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Stimulator of interferon genes (STING) has recently been found to play a crucial role in cardiac sterile inflammation and dysfunction. The role of stimulator of interferon genes (STING) in cardiac sterile inflammation and dysfunction has been recently discovered. This study aims to examine the involvement of STING in pathological cardiac remodeling and the mechanisms that govern the activation of the STING pathway. To investigate this, transverse aortic constriction (TAC) was performed on STING knockout mice to induce pressure overload-induced cardiac remodeling. Subsequently, cardiac function, remodeling, and inflammation levels were evaluated. The STING pathway was found to be activated in the pressure overload-stressed heart and angiotensin II (Ang II)-stimulated cardiac fibroblasts. Loss of STING expression led to a significant reduction in inflammatory responses, mitochondrial fragmentation, and oxidative stress in the heart, resulting in attenuated cardiac remodeling and dysfunction. Furthermore, the exacerbation of pressure overload-induced STING-mediated inflammation and pathological cardiac remodeling was observed when mitophagy was suppressed through the silencing of Parkin, an E3 ubiquitin ligase. Taken together, these findings indicate that STING represents a newly identified and significant molecule implicated in the process of pathological cardiac remodeling and that mitophagy is an upstream mechanism that regulates STING activation. Targeting STING may therefore provide a novel therapeutic strategy for pathological cardiac remodeling and heart failure.

Abstract Introduction Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) has been increasingly replaced by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in the treatment of human immunodeficiency virus (HIV) owing to its more favorable pharmacokinetics and fewer drug–drug interactions. However, the effect of this switch on plasma lipids and lipidomic profiles remains poorly characterized. Methods HIV infected patients on an E/C/F/TAF regimen were recruited into the study and followed up every 12 weeks. Participants were divided into E/C/F/TAF and B/F/TAF groups depending on whether they were switched to B/F/TAF during follow-up. Clinical information and blood samples were collected at 0, 12, and 24 weeks, and lipidomic analysis was performed using liquid chromatography mass spectrometry. Results No significant differences were observed between the groups at baseline. At week 24, patients switched to B/F/TAF had lower triglyceride [mmol/L; 1.23 (0.62) versus 2.03 (0.75), P = 0.001] and very low-density lipoprotein cholesterol [mmol/L; 0.64 (0.26) versus 0.84 (0.32), P = 0.037) compared with patients who continued E/C/F/TAF therapy. Small decrease from baseline in Framingham general cardiovascular risk score (FRS) was observed in the B/F/TAF arm [week (W) 0: 2.59 (1.57) versus W24: 2.18 (1.01), P = 0.043]. Lipidomic analysis indicated that E/C/F/TAF treatment increased the levels of several diglycerides (DGs), triacylglycerols (TAGs), and lyso-phosphatidylcholines (LPCs), whereas switching to B/F/TAF led to increased sphingolipids and glycerophospholipids. After adjusting for demographic and clinical parameters, only DG (16:0/18:2), DG (18:2/22:6), DG (18:3/18:2), DG (20:5/18:2), TAG (18:3/18:2/21:5), TAG (20:5/18:2/22:6), and LPC (22:6) were found to be significantly associated with FRS (regression coefficient of 0.17–6.02, P

Abstract Background We have reported a positive correlation between S100 calcium-binding protein (S100) A8/S100A9 and sepsis-induced lung damage before. However, limited knowledge exists concerning the biological role of S100A8/A9 in pulmonary vascular endothelial barrier dysfunction, as well as the diagnostic value of S100A8/A9 in sepsis. Methods Sepsis was induced in C57BL/6J mice and S100A9-knockout (KO) mice through the cecal ligation and puncture (CLP). Pulmonary vascular leakage was determined by measuring extravasated Evans blue (EB). Reverse transcription polymerase chain reaction and the histological score were used to evaluate inflammation and lung injury, respectively. Recombinant S100A8/A9 (rhS100A8/A9) was used to identify the effects of S100A8/A9 on endothelial barrier dysfunction in human umbilical vein endothelial cells (HUVECs). Additionally, the diagnostic value of S100A8/A9 in sepsis was assessed using receiver operating characteristic. Results S100A8/A9 expression was up-regulated in the lungs of CLP-operated mice. S100A9 KO significantly reversed CLP-induced hypothermia and hypotension, resulting in an improved survival rate. S100A9 KO also decreased the inflammatory response, EB leakage, and histological scores in the lungs of CLP-operated mice. Occludin and VE-cadherin expressions were decreased in the lungs of CLP-operated mice; However, S100A9 KO attenuated this decrease. Moreover, CLP-induced signal transducer and activator of transcription 3 (STAT3) and p38/extracellular signal-regulated kinase (ERK) signalling activation and apoptosis were mitigated by S100A9 KO in lungs. In addition, rhS100A8/A9 administration significantly decreased occludin and VE-cadherin expressions, increased the phosphorylated (p)-ERK/ERK, p-p38/p38, and B-cell leukaemia/lymphoma 2 protein (Bcl-2)-associated X protein/Bcl-2 ratios in HUVECs. Conclusion The present study demonstrated S100A8/A9 aggravated sepsis-induced pulmonary inflammation, vascular permeability, and lung injury. This was achieved, at least partially, by activating the P38/STAT3/ERK signalling pathways. Moreover, S100A8/A9 showed the potential as a biomarker for sepsis diagnosis.

Abstract Background Patients infected with HIV are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. The genotype and viral biological behavior of EBV infection in patients with human immunodeficiency virus-1 (HIV) in China remain unclear. This study analyzed the characteristics of EBV in patients infected with HIV in southeastern China. Methods A total of 162 HIV-infected patients and 52 patients without HIV were enrolled in this study. EBV viral load in blood was determined by fluorescence quantitative PCR. EBV typing was performed using saliva according to polymorphisms in the EBNA3C region. EBV LMP-1 carboxy terminus (C-ter) was sequenced, and compared with the epidemic strains in the world. Results Among HIV infected patients, the EBV strain variant was mainly EBV-1, while EBV-2 had a higher viral load than EBV-1 (P = 0.001) and EBV-1/2 (P = 0.002). HIV infected patients had higher active virus replication. The EBV LMP-1 variants were mainly the China1 variant. HIV-infected patients had different nucleic acid positions of 30-bp deletion (del30) and had a higher incidence of high 33-bp tandem repeats (rep33) copies than non-HIV-infected patients. There was a difference in the mutations of EBV LMP-1 C-ter del30 and ins15 between HIV infected patients and the control group (P

Optical microcavities offer a promising platform for highly efficient light–matter interactions. Recently, the combination of microresonators and 2D materials in nanoscale has further enriched the optoelectronics of the microcavity geometries, spurring broad advances ranging from lasers, nonlinear converters, modulators to sensors. Here, we report the concept of a Brillouin laser sensor, by depositing graphene on an over-modal microsphere. Driven by a single continuous-wave pump at 1550 nm, multiple Brillouin lasers from distinct mode families are co-generated in a single device. The Brillouin lasers excited in the high Q cavity produce heterodyne beating notes with phase noise down to −161 dBc/Hz at 1 MHz offset, not only enabling label-freely identifiable detection of multispecies gas molecules adsorbed on the graphene in situ but also rendering it possible to trace individual molecules. Such a combination of graphene optoelectronics and Brillouin lasers in microcavities demonstrates a novel physical paradigm and offers insights into powerful tools for fast and precise optical sensing.

Abstract Background Patients with human immunodeficiency virus-associated cryptococcal meningitis (HIV-CM) have persistent intracranial inflammation despite negative cerebrospinal fluid (CSF) fungal cultures after optimal treatment for CM, which could be devastating for the central nervous system. However, a definitive treatment strategy for persistent intracranial inflammation despite optimal antifungal therapies is undefined. Methods We identified 14 HIV-CM patients with persistent intracranial inflammation and conducted a 24-week, prospective, interventional study. All participants received lenalidomide (25 mg, p.o.) on days 1 to 21 of a 28-day cycle. Follow-up lasted for 24 weeks with visits at baseline and weeks 4, 8, 12, and 24. The primary endpoint was the change in clinical manifestations, routine CSF parameters, and MRI findings after lenalidomide treatment. An exploratory analysis was made on changes in cytokine levels in CSF. Safety and efficacy analyses were undertaken in patients who received at least one dose of lenalidomide. Results Of 14 participants, 11 patients completed the 24 weeks of follow-up. Rapid clinical remission following lenalidomide therapy was observed. Clinical manifestations (fever, headache, altered mentation) were reversed fully by week-4 and remained stable during follow-up. A significant reduction in white blood cell (WBC) count in CSF was noted occurred at week-4 (P = 0.009). The median protein concentration in CSF decreased from 1.4 (0.7–3.2) g/L at baseline to 0.9 (0.6–1.4) at week-4 (P = 0.004). The median albumin concentration in CSF decreased from 79.2 (48.4–149.8) mg/L at baseline to 55.3 (38.3–89.0) mg/L at week-4 (P = 0.011). The WBC count, protein level, and albumin level in CSF remained stable and approached a normal range through week-24. There was no significant change in immunoglobulin-G, intracranial pressure (ICP), or chloride-ion concentration at each visit. Brain MRI demonstrated multiple lesions to be absorbed post-therapy. Levels of tumor necrosis factor-α granulocyte colony stimulating factor, interleukin (IL)-6, and IL-17A decreased significantly during 24-week follow-up. Two (14.3%) patients had mild skin rash, which resolved spontaneously. Lenalidomide-related serious adverse events were not observed. Conclusion Lenalidomide could improve persistent intracranial inflammation in HIV-CM patients significantly and was well tolerated without serious adverse events observed. And the additional randomized controlled study is required to further validate the finding.

Introduction: Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, the pathophysiological basis of HFpEF remains poorly understood. Objective: The aim of the present study was to investigate the role of inducible nitric oxide synthase (iNOS) and its underlying mechanism in a high-fat diet and Nω-nitro-L-arginine methyl ester-induced HFpEF mouse model. Methods: The selective iNOS inhibitor L-NIL was used to examine the effects of short-term iNOS inhibition, whereas the long-term effects of iNOS deficiency were evaluated using iNOS-null mice. Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation were then measured. Results: The results demonstrated that both pharmacological inhibition and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress and Akt S-nitrosylation, leading to an ameliorated HFpEF phenotype in mice. In vitro, iNOS directly induced Akt S-nitrosylation at cysteine 224 residues , leading to oxidative stress, while inhibiting insulin-mediated glucose uptake in myocytes. Conclusion: Altogether, the present findings suggested an important role for iNOS in the pathophysiological development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.

Characterisation of macrophages from human carotid artery plaques and in vitro assays reveal that macrophages regulate vascular smooth muscle cell function during atherosclerosis progression through the IL-1β/STAT3 axis.

Background: S100 calcium-binding protein A9 (S100A9) is a danger-associated molecular pattern molecule that mediates the inflammatory response. Inflammation is essential in aging-related cardiovascular diseases. However, less is known regarding the role of S100A9 in vascular aging. Methods: S100A9 null mice were used to investigate the role of S100A9 in aging-related pathologies. Artery rings were used to measure the functional characteristics of vascular with a pressurized myograph. Telomere length, Sirtuin activity, oxidative stress, and endothelial nitric oxide synthetase (eNOS) activity were used to elevate vascular senescence. Intraperitoneal glucose tolerance (IPGTT) and insulin sensitivity test (IST) were employed to investigate the effects of S100A9 on insulin resistance. Inflammation response was reflected by the concentration of inflammatory cytokines. The Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) inhibitors were used to identify the downstream molecular mechanisms of S100A9 in aging-induced senescence in endothelial cells. Results: S100A9 expression in vascular increased with aging in mice and humans. Deficiency of S100A9 alleviated vascular senescence in aged mice, as evidenced by increased telomere length, Sirtuin activity, and eNOS activity. Meanwhile, S100A9 knockout improved endothelium-dependent vasodilatation and endothelial continuity in aged mice. Moreover, the increased insulin resistance, oxidative stress, and inflammation were mitigated by S100A9 deletion in aged mice. In vitro, S100A9 induced senescence in endothelial cells, and that effect was blunted by TLR4 but not RAGE inhibitors. Conclusion: The present study suggested that S100A9 may contribute to aging-related pathologies and endothelial dysfunction via the TLR4 pathway. Therefore, targeting S100A9/TLR4 signaling pathway may represent a crucial therapeutic strategy to prevent age-related cardiovascular diseases.

Excessive oxidative stress is a major causative factor of endothelial dysfunction in hypertension. As an endogenous pro-oxidant, thioredoxin-interacting protein (TXNIP) contributes to oxidative damage in various tissues. The present study aimed to investigate the role of TXNIP in mediating endothelial dysfunction in hypertension. In vivo, an experimental model of acquired hypertension was established with two-kidney, one-clip (2K1C) surgery. The expression of TXNIP in the vascular endothelial cells of multiple vessels was significantly increased in hypertensive rats compared with sham-operated rats. Resveratrol, a TXNIP inhibitor, suppressed vascular oxidative damage and increased the expression and activity of eNOS in the aorta of hypertensive rats. Notably, impaired endothelium-dependent vasodilation was effectively improved by TXNIP inhibition in hypertensive rats. In vitro, we observed that Ang II increased the expression of TXNIP in primary human aortic endothelial cells (HAECs) and that TXNIP knockdown by RNA interference alleviated cellular oxidative stress damage and mitigated the impaired eNOS activation and intracellular nitric oxide (NO) production observed in Ang II-treated HAECs. However, inhibiting thioredoxin (TRX) with PX-12 completely blunted the protective effect of silencing TXNIP. In addition, TXNIP knockdown facilitated TRX expression and promoted TRX nuclear translocation to further activate AP1 and REF1. TRX overexpression exhibited favorable effects on eNOS/NO homeostasis in Ang II-treated HAECs. Thus, TXNIP contributes to oxidative stress and endothelial dysfunction in hypertension, and these effects are dependent on the antioxidant capacity of TRX, suggesting that targeting TXNIP may be a novel strategy for antihypertensive therapy.

Abstract. Background:. Diabetes is a risk factor for acquisition of cryptococcal meningitis (CM). However, the effects of diabetes on outcomes of CM patient have not been fully studied. Methods:. In this retrospective study, 49 diabetic CM patients and 98 non-diabetic CM patients from January 2008 to December 2018 in the First Affiliated Hospital of Zhejiang University were included by propensity score-matched method (1:2). Demographic characteristics, symptoms, and clinical assay parameters between the two groups were compared. Kaplan-Meier analysis and Cox proportional hazards model were used to assess factors associated with 10-week mortality. Results:. The mean age of diabetic patients was 58.2 ± 13.8 years; 71.4% (35/49) were more than 50 years old and 46.9% were male. No difference in symptoms was found between diabetic and non-diabetic CM patients. The Charlson comorbidity score was higher in the diabetic group (1.9 vs. 0.7, P

Abstract Background The impact of ventriculoperitoneal shunt on cerebrospinal fluid (CSF) biochemical profiles in HIV-associated cryptococcal meningitis (HCM) patients remains unclear. Methods Twenty-nine HCM patients who underwent ventriculoperitoneal shunt (the VPS group) and 57 HCM patients who did not undergo ventriculoperitoneal shunt (the non-VPS group) were enrolled in this propensity score matching analysis. Demographic characteristics, symptoms, CSF biochemical profiles, and adverse events were compared between the two groups. The Kaplan–Meier method was used to analyze the survival rate. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for increased CSF protein levels. Results After 24 weeks of treatment, the intracranial pressure was significantly lower in the VPS group than in the non-VPS group (mmH2O; 155.0 [120.0–190.0] vs. 200.0 [142.5–290.0]; P = 0.025), and the rate of neuroimaging improvement was significantly higher in the VPS group (16/17 [94.1%] vs. 2/10 [20%]; P

Savolitinib, a small-molecule inhibitor of the receptor tyrosine kinase mesenchymal-epithelial transition (MET) factor, was approved for the treatment of non-small cell lung cancer (NSCLC) by the China National Medical Products Administration in June 2021. Its safety for NSCLC treatment has been confirmed in several prospective cohort studies. Herein, we report a rare case of shock, a serious adverse event, after treatment with savolitinib in an HIV-1–positive patient with advanced NSCLC. A 38-year-old man with an 8-year history of HIV-1 positivity was diagnosed with NSCLC 5 years ago; the lung cancer recurred after surgical resection. Despite chemotherapy, immunotherapy, and targeted therapy, tumor progression continued. He received savolitinib because of MET amplification. In the first 2 weeks of savolitinib use, he developed a mild rash on his trunk. In the following month, he was hospitalized for fever and circulatory shock thrice after taking savolitinib 400 mg. He had no urticaria or eosinophilia. During the three hospitalizations, he was negative for pathogens. His condition gradually improved after treatment with antibiotics, steroids, and vasopressors. Attention should be paid to the occurrence of septic shock-like presentations when using savolitinib in HIV-1 patients with NSCLC.

BackgroundThe HIV-1 reservoir is a major barrier to curative strategies. Inflammation is an important factor for HIV-1 reservoir persistence. Lenalidomide regulates inflammatory cytokines efficiently. We examined whether lenalidomide could inhibit HIV-1 transcription and reduce systemic inflammation in people living with HIV.MethodsLenalidomide was administered orally for 48 weeks to patients with HIV-associated cryptococcal meningitis (HIV-CM). A HIV-1 latency model was treated with or without lenalidomide ex vivo for 5 days. The primary endpoints were change in HIV reservoir markers and inflammatory cytokines in both the cohort and cell model.ResultsThirteen participants were enrolled from May 2019 to September 2020. The median change in cell-associated (CA) HIV RNA between baseline and 48 weeks was 0.81 log10 copies/million peripheral blood mononuclear cells (PBMCs). The CA HIV RNA decreased significantly in the cohort (P = 0.021). Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) gradually diminished with lenalidomide treatment until 48 weeks (P = 0.007, P = 0.014, respectively). C-reactive protein/IL-6/TNF-α and CA HIV RNA were significantly correlated (P = 0.0027, 0.0496, and 0.0346, respectively). Lenalidomide also significantly decreased HIV core P24 (P = 0.0038) and CA HIV RNA in CD8-depleted PBMCs (P = 0.0178) ex vivo. TNF-α and IL-6 were significantly reduced in the CD8-depleted PBMC supernatant (P = 0.004, P

Abstract O-GlcNAcylation, an energy-sensitive posttranslational modification, can regulate the activity of endothelial nitric oxide synthase (eNOS). Previous studies found that Thr866 is the key site for low-glucose-mediated regulation of eNOS O-GlcNAc. However, it is not known whether this activity functions through the Thr866 site concomitant with other physical and chemical factors. Therefore, we first explored the effects of physical and chemical factors on eNOS O-GlcNAc and its Thr866 site. In this study, hypertonic stress, hyperthermia and hydrogen peroxide all increased the expression levels of eNOS O-GlcNAc, whereas hypoxia and high levels of alcohol had no effect. on the expression levels of eNOS O-GlcNAc; by contrast, low pH led to a decrease in eNOS O-GlcNAc levels. Notably, eNOS O-GlcNAc protein levels were unchanged after Thr866 site mutation only under hypertonic conditions, suggesting that hypertonic stress may act through the Thr866 site. Upon exploring the mechanism of hypertonic stress on eNOS O-GlcNAc activity and function, we found that hypertonic stress can upregulate the expression of O-linked N-acetylglucosamine (GlcNAc) transferase (OGT), which is dependent on AMPK. When AMPK was knocked out, the upregulation of OGT expression and increased O-GlcNAc modifications induced by hypertonic stress were reversed.

Background: Although the past decade has witnessed substantial scientific progress with the advent of cardioprotective pharmacological agents, most have failed to protect against myocardial ischemia/reperfusion (I/R) injury in diabetic hearts. This study was aimed at investigating the role of stimulator of interferon genes (STING) in I/R injury in diabetic mice and further exploring the underlying mechanisms. Methods: Type 2 diabetic mice were subjected to I/R or sham operation to investigate the role of STING. STING knockout mice were subjected to 30 minutes of ischemia followed by reperfusion for 24 hours. Finally, myocardial injury, cardiac function, and inflammation levels were assessed. Results: STING pathway activation was observed in diabetic I/R hearts, as evidenced by increased p-TBK and p-IRF3 expression. STING knockout significantly decreased the ischemic area and improved cardiac function after I/R in diabetic mice. STING knockout also elicited cardio-protective effects by decreasing serum cardiac troponin T and lactate dehydrogenase levels, thus diminishing the inflammatory response in the heart after I/R in diabetic mice. In vitro , STING inhibition decreased the expression of hypoxia-re-oxygenation-induced inflammatory cytokines. Conclusions: Targeting STING inhibits inflammation and prevents I/R injury in diabetic mice. Thus, STING may be a potential novel therapeutic target against myocardial I/R injury in diabetes.

Abstract Background Ketogenic diet (KD) has been proposed to be an effective lifestyle intervention in metabolic syndrome. However, the effects of KD on cardiac remodeling have not been investigated. Our aim was to investigate the effects and the underling mechanisms of KD on cardiac remodeling in spontaneously hypertensive rats (SHRs). Methods 10-week-old spontaneously hypertensive rats were subjected to normal diet or ketogenic diet for 4 weeks. Then, their blood pressure and cardiac remodeling were assessed. Cardiac fibroblasts were isolated from 1- to 3-day-old neonatal pups. The cells were then cultured with ketone body with or without TGF-β to investigate the mechanism in vitro. Results 4 weeks of KD feeding aggravated interstitial fibrosis and cardiac remodeling in SHRs. More interestingly, ketogenic diet feeding increased the activity of mammalian target of rapamyoin (mTOR) complex 2 pathway in the heart of SHRs. In addition, β-hydroxybutyrate strengthened the progression of TGF-β-induced fibrosis in isolated cardiac fibroblasts. mTOR inhibition reversed this effect, indicating that ketone body contributes to cardiac fibroblasts via mTOR pathway. Conclusions These data suggest that ketogenic diet may lead to adverse effects on the remodeling in the hypertensive heart, and they underscore the necessity to fully evaluate its reliability before clinical use.

Abstract. Kaposi sarcoma-associated herpesvirus (KSHV) triggers the development of Kaposi sarcoma, a skin malignancy that is one of the most widespread defining symptoms in acquired immunodeficiency syndrome patients. KSHV manifests in two distinct cycles, a chronic latent cycle and an acute lytic cycle. Current clinical anti-herpesvirus therapeutic agents are predominantly composed of nucleoside analogues that target viral replication in the lytic cycle only, while KSHV latent genes are at the basis tumorigenesis. Currently, there are no effective therapies targeting latent KSHV infections. Therefore, the aim of this study was to identify putative therapeutic compounds with inhibitory activity against latent KSHV. The KSHV-infected primary effusion lymphoma cell line BC-3 was used to study antiviral activity of glycyrrhizic acid (GA), Allicin, and epigallocatechin-3-gallate (EGCG) against latent and lytic KSHV. Activity of GA, Allicin, EGCG, and the established anti-lytic cycle control compound ganciclovir was quantified by real-time polymerase chain reaction of nuclear and virion KSHV DNA yields after treatment compared with the untreated control. GA and Allicin showed antiviral activity against both latent and lytic KSHV, while EGCG displayed activity against lytic KSHV only. Therefore, GA and Allicin are interesting compounds for further development of anti-KSHV therapy against latent cycle infections.

Abstract Background Indoleamine 2, 3-dioxygenase (IDO) is a key enzyme in the degradation of tryptophan (Trp) to kynurenine (Kyn). We measured IDO activity as the Kyn to Trp ratio, and investigated whether IDO could be used to assess prognosis of acquired immune deficiency Sydrome (AIDS) patients with pneumocystis pneumonia (PCP). Methods The Kyn and Trp concentration were measured by UPLC-MS/MS in plasma samples. A total of 49 AIDS-PCP patients were included in the analysis. Clinical characteristics and Kyn/Trp ratio were compared between survivors and non-survivors. Results Kyn/Trp ratio was significantly lower after anti-PCP treatment in AIDS patients with PCP (P 300 mmHg (P = 0.007). Kyn/Trp ratio, D-dimer and CRP showed much higher AUC for predicting death of AIDS-PCP patients. Kyn/Trp ratio was useful for predicting the mortality of AIDS-PCP due to a significantly higher Kyn/Trp ratio in the non-survivors (P = 0.002). And the high Kyn/Trp ratio group had higher mortality rate than low Kyn/Trp group (32.1% vs. 9.1%, respectively, p = 0.024). Conclusion Activation of the kynurenine pathway is associated with the severity and fatal outcomes of AIDS patients with pneumocystis pneumonia.

Increasing evidence has indicated that modulation of epigenetic mechanisms, especially methylation and long-non-coding RNA (lncRNA) regulation, plays a pivotal role in the process of atherosclerosis; however, few studies focused on revealing the epigenetic-related subgroups during atherosclerotic progression using unsupervised clustering analysis. Hence, we aimed to identify the epigenetics-related differentially expressed genes associated with atherosclerosis subtypes and characterize their clinical utility in atherosclerosis. Eighty samples with expression data (GSE40231) and 49 samples with methylation data (GSE46394) from a large artery plaque were downloaded from the GEO database, and aberrantly methylated–differentially expressed (AMDE) genes were identified based on the relationship between methylation and expression. Furthermore, we conducted weighted correlation network analysis (WGCNA) and co-expression analysis to identify the core AMDE genes strongly involved in atherosclerosis. K-means clustering was used to characterize two subtypes of atherosclerosis in GSE40231, and then 29 samples were recognized as validation dataset (GSE28829). In a blood sample cohort (GSE90074), chi-square test and logistic analysis were performed to explore the clinical implication of the K-means clusters. Furthermore, significance analysis of microarrays and prediction analysis of microarrays (PAM) were applied to identify the signature AMDE genes. Moreover, the classification performance of signature AMDE gene-based classifier from PAM was validated in another blood sample cohort (GSE34822). A total of 1,569 AMDE mRNAs and eight AMDE long non-coding RNAs (lncRNAs) were identified by differential analysis. Through the WGCNA and co-expression analysis, 32 AMDE mRNAs and seven AMDE lncRNAs were identified as the core genes involved in atherosclerosis development. Functional analysis revealed that AMDE genes were strongly related to inflammation and axon guidance. In the clinical analysis, the atherosclerotic subtypes were associated with the severity of coronary artery disease and risk of adverse events. Eight genes, including PARP15, SERGEF, PDGFD, MRPL45, UBR1, STAU1, WIZ, and LSM4, were selected as the signature AMDE genes that most significantly differentiated between atherosclerotic subtypes. Ultimately, the area under the curve of signature AMDE gene-based classifier for atherosclerotic subtypes was 0.858 and 0.812 in GSE90074 and GSE34822, respectively. This study identified the AMDE genes (lncRNAs and mRNAs) that could be implemented in clinical clustering to recognize high-risk atherosclerotic patients.

Phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P3] is a phosphorylated derivative of phosphatidylinositol 4-phosphate [PI(4)P] and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which recruit and activate AKT in the plasma membrane (PM) to promote cellular survival. ORP5 anchors at the endoplasmic reticulum (ER)-PM contact sites and acts as a PI(4)P and PI(4,5)P2/phosphatidylserine (PS) exchanger. Here, a lipidomics analysis of the sensorimotor cortex revealed that transient middle cerebral artery occlusion (tMCAO) disturbs the homeostasis of phosphatidylinositols (PIs) and PS between the PM and ER. Conditional knockout mice showed that ORP5 contributes to this abnormal distribution. Abolishing the ORP5 gene significantly inhibited apoptosis and autophagy. RNA sequencing and RNA pull down analyses confirmed a competing endogenous RNA pathway in which circ_0001449 sponges miR-124-3p and miR-32-5p to promote Osbpl5 translation. Our data showed that circRNA_0001449 regulates membrane homeostasis via ORP5 and is involved in the AKT survival pathway.

Purpose. Serum cytokines/chemokines play important roles in cryptococcal meningitis, but it is unclear whether cytokines/chemokines in cerebrospinal fluid (CSF) contribute to high intracranial pressure (HICP) in HIV-associated cryptococcal meningitis (HCM). Methods. CSF cytokines/chemokines were assayed in 17 HIV-uninfected patients, 26 HIV-infected patients without CNS infection, and 39 HCM patients at admission. Principal component analysis and correlation and logistic regression analyses were used to assess the relationships between these parameters. Results. The CSF Th1, Th2, and macrophage cytokines showed an obvious increase in HCM patients as compared to the HIV-uninfected patients and HIV-infected patients without CNS infection. CSF IL-6, GM-CSF, and IL-8 were positively correlated with CSF fungal burden. Serum CD4 count, CSF Th1 cytokines (TNF-α, TNF-β, IL-12, IL-1β, and INF-α2), and Th2 cytokines (IL-5 and IL-6) were closely related to cryptococcal meningitis. Furthermore, both Th1 cytokines (TNF-α, TNF-β, INF-γ, and IL-12) and Th2 cytokines (IL-4 and IL-10) contribute to HICP. Conclusion. Overall, the present findings indicated that both pro- and anti-inflammatory cytokines of Th1, Th2, and macrophage origin contributed to the development of HCM. Specifically, the chemokine and cytokine cascade caused by skewing of the Th1-Th2 balance and reduced CD4 count were found to be important contributors to HICP. Summary. Our research suggested that chemokine and cytokine cascade caused by skewing of the Th1-Th2 balance in HIV-infected patients played more important role than Cryptococcus numbers and size in CSF on the development of high intracranial pressure in HIV-associated cryptococcal meningitis, providing a new understanding of mechanisms of HCM.

Background and Objectives. Pneumocystis pneumonia (PCP) is a common opportunistic infection in acquired immune deficiency syndrome (AIDS) patients that continues to result in a high mortality rate. To develop a better treatment strategy and improve PCP prognosis, a cohort study was conducted to evaluate the therapeutic potential of echinocandin treatment for AIDS patients with PCP (AIDS-PCP). Methods. The AIDS-PCP patients were analyzed in our retrospective cohort study that were hospitalized in The First Affiliated Hospital of Zhejiang University during 2013–2018. The antifungal effects of echinocandins were evaluated in two subgroups that were classified by oxygenation as a proxy for the disease state: PaO2/FiO2>200 mmHg and PaO2/FiO2≤200 mmHg. Intergroup comparisons and survival curves were used to evaluate the effectiveness of the two AIDS-PCP treatment regimens. Results. During the follow-up, 182 AIDS-PCP patients were diagnosed and analyzed in the study. After excluding 55 patients with other superinfections and five patients that were treated with HAART, the remaining 122 patients were enrolled in the study. The group treated with echinocandins combined with trimethoprim-sulfamethoxazole (TMP-SMZ) and clindamycin exhibited a lower mortality rate (9.62%, 5/52) than did the group with TMP-SMZ and clindamycin treatment (20%, 14/70). For AIDS-PCP patients in the PaO2/FiO2>200 mmHg subgroup, treatment with echinocandins combined with TMP-SMZ and clindamycin significantly reduced their mortality rate (4.44% (2/45) vs. 18.18% (10/55), P=0.035). Conclusion. The results of this study indicate that treatment with echinocandins in combination with the standard TMP-SMZ and clindamycin regimen can improve the prognosis and reduce the mortality rate in patients with mild to moderate AIDS-PCP disease.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is one of the most deadly, prevalent, and costly diseases in Asia. However, no prognostic model has been developed that is based specifically on data gathered from Asian patients with ACLF. The aim of the present study was to quantify the survival time of ACLF among Asians and to develop a prognostic model to estimate the probability of death related to ACLF. METHODS: We conducted a retrospective observational cohort study to analyze clinical data from 857 patients with ACLF/pre-ACLF who did not undergo liver transplantation. Kaplan-Meier and Cox proportional hazards regression model were used to estimate survival rates and survival affected factors. The area under the receiver operating characteristic curve (auROC) was used to evaluate the performance of the models for predicting early mortality. RESULTS: The mortality rates among patients with pre-ACLF at 12 weeks and 24 weeks after diagnosis were 30.5% and 33.2%, respectively. The mortality rates among patients with early-stage ACLF at 12 weeks and 24 weeks after diagnosis were 33.9% and 37.1%, respectively. The difference in survival between pre-ACLF patients and patients in the early stage of ACLF was not statistically significant. The prognostic model identified 5 independent factors significantly associated with survival among patients with ACLF and pre-ACLF: the model for end-stage liver disease (MELD) score; age, hepatic encephalopathy; triglyceride level and platelet count. CONCLUSION: The findings of the present study suggest that the Chinese diagnostic criteria of ACLF might be broadened, thus enabling implementation of a novel model to predict ACLF-related death after comprehensive medical treatment.