Hepatitis B virus (HBV)-specific CD8 T cells are functionally exhausted in chronic hepatitis B infection, and this condition can be corrected only partially through the modulation of inhibitory ...pathways, which suggests that a more complex molecular interplay underlies T cell exhaustion. To gain broader insight into this process and identify additional targets for the restoration of T cell function, we compared the transcriptome profiles of HBV-specific CD8 T cells from patients with acute and chronic disease with those of HBV-specific CD8 T cells from patients able to resolve HBV infection spontaneously and influenza (FLU)-specific CD8 T cells from healthy participants. The results indicate that exhausted HBV-specific CD8 T cells are markedly impaired at multiple levels and show substantial downregulation of various cellular processes centered on extensive mitochondrial alterations. A notable improvement of mitochondrial and antiviral CD8 functions was elicited by mitochondrion-targeted antioxidants, which suggests a central role for reactive oxygen species (ROS) in T cell exhaustion. Thus, mitochondria represent promising targets for novel reconstitution therapies to treat chronic hepatitis B infection.
Background: A number of metabolic changes are caused by childhood obesity, including insulin resistance, diabetes, and dyslipidemia. To counteract them, lifestyle modification with changes in dietary ...habits and physical activity is the primary intervention. Anthropometric parameters may not identify all positive changes associated with lifestyle modifications, whereas circulating adipokines may represent an alternative as biomarkers. The aim of this study was to evaluate adiponectin and leptin levels as markers of positive metabolic outcomes in childhood obesity.
Methods: Changes in clinical, anthropometric, and metabolic parameters, including adiponectin and leptin, were assessed in 104 overweight and obese children before and after 1 yr of lifestyle intervention. Obesity and overweight were defined according to the Italian body mass index reference tables for age and sex. Fifty-four normal-weight children were evaluated as controls. Forty-eight of the children (47.5%) returned for follow-up at 1 yr.
Results: Compared with normal-weight children, overweight and obese subjects differed significantly at baseline for glycemia, insulinemia, homeostasis model assessment for insulin resistance, adiponectinemia (5.8 vs. 18.2 μg/ml in controls), low-density lipoprotein-cholesterol, and triglycerides. These parameters were all higher in the overweight/obese children. At follow-up, most parameters improved in overweight/obese children. The most significant changes were observed in adiponectin concentration, which increased by 245% (P < 0.0001), reaching the levels observed in normal-weight children. Leptin levels showed changes unrelated to positive metabolic outcomes, remaining high at 1 yr of follow-up in overweight/obese children. Regardless of changes in weight status, children with lifestyle intervention reported changes in homeostasis model assessment for insulin resistance and in adiponectin that were associated with loss of fat mass.
Conclusions: After lifestyle intervention, adiponectin increased regardless of changes in weight, whereas no consistent changes was observed in serum leptin. Therefore, circulating adiponectin may represent a good biomarker to evaluate the efficacy of lifestyle intervention in overweight/obese children.
Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug ...therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents.
Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to ...EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms
and
, as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.
Control of prolactin excess is associated with the improvement in gluco-insulinemic and lipid profile. The current study aimed at investigating the effects of pituitary surgery and medical therapy ...with high dose cabergoline (≥2mg/week) on metabolic profile in patients with prolactinoma resistant to cabergoline conventional doses (<2mg/week).
Thirty-four patients (22 men, 12 women, aged 33.9 ± 12.5 years) with prolactinoma (4 microadenomas and 30 macroadenomas) were included in the present study. Among them 17 (50%) received pituitary surgery (PS, Group1) and 17 (50%) medical therapy with high dose cabergoline (Group 2).
In the whole patient cohort, anthropometric (weight, BMI) and biochemical (fasting glucose and insulin, triglycerides, total, HDL and LDL-cholesterol, HOMA-IR, HOMA-β and ISI0) parameters were evaluated before and within 12 months after treatment.
In Group 1, prolactin (p=0.002), total cholesterol (p=0.012), and triglycerides (p=0.030) significantly decreased after pituitary surgery compared to the baseline. Prolactin significantly correlated with fasting glucose (r=0.056, p=0.025). In Group 2, fasting insulin (p=0.033), HOMA-β (p=0.011) and ISI0 (p=0.011) significantly improved compared to baseline. Postoperative cabergoline dose significantly correlated with Δfasting glucose (r=-0.556, p=0.039) and ΔLDL cholesterol (r=- 0.521, p=0.046), and was the best predictor of ΔLDL cholesterol (r
0.59, p=0.002) in Group 1.
The rapid decrease in PRL levels induced by PS might improve lipid metabolism, whereas HD-CAB might exert a beneficial impact on both insulin secretion and peripheral sensitivity, thus inducing a global metabolic improvement.
Background & Aims The antiviral function of peripheral hepatitis B virus (HBV)-specific T cells can be increased in patients with chronic hepatitis B by blocking the interaction of programmed death ...(PD)-1 with its ligand PD-L1. However, no information is available about the effects of this blockade on intrahepatic lymphocytes. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic and circulating HBV-specific T cells in patients with chronic hepatitis B. Methods A total of 42 patients with chronic HBV infection who underwent liver biopsy were studied. The ex vivo phenotype of peripheral and intrahepatic HBV-specific CD8+ T cells was assessed by flow cytometry with class I tetramers and antibodies to T-cell differentiation molecules. Functional recovery was evaluated by analyzing expansion and production of interferon (IFN)-γ and interleukin (IL)-2 after short-term incubation of T cells with HBV peptides in the presence of anti-PD-L1 or control antibodies. Results Intrahepatic HBV-specific CD8+ cells expressed higher levels of PD-1 and lower levels of CD127 than their peripheral counterparts. Blockade of PD-1/PD-L1 interaction increased CD8+ cell proliferation and IFN-γ and IL-2 production by circulating intrahepatic lymphocytes, even though anti-PD-L1 had a stronger effect on intrahepatic compared with peripheral T cells. Conclusions T-cell exhaustion by high antigen concentrations promotes HBV-specific T-cell dysfunction by affecting phenotype and function of peripheral and intrahepatic T cells. By restoring antiviral T-cell functions, not only in peripheral but also in intrahepatic lymphocytes, anti-PD-L1 might be a good therapeutic candidate for chronic HBV infection.
Measurements of two- and multi-particle angular correlations in pp collisions at s=5,7, and 13TeV are presented as a function of charged-particle multiplicity. The data, corresponding to integrated ...luminosities of 1.0pb−1 (5 TeV), 6.2pb−1 (7 TeV), and 0.7pb−1 (13 TeV), were collected using the CMS detector at the LHC. The second-order (v2) and third-order (v3) azimuthal anisotropy harmonics of unidentified charged particles, as well as v2 of KS0 and Λ/Λ‾ particles, are extracted from long-range two-particle correlations as functions of particle multiplicity and transverse momentum. For high-multiplicity pp events, a mass ordering is observed for the v2 values of charged hadrons (mostly pions), KS0, and Λ/Λ‾, with lighter particle species exhibiting a stronger azimuthal anisotropy signal below pT≈2GeV/c. For 13 TeV data, the v2 signals are also extracted from four- and six-particle correlations for the first time in pp collisions, with comparable magnitude to those from two-particle correlations. These observations are similar to those seen in pPb and PbPb collisions, and support the interpretation of a collective origin for the observed long-range correlations in high-multiplicity pp collisions.
We aimed to compare discharge opioid prescriptions pre- and post-ERAS implementation.
ERAS programs decrease inpatient opioid use, but their relationship with postdischarge opioids remains unclear.
...All patients undergoing hysterectomy between October 2016 and November 2020 and pancreatectomy or hepatectomy between April 2017 and November 2020 at 1 tertiary care center were included. For each procedure, ERAS was implemented during the study period. PSM was performed to compare pre - versus post-ERAS patients on discharge opioids (number of pills and oral morphine equivalents). Patients were matched on age, sex, race, payor, American Society of Anesthesiologists score, prior opioid use, and procedure. Sensitivity analyses in open versus minimally invasive surgery cohorts were performed.
A total of 3983 patients were included (1929 pre-ERAS; 2054 post-ERAS). Post-ERAS patients were younger (56.0 vs 58.4 years; P < 0.001), more often female (95.8% vs 78.1%; P < 0.001), less often white (77.2% vs 82.0%; P < 0.001), less often had prior opioid use (20.1% vs 28.1%; P < 0.001), and more often underwent hysterectomy (91.1% vs 55.7%; P < 0.001). After PSM, there were no significant differences between cohorts in baseline characteristics. Matched post-ERAS patients were prescribed fewer opioid pills (17.4 pills vs 22.0 pills; P < 0.001) and lower oral morphine equivalents (129.4 mg vs 167.6 mg; P < 0.001) than pre-ERAS patients. Sensitivity analyses confirmed these findings open (18.8 pills vs 25.4 pills; P < 0.001 \ 138.9 mg vs 198.7 mg; P < 0.001); minimally invasive surgery (17.2 pills vs 21.1 pills; P < 0.001 \ 127.1 mg vs 160.1 mg; P < 0.001).
Post-ERAS patients were prescribed significantly fewer opioids at discharge compared to matched pre-ERAS patients.
The IELSG38 trial was conducted to investigate the effects of subcutaneous (SC) rituximab on the complete remission (CR) rate and the benefits of SC maintenance in patients with extranodal marginal ...zone lymphoma (MZL) who received frontline treatment with chlorambucil plus rituximab. Study treatment comprised an induction phase with chlorambucil 6 mg/m2/day orally on weeks 1-6, 9-10, 13-14, 17-18, and 21-22, and rituximab 375 mg/m2 intravenously on day 1 of weeks 1-4, and 1400 mg SC on weeks 9, 13, 17, and 21. Then, a maintenance phase followed with rituximab administered at 1400 mg SC every two months for two years. Of the 112 patients enrolled, 109 were evaluated for efficacy. The CR rates increased from 52% at the end of the induction phase to 70% upon completion of the maintenance phase. With a median follow-up of 5.8 years, the 5-year event-free, progression-free, and overall survival rates were 87% (95% CI, 78-92), 84% (95% CI, 75-89), and 93% (95% CI, 86-96), respectively. The most common grade ≥3 toxicities were neutropenia (33%) and lymphocytopenia (16%). Six patients experienced treatment-related serious adverse events, including fever of unknown origin, sepsis, pneumonia, respiratory failure, severe cerebellar ataxia, and fatal acute myeloid leukemia. The trial showed that subcutaneous rituximab did not improve the complete remission rate at the conclusion of the induction phase, which was the main endpoint. Nevertheless, SC maintenance might have facilitated long-term disease control, potentially contributing to enhanced event-free and progression-free survival.
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