tbuckley/cabot-search huggingface dataset:
A cohort study of sodium-glucose cotransporter-2 inhibitors after acute kidney injury among Veterans with diabetic kidney disease
Authors: Daniel P. Murphy, Julian Wolfson, Scott Reule, Kirsten L. Johansen, Areef Ishani, Paul E. Drawz
Journal: Kidney International (2024)

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for several adverse outcomes among patients with diabetic kidney disease. Yet, optimal timing for SGLT2i after acute kidney injury (AKI) is uncertain, as are the providers responsible for post-AKI SGLT2i initiation. Using a retrospective cohort of United States Veterans with diabetes mellitus type 2 and proteinuria, we examined encounters by provider specialty before SGLT2i initiation and subsequent all-cause mortality after hospitalization with AKI, defined by a 50% or more rise in serum creatinine. Covariates included recovery, defined by return to a110% or less of baseline creatinine, and time since AKI hospitalization. Among 21,330 eligible Veterans, 7,798 died (37%) and 6,562 received a SGLT2i (31%) over median follow-up of 2.1 years. Post-AKI SGLT2i use was associated with lower mortality risk [adjusted hazard ratio 0.63 (95% confidence interval 0.58-0.68)]. Compared with neither SGLT2i use nor recovery, mortality risk was similar with recovery without SGLT2i use [0.97 (0.91-1.02)] but was lower without recovery prior to SGLT2i use [0.62 (0.55-0.71)] and with SGLT2i use after recovery [0.60 (0.54-0.67)]. Finally, the effect of SGLT2i was stable over time (P for time-interaction 0.19). Thus, we observed reduced mortality with SGLT2i use after AKI among Veterans with diabetic kidney disease whether started earlier or later or before or after observed recovery. Hence, patients with diabetic kidney disease who receive a SGLT2i earlier after AKI experience no significant harm impacting mortality and experience a lower mortality risk than those who do not.
Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria
Authors: Kassoum Kayentao, Aissata Ongoiba, Anne C Preston, Sara A Healy, Zonghui Hu, Jeff Skinner, Safiatou Doumbo, Jing Wang, Hamidou Cisse, Didier Doumtabe, Abdrahamane Traore, Hamadi Traore, Adama Djiguiba, Shanping Li, Mary E Peterson, Shinyi Telscher, Azza H Idris, William C Adams, Adrian B McDermott, Sandeep Narpala, Bob C Lin, Leonid Serebryannyy, Somia P Hickman, Andrew J McDougal, Sandra Vazquez, Matthew Reiber, Judy A Stein, Jason G Gall, Kevin Carlton, Philipp Schwabl, Siriman Traore, Mamadou Keita, Amatigué Zéguimé, Adama Ouattara, M'Bouye Doucoure, Amagana Dolo, Sean C Murphy, Daniel E Neafsey, Silvia Portugal, Abdoulaye Djimdé, Boubacar Traore, Robert A Seder, Peter D Crompton
Journal: New England Journal of Medicine (2024)

BackgroundSubcutaneous administration of the monoclonal antibody L9LS protected adults against controlled Plasmodium falciparum infection in a phase 1 trial. Whether a monoclonal antibody administered subcutaneously can protect children from P. falciparum infection in a region where this organism is endemic is unclear.MethodsWe conducted a phase 2 trial in Mali to assess the safety and efficacy of subcutaneous administration of L9LS in children 6 to 10 years of age over a 6-month malaria season. In part A of the trial, safety was assessed at three dose levels in adults, followed by assessment at two dose levels in children. In part B of the trial, children were randomly assigned, in a 1:1:1 ratio, to receive 150 mg of L9LS, 300 mg of L9LS, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection, as detected on blood smear performed at least every 2 weeks for 24 weeks. A secondary efficacy end point was the first episode of clinical malaria, as assessed in a time-to-event analysis.ResultsNo safety concerns were identified in the dose-escalation part of the trial (part A). In part B, 225 children underwent randomization, with 75 children assigned to each group. No safety concerns were identified in part B. P. falciparum infection occurred in 36 participants (48%) in the 150-mg group, in 30 (40%) in the 300-mg group, and in 61 (81%) in the placebo group. The efficacy of L9LS against P. falciparum infection, as compared with placebo, was 66% (adjusted confidence interval [95% CI], 45 to 79) with the 150-mg dose and 70% (adjusted 95% CI, 50 to 82) with the 300-mg dose (P<0.001 for both comparisons). Efficacy against clinical malaria was 67% (adjusted 95% CI, 39 to 82) with the 150-mg dose and 77% (adjusted 95% CI, 55 to 89) with the 300-mg dose (P<0.001 for both comparisons).ConclusionsSubcutaneous administration of L9LS to children was protective against P. falciparum infection and clinical malaria over a period of 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05304611.)
Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows
Authors: Andrea Giustina, John P Bilezikian, Robert A Adler, Giuseppe Banfi, Daniel D Bikle, Neil C Binkley, Jens Bollerslev, Roger Bouillon, Maria Luisa Brandi, Felipe F Casanueva, Luigi di Filippo, Lorenzo M Donini, Peter R Ebeling, Ghada El-Hajj Fuleihan, Angelo Fassio, Stefano Frara, Glenville Jones, Claudio Marcocci, Adrian R Martineau, Salvatore Minisola, Nicola Napoli, Massimo Procopio, René Rizzoli, Anne L Schafer, Christopher T Sempos, Fabio Massimo Ulivieri, Jyrki K Virtanen
Journal: Endocrine Reviews (2024)

Abstract The 6th International Conference, “Controversies in Vitamin D,” was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.
Folate‐PEG‐PROTAC Micelles for Enhancing Tumor‐Specific Targeting Proteolysis In Vivo
Authors: Junhui Ma, Lei Fang, Zhengjun Sun, Meijing Li, Ting Fan, Guangya Xiang, Xiang Ma
Journal: Advanced Healthcare Materials (2024)

Abstract Proteolysis targeting chimeras (PROTACs) technology is rapidly developed as a novel and selective medicinal strategy for the degradation of cellular proteins in cancer therapy. However, the applications of PROTACs as heterobifunctional molecules are largely limited by high molecular weight, low bioavailability, poor permeability, insufficient targeting, and low efficacy in vivo. Herein, self‐assembling micelles of FA‐PEG‐PROTAC are designed for cancer cell selective targeting and reductive‐response proteolysis in tumor‐bearing mice. FA‐PEG‐PROTAC is prepared by conjugating folic acid (FA)‐PEG with EGFR‐targeting PROTAC via a disulfide bond. The FA‐PEG‐PROTAC micelles, formed by self‐assembling, are demonstrated to significantly improve tumor targeting efficacy and exhibit excellent anti‐tumor efficacy in the mouse xenograft model compared to the traditional PROTACs. The strategy of applying self‐assembled FA‐PEG‐PROTAC micelles in tumor therapy can not only improve targeted proteolysis efficiency but also broaden applications in the development of PROTAC‐based drugs.
CT‐Visible Microspheres Enable Whole‐body In Vivo Tracking of Injectable Tissue Engineering Scaffolds
Authors: Annalisa Bettini, Peter Stephen Patrick, Richard M. Day, Daniel J. Stuckey
Journal: Advanced Healthcare Materials (2024)

Abstract Targeted delivery and retention are essential requirements for implantable tissue‐engineered products. Non‐invasive imaging methods that can confirm location, retention, and biodistribution of transplanted cells attached to implanted tissue engineering scaffolds will be invaluable for the optimization and enhancement of regenerative therapies. To address this need, an injectable tissue engineering scaffold consisting of highly porous microspheres compatible with transplantation of cells is modified to contain the computed tomography (CT) contrast agent barium sulphate (BaSO 4 ). The trackable microspheres show high x‐ray absorption, with contrast permitting whole‐body tracking. The microspheres are cellularized with GFP+ Luciferase+ mesenchymal stem cells and show in vitro biocompatibility. In vivo, cellularized BaSO 4 ‐loaded microspheres are delivered into the hindlimb of mice where they remain viable for 14 days. Co‐registration of 3D‐bioluminescent imaging and µCT reconstructions enable the assessment of scaffold material and cell co‐localization. The trackable microspheres are also compatible with minimally‐invasive delivery by ultrasound‐guided transthoracic intramyocardial injections in rats. These findings suggest that BaSO 4 ‐loaded microspheres can be used as a novel tool for optimizing delivery techniques and tracking persistence and distribution of implanted scaffold materials. Additionally, the microspheres can be cellularized and have the potential to be developed into an injectable tissue‐engineered combination product for cardiac regeneration.
High-dimensional Mass Cytometry identified circulating Natural Killer T-cell subsets associated with protection from Cytomegalovirus infection in kidney transplant recipients
Authors: Laura Donadeu, Thomas Jouve, Sofia Bin, Susan Hartzell, Elena Crespo, Alba Torija, Marta Jarque, Delphine Kervella, José Zúñiga, Weijia Zhang, Zeguo Sun, Alberto Verlato, Mónica Martínez-Gallo, Cristina Font-Miñarro, Maria Meneghini, Nestor Toapanta, Irina B Torres, Joana Sellarés, Manel Perelló, Hannah Kaminski, Lionel Couzi, Alexandre Loupy, Gaetano La Manna, Francesc Moreso, Paolo Cravedi, Oriol Bestard
Journal: Kidney International (2024)

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.Graphical abstract
Development of a compact bidirectional promoter-driven dual chimeric antigen receptor (CAR) construct targeting CD19 and CD20 in the Sleeping Beauty (SB) transposon system
Authors: Asmita Khaniya, S M Ali Hossieni Rad, Josh Halpin, Supannikar Tawinwung, Alexander McLellan, Koramit Suppipat, Nattiya Hirankarn
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background A bidirectional promoter-driven chimeric antigen receptor (CAR) cassette provides the simultaneous expression of two CARs, which significantly enhances dual antigen-targeted CAR T-cell therapy. Methods We developed a second-generation CAR directing CD19 and CD20 antigens, incorporating them in a head-to-head orientation from a bidirectional promoter using a single Sleeping Beauty transposon system. The efficacy of bidirectional promoter-driven dual CD19 and CD20 CAR T cells was determined in vitro against cell lines expressing either, or both, CD19 and CD20 antigens. In vivo antitumor activity was tested in Raji lymphoma-bearing immunodeficient NOD-scid IL2Rgamma null (NSG) mice. Results Of all tested promoters, the bidirectional EF-1 α promoter optimally expressed transcripts from both sense (CD19-CAR) and antisense (GFP.CD20-CAR) directions. Superior cytotoxicity, cytokine production and antigen-specific activation were observed in vitro in the bidirectional EF-1 α promoter-driven CD19/CD20 CAR T cells. In contrast, a unidirectional construct driven by the EF-1 α promoter, but using self-cleaving peptide-linked CD19 and CD20 CARs, showed inferior expression and in vitro function. Treatment of mice bearing advanced Raji lymphomas with bidirectional EF-1 α promoter-driven CD19/CD20 CAR T cells effectively controlled tumor growth and extended the survival of mice compared with group treated with single antigen targeted CAR T cells. Conclusion The use of bidirectional promoters in a single vector offers advantages of size and robust CAR expression with the potential to expand use in other forms of gene therapies like CAR T cells.
A Randomized, Double-blind, Phase III Study Assessing Clinical Similarity of SB17 (Proposed Ustekinumab Biosimilar) to Reference Ustekinumab in Subjects with Moderate to Severe Plaque Psoriasis
Authors: Steven R. Feldman, Joanna Narbutt, Giampiero Girolomoni, Jan Brzezicki, Nataliya Reznichenko, Maria Agnieszka Zegadło-Mylik, Grazyna Pulka, Magdalena Dmowska-Stecewicz, Elżbieta Kłujszo, Dmytro Rekalov, Lidia Rajzer, Jiyoon Lee, Minkyung Lee, Young Hee Rho
Journal: Journal of the American Academy of Dermatology (2024)
Intranasal antihistamines and corticosteroids in allergic rhinitis: A systematic review and meta-analysis
Authors: Bernardo Sousa-Pinto, Rafael José Vieira, Jan Brozek, António Cardoso-Fernandes, Nuno Lourenço-Silva, Renato Ferreira-da-Silva, André Ferreira, Sara Gil-Mata, Anna Bedbrook, Ludger Klimek, João A Fonseca, Torsten Zuberbier, Holger J Schünemann, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2024)

There is insufficient systematized evidence on the effectiveness of individual intranasal medications in allergic rhinitis (AR). We sought to perform a systematic review to compare the efficacy of individual intranasal corticosteroids and antihistamines against placebo in improving the nasal and ocular symptoms and the rhinoconjunctivitis-related quality of life of patients with perennial or seasonal AR. The investigators searched 4 electronic bibliographic databases and 3 clinical trials databases for randomized controlled trials (1) assessing adult patients with seasonal or perennial AR and (2) comparing the use of intranasal corticosteroids or antihistamines versus placebo. Assessed outcomes included the Total Nasal Symptom Score, the Total Ocular Symptom Score, and the Rhinoconjunctivitis Quality-of-Life Questionnaire. The investigators performed random-effects meta-analyses of mean differences for each medication and outcome. The investigators assessed evidence certainty using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. This review included 151 primary studies, most of which assessed patients with seasonal AR and displayed unclear or high risk of bias. Both in perennial and seasonal AR, most assessed treatments were more effective than placebo. In seasonal AR, azelastine-fluticasone, fluticasone furoate, and fluticasone propionate were the medications with the highest probability of resulting in moderate or large improvements in the Total Nasal Symptom Score and Rhinoconjunctivitis Quality-of-Life Questionnaire. Azelastine-fluticasone displayed the highest probability of resulting in moderate or large improvements of Total Ocular Symptom Score. Overall, evidence certainty was considered "high" in 6 of 46 analyses, "moderate" in 23 of 46 analyses, and "low"/"very low" in 17 of 46 analyses. Most intranasal medications are effective in improving rhinitis symptoms and quality of life. However, there are relevant differences in the associated evidence certainty.
Interferon-gamma signature as prognostic and predictive marker in macroscopic stage III melanoma
Authors: Judith M Versluis, Stephanie A Blankenstein, Petros Dimitriadis, James S Wilmott, Robert Elens, Willeke A M Blokx, Winan van Houdt, Alexander Maxwell Menzies, Yvonne M Schrage, Michel W J M Wouters, Joyce Sanders, Annegien Broeks, Richard A Scolyer, Karijn P M Suijkerbuijk, Georgina V Long, Alexander C J van Akkooi, Christian U Blank
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background A substantial proportion of patients with macroscopic stage III melanoma do not benefit sufficiently from adjuvant anti-PD-1 therapy, as they either recur despite therapy or would never have recurred. To better inform adjuvant treatment selection, we have performed translational analyses to identify prognostic and predictive biomarkers. Patients and methods Two cohorts of patients with macroscopic stage III melanoma from an ongoing biobank study were included. Clinical data were compared between an observation cohort (cohort 1) and an adjuvant intention cohort (cohort 2). RNA sequencing for translational analyses was performed and treatment subgroups (cohort 1A and cohort 2A) were compared for possible biomarkers, using a cut-off based on the treatment-naïve patients. In addition, two validation cohorts (Melanoma Institute Australia (MIA) and University Medical Centre Utrecht (UMCU)) were obtained. Results After a median follow-up of 26 months of the 98 patients in our discovery set, median recurrence-free survival (RFS) was significantly longer for the adjuvant intention cohort (cohort 2, n=49) versus the observation cohort (cohort 1, n=49). Median overall survival was not reached for either cohort, nor significantly different. In observation cohort 1A (n=24), RFS was significantly longer for patients with high interferon-gamma (IFNγ) score (p=0.002); for adjuvant patients of cohort 2A (n=24), a similar trend was observed (p=0.086). Patients with high B cell score had a longer RFS in cohort 1A, but no difference was seen in cohort 2A. The B cell score based on RNA correlated with CD20 + cells in tumor area but was not independent from the IFNγ score. In the MIA validation cohort (n=44), longer RFS was observed for patients with high IFNγ score compared with low IFNγ score (p=0.046), no difference in RFS was observed according to the B cell score. In both the observation (n=11) and the adjuvant (n=11) UMCU validation cohorts, no difference in RFS was seen for IFNγ and B cell. Conclusions IFNγ has shown to be a prognostic marker in both patients who were and were not treated with adjuvant therapy. B cell score was prognostic but did not improve accuracy over IFNγ. Our study confirmed RFS benefit of adjuvant anti-PD-1 for patients with macroscopic stage III melanoma.
Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD
Authors: Long Yang, Kunwei Niu, Jianlin Wang, Weiwei Shen, Rui Jiang, Lu Liu, Wenjie Song, Xudan Wang, Xuan Zhang, Ruohan Zhang, Dan Wei, Ming Fan, Lintao Jia, Kaishan Tao
Journal: Journal of Hepatology (2024)

Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. The lack of a detailed understanding of oncogenic signaling or global gene expression alterations has impeded clinical iCCA diagnosis and therapy. The role of protein lactylation, a newly unraveled post-translational modification that orchestrates gene expression, remains largely elusive in the pathogenesis of iCCA.
Beyond the modified dot-probe task: A meta-analysis of the efficacy of alternate attention bias modification tasks across domains
Authors: Tessa Rooney, Louise Sharpe, Jemma Todd, Stefan Carlo Michalski, Dimitri Van Ryckeghem, Geert Crombez, Ben Colagiuri
Journal: Clinical Psychology Review (2024)

Attention biases towards disease-relevant cues have been implicated in numerous disorders and health conditions, such as anxiety, cancer, drug-use disorders, and chronic pain. Attention bias modification (ABM) has shown that changing attention biases can change related emotional processes. ABM most commonly uses a modified dot-probe task, which has received increasing criticism regarding its reliability and inconsistent findings. The purpose of the present review was thus to systematically review and meta-analyse alternative tasks used in ABM research. We sought to examine whether alternative tasks significantly changed attention biases and emotional outcomes, and critically examined whether relevant sample, task and intervention characteristics moderated each of these effect sizes. Seventy-four (completer n = 15,294) study level comparisons were included in the meta-analysis. Overall, alternative ABM designs had a medium effect on changing biases (g = 0.488), and a small, but significant effect on improving clinical outcomes (g = 0.117). We found this effect to be significantly larger for studies which successfully changed biases compared to those that did not. Across all tasks, it appeared that targeting engagement biases results in the largest change to attention biases. Importantly, we found tasks incorporating gaze-contingency – encouraging engagement with non-biased stimuli – show the most promise for improving emotional outcomes.
Exosomes loaded a smart bilayer-hydrogel scaffold with ROS-scavenging and macrophage-reprogramming properties for repairing cartilage defect
Authors: Xiaoqing Lu, Shimin Dai, Benzhao Huang, Shishuo Li, Peng Wang, Zhibo Zhao, Xiao Li, Ningbo Li, Jie Wen, Yunhan Sun, Zhentao Man, Bing Liu, Wei Li
Journal: Bioactive Materials (2024)