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Background The aim of the present study was to establish a competing risk nomogram to predict parotid gland cancer-specific mortality (PGC-SM). Methods Seven thousand nine hundred and sixty-two patients extracted from SEER database were randomly categorized into training and validation sets. The competing risk model was used to identify factors associated with PGC-SM. The nomogram was evaluated via concordance indexes (C-indexes), calibration plots, and decision curve analysis (DCA). Results Male, elderly, white, widowed, larger tumor, no surgery, advanced tumor grade, lymph node (LN) metastasis, adenocarcinoma (ADC), and higher TNM stage were associated with higher incidence of PGC-SM. Calibration plots showed that the nomogram was well calibrated. C-indexes for nomogram were 0.84 (95% CI: 0.81-0.86) and 0.84 (95% CI: 0.82-0.86) in training and validation sets, respectively. DCA demonstrated the clinical usefulness of nomogram. Conclusions The competing risk nomogram shows high performance in predicting PGC-SM, which might enable clinicians formulate suitable treatment protocols for patients with parotid gland carcinoma (PGC).

Background Proteus syndrome (PS) is an extremely rare disease characterized by excessive chimeric growth of cells, and progressive and irregular asymmetrical hyperplasia. Case presentation Herein, a PS case with atypical clinical features and syndromes was reported, to improve the understanding of the diagnosis and treatment of the disease. The case was a 3-year-and-11-month-old male child. He was admitted due to a primary diagnosis of McCune-Albright syndrome. After admission, the lesion samples from the milk coffee spots, and nodular thickening skin at hands and feet were subjected to genetic screening. Genetic testing results confirmed the diagnosis of PS. Conclusions Based on the clinical manifestations, laboratory tests, imaging data, and literature reviewing, the etiology, diagnosis, treatment and prognosis of PS have been analyzed and discussed.

Aflatoxin B1 (AFB1) is a common toxic mycotoxin and is detectable in pregnant women. Animal studies have revealed that AFB1 caused the lysis of erythrocytes and a decrease in hemoglobin. We conducted a prospective cohort study in Guangxi, China, in order to evaluate the association between AFB1 exposure and anemia in pregnant women during the entire pregnancy. A total of 616 pregnant women from the Guangxi Zhuang Birth Cohort were included in the study. Serum AFB1-albumin (AFB1-ALB) adduct levels were measured. The effect of AFB1-ALB adducts on hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were analyzed by using multivariable linear regression. The risks of anemia from AFB1-ALB adduct exposure were assessed by multivariable logistic regression. We found that the AFB1-ALB adduct was significantly associated with a decrease in Hb (β = −4.99, 95% CI: −8.42, −1.30), MCV (β = −4.58, 95% CI: −7.23, −1.94), MCH (β = −1.86, 95% CI: −2.87, −0.85), and MCHC (β = −5.23, 95% CI: −8.28, −2.17) in the first trimester with the third tertile of AFB1-ALB adducts when compared with the first tertile. Furthermore, the third tertile of the AFB1-ALB adduct significantly increased the risk of anemia by 2.90 times than compared to the first tertile in the first trimester (OR = 3.90, 95% CI: 1.67, 9.14). A significant positive does–response relationship existed between AFB1-ALB adduct levels and anemia risk (Ptrend = 0.001). When dividing anemia types, we only found that the third tertile of AFB1-ALB adduct increased the risk of microcytic hypochromic anemia (MHA) in the first trimester (OR = 14.37, 95% CI: 3.08, 67.02) and second trimester (OR = 4.75, 95% CI: 1.96, 11.51). These findings demonstrate the correlation between maternal AFB1 exposure during early pregnancy and risk of anemia, especially MHA, and during different trimesters in Southern China. More efforts should be made to diminish AFB1 exposure for pregnant women.

Bisphenols have endocrine-disrupting effects, which may disrupt hemoglobin (Hb) homeostasis and lead to anemia. However, the effects of bisphenols on anemia remain unknown. Therefore, we assessed the effects of single- and multiple-exposure to bisphenols on Hb levels and anemia of pregnant women.The study involved 2035 pregnant women from Guangxi Zhuang Birth Cohort in China. Generalized linear regression, principal component analysis (PCA), quantile g-computation (Qgcomp), and Bayesian kernel machine regression (BKMR) were performed to examine the effects of serum bisphenols on Hb levels and the risk of anemia.After adjustment, elevated bisphenol A (BPA) levels were correlated with decreased Hb concentrations (β = -0.51; 95%CI: -0.92, -0.10) in the first trimester, and these correlations were more sensitive in mothers of males. Compared with the low-exposure group, bisphenol B (BPB) levels in the high-exposure group led to a 1.52 g/L (95%CI: -3.01, -0.03) decrease in Hb levels in the second trimester; tetrabromobisphenol A (TBBPA) levels in the high-exposure group led to a higher the risk of anemia in the third trimester (OR = 1.46; 95%CI: 1.07, 1.99); bisphenol F (BPF) in the high-exposure group led to lower Hb levels (β = -2.42; 95%CI:-4.69, -0.14) in mothers of male fetuses in the third trimester. Qgcomp showed that elevated levels of bisphenol mixture was correlated with (β = -1.42; 95%CI: -2.61, -0.24) decrease in Hb levels in the second trimester. PCA revealed a negative association between PC2 and Hb levels in the first trimester (β = -0.89; 95%CI: -1.61, -0.17). Similarly, a negative relationship was observed between PC1 and Hb levels in the third trimester among mothers with male fetuses (β = -1.00; 95%CI: -1.94, -0.06).Prenatal exposure to single and mixed bisphenols may decrease Hb levels and increase the risk of anemia during pregnancy, the associations may be greater in mothers with male fetuses than those with female fetuses.

The highest prevalence of hyperuricemia was found in Zhuang minority adults in two national surveys in China, with only 1% Zhuang study subjects. However, the prevalence of hyperuricemia and the associated factors in Zhuang adults have not been well-addressed. A cross-sectional study was conducted to explore the prevalence of hyperuricemia and the common comorbidities, and the associated factors in Zhuang adults based on the Guangxi Ethnic Minority Population Cohort. Among 11,175 Zhuang adults aged 35–74 years, the age- and sex-standardized prevalence rate was 18.1% for hyperuricemia and 1.1% for gout. The standardized prevalence rate and awareness rate were 31.6% and 32.3%, respectively, for hypertension, and were 5.1% and 48.2%, respectively, for diabetes. High education level, history of coronary heart disease (CHD), hypertension, being a current drinker, high body mass index (BMI), central obesity, hyper-triglyceride (hyper-TG), hyper-total cholesterol (hyper-TC), hypo-high density lipoprotein cholesterol (hypo-HDL-C), and abnormal aspartate aminotransferase (AST) were risk factors, while smoking and diabetes were protective factors of hyperuricemia in males. Older age, being single/divorced, having a high education level, hypertension, drinking tea, high BMI, central obesity, hyper-TG, hyper-TC, hypo-HDL-C, and abnormal alanine aminotransferase (ALT) were risk factors in females. The high prevalence of hyperuricemia but low prevalence of gout and common comorbidities in Zhuang adults may be due to a lag effect of lifestyle changes. Health education and health management should be strengthened to prevent the progression of comorbidities, considering the lag effect and low awareness rate.

We investigated cross-sectional associations between children’s neurodevelopment and their gut microbiota composition. Study children (36 months of age) lived in rural China (n = 46). Neurodevelopment was assessed using the Bayley Scales of Infant Development, 2nd Edition, yielding the Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI). Children's gut microbiota was assessed using 16S rRNA gene profiling. Microbial diversity was characterized using alpha diversity patterns. Additionally, 3 coabundance factors were determined for the 25 most abundant taxa. Multivariable linear regression models were constructed to examine the relationships between Bayley scores (MDI and PDI) and children's gut microbiota. In adjusted models, MDI and PDI scores were not associated with alpha diversity indices. However, in adjusted models, MDI and PDI scores were positively associated with the first coabundance factor, which captured positive loadings for the genera Faecalibacterium, Sutterella, and Clostridium cluster XIVa. For an interquartile range increase in the first coabundance factor, MDI scores increased by 3.9 points [95% confidence interval (CI): 0, 7.7], while PDI scores increased by 8.6 points (95% CI 3.1, 14). Our results highlight the potential for gut microbial compositional characteristics to be important correlates of children's Bayley Scales performance at 36 months of age.

Increasing evidence has shown that long non-coding RNAs (lncRNAs) are important in hepatocellular carcinoma (HCC) development and progression. In this study, we aim to evaluate the expression of lncRNA FAM99B and its biological function in HCC. The expression level of FAM99B in HCC was assessed based on data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), verified using quantitative real-time polymerase chain reaction (qRT-PCR). HCCLM3 was transfected with lentivirus containing full-length FAM99B to obtain stable overexpressing cell line. Cell Counting Kit 8, clone formation, and transwell assays were used to investigate the effects of FAM99B in HCC progression. In addition, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and PANTHER pathway analyses were conducted to investigate the underlying molecular mechanisms. FAM99B was found to be downregulated in HCC tissues compared with adjacent normal tissues based on TCGA, GEO, and qRT-PCR data. Our results revealed that downregulated FAM99B was significantly associated with vascular invasion, advanced histologic grade, and T stage. Kaplan–Meier analysis using TCGA data indicated that decreased FAM99B levels were significantly associated with poor overall survival in patients with HCC. Moreover, overexpression of FAM99B significantly inhibited cell proliferation, migration, and invasion in vitro. Pathway analyses showed that the co-expressed genes of FAM99B mainly participated in the pathways “Metabolic pathways” and “Blood coagulation”. Our results suggest that FAM99B may serve as a tumor suppressor in HCC and may provide a promising therapy target for patients with HCC.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Th17 has been shown to play am important role in the pathogenesis of RA. Accumulating data suggest the involvement of NLRP3 inflammasome in Th17 differentiation in autoimmune diseases. In the current study, we found that NLRP3 inflammasome is activated in CD4 T cells from RA patients. The activation of NLRP3 inflammasome was correlated with disease activities and IL-17A concentration in RA sera. Knockdown of NLRP3 suppressed Th17 differentiation. In addition, caspase-1 or IL-1 receptor inhibitor inhibits Th17 differentiation significantly. Further, ROS production is increased in CD4 T cells from RA patients. The inhibition of ROS production decreased NLRP3 inflammasome activation and IL-1β production in CD4 T cells, leading to the suppression of Th17 differentiation. These findings suggest a pathogenic role of NLRP3 inflammasome in RA by promoting Th17 cell differentiation. NLRP3 inflammasome could be a potential therapeutic target for the treatment of RA.

Hepatocellular carcinoma (HCC) is a highly malignant tumor. In this study, we sought to identify a novel biomarker for HCC by analyzing transcriptome and clinical data. The R software was used to analyze the differentially expressed genes (DEGs) in the datasets GSE74656 and GSE84598 downloaded from the Gene Expression Omnibus database, followed by a functional annotation. A total of 138 shared DEGs were screened from two datasets. They were mainly enriched in the “Metabolic pathways” pathway (Padj = 8.21E-08) and involved in the carboxylic acid metabolic process (Padj = 0.0004). The top 10 hub genes were found by protein-protein interaction analysis and were upregulated in HCC tissues compared to normal tissues in The Cancer Genome Atlas database. Survival analysis distinguished 8 hub genes CENPE, SPDL1, Hyaluronan-mediated motility receptor, Rac GTPase activating protein 1, Thyroid hormone receptor interactor 13, cytoskeleton-associated protein (CKAP) 2, CKAP5, and Integrin subunit beta 3 binding protein (ITGB3BP) were considered as prognostic hub genes. Multivariate cox regression analysis indicated that all the prognostic hub genes were independent prognostic factors for HCC. Furthermore, the receiver operating characteristic curve revealed that the 8-hub genes model had better prediction performance for overall survival compared to the T stage (p = 0.008) and significantly improved the prediction value of the T stage (p = 0.002). The Human Protein Atlas showed that the protein expression of ITGB3BP was upregulated in HCC, so the expression of ITGB3BP was further verified in our cohort. The results showed that ITGB3BP was upregulated in HCC tissues and was significantly associated with lymph node metastasis.

The persistent inflammation aggravated by a disordered immune response is considered to be the major cause of CD4+ T cell depletion in lymphoid tissue, which impels the progression of AIDS. Here, we report that heat shock factor 1 (HSF1) works as an innate repressor of HIV-induced inflammation. The activation of HSF1 was found to accompany inflammation during HIV infection. Further research uncovered that HSF1 activation inhibited HIV-induced inflammation. In addition, HSF1 overexpression suppressed the inflammatory response induced by HIV, while HSF1 deficiency exacerbated that inflammation. Mechanistically, HSF1 was found to compete with nuclear factor-κB (NF-κB) in the nucleus. Generally, our report highlights that HSF1 is an important host factor in regulating HIV-induced inflammation and may work as a potential target for curing AIDS.

Background. Despite a rapid popular of early onset type 2 diabetes (defined as diagnosis at Methods. A cross-sectional survey of 1736 consecutive patients with T2DM was conducted. Macrovascular complications and risk factors were documented. Another nondiabetic population matched with age and sex was as a control group. Logistic regression analysis was performed to obtain odds ratios (OR) for macrovascular complications in early and late onset T2DM, respectively. Results. The final analysis consisted of 1036 late onset and 219 early onset T2DM patients. The mean HbA1c in the early onset group was higher than that in the late onset group (9.1 ± 2.4% versus 8.3 ± 2.2%, P=0.039) despite a higher proportion of patients in the early onset group receiving insulin treatment (73.1% versus 58.7%, P<0.001). Compared to the control, early onset patients had higher blood pressure and worse lipid profiles (all P<0.01). More than half of the early onset T2DM patients already had macro- and microvascular complications, despite of their young age (39.5 ± 10.8) and short DM duration (6.6 ± 8.0). In the early onset group, women had a ~3-fold hazard of atherosclerotic plaques compared with men (OR 3.22, 95% CI 1.53–6.78). Conclusions. Patients with early onset T2DM have worse glycemic control and higher burden of atherogenic risk factors. The prevalence of macro- and microvascular complications is astonishingly high in these young adults with T2DM. Moreover, young women with T2DM are more susceptible to cardiovascular complications than their male counterpart.

Disruption of the cell cycle pathway has previously been related to development of human cancers. However, associations between genetic variants of cell cycle pathway genes and prognosis of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we evaluated the associations between 24 potential functional single nucleotide polymorphisms (SNPs) of 16 main cell cycle pathway genes and disease‐free survival (DFS) of 271 HCC patients who had undergone radical surgery resection. We identified two SNPs, i.e., SMAD3 rs11556090 A>G and RBL2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false‐positive report probability (FPRP)

MicroRNAs (miRNAs) can regulate gene expression at post-transcriptional levels, thereby influence cancer risk. The aim of the current study is to investigate association between miR-199a rs74723057 and MET rs1621 and HCC risk in 1032 HCC patients and 1060 cancer-free controls. These two SNPs were genotyped by using the Agena MassARRAY genotyping system. Odds ratio (OR) and 95% confidence interval (95%CI) were calculated to assess the strength of the associations. We found that compared with the wild-type AA genotype of MET rs1621, the variant GG genotype was associated with a decreased risk for HCC (OR = 0.24, 95% CI = 0.06-0.96, P = 0.043). No association between miR-199a rs74723057 and HCC risk was observed. In addition, an interaction effect on HCC risk between the selected two SNPs was found. Among those who carried the CG/GG genotypes of miR-199a rs74723057, those who carried the GG genotype of MET rs1621 had a reduced risk of HCC, when compared with those who carried the AG/AA genotypes of MET rs1621 (OR = 0.15, 95% CI = 0.03~0.73, P for interaction = 0.018). Our results suggest that MET rs1621 polymorphism, alone and combined with miR-199a rs74723057, may influence susceptibility to HCC. Further large-scale association studies and functional studies are needed to validate our findings.

This study investigated the effects of hypothermia induced before cardiac arrest or after return of spontaneous circulation (ROSC) on cardiac function and myocardial mitochondrial injury after ROSC in a rat cardiac arrest model. Sixty healthy, male Wistar rats were randomly divided into the Normothermia group, pre-arrest hypothermia (Pre-HT) group, and post-resuscitation hypothermia (Post-HT) group. The rats underwent 8 min of untreated ventricular fibrillation followed by cardiopulmonary resuscitation. Twelve rats in each group were used to evaluate the left ventricular ejection fraction before ventricular fibrillation and 4 h after ROSC. Survival was determined at 24 h after ROSC. The remaining eight rats in each group were used to detect for heart malondialdehyde, reduced glutathione, adenosine triphosphate levels and mitochondrial histology. Oxygen consumption rate and mitochondrial membrane potential were evaluated 4 h after ROSC; 10 of 12 rats in Pre-HT group, 5 of 12 in Post-HT group, and 6 of 12 in normothermia group were successfully resuscitated. The survival rate of each group was 66.7%, 33.3%, and 25%, respectively. Rats in the Pre-HT group showed less alteration of the mitochondrial ultrastructure and oxidative stress injury, better maintenance of adenine nucleotides, and more preservation of the mitochondrial membrane potential and respiratory function when compared with rats in the Post-HT and normothermia groups. Transient hypothermia is an effective preconditioning stimulus to induce ischemic tolerance in a cardiac arrest model and worthy of further evaluation for potential clinical use. Impact statement In this paper, we investigated the effects of hypothermia induced before ischemia or after ROSC on cardiac function, oxidative stress damage, and myocardial mitochondrial ischemia–reperfusion injury after cardiac arrest in a rat model with VF. We demonstrated that pre-arrest hypothermia conferred greater cardio-protective benefits than delayed post-resuscitation hypothermia, reduced the number of defibrillations required and dosages of epinephrine during CPR, decreased oxidative stress, ameliorated mitochondrial dysfunction, and subsequently improved survival rate.

The p53 tumor suppressor and its negative regulator, murine double minute 2 (MDM2), play critical roles in carcinogenesis. P53 codon 72 and MDM2 309T>G polymorphisms could influence p53 and MDM2 function, respectively, and might affect cancer susceptibility. We therefore investigated the association between these two SNPs, alone or in combination, and the risk of hepatocellular carcinoma (HCC) in Chinese. In this case-control study, we genotyped p53 codon 72 and MDM2 309T>G polymorphisms in 985 HCC cases and 992 cancer-free age- and sex-matched controls and evaluated their associations with the risk of HCC. Although no significant main effects were found for these two SNPs in the single-locus analysis and stratified analysis by age, sex, smoking, drinking, and hepatitis B virus (HBV) infection, we found that individuals carrying at least one G allele of the MDM2 309T>G polymorphism had statistically significant increased risk of HCC among those with the p53 Pro/Pro genotype (adjusted odds ratio (OR) = 2.23, 95 % confidence interval (95%CI) = 1.20-4.14 for TG genotype; adjusted OR = 2.67, 95%CI = 1.32-5.42 for GG genotype), and the interaction between p53 codon 72 and MDM2 309T>G was significant (P interaction = 0.017). Our findings suggest that the interaction of p53 codon 72 and MDM2 309T>G may play an important role in the etiology of HCC. More studies with well-designed and large sample sizes are required to validate these observations.

To investigate long noncoding (lnc)-RNA and mRNA expression profiles in post-cardiac arrest (CA) brains, an external transthoracic electrical current was applied for 8 min to induce CA (the CA group). A total of 4 rats received sham-operations and served as the blank control (BC) group. Upon return of spontaneous circulation (ROSC), lncRNA and mRNA expression in the rat cerebral cortex was assayed with high-throughput Agilent lncRNA and mRNA microarrays. In total, 37 lncRNAs were upregulated and 21 lncRNAs were downregulated in the CA group, and 258 mRNA transcripts were differentially expressed with 177 mRNAs upregulated and 81 mRNAs downregulated in the CA group. The differentially expressed lncRNAs in the CA group were co-expressed with thousands of mRNAs. The differentially expressed lncRNAs could be clustered into >100 signaling pathways and processes according to Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes analyses. The most common predicted functions involved metabolic pathways, protein synthesis, transport and degradation during CA-ROSC. CA-ROSC led to significant alterations in cerebral lncRNA and mRNA expression profiles. Thus, lncRNA-mRNA network interactions have the potential to regulate vital metabolic pathways and processes involved in CA-ROSC.

Non-pharmacological therapies, especially the physical maneuvers, are viewed as important and promising strategies for reducing syncope recurrences in vasovagal syncope (VVS) patients. We observed the efficacy of a modified Valsalva maneuver (MVM) in VVS patients. 72 VVS patients with syncope history and positive head-up tilt table testing (HUTT) results were randomly divided into conventional treatment group (NVM group, n = 36) and conventional treatment plus standard MVM for 30 days group (MVM group, n = 36). Incidence of recurrent syncope after 12 months (6.5% vs. 41.2%, P

This study aimed to determine whether SNPs of cytokine genes influence survival of hepatocellular carcinoma (HCC) patients after radical surgery resection. We evaluated 14 SNPs of eight cytokine genes in 263 patients treated with radical surgery resection of HCC. Categorical variables were compared by the χ2 test and Fisher's exact test. The Kaplan–Meier methods with log-rank test and Cox regression models were used to compare survival of resected HCC patients according to the genotype. Among the 14 studied SNPs of cytokine genes, only the TNF-α-863 (CA + CC) genotypes were revealed to be significant independent predictors of prolonged overall survival (OS) after HCC radical surgery resection (HR: 0.586, 95% CI: 0.355–0.968), considering for other clinical factors in a Cox proportional hazard model. Meanwhile, no significant association was found between the 14 SNPs and relapse-free survival (RFS) of resected HCC patients. In addition, combination analysis with the Th1 cytokine (IFN-γ, IL-2, IL-12B, TGF-β1) or Th2 cytokine (IL-6, IL-10) genetic polymorphisms by the Kaplan–Meier method and Cox multivariate analysis did not reveal any significant association between OS and RFS of resected HCC patients.

This study was designed to validate thrombospondin 1 (TSP-1), vascular endothelial-cadherin complex (VE-cad), insulin-like growth factor 2 (IGF-2), and amyloid precursor protein (APP) and assess their diagnostic value in ventricular septal defect (VSD). We investigated the serum levels of TSP-1, VE-cad, IGF-2, and APP by enzyme-linked immunosorbent assay in a hospital-based case–control study that included 40 VSD children and 40 healthy controls. Logistic regression analysis was applied to evaluate the relationship of the proteins and VSD, and receiver operating characteristic (ROC) curve was used to assess the diagnostic value of the significant proteins. The serum levels of TSP-1, VE-cad, and IGF-2 were significantly higher in VSD patients than those in healthy controls (p

The present study was designed to evaluate the effects of ulinastatin (UTI) on cardiac dysfunction after cardiopulmonary resuscitation (CPR).A total of 48 healthy adult male New Zealand rabbits were untreated for 8 minutes after the induction of ventricular fibrillation (VF) by an external transthoracic alternating current and then treated by CPR. These rabbits were then randomly divided into the control and UTI groups after the return of spontaneous circulation (ROSC) and were observed for 8 hours after the ROSC. Before CPR and after ROSC at 2, 4, and 8 hours, blood samples were collected to determine the levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), malondialdehyde (MDA), cardiac troponin I (cTnI), and N-terminal probrain natriuretic peptide (NT-proBNP), and the left ventricular ejection fraction (EF) was measured by echocardiography.Nineteen of 24 rabbits in the control group and 18 of 24 in the UTI group were successfully resuscitated. The plasma levels of TNF-α, IL-6, MDA, cTnI, and NT-proBNP were significantly increased, accompanying a deceased EF in the control group, but the cotreatment with UTI decreased the plasma levels of TNF-α, IL-6, MDA, cTnI, and NT-proBNP (P.05), attenuating the myocardial injury and improving the EF in the UTI group. Only 9 of 19 animals in the control group but 14 of 18 animals in the UTI group survived longer than 8 hours (P = .011).The progression of proinflammatory responses, oxidative stress, and myocardial injury have been linked to the reduced EF after VF/CPR, and the administration of UTI at a cardioprotective dosage preserved the cardiac function after VF/CPR.

The persistence of HIV in resting memory CD4+ T cells at a latent state is considered as the major barrier on the path to achieve a cure for HIV. Proteasome inhibitors (PIs) were previously reported as latency reversing agents (LRAs) but the mechanism underlying this function is yet unclear. Here we demonstrate that PIs reactivate latent HIV ex vivo without global T cell activation, and may facilitate host innate immune responses. Mechanistically, latent HIV reactivation induced by PIs is mediated by heat shock factor 1 (HSF1) via the recruitment of the heat shock protein (HSP) 90-positive transcriptional elongation factor b (p-TEFb) complex. Specifically, HSP90 downstream HSF1 gives positive feedback to the reactivation process through binding to cyclin-dependent kinase 9 (CDK9) and preventing it from undergoing degradation by the proteasome. Overall, these findings suggest proteasome inhibitors as potential latency reversing agents. In addition, HSF1/HSP90 involved in HIV transcription elongation, may serve as therapeutic targets in HIV eradication.

Background Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths. The average survival and 5-year survival rates of HCC patients still remains poor. Thus, there is an urgent need to better understand the mechanisms of cancer progression in HCC and to identify useful biomarkers to predict prognosis. Methods Public data portals including Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) profiles were used to retrieve the HCC-related microarrays and to identify potential genes contributed to cancer progression. Bioinformatics analyses including pathway enrichment, protein/gene interaction and text mining were used to explain the potential roles of the identified genes in HCC. Quantitative real-time polymerase chain reaction analysis and Western blotting were used to measure the expression of the targets. The data were analysed by SPSS 20.0 software. Results We identified 80 genes that were significantly dysregulated in HCC according to four independent microarrays covering 386 cases of HCC and 327 normal liver tissues. Twenty genes were consistently and stably dysregulated in the four microarrays by at least 2-fold and detection of gene expression by RT-qPCR and western blotting showed consistent expression profiles in 11 HCC tissues compared with corresponding paracancerous tissues. Eleven of these 20 genes were associated with disease-free survival (DFS) or overall survival (OS) in a cohort of 157 HCC patients, and eight genes were associated with tumour pathologic PT, tumour stage or vital status. Potential roles of those 20 genes in regulation of HCC progression were predicted, primarily in association with metastasis. INTS8 was specifically correlated with most clinical characteristics including DFS, OS, stage, metastasis, invasiveness, diagnosis, and age. Conclusion The significantly dysregulated genes identified in this study were associated with cancer progression and prognosis in HCC, and might be potential therapeutic targets for HCC treatment or potential biomarkers for diagnosis and prognosis. Electronic supplementary material The online version of this article (doi:10.1186/s13046-016-0403-2) contains supplementary material, which is available to authorized users.

To investigate the associiations between the polymorphisms of cell cycle pathway genes and the risk of hepatocellular carcinoma (HCC).We enrolled 1127 cases newly diagnosed with HCC from the Tumor Hospital of Guangxi Medical University and 1200 non-tumor patients from the First Affiliated Hospital of Guangxi Medical University. General demographic characteristics, behavioral information, and hematological indices were collected by unified questionnaires. Genomic DNA was isolated from peripheral venous blood using Phenol-Chloroform. The genotyping was performed using the Sequenom MassARRAY iPLEX genotyping method. The association between genetic polymorphisms and risk of HCC was shown by P-value and the odd ratio (OR) with 95% confidence interval (CI) using the unconditional logistic regression after adjusting for age, sex, nationality, smoking, drinking, family history of HCC, and hepatitis B virus (HBV) infection. Moreover, stratified analysis was conducted on the basis of the status of HBV infection, smoking, and alcohol drinking.The HCC risk was lower in patients with the MCM4 rs2305952 CC (OR = 0.22, 95%CI: 0.08-0.63, P = 0.01) and with the CHEK1 rs515255 TC, TT, TC/TT (OR = 0.73, 95%CI: 0.56-0.96, P = 0.02; OR = 0.67, 95%CI: 0.46-0.97, P = 0.04; OR = 0.72, 95%CI: 0.56-0.92, P = 0.01, respectively). Conversely, the HCC risk was higher in patients with the KAT2B rs17006625 GG (OR = 1.64, 95%CI: 1.01-2.64, P = 0.04). In addition, the risk was markedly lower for those who were carriers of MCM4 rs2305952 CC and were also HBsAg-positive and non-drinking and non-smoking (P0.05, respectively) and for those who were carriers of CHEK1 rs515255 TC, TT, TC/TT and were also HBsAg-negative and non-drinking (P0.05, respectively). Moreover, the risk was higher for those who were carriers of KAT2B rs17006625 GG and were also HBsAg-negative (P0.05).Of 12 cell cycle pathway genes, MCM4, CHEK1 and KAT2B polymorphisms may be associated with the risk of HCC.

The associations between DNA repair capacity (DRC), DNA repair gene polymorphisms, and the incidence of hepatocellular carcinoma (HCC) have not been determined in high-risk areas. The aims of this study were to investigate whether DRC is related to the incidence of HCC and to determine whether polymorphisms in the DNA repair genes that regulate DRC are associated with the risk of HCC. First, a small case–control study was conducted to examine the association between DRC and the incidence of HCC and the environmental and genetic factors regulating DRC. Then, a large case–control study was conducted to determine whether those DNA repair gene polymorphisms shown to regulate DRC were related to the risk of HCC. The median DRC was significantly lower among the cases (0.80) than the controls (0.93). A multivariate linear regression analysis showed that the HBsAg status (p

Objective Recent studies have shown the existence of autophagy in cerebral ischemia; however, there has been no research on the role of autophagy in cerebral injury after cardiopulmonary resuscitation (CPR). This study was conducted to determine the role of autophagy in an animal model of ventricular fibrillation (VF)/CPR. Methods Experiment 1: A total of 48 adult Wistar rats were untreated for 7 minutes after induction of VF using an external transthoracic alternating current, and subsequent CPR was performed to observe the existence of autophagy after the return of spontaneous circulation (ROSC). Experiment 2: A total of 72 rats were pretreated with intracerebroventricular injection of physiologic saline (control group), the autophagy inducer (rapamycin group), or the autophagy inhibitor 3-methyladenine (3-methyladenine group) before ROSC to evaluate the contribution of autophagy to neuronal injury after ROSC. Results The activation of autophagy was attenuated 2 to 4 hours after ROSC, which was related to the activity decrease of 5′-adenosine monophosphate–activated protein kinase after ROSC. Rapamycin treatment significantly increased the expressions of LC3-II and Beclin-1 after ROSC, attenuated the activation of caspase-3, promoted neuronal survival and decreased neuronal apoptosis, and improved the neurologic deficit score after CPR. Conclusions The activation of autophagy after ROSC offered a remarkable tolerance to VF/CPR ischemic insult and improved the neurologic outcomes.

The forkhead box O (FOXO) transcription factors play important roles in various cancer development including Hepatocellular Carcinoma (HCC). In this study we conducted a hospital-based case control study including 1049 cases (HCC patients) and 1052 controls (non-tumor patients) to examine whether single nucleotide polymorphisms (SNPs) within microRNA (miRNA) target sites of FOXO genes confer HCC susceptibility. A total of three miRNA target site SNPs in the 3’ untranslated regions (UTR) of FOXO1 (rs17592236), FOXO3 (rs4946936) and FOXO4 (rs4503258) were analyzed. No statistically significant differences were found in genotype distribution for rs17592236, rs4946936, and rs4503258 between the HCC patient group and the tumor-free control group using single factor chi-square analysis (P>0.05). However, multivariate logistic regression analysis showed that the CT/TT genotype in rs17592236 was significantly associated with decreased risk of HCC development (P = 0.010, OR = 0.699, 95% CI: 0.526–0.927) as compared to the CC genotype in rs17592236. Additionally, a genetic interaction was found between rs17592236 and rs4503258 (P = 0.003, OR = 0.755, 95% CI: 0.628–0.908). Functional dual luciferase reporter assays verified that the rs17592236 SNP was a target site of human miRNA miR-137. Together, these results indicate that the rs17592236 polymorphism is associated with decreasing of HCC hereditary susceptibility likely through modulating the binding affinity of miR-137 to the 3’UTR in FOXO1 messenger RNA (mRNA). Further knowledge obtained from this study may provide important evidence for the prevention and targeted therapy of HCC.

To explore the relationship between the single-nucleotide polymorphism of DNA repair gene hOGG1 and the susceptibility to hepatocellular carcinoma (HCC), and the interaction between hOGG1 and environmental risk factors in a hepatocarcinoma high risk area.This hospital-based case control study was conducted in 500 HCC patients and 507 controls. The polymorphism of hOGG1-Ser326Cys was genotyped by a real time polymerase chain reaction-TaqMan MGB.The allele mutation frequencies of hOGG1-326Cys in the case group and control group were 24.60% and 10.75% respectively (P0.05). The genotype frequencies of hOGG1 Ser/Ser, Ser/Cys, Cys/Cys were 71.40%, 8.00% and 20.6% in the case group, and were 84.22%, 10.06% and 5.72% in the control group respectively (P0.05). Compared with the wild hOGG1-326Ser/Ser genotype, the mutant hOGG1 allele increased the risk of HCC (OR = 2.14, 95% CI: 1.57 -2.91). The hOGG1-326Cys allele was the major determinant factor for the risk of HCC. The interaction of hOGG1-326Cys allele with chronic HBV infection (OR = 38.15, 95% CI: 18.90 - 61.71) tremendously increased the risk of HCC. The synergy index of multiplicative interaction is 0.61 and the synergy index of additive interaction is 1.31.The hOGG1-326Cys allele may contribute to the risk of HCC. The synergistic interaction between hOGG1-326Cys allele and chronic HBV infection might modify the risk of HCC. Further studies with larger sample size are warranted to confirm these findings.