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Is it Possible to Have Coexisting Exogenous and Endogenous Cushing's Syndrome?
Cureus
Sana Rafi, Nada El Idrissi Dfali, Ghizlane Elmghari +1 more
The coexistence of exogenous and endogenous Cushing's syndrome is exceptionally rare. Here, we report the case of a 40-year-old female patient who had been self-medicating with dexamethasone for three years and who presented with asthenia and abdominal pain ten days after discontinuing corticosteroid therapy. The initial clinical suspicion was adrenal insufficiency following corticosteroid withdrawal; however, the patient's 8 a.m. serum cortisol level was elevated at 46 µg/dL. The possibility of concomitant endogenous Cushing's syndrome was therefore considered. Hormonal investigations confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome, and magnetic resonance imaging of the pituitary region revealed a pituitary macroadenoma measuring 14 × 15 × 12 mm. The patient underwent transsphenoidal surgery with an uneventful postoperative course. Hormonal evaluation should be considered in patients receiving prolonged corticosteroid therapy when clinical manifestations persist after corticosteroid withdrawal, particularly in the presence of persistent hypercortisolism or absence of expected hypothalamic-pituitary-adrenal axis suppression.
Survival and Hemodynamic Effects of Parenteral Prostanoids in High-Altitude Group 1 Pulmonary Hypertension: A Retrospective Cohort Study.
Pulm Med
Rafael Conde-Camacho, Eduardo Tuta-Quintero, Mauricio González +4 more
In Latin America, the evidence regarding the use of prostanoids at high altitude in patients with Group 1 pulmonary hypertension (PH-1) is limited. Therefore, it is essential to describe the clinical characteristics and outcomes associated with prostanoid treatment in this population.
Combined antimicrobial and pro-healing effects of cathelicidins in a polysaccharide-based hydrogel scaffold: treatment of carbapenemase-resistant Pseudomonas aeruginosa wound infections in a porcine model.
Int J Pharm
Antonín Pavelka, Břetislav Lipový, Lubomír Janda +14 more
Given the global rise in antibiotic resistance, this study focuses on developing an alternative treatment for deep skin and soft tissue infections (SSTIs) caused by a carbapenem-resistant Pseudomonas aeruginosa. An injectable hydrogel composed of polyvinyl alcohol and chitosan was developed as a stable carrier for the porcine cathelicidins PR-39 and Protegrin-1. In vitro tests demonstrated that the addition of 8 mM EDTA fully restores the activity of antibacterial peptides in fetal bovine serum and eliminates the influence of divalent cations. In a porcine model, the application of this hydrogel resulted in a significant reduction in bacterial load after only two doses, with levels dropping below 105 CFU/g of tissue. In addition to eliminating the infection, the treated group showed early granulation tissue formation, reduced necrosis and inflammation, and the development of a continuous epidermis, all of which were completely absent in the untreated group. The research confirms that the combination of cathelicidins and EDTA in a hydrogel carrier represents a highly effective approach for treating complicated bacterial infections.
Synthesis of scarless circular RNAs expressing long-acting GLP-1RAs for type 2 diabetes therapy.
J Adv Res
Yude Lin, Zhibo Huang, Zhiwei Xiao +8 more
Glucagon-like peptide-1 (GLP-1) is a prominent therapeutic agent capable of normalizing fasting blood glucose levels in diabetic patients. While GLP-1-expressing mRNA encapsulated in lipid nanoparticles (LNPs) has been evaluated for diabetes treatment in primate models, circular RNAs (circRNAs) represent a more stable alternative to linear mRNA, offering significant potential for the development of next-generation GLP-1-encoding RNA therapeutics.
American Society for Metabolic and Bariatric Surgery statement on the treatment options for patients with non-response and weight recurrence after metabolic and bariatric surgery.
Surg Obes Relat Dis
Vosburg Ralph Wesley, Carter Jonathan, Azagury Dan +5 more
Metabolic and bariatric surgery (MBS) is the most effective treatment for severe obesity, producing durable weight loss and improvement in obesity-related comorbidities. However, a subset of patients experience inadequate weight loss (non-response, NR) or weight recurrence (WR), which can lead to persistence or recurrence of metabolic disease, diminished quality of life, and warrants for further treatment interventions.
Association Between Glucagon-Like Peptide-1 Receptor Agonists and Suicidality: A Systematic Review.
Diabetes Obes Metab
Timothy H Chan, Leon E Cosler, Michael R Gionfriddo +3 more
We aimed to examine the association between GLP-1 RA use and suicidal ideation or behaviours through a systematic review of observational studies.
GLP-1 Receptor Agonist Treatment and Health Outcomes in Methadone-Treated Patients with Opioid Use Disorder and Diabetes.
J Gen Intern Med
Jane Y Pan, Igor Elman, Krisha Panchal +4 more
To investigate whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in methadone-treated patients with opioid use disorder (OUD) and type 2 diabetes (T2D) is associated with improved cardiometabolic and mental health outcomes.
Efficacy and safety of pharmacologic therapies in acromegaly: a systematic literature review and network meta-analysis.
J Clin Endocrinol Metab
Roberto Salvatori, Raffaella M Colzani, Noemi Hummel +6 more
There are limited head-to-head trials comparing pharmacological treatments for acromegaly.
A complete human pancreatic cancer genome.
bioRxiv
Justin Wagner, Ayse G Keskus, Keisuke K Oshima +76 more
Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine. 1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions. 1-3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres. 4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.
Nuclear Speckles Regulate Splicing During Muscle Stem Cell Activation and Aging.
bioRxiv
Steve D Guzman, Pamela Duran, Yu Xiao +4 more
Skeletal muscle contains a population of adult stem cells called satellite cells or muscle stem cells (MuSCs) that are responsible for regeneration after injury. MuSCs utilize gene expression programs to maintain quiescence and differentiate after injury and a key regulator of gene expression is splicing, which uniquely changes when transcripts interact with nuclear speckles (NS). NS are membrane-less biomolecular condensates that phase separate proteins, RNAs and chromatin, but how these organelles regulate molecular processes in MuSCs remains unknown. Herein, we build a comprehensive and systems-level understanding of NS influence on alternative splicing, transcriptional regulation and stem cell function before and after injury and in aging. We establish that NS increased in size and number in MuSCs following injury and influence MuSC activation dynamics. We generated a catalog of isoform-resolved splicing events and linked how RNA interactions with NS amplify splicing completion during the injury response. In old age, MuSCs lose NS, yet shifted towards longer, more completely spliced isoforms enriched for RNA binding protein motifs and multivalency. Our studies unveil evidence that RNA interactions with NS shape stem cell state and regenerative responses but are attenuated in old age.
In vivo base editing via single myotrophic adeno-associated viruses in dystrophic mouse muscle and satellite cells.
bioRxiv
Kuan-Hung Lin, Amy Lam, Samuel van Ooijen +7 more
Duchenne muscular dystrophy (DMD) is the most common, lethal X-linked neuromuscular disorder of childhood and is caused by mutations in the Dmd gene that disrupt dystrophin expression. Although adeno-associated virus-mediated gene therapies hold tremendous promise for DMD treatment, their clinical applications have been limited by dose-dependent vector and genome-level toxicities. Here, we developed and tested a single-vector adenine base editing strategy as a potentially safer genome editing approach to recode the pathogenic nonsense mutation into a benign missense mutation in mdx 4cv DMD mouse model. Delivered using a muscle-tropic adeno-associated virus (MyoAAV) at a clinically-feasible dose (4E13 VG/kg), this strategy enabled detectable molecular recoding of the mdx 4cv mutation in mice ranging in age from 3 days to 6 months. Yet, the overall efficiency and therapeutic impact of in vivo base editing with this system was highest in mice treated at the juvenile stage, with animals administered MyoAAV vectors at 3 weeks of age showing robust recovery of dystrophin expression and significant improvement in muscle contractile properties only one month later. Notably, introduction of adenine base editors either earlier in development, in neonatal mice, or later, in adulthood, yielded substantially lower editing efficiencies, particularly in muscle satellite cells whose editing is essential to ensure durable rescue of dystrophin expression in growing and regenerating muscle. Taken together, these results demonstrate the therapeutic potential of single-vector adenine base editing for DMD and underscore the importance of recipient age and disease stage in achieving optimal treatment outcomes for this and other genetic muscle disorders.
Impact of Tirzepatide Therapy on Thyroid Disease: Understanding Risks and Emerging Insights.
Clin Obes
Emiliano G Manueli Laos, Bianca Serafica, Andres Fontaine-Nicola +6 more
The dual GLP-1/GIP agonist tirzepatide is a highly effective anti-obesity therapy. While promising, it is associated with potential adverse effects, including thyroid disease reported in animal models. Due to limited human data, this study seeks to identify and characterise risk factors for thyroid disease development in patients undergoing 1 year of tirzepatide treatment. This study retrospectively analysed medical records of patients completing a 12-month course of tirzepatide (2.5-15 mg weekly) between September 2023 and September 2024. The primary endpoint is the development or worsening of any thyroid disease including DIT, Hashimoto thyroiditis, Graves' disease, benign neoplasms, goitre, and thyroid cancer. In 527 patients on tirzepatide, 28 (5.3%) developed or had progression of thyroid disease. The most frequent diagnoses were Nodular/Goitre Disease and Drug-Induced Thyroiditis. Multivariate analysis showed that a history of End-Stage Renal Disease (OR = 2.94) and baseline thyroid disease (OR = 3.78) were significant risk factors. Baseline thyroid disease and end-stage renal disease are significantly associated with an increased risk of new or recurrent thyroid disorders during tirzepatide treatment. These conditions should be classified as high risk, warranting periodic thyroid testing and further large-scale prospective validation.
Effects of Tirzepatide on Body Composition, Metabolic Parameters, and Sleep Outcomes: A Real-World One-Year Prospective Study.
Cureus
Nikos Adamidis, Theodora Margariti, Vasiliki E Georgakopoulou +7 more
Background Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial efficacy in reducing body weight and improving glycemic control in randomized trials; however, real-world data on its long-term effects remain limited. Our objective was to evaluate the one-year effects of tirzepatide on body composition, metabolic parameters, inflammation, and sleep-related outcomes in a real-world setting. Methods In this prospective study, 164 consecutive adult participants receiving tirzepatide in routine clinical practice were followed longitudinally. Anthropometric measurements, bioelectrical impedance-derived body composition indices, glycemic markers, inflammatory and biochemical parameters, and sleep-related indices were assessed at baseline and follow-up. Changes (D variables) were calculated as follow-up minus baseline values. Statistical analyses included descriptive statistics, paired comparisons, and correlation analyses. Results Tirzepatide treatment was associated with significant weight reduction (change in body weight (DWeight) -8.66 ± 8.02 kg), primarily driven by decreases in fat mass (change in fat mass (DFM) -11.34 ± 10.86 kg) and waist circumference (change in waist circumference (DWC) -10.11 ± 10.10), with relative preservation of lean mass (change in fat-free mass (DFFM) 0.87 ± 14.56 kg). Improvements were observed in glycemic control (change in glycated hemoglobin (DHbA1c) -0.59 ± 0.56%) and insulin resistance (change in homeostasis model assessment of insulin resistance (DHOMA-IR) -0.52 ± 0.29), along with reductions in inflammatory markers (change in C-reactive protein (DCRP) -1.48 ± 2.39 mg/L) and liver enzymes (change in aspartate aminotransferase (DAST) and alanine aminotransferase (DALT)). Sleep-disordered breathing improved, with a reduction in apnea-hypopnea index (change in apnea-hypopnea index (DAHI) -6.64 ± 6.63 events/h). Sex-specific differences were observed, with greater FM reduction in females and greater improvement in IR and sleep apnea indices in males. Conclusions In a real-world setting, tirzepatide demonstrates sustained benefits across adiposity, metabolic function, inflammation, and sleep outcomes over one year, with preservation of lean mass. These findings support its role as a comprehensive metabolic therapy.
Liraglutide and Recurrent Stroke by Baseline Insulin Resistance: A Post Hoc Analysis of the LAMP Trial.
Stroke
Longyan Lu, Bing Yang, Yao Wang +10 more
Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events in type 2 diabetes. Although body mass index does not seem to modify these effects, whether insulin resistance influences treatment efficacy remains unclear.
GLP-1 agonist liraglutide decreases operant methamphetamine intake in rats under conditions of short- but not extended-access to the drug.
Front Pharmacol
Maria Hrickova, Sefa Furkan Demirci, Petra Amchova +1 more
Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a therapeutic strategy for reducing drug craving and intake. However, their efficacy in methamphetamine use disorder remains unexplored. This study assessed the effects of repeated liraglutide treatment on methamphetamine intravenous self-administration in rats.
GLP-1 Agonists in Orthopedic Surgery: A Narrative Review of Bone Health and Surgical Implications.
HSS J
Mateo Restrepo Mejia, Justin Tiao, Alexander Yu +4 more
Glucagon-like peptide-1 (GLP-1) receptor agonists, commonly used for glycemic control in patients with type 2 diabetes and for weight loss in obese patients, have been increasingly used due to their effectiveness in treating these conditions and in reducing cardiovascular events. Yet evidence is limited surrounding their impact on bone health and on patients undergoing orthopedic procedures. This narrative review explores the mechanisms of action of GLP-1 agonists, their effects on bone health, and the implications of their use in perioperative patents undergoing orthopedic surgery, with an emphasis on spine surgery. Basic science studies suggest that GLP-1 agonists may enhance bone mineral density and reduce bone resorption through various molecular pathways; clinical studies of their impact on fracture risk and bone health show mixed results. Also, the perioperative use of GLP-1 agonists poses challenges due to their effects on gastric motility and potential medication interactions. Nonetheless, achieving proper glycemic control with GLP-1 agonists may benefit patients with diabetes or obesity undergoing orthopedic procedures, particularly in preoperative weight management and glycemic control. Further research is needed to clarify their long-term effects on bone health and their perioperative use in orthopedic patients.
Decoding the hallmarks of GLP-1RA weight-loss super-responders.
Biol Methods Protoc
A J Venkatakrishnan, Karthik Murugadoss, Venky Soundararajan
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped obesity treatment, yet weight-loss outcomes remain highly uneven in real-world care. Using a federated biomedical platform, we analyzed 135 349 individuals treated with semaglutide and tirzepatide formulations and stratified them as "super responders" (>15% weight loss), "moderate responders" (5%-15% weight loss), "minimal weight-loss group" (<5% weight loss), and "weight regainers." Ozempic, Wegovy, Mounjaro, and Zepbound had similar proportions of patients classified as moderate responders, ranging from 40% to 42%. Rates of super responders were highest for Zepbound (34%), followed by Wegovy (26%), Mounjaro (24%), and Ozempic (10%). Among moderate and super responders, the average weight after 1 year of treatment was similar to the average weight approximately 10 and 20 years prior to treatment initiation, respectively. Compared with patients with minimal or moderate response, super responders were more likely to be younger (mean age 51 years versus 55 years), female (80% versus 58%-65%), and white (90% versus 80%). Baseline clinical characteristics enriched among super responders compared to the minimal response group included fibromyalgia (rate ratio [RR]: 0.2, P = .002) and osteoarthritis (RR = 0.5, P = .001) for Zepbound, and psoriasis (RR = 2.5, P = .03) for Wegovy. These results highlight significant heterogeneity in weight trajectories following sustained exposure to a GLP-1RA therapy and identify factors associated with increased weight loss, likely reflecting a combination of biological, behavioral, and social factors. These insights motivate further prospective analyses to help guide the development of more tailored weight-loss intervention strategies.
Fabrication of fusogenic and magnet-responsive cells for transplantation of an intact mitochondrial network.
Acta Biochim Biophys Sin (Shanghai)
Liqun Xu, Xiao Li, Xing Fan +10 more
Mitochondrial transplantation is a promising treatment for many diseases associated with mitochondrial defects or aging; however, a reliable method for mitochondrial transfer remains urgently needed. In this study, we assemble fusogenic and magnet-responsive cells (FMRCs), which are enucleated stem cells loaded with Fe 3O 4 nanoparticles and further incorporated fusogenic vesicular stomatitis virus glycoprotein G (VSV-G). Mitochondrial transplantation from FMRCs via fusion in the presence of a magnetic force restores normal mitotic activity, mitochondrial membrane potential, ROS levels and ATP production in cells subjected to partial mtDNA depletion or in cybrids harboring mtDNA with a 4977-bp deletion. SNP tracing and qPCR analysis of the mitochondrial and nuclear genomes unequivocally demonstrate that exogenous mitochondria are able to reside stably and predominately. Mitochondrial transplantation stimulate autophagy and thus the clearance of defective endogenous counterparts, resulting in lower mtDNA heteroplasmy. These results suggest that FMRCs are excellent vehicles for mitochondrial transplantation and could be used for the treatment of aging and mitochondria-associated diseases.
An agent-based model suggests how senescent cell behavior and matrix mechanics drive pulmonary fibrosis in aged mice.
bioRxiv
Mackenzie L Skelton, Julie Leonard-Duke, Leilani R Astrab +5 more
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disease of aging, driven by dysregulated fibroblast activation and accompanied by collagen accumulation in the lung interstitium, resulting in tissue stiffening. While the accumulation of senescent cells has been increasingly implicated in IPF pathogenesis, understanding the reciprocal dynamics of senescent fibroblast levels and evolving tissue mechanics is difficult to achieve with experimental approaches alone. To address this limitation, we developed an agent-based model (ABM) of fibroblast activation in the lung that couples cell behavior to the dynamic mechanical changes accompanying fibrosis. This model was parameterized entirely from experimental data in young mice to enable robust validation and then adapted to fit aged mouse biology for additional validation. Both young and aged models accurately reflected changes in collagen accumulation and stiffness burden of experimental systems. We then incorporated senescent cell behavior into the aged model to investigate how senescent cell burden influences fibrosis progression and how cell-cell interactions drive senescent cell accumulation. These simulations identified a unique role for juxtacrine-mediated contact between non-senescent and senescent fibroblasts in expanding the total senescent cell burden. Our ABM also revealed that the timing of immune-mediated senescent cell clearance critically regulates fibrotic outcomes. Together, this ABM provides useful insights into how the interrelated dynamics of tissue mechanics and senescent fibroblasts drive fibrosis progression.
Multimodal Free-Water Imaging Links Cardiometabolic Risk to Periarterial Dysfunction and Amyloid Accumulation in Early Alzheimer's.
Res Sq
Yaqiong Chai, Hedong Zhang, Andrew S Kim +17 more
The brain's waste-clearance (glymphatic) system removes metabolic byproducts via periarterial influx, interstitial exchange, and perivenous efflux. Although dysfunction is implicated in Alzheimer's disease (AD), current imaging markers emphasize perivenous changes and may overlook earlier periarterial impairment. We developed a diffusion MRI framework to quantify periarterial fluid mobility, white matter free water, and perivenous integrity, and applied it to 546 cognitively normal adults (HCP-Aging) and 173 participants across the AD spectrum (ADNI). Periarterial mobility was reduced with higher cardiometabolic risk and amyloid positivity, particularly in AD-vulnerable regions. Free water increased with aging and metabolic burden, whereas perivenous dysfunction was most pronounced in AD. Combined measures predicted amyloid positivity and cognitive impairment (AUC = 0.82). Mediation analyses showed that blood pressure influenced cognition through periarterial dysfunction and amyloid burden. These findings support a staged, compartment-specific trajectory of glymphatic dysfunction, with early periarterial impairment representing a potential biomarker and therapeutic target.