoscopy and EUS for surveillance.
Mast Cells Induce Ductular Reaction Mimicking Liver Injury in Mice Through Mast Cell–Derived Transforming Growth Factor Beta 1 Signaling: [RETRACTED]
Authors: Konstantina Kyritsi, Lindsey Kennedy, Vik Meadows, Laura Hargrove, Jennifer Demieville, Linh Pham, Amelia Sybenga, Debjyoti Kundu, Karla Cerritos, Fanyin Meng, Gianfranco Alpini, Heather Francis
Journal: Hepatology (2020)

Background and Aims Following liver injury, mast cells (MCs) migrate into the liver and are activated in patients with cholestasis. Inhibition of MC mediators decreases ductular reaction (DR) and liver fibrosis. Transforming growth factor beta 1 (TGF‐β1) contributes to fibrosis and promotes liver disease. Our aim was to demonstrate that reintroduction of MCs induces cholestatic injury through TGF‐β1. Approach and Results Wild‐type, KitW‐sh (MC‐deficient), and multidrug resistance transporter 2/ABC transporter B family member 2 knockout mice lacking l‐histidine decarboxylase were injected with vehicle or PKH26‐tagged murine MCs pretreated with 0.01% dimethyl sulfoxide (DMSO) or the TGF‐β1 receptor inhibitor (TGF‐βRi), LY2109761 (10 μM) 3 days before sacrifice. Hepatic damage was assessed by hematoxylin and eosin (H&amp;E) and serum chemistry. Injected MCs were detected in liver, spleen, and lung by immunofluorescence (IF). DR was measured by cytokeratin 19 (CK‐19) immunohistochemistry and F4/80 staining coupled with real‐time quantitative PCR (qPCR) for interleukin (IL)‐1β, IL‐33, and F4/80; biliary senescence was evaluated by IF or qPCR for p16, p18, and p21. Fibrosis was evaluated by sirius red/fast green staining and IF for synaptophysin 9 (SYP‐9), desmin, and alpha smooth muscle actin (α‐SMA). TGF‐β1 secretion/expression was measured by enzyme immunoassay and qPCR. Angiogenesis was detected by IF for von Willebrand factor and vascular endothelial growth factor C qPCR. In vitro, MC‐TGF‐β1 expression/secretion were measured after TGF‐βRi treatment; conditioned medium was collected. Cholangiocytes and hepatic stellate cells (HSCs) were treated with MC‐conditioned medium, and biliary proliferation/senescence was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐5‐(3‐carboxymethoxyphenyl)‐2‐(4‐sulfophenyl)‐2 H ‐tetrazolium and qPCR; HSC activation evaluated for α‐SMA, SYP‐9, and collagen type‐1a expression. MC injection recapitulates cholestatic liver injury characterized by increased DR, fibrosis/TGF‐β1 secretion, and angiogenesis. Injection of MC‐TGF‐βRi reversed these parameters. In vitro, MCs induce biliary proliferation/senescence and HSC activation that was reversed with MCs lacking TGF‐β1. Conclusions Our study demonstrates that reintroduction of MCs mimics cholestatic liver injury and that MC‐derived TGF‐β1 may be a target in chronic cholestatic liver disease.
Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation
Authors: Wai-Kay Seto, Kevin SH Liu, Lung-Yi Mak, Gavin Cloherty, Danny Ka-Ho Wong, Jeffrey Gersch, Yuk-Fai Lam, Ka-Shing Cheung, Ning Chow, Kwan-Lung Ko, Wai-Pan To, James Fung, Man-Fung Yuen
Journal: Gut (2020)

Background Treatment cessation in chronic HBV infection may be durable in certain patient subgroups before hepatitis B surface antigen (HBsAg) seroclearance. The role of serum HBV RNA in determining treatment cessation suitability has not been well-investigated. Methods Nucleos(t)ide analogue (NUC) treatment was discontinued in non-cirrhotic patients with chronic HBV with serum HBsAg &lt;200 IU/mL and fulfilling internationally recommended criteria for treatment cessation. Patients were monitored till 48 weeks with baseline and serial measurements of serum HBsAg, HBV RNA and hepatitis B core-related antigen. NUCs were resumed when HBV DNA reaches &gt;2000 IU/mL regardless of alanine aminotransferase (ALT) levels. Results 114 entecavir-treated patients (median age 58.4 years, median serum HBsAg 54.4 IU/mL) with median treatment duration of 6.7 years were recruited. The 48-week cumulative rate of HBV DNA &gt;2000 IU/mL was 58.1%. End-of-treatment serum HBV RNA and off-treatment serial HBV RNA were both independently associated with HBV DNA &gt;2000 IU/mL (HR 2.959, 95% CI 1.776 to 4.926, p&lt;0.001; HR 2.278, 95% CI 1.151 to 4.525, p=0.018, respectively). Patients with HBV RNA ≥44.6 U/mL had a cumulative 48-week rate of 93.2%, while combining HBV RNA undetectability and HBsAg &lt;10 IU/mL had a cumulative 48-week rate of 9.1%. 24 patients (38.7%) developed off-treatment ALT elevation, highest peak ALT was 1515 U/L. 8 patients (median serum HBsAg 2.6 IU/mL) developed HBsAg seroclearance. Conclusion Serum HBV RNA measurement is essential for deciding on entecavir cessation in patients with chronic HBV, especially with low HBsAg levels. Patients can be stratified on their risk of off-treatment relapse based on both viral determinants. Trial registration number NCT02738554
Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis
Authors: Yemil Atisha‐Fregoso, Susan Malkiel, Kristina M. Harris, Margie Byron, Linna Ding, Sai Kanaparthi, William T. Barry, Wendy Gao, Kristin Ryker, Patti Tosta, Anca D. Askanase, Susan A. Boackle, W. Winn Chatham, Diane L. Kamen, David R. Karp, Kyriakos A. Kirou, S. Sam Lim, Bradley Marder, Maureen McMahon, Samir V. Parikh, William F. Pendergraft, Amber S. Podoll, Amit Saxena, David Wofsy, Betty Diamond, Dawn E. Smilek, Cynthia Aranow, Maria Dall’Era
Journal: Arthritis & Rheumatology (2020)

Objective To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). Methods In a multicenter, randomized, open‐label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients’ peripheral blood were analyzed by flow cytometry. Results Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab ( P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group ( P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. Conclusion The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.
THU0596 ABNORMAL RIGHT VENTRICLE RESERVE ON EXERCISE PREDICTS PULMONARY HYPERTENSION IN MIXED CONNECTIVE TISSUE DISEASE: A CASE REPORT
Authors: J. Su, W. Su, W. Long
Journal: Annals of the Rheumatic Diseases (2020)

Background: Pulmonary hypertension is one of the most common complications in patients with mixed connective tissue disease (MCTD). Patients are usually at the late stage and have irreversible right heart dysfunction when diagnosed as pulmonary hypertension with the rest echocardiography. Early detection of right heart dysfunction before pulmonary hypertension is essential to ensure that patients receive timely and appropriate treatment for this progressive disease. We aimed to use exercise stress echocardiography to detect early right heart dysfunction in patients with CTD and without pulmonary hypertension. Objectives: To present a clinical case of MCTD with normal right ventricular (RV) function at resting but presenting RV dysfunction on exercise, who developed pulmonary hypertension after one-year follow-up. Methods: Case report. The patient was subject to the treadmill exercise stress echocardiography. The autoantibodies including anti-nRNP/Sm, anti-Ro-52, and antinuclear antibody (ANA) were detected. The patient was followed-up to one year. Results: A 31-year-old female patient was admitted to our department in 2018, with a history of MCTD for five years. Autoantibodies testing revealed that the patient was positive for anti-nRNP/Sm (+++), anti-Ro-52 (+++), and ANA (1:3200). Echocardiography revealed no obvious cardiac dysfunction. However, the velocity of tricuspid valve regurgitation was 3.0m/s following treadmill exercise stress. The patient was followed-up to one year. Then, she developed occult pulmonary hypertension with the velocity of tricuspid valve regurgitation of 3.3m/s following treadmill exercise stress. Accordingly, MTX and prednisone were switched to MTX, prednisone, hydroxychloroquine (HCQ) and beraprost. Conclusion: This study showed that treadmill exercise echocardiography could detect right heart dysfunction early before diagnosed as pulmonary hypertension with rest echocardiography in patients with MCTD in its early stage. References: [1]Aithala R, Alex AG, Danda D. Pulmonary hypertension in connective tissue diseases: an update. Int J Rheum Dis. 2017;20(1):5–24. Disclosure of Interests: None declared
Chimeric Antigen Receptor Designed to Prevent Ubiquitination and Downregulation Showed Durable Antitumor Efficacy
Authors: Wentao Li, Shizhen Qiu, Jian Chen, Shutan Jiang, Wendong Chen, Jingwei Jiang, Fei Wang, Wen Si, Yilai Shu, Ping Wei, Gaofeng Fan, Ruijun Tian, Haitao Wu, Chenqi Xu, Haopeng Wang
Journal: Immunity (2020)
AB1075 PRESENCE POWER DOPPLER ULTRASOUND AS A PREDICTOR OF RADIOGRAPHIC DAMAGE IN PATIENTS WITH RHEUMATOID ARTHRITIS
Authors: O. Alekseeva, A. Smirnov, D. Kudinsky, S. Glukhova, A. Volkov, E. Nasonov
Journal: Annals of the Rheumatic Diseases (2020)

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to destructive changes and dysfunction of the joints. Ultrasound (US) is used in current practice as an early diagnostic method for detecting structural damage to articular surfaces. US changes in early RA are considered as one of the ways of predicting disease outcomes. Objectives: to detect power doppler (PD) contribution in evaluation of radiographic RA progression in long term. Methods: 85 RA pts, mean age 53,0 [44,0; 61,0] yrs, mean disease duration 8 [4; 24] months were treated by Treat-To-Target concept. After first year of therapy management was following real clinical practice rules until the termination of the study (4 years FUP). The wrist, MCP2 and MCP3, PIP2, PIP3, MTP2 and MTP5 joints of the clinically dominant side were examined by US (GS and PD). Clinical, laboratory parameters and US examination was performed at baseline, at Mo 3, 6, 9 and 12. The X-ray was conducted before treatment and in the end of the study. Structural damage progression was evaluated by change in the Sharp van der Heijde score (ΔSHS) between baseline and 4 year. We categorized pts into 5 groups according to the occurrence of positive PD: 1) without PD throughout the observational period [the negative (N)], 2) positive PD limited to the period from the baseline to Mo 3 [the therapeutic response (R)], 3) positive PD limited to the period from the baseline to Mo 6-9 [the therapeutic late-response (LR)], 4) intermittent occurrence of PD in the observational period [the intermittently positive (IP)] and 5) with persistent positive PD throughout the observational period [the persistently positive (PP)]. Results: 80% of pts had PD synovitis at baseline. PD-synovitis dropped from 2 [1,0; 6,0] to 0 [0,0; 2,0] scores at Mo 12. RA progression by 4 years FUP was identified in 13% of pts. The X-ray erosion score at 4 years FUP in these groups – N, R, LR, IP and PP - were dependent by PD from baseline to Mo 12 (mean level 1 [0; 2]; 2 [0; 4], 3 [0; 5], 1 [0; 2] and 4,5 [1; 10] respectively), but statistically significant differences were found between N and PP groups. Cox multivariate analysis identified that presence PD-synovitis at baseline was associated with risk of radiographic progression at 4 years (HR 3,68 95% CI 1,03 – 13,15, р = 0,045). Conclusion: Thus, PD-synovitis has a prognostic value for increasing destructive radiographic changes. References: no Disclosure of Interests: None declared