tbuckley/cabot-search huggingface dataset:
A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes
Authors: Christine Bender, Alice E. Wiedeman, Alex Hu, Alyssa Ylescupidez, William K. Sietsema, Kevan C. Herold, Kurt J. Griffin, Stephen E. Gitelman, S. Alice Long, Peter A. Gottlieb, Ruthie Strock, Lexie Chesshir, Maria J. Redondo, Christopher Williams, Mark A. Clements, Wayne V. Moore, Linda A. DiMeglio, Megan Legge, Maureen Mullen, Juan Sanchez, Maria Spall, Stephanie Woerner, Jason L. Gaglia, Brittany Resnick, Nora Bryant, Suzanne Krishfield, Jeanne Turley, Nisha Koshy, Mikayla Mackey, Ines Guttmann-Bauman, Rebecca Fitch, Lynn Bartholow, John H. Shelso, Alaa Al Nofal, Karen Hanisch, Luis Casas, Brenda Thurlow, Michael Gottschalk, Marla Hashiguchi, Lisa Paglia, Angela Lam, Srinath Sanda, Christine Torok, Rebecca Wesch, Daniel J. Moore, William E. Russell, Tyler Jordan Smith, Anne Brown, Faith Brendle, Michael J. Haller, Miriam Cintron, David A. Baidal, Della Matheson, Carlos Blaschke, Antoinette Moran, Elizabeth Pappensus, Janice Leschyshyn, Anne Street
Journal: Science Translational Medicine (2024)

CD4 + CD25 hi CD127 lo/− FOXP3 + regulatory T cells (T regs ) play a key role in preventing autoimmunity. In autoimmune type 1 diabetes (T1D), adoptive transfer of autologous polyclonal T regs has been shown to be safe in adults in phase 1 clinical trials. We explored factors contributing to efficacy of autologous polyclonal expanded T regs (expT regs ) in a randomized phase 2 multi-center, double-blind, clinical trial (Sanford/Lisata Therapeutics T-Rex phase 2 trial, ClinicalTrials.gov NCT02691247). One hundred ten treated children and adolescents with new-onset T1D were randomized 1:1:1 to high-dose (20 × 10 6 cells/kilogram) or low-dose (1 × 10 6 cells/kilogram) treatments or to matching placebo. Cytometry as well as bulk and single-cell RNA sequencing were performed on selected expT regs and peripheral blood samples from participants. The single doses of expT regs were safe but did not prevent decline in residual β cell function over 1 year compared to placebo ( P = 0.94 low dose, P = 0.21 high dose), regardless of age or baseline C-peptide. ExpT regs were highly activated and suppressive in vitro. A transient increase of activated memory T regs was detectable 1 week after infusion in the high-dose cohort, suggesting effective transfer of expT regs . However, the in vitro fold expansion of expT regs varied across participants, even when accounting for age, and lower fold expansion and its associated gene signature were linked with better C-peptide preservation regardless of T reg dose. These results suggest that a single dose of polyclonal expT regs does not alter progression in T1D; instead, T reg quality may be an important factor.
Macroevolutionary dynamics in micro-organisms: generalists give rise to specialists across biomes in the ubiquitous bacterial phylum <i>Myxococcota</i>
Authors: Daniel Padfield, Suzanne Kay, Rutger Vos, Christopher Quince, Michiel Vos
Journal: Molecular Biology and Evolution (2024)

Abstract Prokaryotes dominate the Tree of Life, but our understanding of the macroevolutionary processes generating this diversity is still limited. Habitat transitions are thought to be a key driver of prokaryote diversity. However, relatively little is known about how prokaryotes successfully transition and persist across environments, and how these processes might vary between biomes and lineages. Here, we investigate biome transitions and specialization in natural populations of a focal bacterial phylum, the Myxococcota, sampled across a range of replicated soils and freshwater and marine sediments in Cornwall (UK). By targeted deep sequencing of the protein-coding gene rpoB, we found &amp;gt;2,000 unique Myxococcota lineages, with the majority (77%) classified as biome specialists and with only &amp;lt;5% of lineages distributed across the salt barrier. Discrete character evolution models revealed that specialists in one biome rarely transitioned into specialists in another biome. Instead, evolved generalism mediated transitions between biome specialists. State-dependent diversification models found variation in speciation rates across the tree, but this variation was independent of biome association or specialization. Our findings were robust to phylogenetic uncertainty, different levels of species delineation, and different assumed amounts of unsampled diversity resulting in an incomplete phylogeny. Overall, our results are consistent with a “jack-of-all-trades” tradeoff where generalists suffer a cost in any individual environment, resulting in rapid evolution of niche specialists and shed light on how bacteria could transition between biomes.
Real time tele-reflectance confocal microscopy in clinical dermatologic practice: A prospective observational study
Authors: Larissa M Pastore, Rozina Zeidan, Zaeem Nazir, Rachel Manci, Ucalene Harris, Ashfaq A Marghoob, Stephen W Dusza, Manu Jain
Journal: Journal of the American Academy of Dermatology (2024)
A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results
Authors: E. Hamilton, M. Oliveira, N. Turner, J. García-Corbacho, C. Hernando, E.M. Ciruelos, P. Kabos, M. Ruiz-Borrego, A. Armstrong, M.R. Patel, C. Vaklavas, C. Twelves, V. Boni, J. Incorvati, T. Brier, L. Gibbons, T. Klinowska, J.P.O. Lindemann, C.J. Morrow, A. Sykes, R.D. Baird
Journal: Annals of Oncology (2024)

Background SERENA-1 (NCT03616587) is a Phase 1, multi-part, open-label study of camizestrant in pre- and post-menopausal women with ER+, HER2− advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. Patients and Methods Women aged 18 years or older with metastatic or recurrent ER+, HER2− breast cancer, refractory (or intolerant) to therapy were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, anti-tumor efficacy, pharmacokinetics, and impact on ESR1m circulating tumor (ct)DNA levels were assessed. Results By 9 March 2021, 108 patients received camizestrant monotherapy at 25–450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events (TRSAEs) at doses ≤150 mg. Median tmax was achieved ∼2–4 hours post-dose at all doses investigated, with an estimated half-life of 20–23 hours. Efficacy was observed at all doses investigated, including in patients with prior CDK4/6 inhibitor and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. Conclusions Camizestrant is a next-generation oral SERD and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75, 150 and 300 mg QD doses for Phase 2 testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).
Oxidative DNA damage promotes vascular aging associated with changes in extracellular matrix-regulating proteins
Authors: Kirsty Foote, Marieke Rienks, Lukas Schmidt, Konstantinos Theofilatos, None Yasmin, Matiss Ozols, Alexander Eckersley, Aarti Shah, Nichola Figg, Alison Finigan, Kevin O’Shaughnessy, Ian Wilkinson, Manuel Mayr, Martin Bennett
Journal: Cardiovascular Research (2024)

Vascular aging is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular aging, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular aging.
A 3-Year-Old With Gingival Hemorrhage and Musculoskeletal Pain
Authors: Khanh Trinh, Rinil Patel, Scott M. Peters
Journal: JAMA (2024)

A 3-year-old had spontaneous gingival hemorrhage and bilateral limb weakness with inability to bear weight. He had no preceding oral trauma or recent infection, took no regular medications, and had no recent use of aspirin or nonsteroidal anti-inflammatory drugs; his diet was limited to primarily chicken nuggets and milk. What is the diagnosis and what would you do next?
Foster Care and Health in Medicaid-Enrolled Children Experiencing Parental Opioid Use Disorder
Authors: Angélica Meinhofer, Nisha Chandra, Desislava Byanova, Katherine M. Keyes
Journal: JAMA Network Open (2024)

Importance The burden of the US opioid crisis has fallen heavily on children, a vulnerable population increasingly exposed to parental opioid use disorder (POUD) in utero or during childhood. A paucity of studies have investigated foster care involvement among those experiencing parental opioid use during childhood and the associated health and health care outcomes. Objective To examine the health and health care outcomes of children experiencing POUD with and without foster care involvement. Design, Setting, and Participants This population-based cohort study used nationwide Medicaid claims data from January 1, 2014, to December 31, 2020. Participants included Medicaid-enrolled children experiencing parental opioid use–related disorder during ages 4 to 18 years. Data were analyzed between January 2023 and February 2024. Exposure Person-years with (exposed) and without (nonexposed) foster care involvement, identified using Medicaid eligibility, procedure, and diagnostic codes. Main Outcomes and Measures The main outcomes included physical and mental health conditions, developmental disorders, substance use, and health care utilization. The Pearson χ 2 test, the t test, and linear regression were used to compare outcomes in person-years with (exposed) and without (nonexposed) foster care involvement. An event study design was used to examine health care utilization patterns before and after foster care involvement. Results In a longitudinal sample of 8 939 666 person-years from 1 985 180 Medicaid-enrolled children, 49% of children were females and 51% were males. Their mean (SD) age was 10 (4.2) years. The prevalence of foster care involvement was 3% (276 456 person-years), increasing from 1.5% in 2014 to 4.7% in 2020. Compared with those without foster care involvement (8 663 210 person-years), foster care involvement was associated with a higher prevalence of developmental delays (12% vs 7%), depression (10% vs 4%), trauma and stress (35% vs 7%), and substance use–related disorders (4% vs 1%; P &amp;amp;lt; .001 for all). Foster children had higher rates of health care utilization across a wide array of preventive services, including well-child visits (64% vs 44%) and immunizations (41% vs 31%; P &amp;amp;lt; .001 for all). Health care utilization increased sharply in the first year entering foster care but decreased as children exited care. Conclusions and Relevance In this cohort study of Medicaid-enrolled children experiencing parental opioid use–related disorder, foster care involvement increased significantly between 2014 and 2020. Involvement was associated with increased rates of adverse health outcomes and health care utilization. These findings underscore the importance of policies that support children and families affected by opioid use disorder, as well as the systems that serve them.
Complete vs Culprit-Only Revascularization in Older Patients With Myocardial Infarction and High Bleeding Risk
Authors: Andrea Erriquez, Gianluca Campo, Vincenzo Guiducci, Javier Escaned, Raul Moreno, Gianni Casella, Mila Menozzi, Enrico Cerrato, Giorgio Sacchetta, Alberto Menozzi, Ignacio Amat Santos, Enrique Gutiérrez Ibañes, Roberto Scarsini, Giuseppe Vadalà, Giuseppe Andò, José Luis Díez-Gil, Sergio Musto d’Amore, Alessandro Capecchi, Iginio Colaiori, Francesco Gallo, Rita Pavasini, Andrea Marrone, Graziella Pompei, Valerio Lanzilotti, Dariusz Dudek, Emanuele Barbato, Matteo Tebaldi, Simone Biscaglia
Journal: JAMA Cardiology (2024)

Importance Patients with high bleeding risk (HBR) have a poor prognosis, and it is not known if they may benefit from complete revascularization after myocardial infarction (MI). Objective To investigate the benefit of physiology-guided complete revascularization vs a culprit-only strategy in patients with HBR, MI, and multivessel disease. Design, Setting, and Participants This was a prespecified analysis of the Functional Assessment in Elderly MI Patients With Multivessel Disease (FIRE) randomized clinical trial data. FIRE was an investigator-initiated, open-label, multicenter trial. Patients 75 years or older with MI and multivessel disease were enrolled at 34 European centers from July 2019 through October 2021. Physiology treatment was performed either by angiography- or wire-based assessment. Patients were divided into HBR or non-HBR categories in accordance with the Academic Research Consortium HBR document. Interventions Patients were randomized to either physiology-guided complete revascularization or culprit-only strategy. Main Outcomes and Measures The primary outcome comprised a composite of death, MI, stroke, or revascularization at 1 year. Secondary outcomes included a composite of cardiovascular death or MI and Bleeding Academic Research Consortium (BARC) types 3 to 5. Results Among 1445 patients (mean [SD] age, 81 [5] years; 917 male [63%]), 1025 (71%) met HBR criteria. Patients with HBR were at higher risk for the primary end point (hazard ratio [HR], 2.01; 95% CI, 1.47-2.76), cardiovascular death or MI (HR, 1.89; 95% CI, 1.26-2.83), and BARC types 3 to 5 (HR, 3.28; 95% CI, 1.40-7.64). The primary end point was significantly reduced with physiology-guided complete revascularization as compared with culprit-only strategy in patients with HBR (HR, 0.73; 95% CI, 0.55-0.96). No indication of interaction was noted between revascularization strategy and HBR status for primary and secondary end points. Conclusions and Relevance HBR status is prevalent among older patients with MI, significantly increasing the likelihood of adverse events. Physiology-guided complete revascularization emerges as an effective strategy, in comparison with culprit-only revascularization, for mitigating ischemic adverse events, including cardiovascular death and MI. Trial Registration ClinicalTrials.gov Identifier: NCT03772743
Denosumab-Associated Severe Hypocalcemia in Dialysis-Dependent Patients—Reply
Authors: Steven T. Bird, Kate Gelperin, David J. Graham
Journal: JAMA (2024)

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Error in Key to Figure 1
Journal: JAMA Surgery (2024)

Nicole Lunardi, MD, MSPH; Aida Abou-Zamzam, BA; Katherine L. Florecki, MD; Swathikan Chidambaram, BSc, MBBS; I-Fan Shih, PhD; Alistair J. Kent, MD; Bellal Joseph, MD; James P. Byrne, MD, PhD; Joseph V. Sakran, MD, MPH, MPA
Healthy Vending Machine Products—Food for Thought on a Popular Diet-Related Behavioral Economic Strategy for Public Health
Authors: Brenda Robles, Ranjana N. Wickramasekaran
Journal: JAMA Network Open (2024)

Laura A. Gibson, PhD; Alisa J. Stephens-Shields, PhD; Sophia V. Hua, PhD; Jennifer A. Orr, MSPH; Hannah G. Lawman, PhD; Sara N. Bleich, PhD; Kevin G. Volpp, MD, PhD; Amy Bleakley, PhD; Anne N. Thorndike, MD; Christina A. Roberto, PhD
Antigen-level resolution of commensal-specific B cell responses can be enabled by phage display screening coupled with B cell tetramers
Authors: Sheenam Verma, Matthew J. Dufort, Tayla M. Olsen, Samantha Kimmel, Jasmine C. Labuda, Sam Scharffenberger, Andrew T. McGuire, Oliver J. Harrison
Journal: Immunity (2024)
An emerging strategy: probiotics enhance the effectiveness of tumor immunotherapy via mediating the gut microbiome
Authors: Shuaiming Jiang, Wenyao Ma, Chenchen Ma, Zeng Zhang, Wanli Zhang, Jiachao Zhang
Journal: Gut Microbes (2024)

The occurrence and progression of tumors are often accompanied by disruptions in the gut microbiota. Inversely, the impact of the gut microbiota on the initiation and progression of cancer is becoming increasingly evident, influencing the tumor microenvironment (TME) for both local and distant tumors. Moreover, it is even suggested to play a significant role in the process of tumor immunotherapy, contributing to high specificity in therapeutic outcomes and long-term effectiveness across various cancer types. Probiotics, with their generally positive influence on the gut microbiota, may serve as effective agents in synergizing cancer immunotherapy. They play a crucial role in activating the immune system to inhibit tumor growth. In summary, this comprehensive review aims to provide valuable insights into the dynamic interactions between probiotics, gut microbiota, and cancer. Furthermore, we highlight recent advances and mechanisms in using probiotics to improve the effectiveness of cancer immunotherapy. By understanding these complex relationships, we may unlock innovative approaches for cancer diagnosis and treatment while optimizing the effects of immunotherapy.
Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile
Authors: Gunther Nussbaumer, Martin Benesch, Yura Grabovska, Alan Mackay, David Castel, Jacques Grill, Marta M Alonso, Manila Antonelli, Simon Bailey, Joshua N Baugh, Veronica Biassoni, Mirjam Blattner-Johnson, Alberto Broniscer, Andrea Carai, Giovanna Stefania Colafati, Niclas Colditz, Selim Corbacioglu, Shauna Crampsie, Natacha Entz-Werle, Matthias Eyrich, Lea L Friker, Michael C Frühwald, Maria Luisa Garrè, Nicolas U Gerber, Felice Giangaspero, Maria J Gil-da-Costa, Norbert Graf, Darren Hargrave, Peter Hauser, Ulrich Herrlinger, Marion Hoffmann, Esther Hulleman, Elisa Izquierdo, Sandra Jacobs, Michael Karremann, Antonis Kattamis, Rejin Kebudi, Rolf-Dieter Kortmann, Robert Kwiecien, Maura Massimino, Angela Mastronuzzi, Evelina Miele, Giovanni Morana, Claudia M Noack, Virve Pentikainen, Thomas Perwein, Stefan M Pfister, Torsten Pietsch, Kleoniki Roka, Sabrina Rossi, Stefan Rutkowski, Elisabetta Schiavello, Clemens Seidel, Jaroslav Štěrba, Dominik Sturm, David Sumerauer, Anna Tacke, Sara Temelso, Chiara Valentini, Dannis van Vuurden, Pascale Varlet, Sophie E M Veldhuijzen van Zanten, Maria Vinci, André O von Bueren, Monika Warmuth-Metz, Pieter Wesseling, Maria Wiese, Johannes E A Wolff, Josef Zamecnik, Andrés Morales La Madrid, Brigitte Bison, Gerrit H Gielen, David T W Jones, Chris Jones, Christof M Kramm
Journal: Neuro-Oncology (2024)

Abstract Background The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. Methods We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. Results Median overall survival (OS) was 15.5 months (interquartile range, 10.9–27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2–55.7); grade III: 15.9 months (11.4–26.3); grade IV: 10.4 months (8.8–14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. Conclusions Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).
Ethanolamine enhances adhesion, promotes microcompartment formation, and modulates gene expression in <i>Levilactobacillus brevis</i> ATCC 14869
Authors: Polycronis P. Akouris, Gerrit A. Stuivenberg, John A. Chmiel, Wongsakorn Kiattiburut, Annabel Poon, Gregor Reid, Jeremy P. Burton
Journal: Gut Microbes (2024)

Ethanolamine is an abundant compound in the gastrointestinal tract and a valuable source of carbon and nitrogen for pathogenic bacteria harboring ethanolamine utilization (eut) genes. Eut-positive pathogens can consume free ethanolamine to outcompete commensal microbes, which often lack eut genes, and establish infection. Ethanolamine can also act as a host recognition signal for eut-positive pathogens to upregulate virulence genes during colonization. Therefore, reducing free ethanolamine titers may represent a novel approach to preventing infection by eut-positive pathogens. Interestingly, the commensal microorganism Levilactobacillus brevis ATCC 14869 was found to encode over 18 eut genes within its genome. This led us to hypothesize that L. brevis can compete with eut-positive pathogens by clearing free ethanolamine from the environment. Our results demonstrate that despite being unable to metabolize ethanolamine under most conditions, L. brevis ATCC 14869 responds to the compound by increasing the expression of genes encoding proteins involved in microcompartment formation and adhesion to the intestinal epithelial barrier. The improved intestinal adhesion of L. brevis in the presence of ethanolamine also enhanced the exclusion of eut-positive pathogens from adhering to intestinal epithelial cells. These findings support further studies to test whether L. brevis ATCC 14869 can counter enteric pathogens and prevent or reduce the severity of infections. Overall, the metabolic capabilities of L. brevis ATCC 14869 offer a unique opportunity to add to the armamentarium of antimicrobial therapies as well as our understanding of the mechanisms used by beneficial microbes to sense and adapt to host microenvironments.