The growth hormone secretagogue receptor 1a agonists, anamorelin and ipamorelin, inhibit cisplatin-induced weight loss in ferrets: Anamorelin also exhibits anti-emetic effects via a central mechanism.

This study investigated whether ghrelin mimetics, namely anamorelin and ipamorelin, can alleviate weight loss and inhibition of feeding observed during acute and delayed phases of cisplatin-induced emesis in ferrets. The potential of anamorelin to inhibit electrical field stimulation (EFS)-induced contractions of isolated ferret ileum was compared with ipamorelin. In other experiments, ferrets were administered anamorelin (1-3 mg/kg), ipamorelin (1-3 mg/kg), or vehicle intraperitoneally (i.p.) 30 s before cisplatin (5 mg/kg, i.p.) and then every 24 h, and their behaviour was recorded for up to 72 h. Food and water consumption was measured every 24 h. The effect of anamorelin (10 µg) was also assessed following intracerebroventricular administration. Anamorelin and ipamorelin inhibited EFS-induced contractions of isolated ileum by 94.4 % (half-maximal inhibitory concentration [IC50]=14.0 µM) and 54.4 % (IC50=11.7 µM), respectively. Neither of compounds administered i.p. had any effect on cisplatin-induced acute or delayed emesis, but both inhibited associated cisplatin-induced weight loss on the last day of delayed phase (48-72 h) by approximately 24 %. Anamorelin (10 µg) administered intracerebroventricularly reduced cisplatin-induced acute emesis by 60 % but did not affect delayed emesis. It also improved food and water consumption by approximately 20 %-40 % during acute phase, but not delayed phase, and reduced associated cisplatin-induced weight loss during delayed phase by ∼23 %. In conclusion, anamorelin and ipamorelin administered i.p. had beneficial effects in alleviating cisplatin-induced weight loss during delayed phase, and these effects were seen when centrally administered anamorelin. Anamorelin inhibited cisplatin-induced acute emesis following intracerebroventricular but not intraperitoneal administration, suggesting that brain penetration is important for its anti-emetic mechanism of action.

MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.

BACKGROUND: Calcium (Ca2+) uptake by mitochondria occurs via the mitochondrial Ca2+ uniporter. Mitochondrial Ca2+ uniporter exists as a complex, regulated by 3 MICU (mitochondrial Ca2+ uptake) proteins localized in the intermembrane space: MICU1, MICU2, and MICU3. Although MICU3 is present in the heart, its role is largely unknown. METHODS: We used CRISPR-Cas9 to generate a mouse with global deletion of MICU3 and an adeno-associated virus (AAV9) to overexpress MICU3 in wild-type mice. We examined the role of MICU3 in regulating mitochondrial calcium ([Ca2+]m) in ex vivo hearts using an optical method following adrenergic stimulation in perfused hearts loaded with a Ca2+-sensitive fluorophore. Additionally, we studied how deletion and overexpression of MICU3, respectively, impact cardiac function in vivo by echocardiography and the molecular composition of the mitochondrial Ca2+ uniporter complex via Western blot, immunoprecipitation, and Blue native-PAGE analysis. Finally, we measured MICU3 expression in failing human hearts. RESULTS: MICU3 knock out hearts and cardiomyocytes exhibited a significantly smaller increase in [Ca2+]m than wild-type hearts following acute isoproterenol infusion. In contrast, heart with overexpression of MICU3 exhibited an enhanced increase in [Ca2+]m compared with control hearts. Echocardiography analysis showed no significant difference in cardiac function in knock out MICU3 mice relative to wild-type mice at baseline. However, mice with overexpression of MICU3 exhibited significantly reduced ejection fraction and fractional shortening compared with control mice. We observed a significant increase in the ratio of heart weight to tibia length in hearts with overexpression of MICU3 compared with controls, consistent with hypertrophy. We also found a significant decrease in MICU3 protein and expression in failing human hearts. CONCLUSIONS: Our results indicate that increased and decreased expression of MICU3 enhances and reduces, respectively, the uptake of [Ca2+]m in the heart. We conclude that MICU3 plays an important role in regulating [Ca2+]m physiologically, and overexpression of MICU3 is sufficient to induce cardiac hypertrophy, making MICU3 a possible therapeutic target.

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids.

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

Racial and Ethnic Disparities in Health-Related Outcomes in Crohn's Disease: Results From the National Health and Wellness Survey.

Background: Crohn's disease (CD) is a chronic inflammatory condition affecting the entire gastrointestinal tract that is associated with significant humanistic, clinical, and economic burdens. Few studies have assessed the association between CD severity and patient-reported outcomes (PROs), healthcare resource utilization (HCRU), and medical costs; even fewer have examined differences in disease outcomes among patients of various racial/ethnic groups. Methods: In this cross-sectional study, sociodemographic data, PROs, and economic outcomes for participants with self-reported CD were collected from the National Health and Wellness Survey (2018-2020). Multivariable analyses were used to assess the association of CD severity and race/ethnicity with health-related quality of life (HRQoL), work productivity and activity impairment (WPAI), HCRU, and medical costs. Results: Analyses included 1077 participants with CD (818 non-Hispanic White, 109 non-Hispanic Black, and 150 Hispanic). Participants with self-reported moderate/severe CD reported significantly worse HRQoL and WPAI, greater HCRU, and higher medical costs than those with self-reported mild CD. Non-Hispanic Black participants reported better HRQoL and fewer healthcare provider visits than non-Hispanic White participants. There were no significant differences in PROs between non-Hispanic White and Hispanic groups. Interactions between race/ethnicity and CD severity emerged for some, but not all groups: Specifically, non-Hispanic Black participants with moderate/severe CD reported greater absenteeism and more gastroenterologist visits than non-Hispanic Black participants with mild CD. Conclusions: Participants with moderate/severe CD reported worse PROs, greater HCRU, and higher medical costs than those with mild CD. Additionally, racial/ethnic differences were found across several HCRU and economic outcomes. Further research is needed to better understand factors contributing to burden among patients with varying CD severity across racial/ethnic groups.

Exploring the role of ghrelin and des-acyl ghrelin in chemotherapy-induced nausea and vomiting.

Ghrelin and its mimetics have been shown to reduce cisplatin-induced emesis in preclinical studies using ferrets and shrews. This study investigated the effectiveness of ghrelin and des-acyl ghrelin (DAG) in antagonizing cisplatin-induced emesis and physiological changes indicative of nausea in Suncus murinus. Animals implanted with radiotelemetry devices were administered ghrelin (0.2, 1.0, and 5.0 µg/day), DAG (0.2, 1.0, and 5.0 µg/day), or saline (14 µL/day) intracerebroventricularly 4 days before and 3 days after treatment with cisplatin (30 mg/kg). At the end, the anti-apoptotic potentials of ghrelin and DAG were assessed by measuring Bax expression and cytochrome C activity. Neurotransmitter changes in the brain were evaluated using liquid chromatography-mass spectrometry analysis. Ghrelin and DAG reduced cisplatin-induced emesis in the delayed (24-72 h) but not the acute phase (0-24 h) of emesis. Ghrelin also partially reversed the inhibitory effects of cisplatin on food intake without affecting gastrointestinal myoelectrical activity or causing hypothermia; however, ghrelin or DAG did not prevent these effects. Ghrelin and DAG could attenuate the cisplatin-induced upregulation of Bax and cytochrome C in the ileum. Cisplatin dysregulated neurotransmitter levels in the frontal cortex, amygdala, thalamus, hypothalamus, and brainstem, and this was partially restored by low doses of ghrelin and DAG. Our findings suggest that ghrelin and DAG exhibit protective effects against cisplatin-induced delayed emesis. The underlying antiemetic mechanism may involve GHSR and/or unspecified pathways that modulate the neurotransmitters involved in emesis control in the brain and an action to attenuate apoptosis in the gastrointestinal tract.

Mechanisms of reduced myocardial energetics of the dystrophic heart.

Heart disease is a leading cause of death in patients with Duchenne muscular dystrophy (DMD), characterized by the progressive replacement of contractile tissue with scar tissue. Effective therapies for dystrophic cardiomyopathy will require addressing the disease before the onset of fibrosis, however, the mechanisms of the early disease are poorly understood. To understand the pathophysiology of DMD, we perform a detailed functional assessment of cardiac function of the mdx mouse, a model of DMD. These studies use a combination of functional, metabolomic, and spectroscopic approaches to fully characterize the contractile, energetic, and mitochondrial function of beating hearts. Through these innovative approaches, we demonstrate that the dystrophic heart has reduced cardiac reserve and is energetically limited. We show that this limitation does not result from poor delivery of oxygen. Using spectroscopic approaches, we provide evidence that mitochondria in the dystrophic heart have attenuated mitochondrial membrane potential and deficits in the flow of electrons in complex IV of the electron transport chain. These studies provide evidence that poor myocardial energetics precede the onset of significant cardiac fibrosis and likely results from mitochondrial dysfunction centered around complex IV and reduced membrane potential. The multimodal approach used here implicates specific molecular components in the etiology of reduced energetics. Future studies focused on these targets may provide therapies that improve the energetics of the dystrophic heart leading to improved resiliency against damage and preservation of myocardial contractile tissue.NEW & NOTEWORTHY Dystrophic hearts have poor contractile reserve that is associated with a reduction in myocardial energetics. We demonstrate that oxygen delivery does not contribute to the limited energy production of the dystrophic heart even with increased workloads. Cytochrome optical spectroscopy of the contracting heart reveals alterations in complex IV and evidence of depolarized mitochondrial membranes. We show specific alterations in the electron transport chain of the dystrophic heart that may contribute to poor myocardial energetics.

Automatic Mapping of Terminology Items with Transformers.

Biomedical ontologies are a key component in many systems for the analysis of textual clinical data. They are employed to organize information about a certain domain relying on a hierarchy of different classes. Each class maps a concept to items in a terminology developed by domain experts. These mappings are then leveraged to organize the information extracted by Natural Language Processing (NLP) models to build knowledge graphs for inferences. The creation of these associations, however, requires extensive manual review. In this paper, we present an automated approach and repeatable framework to learn a mapping between ontology classes and terminology terms derived from vocabularies in the Unified Medical Language System (UMLS) metathesaurus. According to our evaluation, the proposed system achieves a performance close to humans and provides a substantial improvement over existing systems developed by the National Library of Medicine to assist researchers through this process.

Subtyping Gastrointestinal Surgical Outcomes from Real World Data: A Comprehensive Analysis of UK Biobank.

Chronic gastrointestinal (GI) conditions, such as inflammatory bowel diseases (IBD), offer a promising opportunity to create classification systems that can enhance the accuracy of predicting the most effective therapies and prognosis for each patient. Here, we present a novel methodology to explore disease subtypes using our open-sourced BiomedSciAI toolkit. Applying methods available in this toolkit on the UK Biobank, including subpopulation-based feature selection and multi-dimensional subset scanning, we aimed to discover unique subgroups from GI surgery cohorts. Of a 12,073-patient cohort, a subgroup of 440 IBD patients was discovered with an increased risk of a subsequent GI surgery (OR: 2.21, 95% CI [1.81-2.69]). We iteratively demonstrate the discovery process using an additional cohort (with a narrower definition of GI surgery). Our results show that the iterative process can refine the subgroup discovery process and generate novel hypotheses to investigate determinants of treatment response.