Voriconazole plus flucytosine is not superior to amphotericin B deoxycholate plus flucytosine as an induction regimen for cryptococcal meningitis treatment.

BACKGROUND: The efficacy and side effects of voriconazole plus 5-flucytosine (Vori + 5-FC) versus amphotericin B deoxycholate plus 5-flucytosine (AmBd + 5-FC) as an induction treatment for cryptococcal meningitis are unknown. METHODS: Forty-seven patients treated with Vori + 5-FC and 92 patients treated with AmBd + 5-FC were included in the current study after propensity score matching (PSM) at a ratio of 1:2. Two-week laboratory test results and 90-day mortality were compared between the two groups. RESULTS: After 2 weeks of induction treatment, the CSF Cryptococcus sterile culture rate was 57.1% in the Vori + 5-FC group and 76.5% in the AmBd + 5-FC group (p = .026). No difference was found in the normalization of CSF indicators (glucose, total protein, intracranial pressure and India ink sterile rate) between the two groups. Both the Vori + 5FC regimen and AmBd + 5-FC regimen obviously decreased haemoglobin concentrations, platelet counts and serum potassium levels (all p ≤ .010). Notably, the Vori + 5FC regimen did not influence serum creatinine levels (p = .263), while AmBd + 5FC increased serum creatinine levels (p = .019) after 2-week induction treatment. The Vori + 5-FC group and AmBd + 5-FC group had similar 90-day cumulative survival rates (89.9% vs. 87.8%, p = .926). CONCLUSION: The Vori + 5-FC regimen was associated with low 2-week CSF sterile culture and was not superior to AmBd + 5-FC as induction therapy in terms of the 90-day cumulative survival rate of CM patients.

Immunogenicity and safety of COVID-19 vaccines among people living with HIV: A systematic review and meta-analysis.

Available data suggest that the immunogenicity of COVID-19 vaccines might decrease in the immunocompromised population, but data on vaccine immunogenicity and safety among people living with HIV (PLWH) are still lacking. The purpose of this meta-analysis is to compare the immunogenicity and safety of COVID-19 vaccines in PLWH with healthy controls. We comprehensively searched the following databases: PubMed, Cochrane Library, and EMBASE. The risk ratio (RR) of seroconversion after the first and second doses of a COVID-19 vaccine was separately pooled using random-effects meta-analysis. Seroconversion rate was lower among PLWH compared with healthy individuals after the first (RR = 0.77, 95% confident interval (CI) 0.64-0.92) and second doses (RR = 0.97, 95%CI 0.95-0.99). The risk of total adverse reactions among PLWH is similar to the risk in the healthy group, after the first (RR = 0.87, 95%CI 0.70-1.10) and second (RR = 0.83, 95%CI 0.65-1.07) doses. This study demonstrates that the immunogenicity and safety of SARS-CoV-2 vaccine in fully vaccinated HIV-infected patients were generally satisfactory. A second dose was related to seroconversion enhancement. Therefore, we considered that a booster dose may provide better seroprotection for PLWH. On the basis of a conventional two-dose regimen for COVID-19 vaccines, the booster dose is very necessary.

The central nervous system is a potential reservoir and possible origin of drug resistance in hepatitis B infection.

Background: The significance of hepatitis B virus (HBV) in cerebrospinal fluid (CSF) is unclear. Methods: Synchronous serum and CSF samples were collected from 13 patients. HBV DNA, full-length genome, quasispecies, phylogenetic tree, compartmentalization and mutation of the reverse transcriptase (RT) region were performed based on PCR and sequencing methods. Results: HBV DNA was detected in the CSF of 3 antiviral-naïve individuals and 1 individual after successful antiviral therapy. Complete full-length HBV genomes were isolated from the CSF of 5 individuals, including 2 with undetectable serum HBV DNA. Ten individuals exhibited distinct CSF-serum quasispecies, 8 harbored independent CSF-serum genetic compartmentalization and phylogenetic trees, and 5 lamivudine/entecavir-associated resistance mutations only in the CSF. The frequencies of rtL180M and rtM204I/V mutations in both serum and CSF were higher in HIV-HBV-coinfected individuals than in the HBV-monoinfected ones (serum: rtL180M: 3.9% vs. 0, P = 0.004; rtM204I/V: 21.3% vs. 0, P < 0.001; CSF: rtL180M: 7.6% vs. 0, P = 0.026; rtM204I/V 7.6% vs. 1.6%, P = 0.097). Conclusion: CSF is a potential HBV reservoir, and HBV in CSF harbors distinct evolution and mutation characteristics from those in serum. HIV infection increases the possibility of HBV rtL180M and rtM204I/V mutations in both serum and CSF.

Factors Affecting the Prognosis of Patients with Acute Cerebrovascular Occlusion with High National Institutes of Health Stroke Scale Scores Treated with SWIM Technology.

Objective: We aimed to explore the factors affecting the prognosis of patients with acute cerebrovascular occlusion with high National Institutes of Health Stroke Scale (NIHSS) scores treated with the SWIM (Solitaire™ stent retriever-assisted thrombectomy with immediate mechanical aspiration) technique using an intracranial support catheter. Methods: A retrospective analysis was conducted in 72 patients with acute cerebrovascular occlusion who underwent SWIM surgery in the Affiliated Hospital of Chengde Medical University in China between January 2020 and June 2022. The patients were divided into a good prognosis group (Modified Rankin Score [mRS] 0 to 2; n = 30) and a poor prognosis group (mRS score 3 to 6; n = 42) on their mRS scores 3 months after surgery. The THRIVE (TICI, hemorrhage, reocclusion, infarction, vessel, and embolism) score at different time points before and after the SWIM procedure and the postoperative revascularization rate were compared in the 2 NIHSS score groups. Univariate and logistic regression analyses were performed to identify the risk factors that affected the prognosis of patients with acute cerebrovascular occlusion treated with the SWIM procedure. Results: The NIHSS score difference at various time points after SWIM surgery in patients with low to moderate NIHSS scores was significantly higher than in patients with high NIHSS scores (P < .05). The postoperative revascularization rate in patients with high NIHSS scores was 74.36%, which was not significantly different from that in patients with low to moderate scores (84.85%; P > .05). The poor prognosis in patients with acute cerebrovascular occlusion after SWIM surgery was related to age, hypertension, NIHSS score, Glasgow Coma Scale (GCS) score, Essen Stroke Risk Score (ESRS), onset-to-treatment time (OTT) and Alberta Collateral Grading Scale (ACGS) score (P < .05). Logistic regression analysis showed that age, admission NIHSS score and ACGS score were independent risk factors that affected the prognosis in patients with acute cerebrovascular occlusion treated with the SWIM procedure (P < .05). Conclusion: The prognosis in patients with acute cerebrovascular occlusion with high NIHSS scores after SWIM surgery was poor. Advanced age, high NIHSS score and ACGS score were independent risk factors that affected the prognosis in patients with acute cerebrovascular occlusion treated with the SWIM procedure. Overall, incorporating these findings into clinical practice promotes personalized approaches, interdisciplinary collaboration and timely interventions to optimize outcomes in patients undergoing the SWIM procedure for acute cerebrovascular occlusion.

Research progress of biomarkers in the prediction of anti-PD-1/PD-L1 immunotherapeutic efficiency in lung cancer.

Currently, anti-PD-1/PD-L1 immunotherapy using immune checkpoint inhibitors is widely used in the treatment of multiple cancer types including lung cancer, which is a leading cause of cancer death in the world. However, only a limited proportion of lung cancer patients will benefit from anti-PD-1/PD-L1 therapy. Therefore, it is of importance to predict the response to immunotherapy for the precision treatment of patients. Although the expression of PD-L1 and tumor mutation burden (TMB) are commonly used to predict the clinical response of anti-PD-1/PD-L1 therapy, other factors such as tumor-specific genes, dMMR/MSI, and gut microbiome are also promising predictors for immunotherapy in lung cancer. Furthermore, invasive peripheral blood biomarkers including blood DNA-related biomarkers (e.g., ctDNA and bTMB), blood cell-related biomarkers (e.g., immune cells and TCR), and other blood-related biomarkers (e.g., soluble PD-L1 and cytokines) were utilized to predict the immunotherapeutic response. In this review, the current achievements of anti-PD-1/PD-L1 therapy and the potential biomarkers for the prediction of anti-PD-1/PD-L1 immunotherapy in lung cancer treatment were summarized and discussed.

A novel U-shaped relationship between mitochondrial mass and risk of incomplete immune reconstitution in HIV-infected patients on antiviral therapy.

Mitochondrial mass (MM) is considered an essential parameter of the immune system, but the association of MM with incomplete immune reconstitution (IIR) in people living with HIV (PLWH) remains unclear. Here, we tested 2148 blood samples from 1999 PLWH by flow cytometry in China between August 2021 and February 2022. A novel U-shaped relationship, determined by multivariable smooth curve fitting and piecewise-linear mixed-effect model, was observed between the ratio of MM to SD (MM/SD) and IIR, with a threshold cutoff of 2.8. For MM/SD <2.8, per SD increment of MM was independently associated with 30%, 30%, 20%, and 20% decreased risk of CD4+ T-cell counts <500 cells/µL after 4 years of treatment and CD4+ T-cell counts <350 cells/µL after 4, 5, 6 years of treatment, respectively. Our study suggested that increasing MM may indicate the low risk of IIR for PLWH with MM/SD <2.8.

Metagenomic Next-Generation Sequencing for the Diagnosis of Suspected Opportunistic Infections in People Living with HIV.

Objective: The diagnosis of suspected opportunistic infections in HIV patients is challenging due to the wide range of potential causes. This study used mNGS to analyse specimens of suspected opportunistic infections in HIV patients from a single centre to explore this method's applicability as a diagnostic tool compared to that of CMTs. Methods: We retrospectively investigated 46 suspected opportunistic infections in people living with HIV(PLWH) Hospitalized at Hangzhou Xixi hospital from January 2020 to August 2021. In total, we collected 49 samples (3 patients provided 2 samples) and sent them out for mNGS. Results: mNGS had a better detection rate for fungi and nontuberculous mycobacteria than that of CMTs. Specifically, the diagnostic detection rate of fungi (11 vs 19, P<0.05) and nontuberculous mycobacteria (1 vs 6, p<0.05) was significantly higher; there was no difference in detection rate for other pathogens (bacteria, Mycobacterium tuberculosis, or viruses). The sensitivity of mNGS was 90.91%, 50%, 0%, 100%, and 100% for detecting fungi, bacteria, Mycobacterium tuberculosis, nontuberculous mycobacteria, and viruses, respectively; the corresponding specificities were 74.29%, 97.73%, 86.36%, 86.67%, and 91.11%. Conclusion: mNGS technology provides an alternative and promising method of identifying suspected opportunistic infections in PLWH. Thus, the best diagnosis strategy may be using a combination of mNGS and CMTs.

Comparing Noninvasive Predictors of Neurosyphilis Among Syphilis Patients With and Without HIV Co-Infection Based on the Real-World Diagnostic Criteria: A Single-Center, Retrospective Cohort Study in China.

Diagnosis of neurosyphilis is currently based on the cerebrospinal fluid (CSF) assessments and CSF-Venereal Disease Research Laboratory (CSF-VDRL) is the traditional "gold standard." In the real world, CSF assessments and CSF-VDRL are not always available. This study aimed to identify noninvasive predictors of neurosyphilis based on real-world clinical parameters and diagnostic criteria in populations with different HIV status. In this retrospective cohort study, syphilis patients with different HIV statuses hospitalized for neurosyphilis screening were retrospectively recruited at an infectious disease hospital. Neurosyphilis was defined by real-world diagnostic criteria. Logistic regression and receiver operating characteristic curve analysis were used to investigate and evaluate predictors of neurosyphilis. In total, 528 patients were enrolled, including 143 syphilis patients without HIV infection and 385 HIV/syphilis-co-infected patients. One hundred twelve and 304 neurosyphilis patients were identified in the HIV-negative and HIV-positive groups, respectively. A high serum toluidine red unheated serum test (TRUST) titer was a robust predictor of neurosyphilis in all participants. An age ≥50 years old [adjusted odds ratio (aOR) = 5.062, 95% confidence interval (CI), 1.449-17.680] in the HIV-negative group and CD4+ T cell count <330/µL (<300 as reference, aOR = 0.552, 95% CI, 0.315-0.966) in the HIV-positive group were predictors of asymptomatic neurosyphilis. In real-world situations, for asymptomatic syphilis patients, relatively old age and a high serum TRUST titer in HIV-negative populations, and CD4+ T cells <330/µL and/or serum TRUST titer >1:64 in HIV-positive populations might predict neurosyphilis.

Epigenetic regulation in premature ovarian failure: A literature review.

Premature ovarian failure (POF), or premature ovarian insufficiency (POI), is a multifactorial and heterogeneous disease characterized by amenorrhea, decreased estrogen levels and increased female gonadotropin levels. The incidence of POF is increasing annually, and POF has become one of the main causes of infertility in women of childbearing age. The etiology and pathogenesis of POF are complex and have not yet been clearly elucidated. In addition to genetic factors, an increasing number of studies have revealed that epigenetic changes play an important role in the occurrence and development of POF. However, we found that very few papers have summarized epigenetic variations in POF, and a systematic analysis of this topic is therefore necessary. In this article, by reviewing and analyzing the most relevant literature in this research field, we expound on the relationship between DNA methylation, histone modification and non-coding RNA expression and the development of POF. We also analyzed how environmental factors affect POF through epigenetic modulation. Additionally, we discuss potential epigenetic biomarkers and epigenetic treatment targets for POF. We anticipate that our paper may provide new therapeutic clues for improving ovarian function and maintaining fertility in POF patients.

Research Progress on the Treatment of Premature Ovarian Failure Using Mesenchymal Stem Cells: A Literature Review.

Premature ovarian failure (POF) has become one of the main causes of infertility in women of childbearing age and the incidence of POF is increasing year by year, seriously affecting the physical and mental health of patients and increasing the economic burden on families and society as a whole. The etiology and pathogenesis of POF are complex and not very clear at present. Currently, hormone replacement therapy is mainly used to improve the symptoms of low estrogen, but cannot fundamentally solve the fertility problem. In recent years, stem cell (SC) transplantation has become one of the research hotspots in the treatment of POF. The results from animal experiments bring hope for the recovery of ovarian function and fertility in patients with POF. In this article, we searched the published literature between 2000 and 2020 from the PubMed database (https://pubmed.ncbi.nlm.nih.gov), and summarized the preclinical research data and possible therapeutic mechanism of mesenchymal stem cells (MSCs) in the treatment of POF. Our aim is to provide useful information for understanding POF and reference for follow-up research and treatment of POF.

Differences in cytokine and chemokine profiles in cerebrospinal fluid caused by the etiology of cryptococcal meningitis and tuberculous meningitis in HIV patients.

The roles of cytokines and chemokines in HIV-associated cryptococcal meningitis (HCM) and HIV-associated tuberculous meningitis (HTBM) are debatable. In sum, 34 HIV-infected patients without meningitis, 44 HCM patients and 27 HTBM patients were enrolled for study. The concentrations of 22 cytokines/chemokines in cerebrospinal fluid (CSF) were assayed at admission. Principal component analysis (PCA), Pearson's and logistic regression analyses were used to assess the role of cytokines/chemokines in HCM and HTBM. We found the levels of T helper (Th)17, Th1 [interleukin (IL)-12p40, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and TNF-ß and Th2 (IL-2/4/5/6/10)] cytokines were elevated in patients with meningitis compared with those in HIV-infected patients without central nervous system (CNS) infection. Furthermore, the IL-1Ra, IL-12p40, IL-17α and monocyte chemotactic protein-1 (MCP-1) levels were higher in HCM patients, while the IFN-γ, regulated upon activation, normal T cell expressed and secreted (RANTES) and interferon-inducible protein-10 (IP)-10 levels were higher in HTBM patients. Elevated CSF concentrations of IL-17a, TNF-ß, IL-5, IL-12p40 and IL-1Rα were closely related to meningitis, but elevated IP-10, MCP-1, RANTES and IFN-γ levels and CSF white blood cells (WBCs) were protective factors against HCM. Our study suggested that HIV-infected patients with low CSF WBCs have a high risk of HCM. Th1, Th2 and Th17 cytokines/chemokines mediate differences in the pathogenesis of HCM and TBM. Overexpressed proinflammatory MCP-1, RANTES, IFN-γ and IP-10 in CSF are protective factors against HCM but not HTBM.

Clinical features and Outcomes of Cryptococcemia patients with and without HIV infection.

BACKGROUND: The effects of cryptococcemia on patient outcomes in those with or without HIV remain unclear. METHODS: One hundred and seventy-nine cryptococcemia patients were enrolled in this retrospective study. Demographic characteristics, blood test results and outcome were compared between the two groups. RESULTS: The diagnosis time of Cryptococcus infection was 2.0(0-6.0) days for HIV-infected patients, 5.0 (1.5-8.0) days for HIV-uninfected patients (p = .008), 2.0 (1.0-6.0) days for cryptococcal meningitis (CM) patients and 6.0 (5.0-8.0) days for non-CM patients (p < .001). HIV infection [adjusted odds ratio (AOR) (95% confidence interval): 6.0(2.3-15.9)], CRP < 15 mg/L [AOR:3.7(1.7-8.1)) and haemoglobin > 110 g/L [AOR:2.5(1.2-5.4)] were risk factors for CM development. Forty-six (25.7%) patients died within 90 days. ICU stay [AOR:2.8(1.1-7.1)], hypoalbuminemia [AOR:2.7(1.4-5.3)], no anti-cryptococcal treatment [AOR:4.7(1.9-11.7)] and altered consciousness [AOR:2.4(1.0-5.5)] were independent risk factors for 90-day mortality in all patients. HIV infection did not increase the 90-day mortality of cryptococcemia patients when anti-Cryptococcus treatment was available. Non-Amphotericin B treatment [AOR:3.4(1.0-11.2)] was associated with 90-day mortality in HIV-infected patients, but age ≥ 50.0 years old [AOR:2.7(1.0-2.9)], predisposing disease [AOR:4.1(1.2-14.2)] and altered consciousness [AOR:3.7(1.1-12.9)] were associated with 90-day mortality in HIV-uninfected patients who accepted anti-Cryptococcus treatment. CONCLUSION: HIV infection increased the incidence of CM rather than mortality in cryptococcemia patients. The predictive model was completely divergent in HIV-infected and HIV-uninfected patients, suggesting that novel strategies for diagnosis and treatment algorithms are urgently needed.

hsa-miR-191-5p inhibits replication of human immunodeficiency virus type 1 by downregulating the expression of NUP50.

MicroRNAs (miRNAs) are important host molecules involved in human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral therapy (ART) can affect the miRNA expression profile, but differentially expressed miRNAs still remain to be identified. In this study, we used gene chips to analyze miRNA expression profiles in peripheral blood mononuclear cells from ART-naive HIV-1 patients and those receiving ART, as well as from uninfected individuals. We measured differences in miRNA expression by quantitative polymerase chain reaction (qPCR) in an expanded sample. We found significant differences in the expression of has-miR-191-5p among the three groups (P < 0.05). Furthermore, we showed that hsa-miR-191-5p has an inhibitory effect on HIV-1 replication in cell models in vitro. We identified CCR1 and NUP50 as target molecules of hsa-miR-191-5p and found that hsa-miR-191-5p inhibits the expression of CCR1 and NUP50. Knockdown of NUP50 resulted in significant inhibition of HIV-1 replication. In summary, our research shows that hsa-miR-191-5p expression is reduced in HIV-1-infected patients and acts an inhibitor of HIV-1 infection via a mechanism that may involve targeted repression of NUP50 expression.

HIV Infection Does Not Increase 10-Week Mortality of Chinese Cryptococcal Meningitis Patients.

The role of HIV infection in precipitating different clinical features in cryptococcal meningitis (CM) patients remains controversial. One hundred twelve CM patients living with HIV/AIDS (CM+HIV+ patients) and 112 CM patients living without HIV/AIDS (CM+HIV- patients) were enrolled after propensity score matching. Demographic characteristics, symptoms, routine blood tests, and biochemical and cerebrospinal fluid (CSF) profiles were compared between the two groups. Kaplan-Meier analysis and Cox proportional hazards model was used to assess 10-week mortality. CM+HIV+ patients frequently occurred in young (mean age 40.3 ± 10.5) and male (89.3%) populations who also experienced leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, and hypoalbuminemia, less headaches (66.9%), and higher cryptococcemia (23.2%) (all p < .050); they also had higher glucose (2.6 ± 1.1 mmol/L), increased smear positivity (78.8%), and decreased white blood cells [8.0 (2.0-28.0) × 106/L] in initial CSF assay (all p < .050). The 10-week cumulative survival rate was 84.6% for CM+HIV+ patients and 88.5% for CM+HIV- patients (p = .345). Age <35.0 years (hazard ratio (HR) 3.0 (1.0-8.9), p = .046), intracranial pressure (ICP) >250.0 mmH2O (HR: 4.8 (1.1-21.6), p = .041), and treatment lacking amphotericin B [HR: 6.5 (1.9-21.4), p = .003] were independent risk factors for 10-week mortality in CM+HIV+ patients. There are significant clinical differences in CM patients living with or without HIV/AIDS. However, the 10-week survival rate was similar between the two groups. Younger population, high ICP, and treatment lacking amphotericin B were independent risk factors for 10-week mortality of Chinese CM+HIV+ patients.

The Prediction of Survival in Hepatocellular Carcinoma Based on A Four Long Non-coding RNAs Expression Signature.

Prognostic stratification in hepatocellular carcinoma (HCC) patients is still challenging. Long non-coding RNAs (lncRNAs) have been proven to play a crucial role in tumorigenesis and progression of cancers. The aim of this study is to develop a useful prognostic index based on lncRNA signature to identify patients at high risk of disease progression. We obtained lncRNA expression profiles from three publicly available datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). By the risk scoring method, we built an individualized four-lncRNA signature (HCCLnc-4) to predict survival of HCC patients in the discovery set (ROC curve, AUC: 0.83, 95% CI: 0.65-1.00, P < 0.05, Kaplan-Meier analysis and log-rank test, P < 0.01). Similar prognostic value of HCCLnc-4 has been further verified in two other independent sets. Stratified analysis and multivariate Cox regression analysis suggested the independence of HCCLnc-4 for prediction of HCC patient survival from traditional clinicopathological factors. Area under curve (AUC) analysis suggested that HCCLnc-4 could compete sufficiently with, or might be even better than classical pathological staging systems to predict HCC patient prognosis in the same data sets. Functional analysis and network analysis suggested the potential implication of lncRNA biomarkers. Our study developed and validated the lncRNA prognostic index of HCC patients, warranting further clinical evaluation and preventive interventions.

Longitudinal Progression of Estimated GFR in HIV-1-Infected Patients with Normal Renal Function on Tenofovir-Based Therapy in China.

PURPOSE: Estimated glomerular filtration rate (eGFR) decline in HIV-1-infected patients exposure to tenofovir disoproxil fumarate (TDF) has been widely assessed using linear models, but nonlinear assumption is not well validated. We constructed a retrospective cohort study to assess whether eGFR decline follows nonlinearity during antiviral therapy. PATIENTS AND METHODS: We examined 823 (299 of TDF users and 524 of non-TDF users) treatment-naïve HIV-1-infected participants (age ≥ 17 years, initial eGFR ≥ 90 mL/min/1.73m2). Estimated GFR trajectories were compared by one-linear and piecewise-linear mixed effects models, before and after propensity score matching, respectively. Whether the incidence of renal dysfunction (reduced renal function [RRF], eGFR < 90 mL/min/1.73 m2 and rapid kidney function decline [RKFD], eGFR > -3 mL/min/1.73 m2/year) follows nonlinearity was assessed by logistic regression. RESULTS: The median follow-up time of this study was 10 (interquartile range, 2-20) months, during which 178 (21.6%) experienced RRF, and 451 (54.8%) experienced RKFD. The slopes (mL/min/1.73 m2/year) of eGFR were -5.31 (95% CI: -6.57, -4.06) before 1.40 years, 4.83 (95% CI: 1.38, 8.28) from years 1.40 to 2.30 and -3.71 (95% CI: -5.97, -1.45) after 2.30 years among TDF users. Within years 1.40-2.30, each year of TDF exposure was associated with a 78% decreased risk of RKFD (95% CI: -91%, -49%). In comparison, eGFR increased slightly at the initiation of antiviral therapy, declined after 2.15 years (-4.96; 95% CI: -5.76, -4.17) among non-TDF users. Such a progression nonlinear trajectory was missed on the assumption of one-linearity, whether in TDF or non-TDF users. CONCLUSION: Over the piecewise mixed-effects analyses with the advantage of revealing the true nature of the exposure outcome relationships, an interesting reverse S-shaped relationship was observed. A routine screen based on nonlinearity could be more helpful for patient management.

Prognostic potential of PRPF3 in hepatocellular carcinoma.

pre-mRNA processing factor 3 (PRPF3) is an RNA binding protein in a core component of the exon junction complex. Abnormal PRPF3 expression is potentially associated with carcinogenesis. However, the biological role of PRPF3 in hepatocellular carcinoma (HCC) remains to be determined. We analyzed PRPF3 expression via multiple gene expression databases and identified its genetic alterations and functional networks using cBioPortal. Co-expressed genes with PRPF3 and its regulators were identified using LinkedOmics. The correlations between PRPF3 and cancer immune infiltrates were investigated via Tumor Immune Estimation Resource (TIMER). PRPF3 was found up-regulated with amplification in tumor tissues in multiple HCC cohorts. High PRPF3 expression was associated with poorer overall survival (OS) and disease-free survival (DFS). Functional network analysis suggested that PRPF3 regulates spliceosome, DNA replication, and cell cycle signaling via pathways involving several cancer-related kinases and E2F family. Notably, PRPF3 expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells. PRPF3 expression showed strong correlations with diverse immune marker sets in HCC. These findings suggest that PRPF3 is correlated with prognosis and immune infiltrating in HCC, laying a foundation for further study of the immune regulatory role of PRPF3 in HCC.

Increased expression of BCL11B and its recruited chromatin remodeling factors during highly active antiretroviral therapy synergistically represses the transcription of human immunodeficiency virus type 1 and is associated with residual immune activation.

Persistence of human immunodeficiency virus 1 (HIV-1) latency and residual immune activation remain major barriers to treatment in patients receiving highly active antiretroviral therapy (HAART). In the present study, we investigated the molecular mechanisms of persistent HIV infection and residual immune activation in HAART-treated patients. We showed that the expression level of B-cell CLL/lymphoma 11B (BCL11B) was significantly increased in CD4+T cells from HIV-infected patients undergoing HAART, and this was accompanied by increased expression of BCL11B-associated chromatin modifiers and inflammatory factors in comparison to healthy controls and untreated patients with HIV. In vitro assays showed that BCL11B significantly inhibited HIV-1 long terminal repeat (LTR)-mediated transcription. Knockdown of BCL11B resulted in the activation of HIV latent cells, and dissociation of BCL11B and its related chromatin remodeling factors from the HIV LTR. Our findings suggested that increased expression of BCL11B and its related chromatin modifiers contribute to HIV-1 transcriptional silencing, and alteration of BCL11B levels might lead to abnormal transcription and inflammation.

Retinoblastoma binding protein 4 represses HIV-1 long terminal repeat-mediated transcription by recruiting NR2F1 and histone deacetylase.

Human immunodeficiency virus (HIV) transcription is closely associated with chromatin remodeling. Retinoblastoma binding protein 4 (RBBP4) is a histone chaperone implicated in chromatin remodeling. However, the role of RBBP4 in HIV-1 infection and the underlying mechanism remain elusive. In the present study, we showed that RBBP4 plays a negative regulatory role during HIV-1 infection. RBBP4 expression was significantly increased in HIV-1-infected T cells. RBBP4 binds to the HIV-1 long terminal repeat (LTR)， represses HIV-1 LTR-mediated transcription through recruiting nuclear receptor subfamily 2 group F member 1(NR2F1) and histone deacetylase 1 and 2 (HDAC1/2) to HIV-1 LTR, and further controls local histone 3 (H3) deacetylation and chromatin compaction. Furthermore, the occupancy of RBBP4, HDAC1/2, and NR2F1 on LTR in HIV-latent J-lat cells was significantly higher than that in HIV-1-activated cells. In conclusion, our results establish RBBP4 as a new potent antiretroviral factor, which may provide theoretical basis for the treatment of HIV in the future.

The association between nonalcoholic fatty liver disease and risk of colorectal adenoma and cancer incident and recurrence: a meta-analysis of observational studies.

BACKGROUND & AIM: Lifestyle modification plays a key role in nonalcoholic fatty liver disease (NAFLD) and colorectal adenoma and/or cancer (CRA/CRC) development. However, the association between NAFLD and the risk of CRA/CRC has not been carefully evaluated. METHODS: In this meta-analysis, we assessed 21 eligible studies including 124,206 participants to determine the association between NAFLD and the risk of incident and recurrent CRA/CRC. RESULTS: NAFLD presence was associated with an increased risk of any incident CRA (aOR: 1.30, 95% CI: 1.19-1.43) and advanced incident CRA/CRC (aOR: 1.57, 95% CI: 1.21-2.04). The severity of NAFLD affected this correlation: compared to mild and/or moderate NAFLD, severe NAFLD was associated with an increased risk of incident CRA/CRC (aOR: 2.19, 95% CI: 1.33-3.60). Although pooled cOR revealed that NAFLD was associated with an increased risk of recurrent CRA/CRC (cOR = 1.73; 95% CI: 1.12-2.68), after adjustment for confounding factors, NAFLD had less correlation with the risk of recurrent CRA/CRC (aOR: 1.81, 95% CI: 0.70-4.65). CONCLUSIONS: The presence and severity of NAFLD are associated with an increased risk of incident CRA/CRC. However, there is insufficient evidence to indicate that NAFLD is associated with an increased risk of recurrent CRA/CRC.