tbuckley/cabot-search huggingface dataset:
In patients with type 2 diabetes and recent MI, colchicine reduced a composite CV outcome at 23 mo
Authors: Eric R. Bates
Journal: Annals of Internal Medicine (2024)

Source CitationRoubille F, Bouabdallaoui N, Kouz S, et al. Low-dose colchicine in patients with type 2 diabetes and recent myocardial infarction in the COLchicine Cardiovascular Outcomes Trial (COLCOT). Diabetes Care. 2024;47:467-470. https://pubmed.ncbi.nlm.nih.gov/38181203/AbstractClinical Impact RatingsGIM/FP/GP: Cardiology: Endocrinology:
Reversal of Intestinal Failure With Teduglutide in <i>PERCC1</i>-Associated Enteropathy: A Case Report
Authors: Emily Stenke, Cara Dunne, Anthea Bryce-Smyth, Michelle Hurley, Ben Pode-Shakked, Yair Anikster, Tricia Tan, Anna Kowalka, Paul Bech, Billy Bourke
Journal: Annals of Internal Medicine (2024)
SCCM issued recommendations for corticosteroid use in acutely ill adults with sepsis, ARDS, or CAP
Authors: Rodolfo A. Estrada, Marcos I. Restrepo
Journal: Annals of Internal Medicine (2024)

Source CitationChaudhuri D, Nei AM, Rochwerg B, et al. 2024 focused update: guidelines on use of corticosteroids in sepsis, acute respiratory distress syndrome, and community-acquired pneumonia. Crit Care Med. 2024;52:e219-e233. https://pubmed.ncbi.nlm.nih.gov/38240492/AbstractClinical Impact RatingsGIM/FP/GP: Infectious Disease: Critical Care: Pulmonology:
Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Alexander G Miethke, Adib Moukarzel, Gilda Porta, Joshue Covarrubias Esquer, Piotr Czubkowski, Felipe Ordonez, Antonella Mosca, Amal A Aqul, Robert H Squires, Etienne Sokal, Daniel D'Agostino, Ulrich Baumann, Lorenzo D'Antiga, Nagraj Kasi, Nolwenn Laborde, Cigdem Arikan, Chuan-Hao Lin, Susan Gilmour, Naveen Mittal, Fang Kuan Chiou, Simon P Horslen, Wolf-Dietrich Huber, Thomas Jaecklin, Tiago Nunes, Anamaria Lascau, Lara Longpre, Douglas B Mogul, Will Garner, Pamela Vig, Vera F Hupertz, Regino P Gonzalez-Peralta, Udeme Ekong, Jane Hartley, Noemie Laverdure, Nadia Ovchinsky, Richard J Thompson
Journal: The Lancet. Gastroenterology & hepatology (2024)
Human gut-associated <i>Bifidobacterium</i> species salvage exogenous indole, a uremic toxin precursor, to synthesize indole-3-lactic acid via tryptophan
Authors: Cheng Chung Yong, Takuma Sakurai, Hiroki Kaneko, Ayako Horigome, Eri Mitsuyama, Aruto Nakajima, Toshihiko Katoh, Mikiyasu Sakanaka, Takaaki Abe, Jin-Zhong Xiao, Miyuki Tanaka, Toshitaka Odamaki, Takane Katayama
Journal: Gut Microbes (2024)

Indole in the gut is formed from dietary tryptophan by a bacterial tryptophan-indole lyase. Indole not only triggers biofilm formation and antibiotic resistance in gut microbes but also contributes to the progression of kidney dysfunction after absorption by the intestine and sulfation in the liver. As tryptophan is an essential amino acid for humans, these events seem inevitable. Despite this, we show in a proof-of-concept study that exogenous indole can be converted to an immunomodulatory tryptophan metabolite, indole-3-lactic acid (ILA), by a previously unknown microbial metabolic pathway that involves tryptophan synthase β subunit and aromatic lactate dehydrogenase. Selected bifidobacterial strains converted exogenous indole to ILA via tryptophan (Trp), which was demonstrated by incubating the bacterial cells in the presence of (2-13C)-labeled indole and l-serine. Disruption of the responsible genes variedly affected the efficiency of indole bioconversion to Trp and ILA, depending on the strains. Database searches against 11,943 bacterial genomes representing 960 human-associated species revealed that the co-occurrence of tryptophan synthase β subunit and aromatic lactate dehydrogenase is a specific feature of human gut-associated Bifidobacterium species, thus unveiling a new facet of bifidobacteria as probiotics. Indole, which has been assumed to be an end-product of tryptophan metabolism, may thus act as a precursor for the synthesis of a host-interacting metabolite with possible beneficial activities in the complex gut microbial ecosystem.
Commensal microbiota-derived metabolite agmatine triggers inflammation to promote colorectal tumorigenesis
Authors: Yu Lu, Aoxi Cui, Xiaobo Zhang
Journal: Gut Microbes (2024)

Colorectal cancer (CRC), a malignant tumor worldwide, is associated with gut microbiota. The influence of gut microbe-derived metabolites on CRC has attracted a lot of attention. However, the role of immunity mediated by commensal microbiota-derived metabolites in tumorigenesis of CRC is not intensively explored. Here we monitored the gut microbial dysbiosis in CRC mouse model (ApcMin/+ model) without dietary and pharmacological intervention, followed by characterized of metabolites enriched in CRC model mice. Profound changes of gut microbiome (bacteriome) were observed during intestinal disorders. Metabolomic profiling indicated that agmatine, derived from the gut bacteria i.e. Blautia, Odoribacter, Alistipes and Paraprevotella, could interact with Rnf128 to suppress the Rnf128-mediated ubiquitination of β-catenin to further upregulate the downstream targets of β-catenin including Cyclin D1, Lgr5, CD44 and C-myc, thus activating Wnt signaling. The activated Wnt signaling pathway promoted dysplasia of intestinal cells and inflammatory infiltration of lymphocytes via inducing the upregulation of pro-inflammatory cytokines (IL-6 and TNF-α) and downregulation of anti-inflammatory cytokine (IL-10), thereby contributing to colorectal carcinogenesis. Therefore, our study presented novel insights into the roles and mechanisms of gut microbiota in pathogenesis of CRC.
Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences
Authors: Milena Radoman, Nia Fogelman, Cheryl Lacadie, Dongju Seo, Rajita Sinha
Journal: American Journal of Psychiatry (2024)

Objective: Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue–induced craving compared with neutral cue–induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. Methods: Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. Results: Significant increases in both stress and alcohol cue–induced craving relative to neutral cue–induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. Conclusions: Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.
Vaccines as Immunotherapies for Substance Use Disorders
Authors: Thomas R. Kosten
Journal: American Journal of Psychiatry (2024)

Substance use disorders (SUD) present a worldwide challenge with few effective therapies except for the relative efficacy of opioid pharmacotherapies, despite limited treatment access. However, the proliferation of illicit fentanyl use initiated a dramatic and cascading epidemic of lethal overdoses. This rise in fentanyl overdoses regenerated an interest in vaccine immunotherapy, which, despite an optimistic start in animal models over the past 50 years, yielded disappointing results in human clinical trials of vaccines against nicotine, stimulants (cocaine and methamphetamine), and opioids. After a brief review of clinical and selected preclinical vaccine studies, the "lessons learned" from the previous vaccine clinical trials are summarized, and then the newest challenge of a vaccine against fentanyl and its analogs is explored. Animal studies have made significant advances in vaccine technology for SUD treatment over the past 50 years, and the resulting anti-fentanyl vaccines show remarkable promise for ending this epidemic of fentanyl deaths.
Phase II Study to Determine the Antitumor Activity and Safety of Simlukafusp Alfa (FAP-IL2v) Combined with Atezolizumab in Esophageal Cancer
Authors: Hans Prenen, Sanjeev Deva, Bhumsuk Keam, Colin R. Lindsay, Iwona Lugowska, James C. Yang, Federico Longo, Maria de Miguel, Mariano Ponz-Sarvise, Myung-Ju Ahn, Mahmut Gumus, Stephane Champiat, Antoine Italiano, Sebastien Salas, Ruth Perets, Cagatay Arslan, Byoung C. Cho, Stefan Evers, Christophe Boetsch, Daniel Marbach, David Dejardin, Nassim Sleiman, Caroline Ardeshir, Muriel Richard, Jehad Charo, Anton Kraxner, Nino Keshelava, Volker Teichgräber, Victor Moreno
Journal: Clinical Cancer Research (2024)

Abstract Purpose: In this study, we report the results from the esophageal squamous cell carcinoma (SCC) cohort of a phase II, noncomparative, basket study evaluating the antitumor activity and safety of fibroblast activation protein–IL2 variant (FAP-IL2v) plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). Patients and Methods: Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 to 1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor–naïve. Patients received FAP-IL2v 10 mg plus atezolizumab 1,200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks and then every 2 weeks plus atezolizumab 840 mg intravenously every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Results: In the response-evaluable population (N = 34), the best confirmed ORR was 20.6% [95% confidence interval (CI), 10.4–36.8], with a complete response seen in 1 patient and partial responses in 6 patients. The disease control rate was 44.1% (complete response = 2.9%; partial response = 17.6%; stable disease = 23.5%), and the median duration of response was 10.1 mon/ths (95% CI, 5.6–26.7). The median progression-free survival was 1.9 months (95% CI, 1.8–3.7). Analysis of response by PDL1 expression (Ventana SP263) resulted in an ORR of 26.7% for patients with PDL1-positive tumors (tumor area positivity cutoff ≥1%; n = 15) and 7.1% for patients with PDL1-negative tumors (tumor area positivity cutoff &amp;lt;1%; n = 14). Overall, the treatment combination was tolerable, and adverse events were consistent with the known safety profiles of each drug. Conclusions: FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.
Gene Editing for <i>CEP290</i> -Associated Retinal Degeneration
Authors: Eric A Pierce, Tomas S Aleman, Kanishka T Jayasundera, Bright S Ashimatey, Keunpyo Kim, Alia Rashid, Michael C Jaskolka, Rene L Myers, Byron L Lam, Steven T Bailey, Jason I Comander, Andreas K Lauer, Albert M Maguire, Mark E Pennesi
Journal: New England Journal of Medicine (2024)

BackgroundCEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant).MethodsWe performed a phase 1–2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora–Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire–25 (in adults) or the Children's Visual Function Questionnaire (in children).ResultsEDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.ConclusionsThe safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1–2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.)
HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model
Authors: Christian Ammitzbøll Juul, Trine Bjørnbo Engel, Frederikke Petrine Fliedner, Lars Ringgaard, Rasmus Eliasen, Fredrik Melander, Martin Bak, Andreas Kjær, Jonas Rosager Henriksen, Dennis Ringkjøbing Elema, Anders Elias Hansen, Thomas Lars Andresen
Journal: Journal of Controlled Release (2024)
Unswitched memory B cell deficiency in children with sickle cell disease and response to pneumococcal polysaccharide vaccine
Authors: Venée N. Tubman, Daniel Maysonet, Norma Estrada, Tripti Halder, Lindsey Ramos, Sameera Bhamidipati, Alexandre F. Carisey, Charles G. Minard, Carl E. Allen
Journal: American Journal of Hematology (2024)

Abstract Early mortality in sickle cell disease (SCD) is attributed to increased infections due to loss of splenic function. Marginal zone B cells are important for initial opsonization of pathogens and can be absent in spleen histopathology in SCD. The frequency of unswitched memory B cells (UMBC), the circulating correlate of marginal zone B cells, reflects the immunologic function of the spleen. We hypothesized that asplenia in SCD is associated with alterations in the peripheral blood lymphocyte population and explored whether UMBC deficiency was associated with a clinical phenotype. We analyzed B cell subsets and clinical history for 238 children with SCD and 63 controls. The median proportion of UMBCs was lower in children with SCD compared with controls (4.7% vs. 6.6%, p &lt; .001). Naïve B cells were higher in SCD compared with controls (80.6 vs. 76.3%, respectively, p = .02). UMBC frequency declined by 3.4% per year increase in age in SCD (95% CI: 2%, 4.7%, p &lt; .001), but not in controls. A majority of children in all cohorts had an IgM concentration in the normal range for age and there were no differences between groups ( p = .13). Subjects developed titers adequate for long‐term protection to fewer serotypes in the polysaccharide vaccine than controls (14.7 vs. 19.4, p &lt; .001). In this cohort, bacteremia was rare and specific clinical complications were not associated with UMBC proportion. In summary, UMBC deficiency occurs in SCD and is associated with age. Future studies should investigate B cell subsets prospectively and identify the mechanism of B cell loss in the spleen.
Mild Thermotherapy‐Assisted GelMA/HA/MPDA@Roxadustat 3D‐Printed Scaffolds with Combined Angiogenesis‐Osteogenesis Functions for Bone Regeneration
Authors: Jiaqian You, Yangyang Li, Chong Wang, Huixin Lv, Shaobo Zhai, Manxuan Liu, Xiuyu Liu, Quni Sezhen, Lu zhang, Yidi Zhang, Yanmin Zhou
Journal: Advanced Healthcare Materials (2024)

Early reconstruction of the vascular network is a prerequisite to the effective treatment of substantial bone defects. Traditional 3D printed tissue engineering scaffolds designed to repair large bone defects do not effectively regenerate the vascular network, and rely only on the porous structure within the scaffold for nutrient transfer and metabolic waste removal. This leads to delayed bone restoration and hence functional recovery. Therefore, strategies for generation scaffolds with the capacity to efficiently regenerate vascularization should be developed. This study loads roxarestat (RD), which can stabilize HIF-1α expression in a normoxic environment, onto the mesopore polydopamine nanoparticles (MPDA@RD) to enhance the reconstruction of vascular network in large bone defects. Subsequently, MPDA@RD is mixed with GelMA/HA hydrogel bioink to fabricate a multifunctional hydrogel scaffold (GHM@RD) through 3D printing. In vitro results show that the GHM@RD scaffolds achieve good angiogenic-osteogenic coupling by activating the PI3K/AKT/HSP90 pathway in BMSCs and the PI3K/AKT/HIF-1α pathway in HUVECs under mild thermotherapy. In vivo experiments reveal that RD and mild hyperthermia synergistically induce early vascularization and bone regeneration of critical bone defects. In conclusion, the designed GHM@RD drug delivery scaffold with mild hyperthermia holds great therapeutic value for future treatment of large bone defects.
Correction: Individuals with <i>JAK1</i> variants are affected by syndromic features encompassing autoimmunity, atopy, colitis, and dermatitis
Authors: Michael E. Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A. Kurowski, Elizabeth Feuille, Luis A. Pedroza, Ramsay L. Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O’Jay Stewart, Roosheel Patel, Angelica E. Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K. Chinn, James R. Lupski, Jordan S. Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S. Abul-Husn, Yuval Itan, Joshua D. Milner, Jacinta Bustamante, Dusan Bogunovic
Journal: The Journal of Experimental Medicine (2024)
Long-Term Cardiovascular Outcomes in Children and Adolescents With Hypertension
Authors: Cal H. Robinson, Junayd Hussain, Nivethika Jeyakumar, Graham Smith, Catherine S. Birken, Allison Dart, Janis Dionne, Anika Garg, Sujane Kandasamy, Sabine Karam, Stacey Marjerrison, Andrew M. South, Lehana Thabane, Gita Wahi, Michael Zappitelli, Rahul Chanchlani
Journal: JAMA Pediatrics (2024)

Importance Hypertension affects 6% of all children, and its prevalence is increasing. Childhood hypertension tracks into adulthood and is associated with subclinical cardiovascular disease; however, there is a lack of evidence linking childhood hypertension to cardiovascular outcomes, which may contribute to underdiagnosis and undertreatment. Objective To determine the long-term associated risk of major adverse cardiac events (MACE) among children diagnosed with hypertension. Design, Setting, and Participants This was a population-based, retrospective, matched cohort study conducted from 1996 to 2022. The study included all children (aged 3-18 years) alive in Ontario, Canada, from 1996 to 2021, who were identified using provincial administrative health databases. Children with prior kidney replacement therapy were excluded. Exposure Incident hypertension diagnosis, identified by validated case definitions using diagnostic and physician billing claims. Each case was matched with 5 controls without hypertension by age, sex, birth weight, maternal gestational hypertension, prior comorbidities (chronic kidney disease, diabetes, cardiovascular surgery), and a propensity score for hypertension. Main Outcomes and Measures The primary outcome was MACE (a composite of cardiovascular death, stroke, hospitalization for myocardial infarction or unstable angina, or coronary intervention). Time to MACE was evaluated using the Kaplan-Meier method and Cox proportional hazards regression. Results A total of 25 605 children (median [IQR] age, 15 [11-17] years; 14 743 male [57.6%]) with hypertension were matched to 128 025 controls without hypertension. Baseline covariates were balanced after propensity score matching, and prior comorbidities were uncommon (hypertension vs control cohort: malignancy, 1451 [5.7%] vs 7908 [6.2%]; congenital heart disease, 1089 [4.3%] vs 5408 [4.2%]; diabetes, 482 [1.9%] vs 2410 [1.9%]). During a median (IQR) of 13.6 (7.8-19.5) years of follow-up, incidence of MACE was 4.6 per 1000 person-years in children with hypertension vs 2.2 per 1000 person-years in controls (hazard ratio, 2.1; 95% CI, 1.9-2.2). Children with hypertension were at higher associated risk of stroke, hospitalization for myocardial infarction or unstable angina, coronary intervention, and congestive heart failure, but not cardiovascular death, compared with nonhypertensive controls. Conclusions and Relevance Children diagnosed with hypertension had a higher associated long-term risk of MACE compared with controls without hypertension. Improved detection, follow-up, and control of pediatric hypertension may reduce the risk of adult cardiovascular disease.
Orally available dextran-aspirin nanomedicine modulates gut inflammation and microbiota homeostasis for primary colorectal cancer therapy
Authors: Sheng Ma, Haochen Yao, Xinghui Si, Zichao Huang, Ruoyi Wang, Renming Wan, Zhaohui Tang, Guoqing Wang, Wantong Song
Journal: Journal of Controlled Release (2024)