tbuckley/cabot-search huggingface dataset:
How Would You Manage This Patient With Obesity? Grand Rounds Discussion From Beth Israel Deaconess Medical Center
Authors: Risa B. Burns, Melanie R. Jay, Anne N. Thorndike, Zahir Kanjee
Journal: Annals of Internal Medicine (2024)

In 2022, 1 in 8 people in the world were living with obesity, and lifestyle interventions that include diet, exercise, and behavioral modification have been the foundation for management of obesity. Recently, pharmacologic therapies have been developed for management of obesity, the newest of these being glucagon-like peptide 1 receptor agonists. With the development of new pharmacologic options, the American Gastroenterological Association developed a guideline in 2022 to provide evidence-based recommendations for the pharmacologic management of obesity in adults and recommended, for adults with obesity or overweight with weight-related complications who have had an inadequate response to lifestyle interventions, adding pharmacologic agents to lifestyle interventions over continuing lifestyle interventions alone. In this article, 2 experts review the available evidence to answer the following questions: How effective are lifestyle interventions for the treatment of obesity? How effective are pharmacologic interventions for the treatment of obesity? Given these options, how do you engage in a shared decision-making discussion to develop a mutually agreed-on treatment plan?
Target Trial Emulation for Evaluating Health Policy
Authors: Nicholas J. Seewald, Emma E. McGinty, Elizabeth A. Stuart
Journal: Annals of Internal Medicine (2024)

Target trial emulation is an approach to designing rigorous nonexperimental studies by "emulating" key features of a clinical trial. Most commonly used outside of policy contexts, this approach is also valuable for policy evaluation as policies typically are not randomly assigned. In this article, we discuss the application of the target trial emulation framework in a policy evaluation context. The policy trial emulation framework includes 7 components: the units and eligibility criteria, definitions of the exposure and comparison conditions, assignment mechanism, baseline ("time zero") and follow-up, outcomes, causal estimand, and statistical analysis and assumptions. Policy evaluations that emulate a randomized trial across these dimensions can yield estimates of the causal effects of the policy on outcomes. Using the policy trial emulation framework to conduct and report on research design and methods supports transparent assessment of threats to causal inference in nonexperimental studies intended to assess the effect of a health policy on clinical or population health outcomes.
Diabetes Risk Factors in People With HIV Receiving Pitavastatin Versus Placebo for Cardiovascular Disease Prevention
Authors: Kathleen V. Fitch, Markella V. Zanni, Jennifer Manne-Goehler, Marissa R. Diggs, Arijeet K. Gattu, Judith S. Currier, Gerald S. Bloomfield, Chiu-Bin Hsiao, Samir K. Gupta, Judith A. Aberg, Carlos D. Malvestutto, Carl J. Fichtenbaum, Michael T. Lu, Pamela S. Douglas, Heather J. Ribaudo, Steven K. Grinspoon
Journal: Annals of Internal Medicine (2024)

REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) led to new guidelines for statin use among people with HIV (PWH) with low to moderate risk for atherosclerotic cardiovascular disease (ASCVD). Little is known about the natural history of diabetes mellitus (DM) or mechanisms contributing to statin effects on DM among this population.
School Mask Mandates and COVID-19: The Challenge of Using Difference-in-Differences Analysis of Observational Data to Estimate the Effectiveness of a Public Health Intervention
Authors: Ambarish Chandra, Tracy Beth Høeg, Shamez Ladhani, Vinay Prasad, Ram Duriseti
Journal: Annals of Internal Medicine (2024)

There are considerable challenges when using difference-in-differences (DiD) analysis of ecological data to estimate the effectiveness of public health interventions in rapidly changing situations.
Single-cell analysis of the multiple myeloma microenvironment after gamma-secretase inhibition and CAR T-cell therapy
Authors: David G Coffey, Pinar Ataca Atilla, Erden Atilla, Ola Landgren, Andrew J Cowan, Sylvain Simon, Margot Pont, Melissa L. Comstock, Geoffrey R Hill, Stanley R. Riddell, Damian J Green
Journal: Blood (2024)
Microproteins in cancer: identification, biological functions, and clinical implications
Authors: Damon A. Hofman, John R. Prensner, Sebastiaan van Heesch
Journal: Trends in Genetics (2024)

HighlightsMicroproteins, historically overlooked, are emerging as key players in cancer biology.Advances in genomics and proteomics enable systematic identification of cancer-associated microproteins.Microproteins contribute to cancer pathogenesis, are an important source of cryptic cancer antigens, and may offer novel therapeutic targets.Harnessing the potential of microproteins could revolutionize cancer diagnostics, therapeutics, and immunotherapy.AbstractCancer continues to be a major global health challenge, accounting for 10 million deaths annually worldwide. Since the inception of genome-wide cancer sequencing studies 20 years ago, a core set of ~700 oncogenes and tumor suppressor genes has become the basis for cancer research. However, this research has been based largely on an understanding that the human genome encodes ~19 500 protein-coding genes. Complementing this genomic landscape, recent advances have described numerous microproteins which are now poised to redefine our understanding of oncogenic processes and open new avenues for therapeutic intervention. This review explores the emerging evidence for microprotein involvement in cancer mechanisms and discusses potential therapeutic applications, with an emphasis on highlighting recent advances in the field.
Ferroptosis and pathogenesis of neuritic plaques in Alzheimer's Disease
Authors: Wolfgang J. Streit, Leah Phan, Ingo Bechmann
Journal: Pharmacological Reviews (2024)

Neuritic plaques are pathognomonic and terminal lesions of Alzheimer disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration, neuroinflammation, and iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid-β protein (Aβ), and it is believed that during conversion, amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles However, recent evidence from human postmortem studies suggests a much different mechanism of neuritic plaque formation, where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, neurofibrillary tangles represent the corpses of iron-laden neurons that develop independently of Aβ deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in the human temporal lobe during early, preclinical stages of AD. The findings have allowed the construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. SIGNIFICANCE STATEMENT: This review offers a novel perspective on Alzheimer disease pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. Herein, we review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and ensuing dementia.
Therapeutic advantage of combinatorial CAR T cell and chemo-therapies
Authors: Meghan B. Ward, Amber B. Jones, Giedre Krenciute
Journal: Pharmacological Reviews (2024)

Chimeric antigen receptor (CAR) T cell therapies have transformed outcomes for many patients with hematological malignancies. However, some patients do not respond to CAR T cell treatment, and adapting CAR T cells for solid and brain tumors has been met with many challenges including a hostile tumor microenvironment and poor CAR T cell persistence. Thus, it is unlikely that CAR T cell therapy alone will be sufficient for consistent, complete tumor clearance across cancer patients. Combinatorial therapies of CAR T cells and chemotherapeutics are a promising approach for overcoming this as chemotherapeutics could augment CAR T cells for improved anti-tumor activity or work in tandem with CAR T cells to clear tumors. Herein, we review efforts towards achieving successful CAR T cell and chemical drug combination therapies. We focus on combination therapies with approved chemotherapeutics as these will be more easily translated to the clinic, but also review non-approved chemotherapeutics and drug screens designed to reveal promising new CAR T cell and chemical drug combinations. Together, this review highlights the promise of CAR T cell and chemotherapy combinations with specific focus on how combinatorial therapy overcomes challenges faced by either monotherapy and supports the potential of this therapeutic strategy to improve outcomes for cancer patients. Significance Statement Improving currently available CAR T cell products via combinatorial therapy with chemotherapeutics has the potential to drastically expand the types of cancers and number of patients that could benefit from these therapies when neither alone has been sufficient to achieve tumor clearance. Herein, we provide a thorough review of the current efforts towards studying CAR T and chemotherapy combinatorial therapies and provide perspectives on optimal ways to identify new and effective combinations moving forward.
<b>Bioactives from marine resources as natural health products: A review</b>
Authors: Sarusha Santhiravel, Deepika Dave, Fereidoon Shahidi
Journal: Pharmacological Reviews (2024)

The oceans are a rich source of a myriad of structurally different and unique natural products that are mainly found in invertebrates with potential applications in different disciplines. Microbial infection and cancer are the leading causes of death worldwide. Discovery of new sources of therapy for microbial infections is an urgent requirement due to the emergence of pathogenic microorganisms that are resistant to existing therapies. Marine bioactives have demonstrated to be promising sources for the discovery and development of novel antimicrobial and anticancer compounds. Several marine compounds are confirmed to have antibacterial effects and most marine-based antifungal compounds are cytotoxic. Numerous antitumor marine natural products, derived mainly from sponges or molluscs, and also bryozoans and cyanobacteria, exhibit potent antimitotic activity. In addition, marine biodiversity offers some possible leads or new drugs to treat human immunodeficiency virus (HIV). A majority of marine derived drugs are currently in clinical trials or under preclinical evaluation. Furthermore, marine-based drugs, approved by the US Food and Drug Administration (FDA) are available in the market. This review summarizes the sources, mechanisms of action and potential utilization of marine natural products such as peptides, alkaloids, polyketides, polyphenols, terpenoids and sterols as antifungal, antibacterial, antiviral, and anticancer compounds. <b>Significance Statement</b> Utilization of marine bioactives as natural health products leads to crucial advancement in providing dietary supplements, nutraceuticals, functional foods and pharmaceuticals. Their myriad of application promotes health and plays a role in disease risk reduction. Therapeutic potential of potent compounds from marine organisms and use of their bioactives have promising medicinal value for preventing ailments and advancing pharmaceutical and nutraceutical industries. Their utilization benefits human health globally and contributes to the conservation of marine ecosystem in a transformative / sustainable approach.
<b>International Union of Basic and Clinical Pharmacology. CXVIII. Update on the Nomenclature for Atypical Chemokine Receptors including ACKR5</b>
Authors: Andy Chevigné, Daniel F. Legler, Antal Rot, Silvano Sozzani, Martyna Szpakowska, Marcus Thelen
Journal: Pharmacological Reviews (2024)

Chemokines signal through classical G protein-coupled receptors (GPCRs) to induce cell migration during development, immune homeostasis and multiple diseases. Over the last decade a subfamily of atypical chemokine receptors (ACKRs) was delineated from GPCRs based on their inability to trigger conventional G protein signaling or mediate cell migration in response to chemokines. These receptors nevertheless play an important role within the chemokine system by sequestering, transporting or internalizing chemokines thereby regulating their availability and shaping their gradients. GPR182, the recently deorphanized chemokine receptor, shares about 30% of sequence similarity with its closest relative ACKR3. GPR182 is mainly expressed on endothelial cells and was proposed to act as a scavenger regulating the availability of a large set of chemokines from the CXC, CC and XC families and to act cooperatively with ACKR3 and ACKR4. Unlike other ACKRs, GPR182 was shown to have a strong constitutive interaction with β-arrestins that is required for intracellular receptor trafficking and chemokine scavenging. Chemokine ligation of GPR182 has no additional detectable impact on β-arrestin recruitment. Genetic ablation of GPR182 affects spleen size, myelopoiesis, and serum chemokine levels, indicating its role in chemokine homeostasis and immune regulation. GPR182 was also reported to regulate immune responses to bloodborne antigens and tumorigenesis. Taken together, compelling cumulative evidence indicates that GPR182 does not trigger G protein-mediated signaling but acts as a scavenger for chemokines in vitro and in vivo strongly supporting its inclusion as ACKR5 in the systematic nomenclature of chemokine receptors. Significance Statement The summarized presented findings strongly support the designation of GPR182 as ACKR5 and its formal inclusion in the family of atypical chemokine receptors.
Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics
Authors: Marina E. Wolf
Journal: The Annual Review of Pharmacology and Toxicology (2024)

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation—Ca2+-permeable or CP-AMPARs—mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.
Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases
Authors: Tri Q. Do, Björn C. Knollmann
Journal: The Annual Review of Pharmacology and Toxicology (2024)

Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration–approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.
Cysteinyl Leukotrienes in Allergic Inflammation
Authors: Minkyu Lee, Joshua A. Boyce, Nora A. Barrett
Journal: Annual Review of Pathology Mechanisms of Disease (2024)

The cysteinyl leukotrienes (CysLTs), LTC4, LTD4, and LTE4, are potent lipid mediators derived from arachidonic acid through the 5-lipoxygenase pathway. These mediators produce both inflammation and bronchoconstriction through three distinct G protein–coupled receptors (GPCRs)—CysLT1, CysLT2, and OXGR1 (also known as CysLT3 or GPR99). While CysLT-mediated functions in the effector phase of allergic inflammation and asthma have been established for some time, recent work has demonstrated novel roles for these mediators and their receptors in the induction and amplification of type 2 inflammation. Additionally, in vitro studies and murine models have uncovered diverse regulatory mechanisms that restrain or amplify CysLT receptor activation and CysLT receptor function. This review provides an overview of CysLT biosynthesis and its regulation, the molecular and functional pharmacology of CysLT receptors, and an overview of the established and emerging roles of CysLTs in asthma, aspirin-exacerbated respiratory disease, and type 2 inflammation.
Hearing and vision rehabilitation for people with dementia in five European countries (SENSE-Cog): a randomised controlled trial
Authors: Iracema Leroi, Christopher J Armitage, Elizabeth M Camacho, Anna Pavlina Charalambous, J P Connelly, Fofi Constantinidou, Renaud David, Piers Dawes, Rachel A Elliott, Mark Hann, Alison Holden, Emma Hooper, Sean P Kennelly, Evangelia Kontogianni, Brian A Lawlor, Julie Longobardi, Luke Paterson, Antonis M Politis, David Reeves, Christine Schwimmer, Chryssoula Thodi, Mark Worthington, Wai Kent Yeung, Eric Frison
Journal: The Lancet Healthy Longevity (2024)
Platelet aggregates in lung capillaries in severely decompensated pulmonary hypertension
Authors: Camille Miard, Vincent Thomas de Montpreville, Jean-François Bernaudin, Julien Adam, Chakib Djediat, Francois Stephan
Journal: Thorax (2024)

The mechanism of thrombocytopenia during acute pulmonary hypertension (PH) decompensation may be partly due to platelet aggregation in the lung. Platelet aggregates in explanted lung from 16 lung transplant patients during acute PH decompensation with and without thrombocytopenia were identified by immunohistochemistry. Scanning electron microscopy (SEM) was performed. 7 explant lung controls without PH and thrombocytopenia were also examined. Compared with controls, the median number of platelet aggregates was higher in patients with acute PH decompensation with thrombocytopenia (19.4 [IQR 3.4–38.3] vs 147.5 [IQR 26.5–203.2]). SEM showed capillaries filled with platelet aggregates. Our study suggests that platelets may aggregate in the lungs during acute PH decompensation.
Cell and transcriptomic diversity of infrapatellar fat pad during knee osteoarthritis
Authors: Hayley Peters, Pratibha Potla, Jason S. Rockel, Teodora Tockovska, Chiara Pastrello, Igor Jurisica, Keemo Delos Santos, Shabana Vohra, Noah Fine, Starlee Lively, Kim Perry, Nikita Looby, Sheng Han Li, Vinod Chandran, Katrina Hueniken, Paramvir Kaur, Anthony V. Perruccio, Nizar N. Mahomed, Raja Rampersaud, Khalid Syed, Eric Gracey, Roman Krawetz, Matthew B. Buechler, Rajiv Gandhi, Mohit Kapoor
Journal: Annals of the Rheumatic Diseases (2024)

In this study, we employ a multiomic approach to identify major cell types and subsets, and their transcriptomic profiles within the infrapatellar fat pad (IFP), and to determine differences in the IFP based on knee osteoarthritis (KOA), sex and obesity status. Single-nucleus RNA sequencing of 82 924 nuclei from 21 IFPs (n=6 healthy control and n=15 KOA donors), spatial transcriptomics and bioinformatic analyses were used to identify contributions of the IFP to KOA. We mapped cell subclusters from other white adipose tissues using publicly available literature. The diversity of fibroblasts within the IFP was investigated by bioinformatic analyses, comparing by KOA, sex and obesity status. Metabolomics was used to further explore differences in fibroblasts by obesity status. We identified multiple subclusters of fibroblasts, macrophages, adipocytes and endothelial cells with unique transcriptomic profiles. Using spatial transcriptomics, we resolved distributions of cell types and their transcriptomic profiles and computationally identified putative cell-cell communication networks. Furthermore, we identified transcriptomic differences in fibroblasts from KOA versus healthy control donor IFPs, female versus male KOA-IFPs and obese versus normal body mass index (BMI) KOA-IFPs. Finally, using metabolomics, we defined differences in metabolite levels in supernatants of naïve, profibrotic stimuli-treated and proinflammatory stimuli-treated fibroblasts from obese compared to normal BMI KOA-IFPs. Overall, by employing a multiomic approach, this study provides the first comprehensive map of the cellular and transcriptomic diversity of human IFP and identifies IFP fibroblasts as key cells contributing to transcriptomic and metabolic differences related to KOA disease, sex or obesity.