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In mammalian cells cholesterol can be synthesized endogenously or obtained exogenously through lipoprotein uptake. Plasma membrane (PM) is the primary intracellular destination for both sources of cholesterol, and maintaining appropriate membrane cholesterol levels is critical for cellular viability. The endoplasmic reticulum (ER) acts as a cellular cholesterol sensor, regulating synthesis in response to cellular needs and determining the metabolic fates of cholesterol. Upon reaching the ER, cholesterol can be esterified to facilitate its incorporation into lipoproteins and lipid droplets or converted into other molecules such as bile acids and oxysterols. In recent years, it has become clear that the intracellular redistribution of lipids, including cholesterol, is critical for the regulation of various biological processes. This Review highlights physiology and mechanisms of nonvesicular (protein-mediated) intracellular cholesterol trafficking, with a focus on the role of Aster proteins in PM to ER cholesterol transport.

This study compares infant (0–24 months) respiratory infection presentations to a Northern Italian paediatric emergency department across two post-pandemic winters (2022–2023 vs 2023–2024). Despite an approximate 44% reduction in visits in 2023–2024 (N=176 in 2023–2024 vs N=317 in 2022–2023), infants in the 2023–2024 season experienced significantly higher proportions of ventilatory support (51.1% vs 32.8%, p<0.001) and intensive care unit admission (15.9% vs 1.9%, p<0.001) than those presenting in 2022–2023, with a non-significant trend towards higher hospitalisation (88.1% vs 81.7%, p=0.052). Respiratory syncytial virus re-emerged as the dominant pathogen (43.2% vs 27.7%, p<0.001) in 2023–2024, alongside increased human metapneumovirus and influenza A H1N1. These findings highlight a concerning shift towards increased severity, underscoring the need for ongoing surveillance.

Chromatin modifications are sensitive to environmental and nutritional stimuli. Abnormalities in epigenetic regulation are associated with metabolic disorders such as obesity and diabetes that are often linked with defects in oxidative metabolism. Here, we evaluated the potential of class-specific synthetic inhibitors of histone deacetylases (HDACs), central chromatin-remodeling enzymes, to ameliorate metabolic dysfunction. Cultured myotubes and primary brown adipocytes treated with a class I–specific HDAC inhibitor showed higher expression of Pgc-1α, increased mitochondrial biogenesis, and augmented oxygen consumption. Treatment of obese diabetic mice with a class I– but not a class II–selective HDAC inhibitor enhanced oxidative metabolism in skeletal muscle and adipose tissue and promoted energy expenditure, thus reducing body weight and glucose and insulin levels. These effects can be ascribed to increased Pgc-1α action in skeletal muscle and enhanced PPARγ/PGC-1α signaling in adipose tissue. In vivo ChIP experiments indicated that inhibition of HDAC3 may account for the beneficial effect of the class I–selective HDAC inhibitor. These results suggest that class I HDAC inhibitors may provide a pharmacologic approach to treating type 2 diabetes.

White adipose tissue (WAT) can undergo a phenotypic switch, known as browning, in response to environmental stimuli such as cold. Post-translational modifications of histones have been shown to regulate cellular energy metabolism, but their role in white adipose tissue physiology remains incompletely understood. Here we show that histone deacetylase 3 (HDAC3) regulates WAT metabolism and function. Selective ablation of Hdac3 in fat switches the metabolic signature of WAT by activating a futile cycle of de novo fatty acid synthesis and β-oxidation that potentiates WAT oxidative capacity and ultimately supports browning. Specific ablation of Hdac3 in adipose tissue increases acetylation of enhancers in Pparg and Ucp1 genes, and of putative regulatory regions of the Ppara gene. Our results unveil HDAC3 as a regulator of WAT physiology, which acts as a molecular brake that inhibits fatty acid metabolism and WAT browning. Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.

Background Clinical research coordinators (CRCs) play a vital role in the management and execution of clinical trials, particularly in oncology and hematology. Methods This survey-based study, conducted by the Italian Group of Data Managers and Clinical Research Coordinators (GIDMcrc), explores the responsibilities, job satisfaction and training needs of CRCs across Italy. Results 171 professionals from 20 Italian regions participated in the survey. The results indicate that CRCs predominantly engage in data management, monitoring and regulatory tasks, with significant involvement in activities such as patient registration, data entry and compliance with ethical requirements. However, discrepancies between actual job responsibilities and formal job descriptions were common, leading to reported dissatisfaction regarding workload and training adequacy. Despite the challenges faced, the majority of respondents expressed overall job satisfaction, although just under half of respondents are considering transitions to Clinical Research Organizations (CROs) or pharmaceutical companies due to better opportunities. Conclusions This study highlights the critical need for clearer job definitions and enhanced training programs for CRCs to improve their effectiveness and job satisfaction within the evolving landscape of clinical research.

In recent years, whey proteins (WP) have attracted increasing attention in health and disease for their bioactive functions. The aim of this study was to evaluate the benefit of WP isolate (WPI) supplementation in addition to nutritional counseling in malnourished advanced cancer patients undergoing chemotherapy (CT). In a single‐center, randomized, pragmatic, and parallel‐group controlled trial (ClinicalTrials.gov: NCT02065726), 166 malnourished advanced cancer patients with mixed tumor entities candidate to or undergoing CT were randomly assigned to receive nutritional counseling with (N = 82) or without (N = 84) WPI supplementation (20 g/d) for 3 months. The primary endpoint was the change in phase angle (PhA). Secondary endpoints included changes in standardized PhA (SPA), fat‐free mass index (FFMI), body weight, muscle strength, and CT toxicity (CTCAE 4.0 events). In patients with the primary endpoint assessed (modified intention‐to‐treat population), counseling plus WPI (N = 66) resulted in improved PhA compared to nutritional counseling alone (N = 69): mean difference, 0.48° (95% CI, 0.05 to 0.90) (P = .027). WPI supplementation also resulted in improved SPA (P = .021), FFMI (P = .041), body weight (P = .023), muscle strength (P < .001), and in a reduced risk of CT toxicity (risk difference, −9.8% [95% CI, −16.9 to −2.6]; P = .009), particularly of severe (grade ≥ 3) events (risk difference, −30.4% [95% CI, −44.4 to −16.5]; P = .001). In malnourished advanced cancer patients undergoing CT, receiving nutritional counseling, a 3‐month supplementation with WPI resulted in improved body composition, muscle strength, body weight, and reduced CT toxicity. Further trials, aimed at verifying the efficacy of this nutritional intervention on mid‐ and long‐term primary clinical endpoints in newly diagnosed specific cancer types, are warranted. Whey proteins (WP) have attracted increasing attention in health and disease for their bioactive functions. In malnourished advanced cancer patients undergoing chemotherapy (CT) and receiving nutritional counseling, a 3‐month supplementation with WP resulted in improved body composition, muscle strength, and reduced CT toxicity.

Background Nutritional support, including nutritional counseling and oral nutritional supplements (ONS), has been recommended as a first-line strategy in patients with non-small cell lung cancer (NSCLC). Evidence on the efficacy of immunonutrition during immunotherapy in these patients is positive, but still limited some secondary endpoints, such as treatment toxicity and tolerance. We hypothesize that early systematic provision of ONS with a high-protein-high calorie mixture containing immunonutrients (Impact®) in addition to nutritional counseling, compared to nutritional counseling alone, is beneficial to patients with NSCLC receiving immunotherapy with or without chemotherapy. We designed the present study to evaluate the efficacy of early systematic provision of ONS enriched with immunonutrients compared to nutritional counseling alone, in patients with NSCLC undergoing immunotherapy. Study endpoints were: treatment response (primary endpoint: progression-free survival), treatment tolerance and toxicity, body weight, body composition, protein-calorie intake, quality of life, fatigue, muscle strength and immunological profile. Methods This is a pragmatic, multicentre, randomized (1:1), parallel-group, open label, controlled, pilot clinical trial ( N  = 180). Discussion The improvement of efficacy of nutritional support in oncology still deserves many efforts. Immunonutrition represents a promising approach also in patients with NSCLC, but evidence on its efficacy on clinical outcomes during immunotherapy is still inconclusive. The present pilot study, which guarantees early high-quality nutritional care (assessment and treatment) to all patients in agreement with current guidelines and recommendations, could represent one of the first proofs of efficacy of early oral immunonutrition in patients with cancer undergoing immunotherapy. Further large randomized trials addressing the improvement of supportive care could be hypothesized, accordingly. Trial registration This study is registered on ClinicalTrials.gov Identifier: NCT05384873.

The aim of this study was to evaluate the effects of mannan oligosaccharides (MOS) on gut health and performance in post-weaning piglets. In total, 40 piglets were divided into two experimental groups and fed a basal diet with (TRT) or without (CON) 0.2% mannan oligosaccharides for 35 days. Growth performance was determined weekly and faecal microbial composition on days 0, 14 and 35. On day 36, histometrical evaluations were performed on duodenal, jejunal, ileal, and colon samples. mRNA gene expression of inflammation-related genes was evaluated in samples of ileal Peyer’s patches (IPP). MOS administration improved feed efficiency in the last two weeks of the trial (p < 0.05), and a decreased clostridia content was found in faeces at day 14 (p = 0.05). TRT piglets showed increased duodenal villi height (p < 0.05), and reduced mRNA levels of Tumour Necrosis Factor α (p < 0.05) and Toll-Like Receptor 4 (p < 0.01) in IPP. Our results suggest beneficial effects of MOS supplementation on gut morphology and the expression of inflammation-related genes in post-weaning piglets, accompanied by increased feed efficiency.

In cell models, changes in the ‘accessible’ pool of plasma membrane (PM) cholesterol are linked with the regulation of endoplasmic reticulum sterol synthesis and metabolism by the Aster family of nonvesicular transporters; however, the relevance of such nonvesicular transport mechanisms for lipid homeostasis in vivo has not been defined. Here we reveal two physiological contexts that generate accessible PM cholesterol and engage the Aster pathway in the liver: fasting and reverse cholesterol transport. During fasting, adipose-tissue-derived fatty acids activate hepatocyte sphingomyelinase to liberate sequestered PM cholesterol. Aster-dependent cholesterol transport during fasting facilitates cholesteryl ester formation, cholesterol movement into bile and very low-density lipoprotein production. During reverse cholesterol transport, high-density lipoprotein delivers excess cholesterol to the hepatocyte PM through scavenger receptor class B member 1. Loss of hepatic Asters impairs cholesterol movement into feces, raises plasma cholesterol levels and causes cholesterol accumulation in peripheral tissues. These results reveal fundamental mechanisms by which Aster cholesterol flux contributes to hepatic and systemic lipid homeostasis. Xiao and Kennelly et al. show that Aster-mediated nonvesicular cholesterol transport in the liver regulates hepatic and systemic lipid homeostasis during fasting, as well as reverse cholesterol transport.

Super refractory status epilepticus (SRSE) is a life-threatening condition in which seizures do not respond to third-line anticonvulsant drug therapy. SRSE is associated with high mortality. How often SRSE occurs, what are the risk factors leading to this condition, and what is the effect on clinical outcome of failure to control seizures are poorly defined. Several studies have evaluated magnetic resonance imaging (MRI) findings in status epilepticus (SE), confirming that SE may directly cause selective neuronal necrosis due to excitotoxic mechanisms, as described in clinical case reports and experimental models. The aim of our study is to illustrate, in a case of SRSE, MRI signal changes during time and to describe which cerebral structures are early involved in this difficult clinical condition. We investigated with serial MRI study a patient affected by childhood generalized epilepsy who developed SRSE of unknown etiology during adulthood. MRI scans showed brain signal changes according to progressive electro-clinical worsening, particularly an early involvement of striatum/pallidus. An extended literature exists about transient MRI changes in SE, but not enough about SRSE, because of the difficulties in executing serial MRI studies in patients with such risky condition. MRI findings in SRSE must be investigated with particular care in order to detect early changes in basal ganglia that could suggest severe prognosis.