The Rho guanine dissociation inhibitor α inhibits skeletal muscle Rac1 activity and insulin action.

The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.

Can the DEX/CRH test or markers of oxidative stress distinguish work-related stress from major depressive disorder and normal controls?

Hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity measured by the combined dexamethasone-CRH test (DEX-CRH test) has been found in patients with major depressive disorder (MDD), whereas hypoactivity has been found in patients with work-related stress. We aimed to investigate the DEX-CRH test as a biomarker to distinguish between MDD and work-related stress (exhaustion disorder - ED). We hypothesized that there would be lower cortisol and ACTH response in participants with ED compared to MDD and healthy controls (HC). Also, we explored if the cortisol response of those patients interacted with robust markers of oxidative stress. Thirty inpatients with MDD and 23 outpatients with ED were recruited. Plasma cortisol and ACTH were sampled during a DEX-CRH test. The main outcome measure, area under the curve (AUC) for cortisol and ACTH, was compa-red between MDD vs. ED participants and a historical HC group. Secondary markers of oxidative stress urinary 8-oxodG and 8-oxoGuo; quality of sleep and psychometrics were obtained. Cortisol concentrations were higher in MDD and ED participants compared to HC, and no differences in AUC cortisol and ACTH were found between ED vs. MDD. Compared to ED, MDD participants had higher stress symptom severity and a lower sense of well-being. No differences in oxidative stress markers or quality of sleep between the groups were found. The result indicates that the patients with ED, like patients with MDD, are non-suppressors in DEX-CRH test and not hypocortisolemic as suggested.

Cancer causes dysfunctional insulin signaling and glucose transport in a muscle-type-specific manner.

Metabolic dysfunction and insulin resistance are emerging as hallmarks of cancer and cachexia, and impair cancer prognosis. Yet, the molecular mechanisms underlying impaired metabolic regulation are not fully understood. To elucidate the mechanisms behind cancer-induced insulin resistance in muscle, we isolated extensor digitorum longus (EDL) and soleus muscles from Lewis Lung Carcinoma tumor-bearing mice. Three weeks after tumor inoculation, muscles were isolated and stimulated with or without a submaximal dose of insulin (1.5 nM). Glucose transport was measured using 2-[3 H]Deoxy-Glucose and intramyocellular signaling was investigated using immunoblotting. In soleus muscles from tumor-bearing mice, insulin-stimulated glucose transport was abrogated concomitantly with abolished insulin-induced TBC1D4 and GSK3 phosphorylation. In EDL, glucose transport and TBC1D4 phosphorylation were not impaired in muscles from tumor-bearing mice, while AMPK signaling was elevated. Anabolic insulin signaling via phosphorylation of the mTORC1 targets, p70S6K thr389, and ribosomal-S6 ser235, were decreased by cancer in soleus muscle while increased or unaffected in EDL. In contrast, the mTOR substrate, pULK1 ser757, was reduced in both soleus and EDL by cancer. Hence, cancer causes considerable changes in skeletal muscle insulin signaling that is dependent on muscle-type, which could contribute to metabolic dysregulation in cancer. Thus, the skeletal muscle could be a target for managing metabolic dysfunction in cancer.

Immunotoxicological effects of perfluorooctanesulfonic acid on European seabass are reduced by polyethylene microplastics.

Marine environments receive plastic waste, where it suffers a transformation process into smaller particles. Among them, microplastics (MPs; <5 mm) are ingested by aquatic organisms leading to negative effects on animal welfare. The interactions between MPs, contaminants and organisms are poorly understood. To clarify this issue, European seabass (Dicentrarchus labrax L.) were fed with diets supplemented with 0 (control), polyethylene (PE) MPs (100 mg/kg diet), perfluorooctanesulfonic acid (PFOS, 4.83 µg/kg diet) or PFOS adsorbed to MPs (MPs-PFOS; final concentrations of 4.83 µg and 100 mg of PFOS and MP per kg of feed, respectively). Samples of skin mucus, serum, head-kidney (HK), liver, muscle, brain and intestine were obtained. PFOS levels were high in the liver of fish fed with the PFOS-diet, and markedly reduced when adsorbed to MPs. Compared to the control groups, liver EROD activity did not show any significant changes, whereas brain and muscle cholinesterase activities were decreased in all the groups. The histological and morphometrical study on liver and intestine showed significant alterations in fish fed with the experimental diets. At functional level, all the experimental diets affected the humoral (peroxidase, IgM, protease and bactericidal activities) as well as cellular (phagocytosis, respiratory burst and peroxidase) activities of HK leukocytes, being more marked those effects caused by the PFOS diet. Besides, treatments produced inflammation and oxidative stress as evidenced at gene level. Principal component analysis demonstrated that seabass fed with MPs-PFOS showed more similar effects to MPs alone than to PFOS. Overall, seabass fed with MPs-PFOS diet showed similar or lower toxicological alterations than those fed with MPs or PFOS alone demonstrating the lack of additive effects or even protection against PFOS toxicity.

Insulin resistance in patients with cancer: a systematic review and meta-analysis.

BACKGROUND: Insulin resistance is a critical cause of metabolic dysfunctions. Metabolic dysfunction is common in patients with cancer and is associated with higher cancer recurrence rates and reduced overall survival. Yet, insulin resistance is rarely considered in the clinic and thus it is uncertain how frequently this condition occurs in patients with cancer. METHODS: To address this knowledge gap, we performed a systematic review and a meta-analysis guided by the Preferred Items for Systematic Review and Meta-Analyses (PRISMA) statement. We included studies assessing insulin resistance in patients with various cancer diagnoses, using the gold-standard hyperinsulinemic-euglycemic clamp method. Studies eligible for inclusion were as follows: (1) included cancer patients older than 18 years of age; (2) included an age-matched control group consisting of individuals without cancer or other types of neoplasms; (3) measured insulin sensitivity using the hyperinsulinemic-euglycemic clamp method. We searched the databases MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published from database inception through March 2023 with no language restriction, supplemented by backward and forward citation searching. Bias was assessed using funnel plot. FINDINGS: Fifteen studies satisfied the criteria. The mean insulin-stimulated rate of glucose disposal (Rd) was 7.5 mg/kg/min in control subjects (n = 154), and 4.7 mg/kg/min in patients with a cancer diagnosis (n = 187). Thus, the Rd mean difference was -2.61 mg/kg/min [95% confidence interval, -3.04; -2.19], p<.01). Heterogeneity among the included studies was insignificant (p=.24). INTERPRETATION: These findings suggest that patients with a cancer diagnosis are markedly insulin resistant. As metabolic dysfunction in patients with cancer associates with increased recurrence and reduced overall survival, future studies should address if ameliorating insulin resistance in this population can improve these outcomes thereby improving patient care.Key pointsMetabolic dysfunction increases cancer recurrence rates and reduces survival for patients with cancer.Insulin resistance is a critical cause of metabolic dysfunctions.To date, no comprehensive compilation of research investigating insulin resistance in cancer patients has been produced.In this meta-analysis, we found that patients with various cancers were markedly insulin-resistant.

Exercise increases phosphorylation of the putative mTORC2 activity readout NDRG1 in human skeletal muscle.

In mice, exercise is suggested to activate the mechanistic target of rapamycin complex 2 (mTORC2) in skeletal muscle, and mTORC2 is required for normal muscle glucose uptake during exercise. Whether this translates to human skeletal muscle and what signaling pathways facilitate the exercise-induced mTORC2 activation is unknown. We herein tested the hypothesis that exercise increases mTORC2 activity in human skeletal muscle and investigated if ß2-adrenergic receptor (AR) activation mediates exercise-induced mTORC2 activation. We examined several mTORC2 activity readouts (p-NDRG1 Thr346, p-Akt Ser473, p-mTOR S2481, and p-Akt Thr450) in human skeletal muscle biopsies after uphill walking or cycling exercise. In mouse muscles, we assessed mTORC2 activity readouts following acute activation of muscle ß2-adrenergic or GS signaling and during in vivo and ex vivo muscle contractions. Exercise increased phosphorylation of NDRG1 Thr346 in human soleus, gastrocnemius, and vastus lateralis muscle, without changing p-Akt Ser473, p-Akt Thr450, and p-mTOR Ser2481. In mouse muscle, stimulation of ß2-adrenergic or GS signaling and ex vivo contractions failed to increase p-NDRG1 Thr346, whereas in vivo contractions were sufficient to induce p-NDRG1 Thr346. In conclusion, the mTORC2 activity readout p-NDRG1 Thr346 is a novel exercise-responsive signaling protein in human skeletal muscle. Notably, contraction-induced p-NDRG1 Thr346 appears to require a systemic factor. Unlike exercise, and in contrast to published data obtained in cultured muscles cells, stimulation of ß2-adrenergic signaling is not sufficient to trigger NDRG1 phosphorylation in mature mouse skeletal muscle.NEW & NOTEWORTHY The mTORC2 readout p-NDRG Thr346 is a novel exercise-responsive protein in human skeletal muscle. ß2-AR and GS signaling are not sufficient to induce mTORC2 signaling in adult muscle. In vivo, but not ex vivo, contraction induced p-NDRG Thr346, which indicates requirement of a systemic factor for exercise-induced mTORC2 activation.

Encapsulation of Capacitive Micromachined Ultrasonic Transducers (CMUTs) for the Acoustic Communication between Medical Implants.

The aim of this work was to extend conventional medical implants by the possibility of communication between them. For reasons of data security and transmitting distances, this communication should be realized using ultrasound, which is generated and detected by capacitive micromachined ultrasonic transducers (CMUTs). These offer the advantage of an inherent high bandwidth and a high integration capability. To protect the surrounding tissue, it has to be encapsulated. In contrast to previous results of other research groups dealing with the encapsulation of CMUTs, the goal here is to integrate the CMUT into the housing of a medical implant. In this work, CMUTs were designed and fabricated for a center frequency of 2 MHz in water and experimentally tested on their characteristics for operation behind layers of Polyether ether ketone (PEEK) and titanium, two typical materials for the housings of medical implants. It could be shown that with silicone as a coupling layer it is possible to operate a CMUT behind the housing of an implant. Although it changes the characteristics of the CMUT, the setup is found to be well suited for communication between two transducers over a distance of at least 8 cm.

Exercise-A Panacea of Metabolic Dysregulation in Cancer: Physiological and Molecular Insights.

Metabolic dysfunction is a comorbidity of many types of cancers. Disruption of glucose metabolism is of concern, as it is associated with higher cancer recurrence rates and reduced survival. Current evidence suggests many health benefits from exercise during and after cancer treatment, yet only a limited number of studies have addressed the effect of exercise on cancer-associated disruption of metabolism. In this review, we draw on studies in cells, rodents, and humans to describe the metabolic dysfunctions observed in cancer and the tissues involved. We discuss how the known effects of acute exercise and exercise training observed in healthy subjects could have a positive outcome on mechanisms in people with cancer, namely: insulin resistance, hyperlipidemia, mitochondrial dysfunction, inflammation, and cachexia. Finally, we compile the current limited knowledge of how exercise corrects metabolic control in cancer and identify unanswered questions for future research.

Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation.

Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.

Pretreatment resistance mutations and treatment outcomes in adults living with HIV-1: a cohort study in urban Malawi.

BACKGROUND: Pre-treatment drug resistance (PDR) among antiretroviral drug-naïve people living with HIV (PLHIV) represents an important indicator for the risk of treatment failure and the spread of drug resistant HIV variants. We assessed the prevalence of PDR and treatment outcomes among adults living with HIV-1 in Lilongwe, Malawi. METHODS: We selected 200 participants at random from the Lighthouse Tenofovir Cohort Study (LighTen). Serum samples were drawn prior to treatment initiation in 2014 and 2015, frozen, and later analyzed for the presence of HIV-1 drug resistance mutations. Amplicons were sequenced and interpreted by Stanford HIVdb interpretation algorithm 8.4. We assessed treatment outcomes by evaluating clinical outcome and viral suppression at the end of the follow-up period in October 2019. RESULTS: PDR testing was successful in 197 of 200 samples. The overall NNRTI- PDR prevalence was 13.7% (27/197). The prevalence of intermediate or high level NNRTI- PDR was 11.2% (22/197). The most common mutation was K103N (5.6%, 11/197), followed by Y181C (3.6%, 7/197). In one case, we detected an NRTI resistance mutation (M184V), in combination with multiple NNRTI resistance mutations. All HIV-1 isolates analyzed were of subtype C. Of the 27 patients with NNRTI- PDR, 9 were still alive, on ART, and virally suppressed at the end of follow-up. CONCLUSION: The prevalence of NNRTI- PDR was above the critical level of 10% suggested by the Global Action Plan on HIV Drug Resistance. The distribution of drug resistance mutations was similar to that seen in previous studies from the region, and further supports the introduction of integrase inhibitors in first-line treatment in Malawi. Furthermore, our findings underline the need for continued PDR surveillance and pharmacovigilance in Sub-Saharan Africa.

Multi- and transgenerational effects following early-life exposure of zebrafish to permethrin and coumarin 47: Impact on growth, fertility, behavior and lipid metabolism.

Transgenerational effects induced by environmental stressors are a threat to ecosystems and human health. However, there is still limited observation and understanding of the potential of chemicals to influence life outcomes over several generations. In the present study, we investigated the effects of two environmental contaminants, coumarin 47 and permethrin, on exposed zebrafish (F0) and their progeny (F1-F3). Coumarin 47 is commonly found in personal care products and dyes, whereas permethrin is used as a domestic and agricultural pyrethroid insecticide/insect repellent. Zebrafish (F0) were exposed during early development until 28 days post-fertilization and their progeny (F1-F3) were bred unexposed. On one hand, the effects induced by coumarin 47 suggest no multigenerational toxicity. On the other hand, we found that behavior of zebrafish larvae was significantly affected by exposure to permethrin in F1 to F3 generations with some differences depending on the concentration. This suggests persistent alteration of the neural or neuromuscular function. In addition, lipidomic analyses showed that permethrin treatment was partially correlated with lysophosphatidylcholine levels in zebrafish, an important lipid for neurodevelopment. Overall, these results stress out one of the most widely used pyrethroids can trigger long-term, multi- and possibly transgenerational changes in the nervous system of zebrafish. These neurobehavioral changes echo the effects observed under direct exposure to high concentrations of permethrin and therefore call for more research on mechanisms underlying effect inheritance.

Screening and systematic follow-up for cardiopulmonary comorbidity in elective surgery for colorectal cancer: a randomised feasibility study.

BACKGROUND: One third of patients with colorectal cancer (CRC) have comorbidity, which impairs their postoperative outcomes. Scoring systems may predict mortality, but there is limited evidence of effective interventions in high-risk patients. Our aim was to test a trial setup to assess the effect of extra postoperative medical visits and follow-up on 1-year mortality and other outcomes in patients with cardiopulmonary risk factors undergoing elective surgery for colorectal tumours. METHODS: Patients preoperatively screened positive for cardiopulmonary comorbidity were eligible. On postoperative day 4, they were randomised to either routine follow-up (RFU) or RFU with one extra medical visit and additional visits to the Cardiology and Respiratory Medicine Clinics 1 and 3 months postoperatively. The primary outcome measure was 1-year mortality; secondary outcome measures were length of stay (LOS), complications, and readmissions. RESULTS: Of 673 screened patients 326 (48%) were found eligible, 108 declined participation, and 198 were randomised. Postoperative medical problems and/or need for intervention were found in 15-23% of the patients at the extra medical visits. The 90-day mortality was 0 and the 1-year mortality only 2.6% with no differences between the two groups. LOS and complication rates did not differ, but there were significantly fewer readmissions in the intervention group. CONCLUSIONS: The 1-year mortality after elective CRC surgery was low, even in the presence of cardiopulmonary risk factors. There was no evidence of reduced mortality with additional medical follow-up in these patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT02328365 registered 31 December 2014 (retrospectively registered).

Benzo[a]pyrene and 2,3-benzofuran induce divergent temporal patterns of AhR-regulated responses in zebrafish embryos (Danio rerio).

Biotests like the fish embryo toxicity test have become increasingly popular in risk assessment and evaluation of chemicals found in the environment. The large range of possible endpoints is a big advantage when researching on the mode of action of a certain substance. Here, we utilized the frequently used model organism zebrafish (Danio rerio) to examine regulative mechanisms in the pathway of the aryl-hydrocarbon receptor (AHR) in early development. We exposed embryos to representatives of two chemical classes known to elicit dioxin-like activity: benzo[a]pyrene for polycyclic aromatic hydrocarbons (PAHs) and 2,3-benzofuran for polar O-substituted heterocycles as a member of heterocyclic compounds in general (N-, S-, O-heterocycles; NSO-hets). We measured gene transcription of the induced P450 cytochromes (cyp1), their formation of protein and biotransformation activity throughout the whole embryonic development until 5 days after fertilization. The results show a very specific time course of transcription depending on the chemical properties (e.g. halogenation, planarity, Kow), the physical decay and the biodegradability of the tested compound. However, although this temporal pattern was not precisely transferable onto the protein level, significant regulation in enzymatic activity over time could be detected. We conclude, that a careful choice of time and end point as well as consideration of the chemical properties of a substance are fairly important when planning, conducting and especially evaluating biotests.

Rac1 muscle knockout exacerbates the detrimental effect of high-fat diet on insulin-stimulated muscle glucose uptake independently of Akt.

KEY POINTS: The actin cytoskeleton regulating GTPase, Rac1, is a novel player in insulin-stimulated glucose uptake in muscle in vivo. High-fat diet (HFD) exacerbates muscle insulin resistance in Rac1 muscle knockout (mKO) mice. Muscle Rac1 KO protects against HFD-induced insulin resistance in fat tissue indicating tissue cross-talk. A fatty diet markedly reduces insulin clearance in mice. ABSTRACT: Insulin resistance and perturbations in glucose metabolism underpin common lifestyle diseases such as type 2 diabetes and obesity. Insulin resistance in muscle is characterized by compromised activity of the GTPase, Ras-related C3 Botulinum toxin substrate 1 (Rac1), yet the role of Rac1 in insulin-stimulated glucose uptake in vivo and diet-induced insulin resistance is unknown. Inducible muscle-specific Rac1 knockout (Rac1 mKO) and wild type (WT) littermate mice were either fed a chow or a 60% high-fat diet (HFD). Insulin-stimulated 2-deoxy-glucose uptake, intracellular signalling, protein expression, substrate utilization, and glucose and insulin tolerance were assessed. In chow-fed mice, in vivo insulin-stimulated glucose uptake was reduced in triceps, soleus and gastrocnemius muscles from Rac1 mKO mice. HFD-induced whole body insulin resistance was exacerbated by the lack of muscle Rac1 and glucose uptake was reduced in all muscles, except for soleus. Muscle Akt (also known as protein kinase B) signalling was unaffected by diet or genotype. In adipose tissue, Rac1 mKO mice were protected from HFD-induced insulin resistance (with respect to both glucose uptake and phosphorylated-Akt), rendering their whole body glucose tolerance comparable to WT mice on HFD. Our findings show that lack of Rac1 exacerbates HFD-induced insulin resistance in skeletal muscle. Whole body glucose tolerance, however, was largely unaffected in Rac1 mKO mice, likely due to improved insulin-stimulated glucose uptake in adipose tissue. We conclude that lack of Rac1 in the context of obesity is detrimental to insulin-stimulated muscle glucose uptake in muscle independently of Akt signalling.

[Stress ulcer prophylaxis: are PPIs truly superior compared to H2 receptor antagonists?] / Stressulkusprophylaxe: Sind PPIs den H2-Rezeptorantagonisten wirklich überlegen?

The S2k-Guideline "Helicobacter pylori and gastroduodenal ulcer disease" offers a statement and comment on the subject of stress ulcer prophylaxis that need a critical response.

Effects of early contrast-enhanced computed tomography on clinical course and complications in patients with acute pancreatitis.

PURPOSE: To investigate the effect of an early contrast-enhanced computed tomography (CECT) on clinical course and complications of acute pancreatitis (AP). MATERIAL AND METHODS: 58 patients with AP who had at least one CECT examination were analyzed retrospectively. Laboratory as well as clinical data, and results from the assessment of disease severity (CT severity index (CTSI) and its modified (MCTSI) version) were analyzed. The primary endpoint was the development of severe complications, defined as death, respiratory failure, acute renal failure, and the need for invasive interventions. Patients were divided into two groups: an early group (CECT within the first 48 h after the onset of symptoms, n = 32) and a late group (CECT > 48 h after the onset of symptoms, n = 26). Multivariate regression analysis was performed to identify risk factors for severe complications. RESULTS: There were no statistically significant differences between both groups concerning baseline characteristics, CTSI, and MCTSI. Complications occurred more often in the early CECT group (p = 0.008). Multivariate logistic regression analysis identified an early CECT and a severe MCTSI as independent risk factors for the occurrence of severe complications (p = 0.02 and p = 0.002, respectively). CONCLUSION: CECT performed within the first 48 h after the onset of symptoms is associated with an unfavorable outcome in AP.

Clinical management of chronic hepatitis B infection: results from a registry at a German tertiary referral center.

PURPOSE: We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular. METHODS: We retrospectively evaluated the medical records of 242 adult (age ≥ 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels >10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance). RESULTS: The mean age was 44 years in CHB patients without HCC (63% male) and about 59 years in patients with HCC (77% male). Antiviral therapy was given to 59% of patients without HCC compared to only 25% in group 1 and 18% in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19% in group 1 vs. 64% in group 2 (p = 0.019), with LTx performed in 12 vs. 45%, respectively. CONCLUSION: Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments.

Molecular Insights From Multiomics Studies of Physical Activity.

Physical activity confers systemic health benefits and provides powerful protection against disease. There has been tremendous interest in understanding the molecular effectors of exercise that mediate these physiologic effects. The modern growth of multiomics technologies-including metabolomics, proteomics, phosphoproteomics, lipidomics, single-cell RNA sequencing, and epigenomics-has provided unparalleled opportunities to systematically investigate the molecular changes associated with physical activity on an organism-wide scale. Here, we discuss how multiomics technologies provide new insights into the systemic effects of physical activity, including the integrative responses across organs as well as the molecules and mechanisms mediating tissue communication during exercise. We also highlight critical unanswered questions that can now be addressed using these high-dimensional tools and provide perspectives on fertile future research directions.

Cocktail effects of tire wear particles leachates on diverse biological models: A multilevel analysis.

Tire wear particles (TWP) stand out as a major contributor to microplastic pollution, yet their environmental impact remains inadequately understood. This study delves into the cocktail effects of TWP leachates, employing molecular, cellular, and organismal assessments on diverse biological models. Extracted in artificial seawater and analyzed for metals and organic compounds, TWP leachates revealed the presence of polyaromatic hydrocarbons and 4-tert-octylphenol. Exposure to TWP leachates (1.5 to 1000 mg peq L-1) inhibited algae growth and induced zebrafish embryotoxicity, pigment alterations, and behavioral changes. Cell painting uncovered pro-apoptotic changes, while mechanism-specific gene-reporter assays highlighted endocrine-disrupting potential, particularly antiandrogenic effects. Although heavy metals like zinc have been suggested as major players in TWP leachate toxicity, this study emphasizes water-leachable organic compounds as the primary causative agents of observed acute toxicity. The findings underscore the need to reduce TWP pollution in aquatic systems and enhance regulations governing highly toxic tire additives.