tbuckley/cabot-search huggingface dataset:
Long-Term Results of the Dasatinib-Blinatumomab Protocol for Adult Philadelphia-Positive ALL
Authors: Robin Foà, Renato Bassan, Loredana Elia, Alfonso Piciocchi, Stefano Soddu, Monica Messina, Felicetto Ferrara, Monia Lunghi, Antonino Mulè, Massimiliano Bonifacio, Nicola Fracchiolla, Prassede Salutari, Paola Fazi, Anna Guarini, Alessandro Rambaldi, Sabina Chiaretti
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We report the long-term results of the frontline trial with dasatinib and blinatumomab in induction/consolidation (GIMEMA LAL2116, D-ALBA) for adult Philadelphia-positive ALL (Ph+ ALL), which enrolled 63 patients of all ages. At a median follow-up of 53 months, disease-free survival, overall survival, and event-free survival are 75.8%, 80.7%, and 74.6%, respectively. No events have occurred among early molecular responders. A significantly worse outcome was recorded for IKZF1 plus patients. Twenty-nine patients—93.1% being in molecular response (ie, complete molecular response or positive nonquantifiable) after dasatinib/blinatumomab—never received chemotherapy/transplant and continued with a tyrosine kinase inhibitor only; 28 patients remain in long-term complete hematologic response (CHR). An allogeneic transplant was carried out in first CHR mainly in patients with persistent minimal residual disease; 83.3% of patients are in continuous CHR. The transplant-related mortality was 12.5% for patients transplanted in first CHR and 13.7% overall. Nine relapses and six deaths have occurred. ABL1 mutations were found in seven cases. The final analysis of the D-ALBA study shows that a chemotherapy-free induction/consolidation regimen on the basis of a targeted strategy (dasatinib) and immunotherapy (blinatumomab) is effective in inducing durable long-term hematologic and molecular responses in adult Ph+ ALL, paving the way for a new era in the management of these patients.
High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure: Need for Patient Phenotyping?
Authors: Davide Eleuteri, Luca Montini, Massimo Antonelli, Domenico L. Grieco
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"High-Dose Inhaled Nitric Oxide in Acute Hypoxemic Respiratory Failure: Need for Patient Phenotyping?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With <i>BRCA</i>-Mutated Metastatic Castration-Resistant Prostate Cancer
Authors: Jaleh Fallah, Jianjin Xu, Chana Weinstock, Michael H. Brave, Erik Bloomquist, Mallorie H. Fiero, Timothy Schaefer, Anand Pathak, Abdelrahmman Abukhdeir, Vishal Bhatnagar, Haw-Jyh Chiu, Tiffany Ricks, Christy John, Salaheldin Hamed, Christal Lee, William F. Pierce, Shyam Kalavar, Reena Philip, Shenghui Tang, Laleh Amiri-Kordestani, Richard Pazdur, Paul G. Kluetz, Daniel Suzman
Journal: Journal of Clinical Oncology (2023)

This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious
On the Origin and Evolution of the Mosquito Male-determining Factor <i>Nix</i>
Authors: James K Biedler, Azadeh Aryan, Yumin Qi, Aihua Wang, Ellen O Martinson, Daniel A Hartman, Fan Yang, Atashi Sharma, Katherine S Morton, Mark Potters, Chujia Chen, Stephen L Dobson, Gregory D Ebel, Rebekah C Kading, Sally Paulson, Rui-De Xue, Michael R Strand, Zhijian Tu
Journal: Molecular Biology and Evolution (2023)

The mosquito family Culicidae is divided into 2 subfamilies named the Culicinae and Anophelinae. Nix, the dominant male-determining factor, has only been found in the culicines Aedes aegypti and Aedes albopictus, 2 important arboviral vectors that belong to the subgenus Stegomyia. Here we performed sex-specific whole-genome sequencing and RNAseq of divergent mosquito species and explored additional male-inclusive datasets to investigate the distribution of Nix. Except for the Culex genus, Nix homologs were found in all species surveyed from the Culicinae subfamily, including 12 additional species from 3 highly divergent tribes comprising 4 genera, suggesting Nix originated at least 133 to 165 million years ago (MYA). Heterologous expression of 1 of 3 divergent Nix open reading frames (ORFs) in Ae. aegypti resulted in partial masculinization of genetic females as evidenced by morphology and doublesex splicing. Phylogenetic analysis suggests Nix is related to femaleless (fle), a recently described intermediate sex-determining factor found exclusively in anopheline mosquitoes. Nix from all species has a conserved structure, including 3 RNA-recognition motifs (RRMs), as does fle. However, Nix has evolved at a much faster rate than fle. The RRM3 of both Nix and fle are distantly related to the single RRM of a widely distributed and conserved splicing factor transformer-2 (tra2). The RRM3-based phylogenetic analysis suggests this domain in Nix and fle may have evolved from tra2 or a tra2-related gene in a common ancestor of mosquitoes. Our results provide insights into the evolution of sex determination in mosquitoes and will inform broad applications of mosquito-control strategies based on manipulating sex ratios toward nonbiting males.
Fetal Overgrowth and Preterm Delivery in Women With Type 1 Diabetes Using Insulin Pumps or Multiple Daily Injections: A Post Hoc Analysis of the EVOLVE Study Cohort
Authors: Ida Holte Thorius, Lise Lotte N. Husemoen, Rikke Baastrup Nordsborg, Amra C. Alibegovic, Mari-Anne Gall, Janne Petersen, Peter Damm, Elisabeth R. Mathiesen
Journal: Diabetes Care (2023)

OBJECTIVE To compare the risk of fetal overgrowth and preterm delivery in pregnant women with type 1 diabetes (T1D) treated with insulin pumps versus multiple daily injections (MDI) and examine whether possible differences were mediated through improved glycemic control or gestational weight gain during pregnancy. RESEARCH DESIGN AND METHODS The risk of pregnancy and perinatal outcomes were evaluated in a cohort of 2,003 pregnant women with T1D enrolled from 17 countries in a real-world setting during 2013–2018. RESULTS In total, 723 women were treated with pumps and 1,280 with MDI. At inclusion (median gestational weeks 8.6 [interquartile range 7–10]), pump users had lower mean HbA1c (mean ± SD 50.6 ± 9.8 mmol/mol [6.8 ± 0.9%] vs. 53.6 ± 13.8 mmol/mol [7.1 ± 1.3%], P &amp;lt; 0.001), longer diabetes duration (18.4 ± 7.8 vs. 14.4 ± 8.2 years, P &amp;lt; 0.001), and higher prevalence of retinopathy (35.3% vs. 24.4%, P &amp;lt; 0.001). Proportions of large for gestational age (LGA) offspring and preterm delivery were 59.0% vs. 52.2% (adjusted odds ratio [OR] 1.36 [95% CI 1.09; 1.70], P = 0.007) and 39.6% vs. 32.1% (adjusted OR 1.46 (95% CI 1.17; 1.82), P &amp;lt; 0.001), respectively. The results did not change after adjustment for HbA1c or gestational weight gain. CONCLUSIONS Insulin pump treatment in pregnant women with T1D, prior to the widespread use of continuous glucose monitoring or automated insulin delivery, was associated with a higher risk of LGA offspring and preterm delivery compared with MDI in crude and adjusted analyses. This association did not appear to be mediated by differences in glycemic control as represented by HbA1c or by gestational weight gain.
Comments on “No-touch endoscopic full-thickness resection technique for gastric gastrointestinal stromal tumors”
Authors: Jiankun Wang, Li Liu, Zhining Fan
Journal: Endoscopy (2023)

See also: No-touch endoscopic full-thickness resection technique for gastric gastrointestinal stromal tumorsEndoscopy 2023; 55(06): 557-562DOI: 10.1055/a-2013-1902 See also: No-touch endoscopic full-thickness resection technique matches the surgical concept as far as possibleEndoscopy 2024; 56(01): 81-82DOI: 10.1055/a-2164-9424
Bioengineered Tubular Biliary Organoids
Authors: Bilge Sen Elci, Mikhail Nikolaev, Saba Rezakhani, Matthias P. Lutolf
Journal: Advanced Healthcare Materials (2023)

Abstract Liver organoids have emerged as promising in vitro models for toxicology, drug discovery, and disease modeling. However, conventional 3D epithelial organoid culture systems suffer from significant drawbacks, including limited culture duration, a nonphysiological 3D cystic anatomy with an inaccessible apical surface, and lack of in vivo‐like cellular organization. To address these limitations, herein a hydrogel‐based organoid‐on‐a‐chip model for the development functional tubular biliary organoids is reported. The resulting constructs demonstrate long‐term stability for a minimum duration of 45 d, while retaining their biliary organoid identity and exhibiting key cholangiocyte characteristics including transport activities, formation of primary cilia, and protective glycocalyx. Additionally, tubular organoids are susceptible to physical and chemical injury, which cannot be applied in such resolution to classical organoids. To enhance tissue‐level complexity, in vitro formation of a perfusable branching network is induced using a predetermined geometry that faithfully mimics the intricate structure of the intrahepatic biliary tree. Finally, cellular complexity is augmented through co‐culturing with vascular endothelial cells and fibroblasts. The models described in this study offer valuable opportunities for investigating biliary morphogenesis and elucidating associated pathophysiological mechanisms.
Low-load blood flow restriction strength training in patients with COPD: a randomised single-blind pilot study
Authors: Dario Kohlbrenner, Manuel Kuhn, Anastasios Manettas, Céline Aregger, Matthias Peterer, Nicola Greco, Noriane A Sievi, Christian Clarenbach
Journal: Thorax (2023)

Objective The objective of this study is to compare the effectiveness of lower limb low-load blood flow restriction training (LL-BFRT) with high-load strength training (HL-ST) as part of an outpatient pulmonary rehabilitation programme on leg strength in patients with chronic obstructive pulmonary disease (COPD). Methods Participants were randomised to LL-BFRT or HL-ST (24 sessions). LL-BFRT was done at 30% 1-repetition maximum (1-RM) with 70% arterial occlusion pressure. HL-ST was done at 70% 1-RM. Primary outcome was isometric strength of knee extensors and flexors. Secondary outcomes were 1-RM, functional exercise capacity, physical activity, symptom burden and health-related quality of life. Perceptions of dyspnoea and leg fatigue were recorded after every exercise. We compared groups with t-tests. Results We included 30 participants (13 women, 17 men, 64 (9) years, forced expiratory volume in 1 s 47 (18)% pred.), 24 completed the study. Isometric knee extensor strength improved to a clinically relevant degree in both legs in both groups (LL-BFRT: right leg 9 (20) Nm, left leg 10 (18) Nm; HL-ST: right leg 15 (26) Nm, left leg 16 (30) Nm, data are mean (SD)), without statistically significant or clinically relevant between-group differences (right leg mean difference= −6.4, 95% CI= −13.20 to 25.92 Nm, left leg mean difference= −5.6, 95% CI= −15.44 to 26.55 Nm). 1 min sit-to-stand test performance improved to a clinically relevant degree only in the LL-BFRT group (4 (4) vs 1 (5) repetitions). Interestingly, physical activity improved to a clinically relevant degree only in the LL-BFRT group (1506 (2441) vs −182 (1971) steps/day). LL-BFRT lowered perceived in-exercise dyspnoea and increased leg fatigue compared with HL-ST in the initial 12 trainings. Conclusion In patients with stable COPD undergoing outpatient pulmonary rehabilitation, LL-BFRT was not superior to HL-ST in improving leg strength. LL-BFRT led to similar strength gains as HL-ST while reducing perceptions of dyspnoea in the initial training phase. Trial registration number NCT04151771 .
Does gut brain axis has an impact on Parkinson’s disease (PD)?
Authors: Ajay Elangovan, Bhawna Dahiya, Laxmi Kirola, Mahalaxmi Iyer, Priyanka Jeeth, Sakshi Maharaj, Nikki Kumari, Vikas Lakhanpal, Tanja Maria Michel, K.R.S. Sambasiva Rao, Ssang-Goo Cho, Mukesh Kumar Yadav, Abilash Valsala Gopalakrishnan, Saraboji Kadhirvel, Nachimuthu Senthil Kumar, Balachandar Vellingiri
Journal: Ageing Research Reviews (2023)
Telitacicept in patients with active systemic lupus erythematosus: results of a phase 2b, randomised, double-blind, placebo-controlled trial
Authors: Di Wu, Jing Li, Dong Xu, Joan T Merrill, Ronald F van Vollenhoven, Yi Liu, Jiankang Hu, Yang Li, Fen Li, Chenghui Huang, Guochun Wang, Xiaomei Li, Jianhong Zhao, Dongbao Zhao, Cibo Huang, Huaxiang Liu, Wei Wei, Guixiu Shi, Fuai Lu, Xiaoxia Zuo, Liqi Bi, Zhijun Li, Xiaoxia Wang, Miaojia Zhang, Ning Tie, Juan Li, Hanyou Mo, Jianmin Fang, Chunde Bao, Fengchun Zhang
Journal: Annals of the Rheumatic Diseases (2023)

This phase 2b, randomised, double-blind, placebo-controlled trial evaluated the efficacy and safety of telitacicept, a novel fusion protein that neutralises signals of B lymphocyte stimulator and a proliferation-inducing ligand, in active systemic lupus erythematosus (SLE).
Gut microbiota predicts severity and reveals novel metabolic signatures in acute pancreatitis
Authors: Christoph Ammer-Herrmenau, Kai L Antweiler, Thomas Asendorf, Georg Beyer, Soeren M Buchholz, Silke Cameron, Gabriele Capurso, Marko Damm, Linh Dang, Fabian Frost, Antonio Gomes, Jacob Hamm, Robert Henker, Albrecht Hoffmeister, Christian Meinhardt, Lukasz Nawacki, Vitor Nunes, Arpad Panyko, Cesareo Pardo, Veit Phillip, Aldis Pukitis, Sebastian Rasch, Diana Riekstina, Ecaterina Rinja, María Lourdes Ruiz-Rebollo, Simon Sirtl, Mark Weingarten, Vasile Sandru, Julia Woitalla, Volker Ellenrieder, Albrecht Neesse
Journal: Gut (2023)

Objective Early disease prediction is challenging in acute pancreatitis (AP). Here, we prospectively investigate whether the microbiome predicts severity of AP (Pancreatitis—Microbiome As Predictor of Severity; P-MAPS) early at hospital admission. Design Buccal and rectal microbial swabs were collected from 424 patients with AP within 72 hours of hospital admission in 15 European centres. All samples were sequenced by full-length 16S rRNA and metagenomic sequencing using Oxford Nanopore Technologies. Primary endpoint was the association of the orointestinal microbiome with the revised Atlanta classification (RAC). Secondary endpoints were mortality, length of hospital stay and severity (organ failure &gt;48 hours and/or occurrence of pancreatic collections requiring intervention) as post hoc analysis. Multivariate analysis was conducted from normalised microbial and corresponding clinical data to build classifiers for predicting severity. For functional profiling, gene set enrichment analysis (GSEA) was performed and normalised enrichment scores calculated. Results After data processing, 411 buccal and 391 rectal samples were analysed. The intestinal microbiome significantly differed for the RAC (Bray-Curtis, p value=0.009), mortality (Bray-Curtis, p value 0.006), length of hospital stay (Bray-Curtis, p=0.009) and severity (Bray-Curtis, p value=0.008). A classifier for severity with 16 different species and systemic inflammatory response syndrome achieved an area under the receiving operating characteristic (AUROC) of 85%, a positive predictive value of 67% and a negative predictive value of 94% outperforming established severity scores. GSEA revealed functional pathway units suggesting elevated short-chain fatty acid (SCFA) production in severe AP. Conclusions The orointestinal microbiome predicts clinical hallmark features of AP, and SCFAs may be used for future diagnostic and therapeutic concepts. Trial registration number NCT04777812 .
Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b open-label trial
Authors: Steven W. Pipe, Peter Collins, Christophe Dhalluin, Gili Kenet, Christophe Schmitt, Muriel Buri, Víctor Jiménez-Yuste, Flora Peyvandi, Guy Young, Johannes Oldenburg, Maria Elisa Mancuso, Kaan Kavakli, Anna Kiialainen, Sonia Deb, Markus Niggli, Tiffany Chang, Michaela Lehle, Karin Fijnvandraat
Journal: Blood (2023)

Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30-0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors.
Effects of sport or physical recreation for adults with physical or intellectual disabilities: a systematic review with meta-analysis
Authors: Leanne Hassett, Marnee J McKay, Jenni Cole, Anne M Moseley, Sakina Chagpar, Minke Geerts, Wing S Kwok, Connie Jensen, Catherine Sherrington, Nora Shields
Journal: British Journal of Sports Medicine (2023)

Objectives To evaluate the effects of sport or physical recreation on participation, mobility and quality of life for adults living with disabilities. Design Systematic review with meta-analysis. Data sources Six databases searched from inception to May 2022. Eligibility criteria Randomised controlled trials including adults living with a physical or intellectual disability, comparing sport or physical recreation to non-active control. Results Seventy-four trials (n=2954; mean age 55 years) were included. Most (70) trials included people with physical disabilities, none evaluated sport and the most common physical recreation activities tested were traditional Chinese exercise (35%), yoga (27%) and dance (18%). Mean frequency and duration was 65 min/session, two times per week for 13 weeks. Most (86%) interventions were led by people with experience and/or training in the recreation activity, and only 37% reported leader experience and/or training working with people with disabilities. Participation was measured as attendance (mean 81%, 30 intervention groups). Physical recreation improved mobility (standardised mean difference (SMD) 0.38, 95% CI 0.07 to 0.69, n=469) and walking endurance (mean difference (MD) 40.3 m, 95% CI 19.5 to 61.1, n=801) with low certainty evidence and balance (Berg Balance Scale, range 0–56 points; MD 3.4 points, 95% CI 2.3 to 4.4, n=906) and quality of life (physical health; SMD 0.37, 95% CI 0.02 to 0.72, n=468) with very low certainty evidence, but not walking speed (MD 0.03 m/s, 95% CI −0.05 to 0.11, n=486). Conclusion Physical recreation may confer multiple benefits for people living with disabilities regardless of the activity chosen, thus offering a potentially enjoyable and scalable strategy to increase physical activity. PROSPERO registration number CRD42018104379.
ForePass endoscopic bypass device for obesity and insulin resistance—metabolic treatment in a swine model
Authors: Giulia Angelini, Manoel Galvao Neto, Ivo Boskoski, Maria Emiliana Caristo, Sara Russo, Luca Proto, Elena Previti, Lisa Olsson, Hobby Aggarwal, Samantha Pezzica, Elisa Ferrari, Vincenzo Bove, Alfredo Genco, Stefan Bornstein, Valentina Tremaroli, Amalia Gastaldelli, Geltrude Mingrone
Journal: Gut (2023)
Lysosomal processing of sulfatide analogs alters target NKT cell specificity and immune responses in cancer
Authors: Kumiko Nishio, Lise Pasquet, Kaddy Camara, Julia DiSapio, Kevin S. Hsu, Shingo Kato, Anja Bloom, Stewart K. Richardson, Joshua A. Welsh, Tianbo Jiang, Jennifer C. Jones, Susanna Cardell, Hiroshi Watarai, Masaki Terabe, Purevdorj B. Olkhanud, Amy R. Howell, Jay A. Berzofsky
Journal: Journal of Clinical Investigation (2023)

In a structure-function study of sulfatides, that typically stimulate type II NKT cells, we made an unexpected discovery. We compared analogues with sphingosine or phytosphingosine chains and 24-carbon acyl chains with 0-1-2 double bonds (C or pC24:0, 24:1, or 24:2). C24:1 and C24:2 sulfatide presented by CD1d monomer on plastic stimulated type II, not type I, NKT-cell hybridomas as expected. Unexpectedly, when presented by bone-marrow-derived DCs (BMDCs), C24:2 reversed specificity to stimulate type I, not type II, NKT-cell hybridomas, mimicking the corresponding βGalCer without sulfate. It induced IFNγ-dependent immunoprotection against CT26 colon-cancer lung metastases, skewed the cytokine profile, and activated cDC1s. This was abrogated by blocking lysosomal processing with bafilomycin A1, or sulfite-blocking or deletion of arylsulfatase A that cleaves off sulfate. Thus, C24:2 is unexpectedly processed in BMDCs from a type II to a type I NKT cell-stimulating ligand, promoting tumor immunity. We believe this is the first discovery of antigen processing of glycosylceramides altering the specificity for the target cell that reverses its function from stimulating type II to stimulating type I NKT cells, introducing protective functional activity in cancer. It also uncovers a new role for antigen processing, not to allow MHC loading but to alter the cell responding.