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Advancing De Novo Lipogenesis: Genetic and Metabolic Insights
No full textDe novo lipogenesis (DNL) is the process whereby cells synthesize fatty acids from acetyl-CoA, contributing to steatosis in fatty liver disease. Two new studies, using genetic mouse models, metabolomics, and pharmacology, identified alternative pathways in DNL and unexpected physiological effects when targeting key enzymes in this pathway
PITX2 Dosage-Dependent Changes in Pacemaker Cell State Underlie Sinus Node Dysfunction and Atrial Arrhythmias
No full textPhysiologically relevant increases in transcription factor dosage and their role in development and disease remain largely unexplored. Genomic deletions upstream of the Paired-like homeodomain transcription factor gene (PITX2), identified in patients with sinus node dysfunction and atrial fibrillation and modeled in mice (delB), rewire the local epigenetic landscape, increasing PITX2 expression. Here, we demonstrate that pacemaker cardiomyocytes in the embryonic delB sinus node ectopically express PITX2 at physiological dosages in a heterogeneous pattern. The prenatal delB sinus node forms discrete subdomains showing PITX2 dosage-dependent mild or severe loss of pacemaker cardiomyocyte identity. Respective subdomain sizes and severity of sinus node dysfunction and atrial arrhythmia susceptibility align with PITX2 dosage. Ectopic PITX2c expression in human induced pluripotent stem cell-derived pacemaker cardiomyocytes causes PITX2 dosage-dependent transcriptional and electrophysiological changes paralleling those in delB mice. Our findings provide a mechanistic link between genetic variation-driven ectopic PITX2 expression, sinus node dysfunction and atrial arrhythmogenesis, illustrating how spatiotemporally defined increases in transcription factor dosage can translate into developmental defects and disease predisposition
Emapalumab Treatment in Patients With Rheumatologic Disease-Associated Hemophagocytic Lymphohistiocytosis in the United States: A Retrospective Medical Chart Review Study
No full textObjective: Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH.
Methods: REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH.
Results: Fifteen of 105 patients (14.3%) had rheumatologic disease-associated HLH. Of these, nine (60.0%) had systemic juvenile idiopathic arthritis, and one (6.7%) had adult-onset Still disease. Median (range) age at HLH diagnosis was 5 (0.9-39) years. Most patients (9 of 15; 60.0%) initiated emapalumab in an intensive care unit. Emapalumab was most frequently initiated for treating refractory or recurrent (10 of 15; 66.7%) disease. Most patients received HLH-related therapies before (10 of 15; 66.7%) and concurrently with (15 of 15; 100.0%) emapalumab. Emapalumab-containing regimens stabilized or achieved physician-determined normalization of most laboratory parameters, including absolute neutrophil count and absolute lymphocyte count (13 of 14; 92.9%), chemokine ligand 9 (9 of 11; 81.8%), and platelets and alanine transaminase (11 of 14; 78.6%), and reduced glucocorticoid dose by 80%. Overall survival and 12-month survival probability from emapalumab initiation were 86.7%.
Conclusion: Emapalumab-containing regimens stabilized or normalized most key laboratory parameters, reduced glucocorticoid dose, and were associated with low disease-related mortality, thereby demonstrating potential benefits in patients with rheumatologic disease-associated HLH
Approach to the Patient: From Endocrinopathy to the Diagnosis of a Histiocytic Disorder
No full textEndocrinopathies are frequently the initial presentation of histiocytic neoplasms, which are rare hematologic disorders affecting multiple organ systems. Langerhans cell histiocytosis and Erdheim-Chester disease are 2 such disorders known to infiltrate the hypothalamus and/or pituitary gland, leading to arginine vasopressin deficiency (AVP-D) and anterior pituitary dysfunction (APD) in 20% to 30% of cases, often as the first manifestation. Conversely, histiocytic disorders account for a notable proportion (10-15%) of all pituitary stalk lesions. The diagnosis of histiocytoses is often delayed in such cases due to the nonspecific presentation of endocrinopathies and pituitary involvement. Consequently, endocrinologists are at the frontline and uniquely positioned to achieve early diagnosis by recognizing the varied nonendocrine features of these disorders. This article provides an overview of the endocrine manifestations of histiocytic disorders and presents a simplified algorithm to guide the diagnostic workup in cases presenting with idiopathic AVP-D or APD. Such cases should be evaluated for histiocytic neoplasms with additional imaging studies and biopsies of suspected disease sites. If no disease site beyond the pituitary is identified, the risks and benefits of a pituitary stalk lesion biopsy must be carefully considered. While treatments of histiocytic neoplasms are highly efficacious, endocrinopathies are considered permanent and require long-term hormone replacement. It remains unclear whether early diagnosis and novel targeted therapies can reverse these endocrine disorders. Therefore, the role of the endocrinologist role is critical in the diagnosis and management of these rare diseases
Nanoparticle Contrast-Enhanced Computed Tomography and Magnetic Resonance Imaging of Vascularization of a Subcutaneous Niche for Islet Transplantation
No full textRevascularization plays a critical role in the successful engraftment of transplanted pancreatic islets, which are inherently rich in capillaries to meet their high metabolic demands. Innovative islet encapsulation strategies such as the NICHE (neovascularized implantable cell homing and encapsulation), generate a prevascularized transplantation site that allows for direct integration of the graft with the systemic circulation. Timing the transplantation is key to maximizing islet engraftment and survival, especially in diabetic individuals, who exhibit impaired wound healing. Therefore, in this study, we explored different methods to assess vascular development within NICHE in vivo in a non-invasive fashion. We effectively tracked neoangiogenesis using nanoparticle contrast-enhanced computed tomography (nCECT), observing a steady increase in vascularization over an 8-week period, which was confirmed histologically. Next, we estimated relative vascularization changes via T2 mapping with magnetic resonance imaging (MRI) before and after islet transplantation. On the first day post-transplantation, we measured a slight decrease in T2 values followed by a significant increase by day 14 attributable to islet revascularization. Our findings underscore the potential of non-invasive imaging techniques to provide insightful information on the readiness of the transplant site within cell encapsulation systems to support cell graft transplantation
A Qualitative Assessment of Changes in Occupational Exposures Among Healthcare Facility Workers
Get PDFAdult-onset asthma, notably prevalent among healthcare professionals, especially nurses, is often attributed to occupational factors such as exposure to cleaning agents. Studies consistently underscore the substantial role of such exposure in work-related asthma among hospital staff. We aimed to (a) identify and characterize current practices in cleaning and aerosolized medication administration; (b) assess changes in practices since a similar 2003 study of Texas healthcare workers; and (c) identify factors contributing to diverse exposures within healthcare job categories. We conducted focus groups with 38 participants in 6 healthcare settings, analyzing current practices, changes since 2003, and factors contributing to exposure diversity. We used a three-step approach for data analysis, including sociodemographic characterization, a scissor-and-sort technique for exposure description, and qualitative content analysis. Participants were primarily healthcare providers (76%) and housekeepers/cleaners (11%) who reported exposure to aerosolized medications, cleaning products, adhesives, and solvents. Participants reported transitioning from cleaning practices to new formulas with reduced odors and shifting from spray cleansers to wipes. Personal protective equipment (PPE) used during cleaning tasks varied, with training differing among job categories. Aerosolized medication administration varied among facilities, with reported medication types and protocol changes over time. The results emphasized the significance of maintaining uniform protection, disseminating knowledge, and consistently adhering to PPE protocols in the healthcare environment. Addressing the identified gaps in comprehension and potential sources of exposure variability requires additional focus on occupational health and safety initiatives
Evolution of Esophageal Adenocarcinoma From Precursor Lesion Stem Cells
Get PDFBackground & aims: Metastatic cancers arise from a decades-long succession of increasingly virulent precursor lesions, each of which represents prospective targets for therapeutic intervention. This evolutionary process has been particularly vivid in esophageal adenocarcinoma (EAC), as this cancer and associated precursor lesions, including Barrett\u27s esophagus (BE), low-grade dysplasia (LGD), and high-grade dysplasia (HGD), coexist in an accessible, 2-dimensional pattern in esophageal mucosa. Given the durability of these precursor lesions, it is likely that they, like EAC, rely on stem cells for their regenerative growth. To assess the role of stem cells in the evolution of EAC, we apply technology that selectively clones stem cells from the gastrointestinal tract to patient-matched endoscopic biopsies from each of the precursor lesions implicated in EAC.
Methods: Histologically validated, endoscopic biopsy series including EAC, HGD, LGD, BE, and normal esophageal mucosa were obtained from patients presenting with EAC. Rare (1:1000) cells from each of these lesions proved clonogenic and were assessed by in vitro differentiation, tumorigenicity in mice, and by molecular genetics.
Results: Each of the lesions in the evolution of EAC possesses a discrete set of clonogenic cells marked by immaturity, enormous proliferative potential, and lesion-specific differentiation fate. DNA sequencing of these clones reveals intralesional heterogeneity and clonal resolution of the mutation progression within a given patient from BE, LGD, HGD, and EAC. High-throughput chemical screens against BE stem cells reveal drug combinations that are similarly effective against stem cells of LGD, HGD, and EAC.
Conclusions: All lesions in the evolution of EAC possess discrete populations of stem cells that are potential therapeutic targets
The Landscape of Malignant Transition: Unraveling Cancer Cell-of-Origin and Heterogeneous Tissue Microenvironment
Get PDFUnderstanding disease progression and sophisticated tumor ecosystems is imperative for investigating tumorigenesis mechanisms and developing novel prevention strategies. Here, we dissected heterogeneous microenvironments during malignant transitions by leveraging data from 1396 samples spanning 13 major tissues. Within transitional stem-like subpopulations highly enriched in precancers and cancers, we identified 30 recurring cellular states strongly linked to malignancy, including hypoxia and epithelial senescence, revealing a high degree of plasticity in epithelial stem cells. By characterizing dynamics in stem-cell crosstalk with the microenvironment along the pseudotime axis, we found differential roles of ANXA1 at different stages of tumor development. In precancerous stages, reduced ANXA1 levels promoted monocyte differentiation toward M1 macrophages and inflammatory responses, whereas during malignant progression, upregulated ANXA1 fostered M2 macrophage polarization and cancer-associated fibroblast transformation by increasing TGF-β production. Our spatiotemporal analysis further provided insights into mechanisms responsible for immunosuppression and a potential target to control evolution of precancer and mitigate the risk for cancer development
Social Determinants of Occupational Injuries Among US-Based Commercial Fishermen: A Systematic Review
Get PDFBACKGROUND: Commercial fishing is a multibillion-dollar industry that supports job growth, small- to large- businesses, and port and city revenue. The commercial fishing industry continues to be one of the most dangerous in the US, with a fatality rate nearly 40 times higher than the national average. Dangers of the fishing industry are multi-faceted and include hazardous working conditions, strenuous labor, long work hours, and harsh weather. Moreover, a vast majority of fishermen suffer from economic insecurity, including safe and affordable housing and food insecurity.
METHODS: We followed the recommendations and standards set by the Campbell and Cochrane Equity Methods Group and the Measurement and Evidence Knowledge Network. The review covered 1992-2022 to assess the state of research and to identify new barriers of and facilitators to injury prevention among commercial fishermen using a social determinants of health lens.
RESULTS: Of 292 articles identified, 27 studies met our inclusion criteria. Out of 27 articles reviewed, social determinants of health factors included the built environment, social & community factors, economic stability, health care access, and educational attainment. A major finding was the inability for fishermen to access primary care services, which was often rooted in being a low-wage, im/migrant, or transient worker, and can further escalate injuries. A secondary finding related to injury was a feedback loop where fishermen\u27s unsafe environments led to a culture of accepting risk and downplaying injury, which further created unsafe environments.
CONCLUSION: Our review shows how injury is connected to social factors, such as a lack of health care access, as well as political-economic factors, such as a lack of sick leave benefits