The tacrolimus-induced glucose homeostasis imbalance in terms of the liver: From bench to bedside.

Tacrolimus (TAC), the mainstay of maintenance immunosuppressive agents, plays a crucial role in new-onset diabetes after transplant (NODAT). Previous studies investigating the diabetogenic effects of TAC have focused on the ß cells of islets. In this study, we found that TAC contributed to NODAT through directly affecting hepatic metabolic homeostasis. In mice, TAC-induced hypoglycemia rather than hyperglycemia during starvation via suppressing gluconeogenetic genes, suggesting the limitation of fasting blood glucose in the diagnosis of NODAT. In addition, TAC caused hepatic insulin resistance and triglyceride accumulation through insulin receptor substrate (IRS)2/AKT and sterol regulatory element binding protein (SREBP1) signaling, respectively. Furthermore, we found a pivotal role of CREB-regulated transcription coactivator 2 (CRTC2) in TAC-induced metabolic disorders. The restoration of hepatic CRTC2 alleviated the metabolic disorders through its downstream molecules (eg, PCK1, IRS2, and SREBP1). Consistent with the findings from bench, low CRTC2 expression in graft hepatocytes was an independent risk factor for NODAT (odds ratio = 2.692, P = .023, n = 135). Integrating grafts' CRTC2 score into the clinical model could significantly increase the predictive capacity (areas under the receiver operating characteristic curve: 0.71 vs 0.79, P = .048). Taken together, in addition to its impact on pancreatic cells, TAC induces "hematogenous diabetes" via CRTC2 signaling. Liver-targeted management may be of help to prevent or heal TAC-associated diabetes.

Psychometric properties and measurement invariance of the 7-item game addiction scale (GAS) among Chinese college students.

BACKGROUND: The 7-item Gaming Addiction Scale (GAS) has been used as a screening tool for addictive game use worldwide, and this study aimed to examine its psychometric properties and measurement invariance among college students in China. METHODS: Full-time students from multiple colleges in China were recruited. A total of 1040 completed questionnaires were used in the final analysis. Reliability of the GAS was assessed by internal consistency and split-half reliability. Validity of the GAS was assessed by structural validity, convergent validity, discriminant validity, and concurrent validity. A series of Multigroup Confirmatory Factor Analysis (MG-CFA) were conducted to test and establish measurement invariance across gender, class standing, family income and parental educational level. RESULTS: Exploratory factor analysis revealed a unidimensional structure of the GAS. The GAS exhibited excellent internal consistency (Cronbach's α = 0.951, theta coefficient = 0.953, omega coefficient = 0.959) and structural validity (χ2 /df = 0.877 (p < 0.05), CFI = 0.999, TIL = 0.996, RMSEA =0.000). Concurrent validity of the GAS was confirmed by its correlation with problematic internet use, sleep quality, nine dimensions of psychiatric symptoms, and substance use. The GAS also demonstrated measurement invariance across father's educational level (Δχ2 (df) = 19.128 (12), ΔCFI = - 0.009, ΔRMSEA = 0.010 for weak factorial model; Δχ2 (df) = 50.109 (42), ΔCFI = - 0.010, ΔRMSEA = 0.007 for strict factorial model.) and mother's educational level (Δχ2 (df) = 6.679 (12), ΔCFI = 0.007, ΔRMSEA = - 0.010 for weak factorial model; Δχ2 (df) =49.131 (42), ΔCFI = - 0.009, ΔRMSEA = - 0.004 for strict factorial model), as well as partial measurement invariance across gender (except for item 2), class standing (except for item 7) and family income (except for item 5). CONCLUSIONS: The Chinese version of the 7-item GAS can be an adequate assessment tool to assess internet gaming disorder among the college student population in China.

Altered microbiomes distinguish Alzheimer's disease from amnestic mild cognitive impairment and health in a Chinese cohort.

OBJECTIVE: (Background): Alzheimer's disease (AD), clinically characterized by the progressive neurodegenerative condition and cognitive impairment, is one of the main causes of disability in elder people worldwide. Recently, several animal studies indicated that the 'gut-brain' axis might contribute to the amyloid deposition of AD. However, data about gut dysbiosis in human AD remains scarce in the literature, especially including the whole process of AD. In this prospective and cross-sectional study, we aimed at identifying differences in microbiome between patients with AD (Pre-onset stage amnestic mild cognitive impairment, aMCI; and AD) and the normal cognition healthy controls (HC). Additionally, the potential association between IM and clinical characteristics of AD was evaluated. METHODS: A total of 97 subjects (33 AD, 32 aMCI, and 32 HC) were recruited in the study. The composition of gut bacterial communities was determined by 16S ribosomal RNA Miseq sequencing. In addition, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict function shift of intestinal microbiota. The Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) or Clinical Dementia Rating (CDR) scores were used to evaluate the severity of cognitive impairment in patients. RESULTS: The fecal microbial diversity was decreased in AD patients compared with aMCI patients and HC. And the microbial composition was distinct among aMCI, AD and healthy control groups. Among bacterial taxa, the proportion of phylum Firmicutes was significantly reduced (P = 0.008), whereas Proteobacteria (P = 0.024) was highly enriched in the AD compared with HC. In addition, similar alterations were observed at the order, class and family levels of these two phyla. And Gammaproteobacteria, Enterobacteriales and Enterobacteriaceae showed a progressive enriched prevalence from HC to aMCI and AD patients. Further, a significant correlation was observed between the clinical severity scores of AD patients and the abundance of altered microbiomes. Moreover, the KEGG results showed the increased modules related to glycan biosynthesis and metabolism in AD and aMCI patients and decreased pathways related to immune system in AD patients. Importantly, the discriminating models based on predominant microbiota could effectively distinguish aMCI and AD from HC (AUC = 0.890, 0.940, respectively), and also AD from aMCI (AUC = 0.925). Notably, the models based on the abundance of family Enterobacteriaceae could distinguish AD from both aMCI (AUC = 0.688) and HC (AUC = 0.698). CONCLUSIONS: Distinct microbial communities, especially enriched Enterobacteriaceae, were associated with patients with AD when compared with predementia stage aMCI and healthy subjects. These novel findings will give new clues to understand the disease and provide new therapeutic target for intervention or a marker for this disease.

Daratumumab added to standard of care in patients with newly diagnosed multiple myeloma: A network meta-analysis.

PURPOSE: To investigate the activity and safety of daratumumab added to standard of care and evaluate the relative efficacy of DRd vs DVMP and other regimens on survival endpoints for untreated myeloma, we undertook this meta-analysis. METHODS: We searched published reports that described the activity and safety of daratumumab added to standard of care for untreated myeloma. RESULTS: Six daratumumab trials were identified, covering 5106 subjects. Daratumumab containing combinations for untreated myeloma attained an impressive complete response or better (≥CR) rate of 24%, very good partial response or better (≥VGPR) rate of 67%, overall response rate (ORR) of 92%. Daratumumab added to standard of care significantly improved progression free survival (PFS): the HR for PFS was 0.52 [0.44, 0.61], P < .001. The HR for overall survival (OS) was 0.73 [0.52, 1.04], P = .09. In the network meta-analysis for patients ineligible for autologous stem-cell transplantation (ASCT), DRd regimen produced significant PFS advantage vs other first-line treatments (VMP HR:0.39 P < .001, Rd HR:0.55 P < .001, MPT HR:0.38 P < .001, and MP HR:0.22 P < .001); DVMP regimen also produced significant PFS advantage vs VMP (HR:0.50 P < .001), MPT (HR:0.49 P < .001), and MP (HR:0.28 P < .001). Among these first-line regimens (DRd, DVMP, VMP, Rd, MPT, and MP), DRd regimen had the highest probability to be the best intervention, with 83.4% and 91.0% probability to reach the longest PFS and OS, respectively. Toxicity consisted primarily of myelosuppression. And, the vital non-hematologic adverse events (AEs) were peripheral sensory neuropathy (41% of all grades) and upper respiratory tract infection (39% of all grades). CONCLUSIONS: Daratumumab added to standard of care could produce clinical benefits in newly diagnosed patients with multiple myeloma. DRd and DVMP could be good combination options for those patients ineligible for ASCT.

Pooled analysis of the reports of carfilzomib/ixazomib combinations for relapsed/refractory multiple myeloma.

We sought to evaluate the activity and safety of carfilzomib-/ixazomib-containing combinations for patients with relapsed/refractory multiple myeloma (RRMM). We searched published reports including carfilzomib-/ixazomib-containing combinations for RRMM. Finally, we identified 11 prospective studies covering 2845 relapsed/refractory patients. Carfilzomib- and ixazomib-containing combinations respectively resulted in an impressive overall response rate (ORR 77 vs. 64%, P = 0.14), very good partial response or better (≥ VGPR 48 vs. 21%, P = 0.001), complete response or better (≥ CR 14 vs. 7%, P = 0.23), and clinical benefit rate (CBR 84 vs. 59%, P = 0.0002). Subgroup analysis showed that the carfilzomib (CFZ) +lenalidomide (LEN) + dexamethasone (DEX) triplet regimen resulted into similar response outcomes to those from CFZ + DEX doublet regimen in ORR (77 vs. 78%, P = 0.91), ≥VGPR (50 vs. 53%, P = 0.84), and ≥ CR (13 vs. 12%, P = 0.96) analysis in these previously heavily pretreated population. And, there were no statistically significant differences between IXA + LEN + DEX triplet regimen and CFZ + LEN + DEX triplet regimen in ORR (85 vs. 78%, P = 0.55), ≥ VGPR (37 vs. 53%, P = 0.19), and ≥ CR (18 vs. 12%, P = 0.70) analysis. There were favorable trend towards proteasome inhibitors (PIs) + IMiDs + DEX in comparison with PIs + alkylating agent + Dex in ORR (79 vs 49%, P < 0.00001), ≥ VGPR analysis (36 vs. 16%, P = 0.008), and ≥ CR (16 vs. 3%, P < 0.00001). Compared with current standard chemotherapy, carfilzomib containing combinations clearly improved overall survival (HR, 0.79; P = 0.01), progression free survival (HR, 0.61; P = 0.0001). Carfilzomib-/ixazomib-containing combinations produced clinical benefit for patients with R/RMM. PIs + IMiDs + DEX triplet regimens could be good options for such relapsed/refractory patients.

TBLR1 fuses to retinoid acid receptor α in a variant t(3;17)(q26;q21) translocation of acute promyelocytic leukemia.

The majority of acute promyelocytic leukemia (APL) cases are characterized by the PML-RARα fusion gene. Although the PML-RARα fusion gene can be detected in >98% of APL cases, RARα is also found to be fused with other partner genes, which are also related to all-trans retinoic acid (ATRA)-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARα fusion gene, TBLR1-RARα (GenBank KF589333), in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q11.2;q21) complex chromosomal rearrangement. To our knowledge, TBLR1-RARα is the 10th RARα chimeric gene that has been reported up to now. TBLR1-RARα contained the B-F domains of RARα and exhibited a distinct subcellular localization. It could form homodimers and also heterodimers with retinoid X receptor α. As a result, TBLR1-RARα exhibited diminished transcriptional activity by recruitment of more transcriptional corepressors compared with RARα. In the presence of pharmacologic doses of ATRA, TBLR1-RARα could be degraded, and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARα could mediate the dissociation and degradation of transcriptional corepressors, consequent transactivation of RARα target genes, and cell differentiation induction in a dose- and time-dependent manner.

A modified prognostic score for critically ill patients with cirrhosis: An observational study.

BACKGROUND AND AIMS: It is controversial whether patients with cirrhosis benefit from the intensive care unit (ICU) management. To identify the patients in whom ICU care may offer recovery, this study aimed to determine specific risk factors and to establish a novel prognostic score for 3-month mortality in critically ill patients with cirrhosis. METHODS: An observational study was performed from August 2008 to May 2014, encompassing 349 critically ill patients with cirrhosis during their ICU stay (a 70% training and 30% validation set). RESULTS: The overall 3-month mortality rate was 68.1% in training cohort. Prothrombin time, serum bilirubin, use of vasopressors, hepatic encephalopathy, and systemic inflammatory response syndrome at admission were identified as being strongly correlated with the 3-month prognosis. Based on these five variables, a modified score for critically ill cirrhosis (MSCIC) was developed. An increasing MSCIC was significantly correlated with a reduction in the rate of survival (P < 0.001). Moreover, excellent predictive power was found when the MSCIC was used (area under the receiver operating characteristic curve: 0.856 ± 0.047), which was significantly better than the prognostic efficiency of Acute Physiology and Chronic Health Evaluation II (P < 0.001), Model for End-stage Liver Disease (P = 0.02), Simplified Acute Physiology Score (P = 0.023), and the Child-Turcotte-Pugh score (P = 0.01); the MSCIC score was slightly better than that of Chronic Liver Failure-Sequential Organ Failure Assessment (P = 0.068). The similar result was obtained in validation set. CONCLUSIONS: The MSCIC is an easily adopted tool with a high prognostic efficacy for patients with advanced cirrhosis; MSCIC may act as a supplement to the clinical judgment of physicians when considering the prognosis.

Alkaline amino acid modification based on biological phytic acid for preparing flame-retardant and antibacterial cellulose-based fabrics.

Cellulose-based fabrics have significant advantages, but their application scenarios are limited due to their flammability. This work used biomass phytic acid and protein decomposition products, alkaline amino acids (arginine, lysine, histidine) to prepare alkaline amino acid flame retardants (PALA, PALL, PALH), and they were utilized to endow Lyocell fabrics with flame-retardant and antibacterial properties. When the weight gain was about 16.0 wt%, PALA exhibited better flame-retardant effect, and the limited oxygen index value of PALA-Lyocell reached 47.1 %. In the cone calorimetry test, PALA showed the best flame-retardant efficiency in reducing flame growth index with a 92.0 % decrease in peak heat release rate. The results of thermogravimetric analysis coupled with Fourier Transform Infrared spectroscopy (TG-FTIR) and char residues indicated that the flame-retardant property of alkaline amino acid flame retardants was formed through the combined action of gas and condensed phases. In the antibacterial test, PALA had the highest antibacterial rate against Staphylococcus aureus at 97.2 %. Mechanical property, handle feeling, and whiteness results had indicated that alkaline amino acid based flame retardants had little effect on the physical properties of Lyocell fabrics. This work confirms alkaline amino acid based flame retardants have functions of flame-retardant and antibacterial properties, providing reference for the practical value of biomass in cellulose-based fabrics.

Intensified therapy followed by autologous stem-cell transplantation (ASCT) versus conventional therapy as first-line treatment of follicular lymphoma: a meta-analysis.

There are two different international standards for the treatment of follicular lymphoma (FL): intensified therapy followed by autologous stem-cell transplantation (ASCT) and conventional therapy in the first-line setting. However, their role remains unclear. Our aim was to define the treatment effect of intensified therapy followed by ASCT compared with conventional therapy as first-line treatment of patients with FL in terms of overall survival (OS) and event-free survival (EFS). We searched for randomised controlled trials in Medline, Embase, the Cochrane controlled trials register and the Science Citation Index (1985 to June 2011). Effect measures used were hazard ratios (HR) for OS, EFS and secondary tumour rate. Two independent review authors extracted data and assessed quality of trials. Four trials were identified, covering a total of 941 subjects. The random-effects summary HR by comparing the treatment effect on OS between intensified and conventional therapy was 0.95 [0.70, 1.30] (p = 0.75), indicating that no additional survival benefit was derived from the intensified therapy followed by ASCT. A significant benefit of intensified therapy followed by ASCT as first-line treatment was detected in terms of EFS: the random-effects summary HR (intensified versus conventional therapy) was 0.59 [0.44, 0.79] (p < 0.001). This meta-analysis showed that despite its superior EFS, intensified therapy followed by ASCT does not improve the OS compared with conventional therapy.

Dysbiosis signature of fecal microbiota in colorectal cancer patients.

The human gut microbiota is a complex system that is essential to the health of the host. Increasing evidence suggests that the gut microbiota may play an important role in the pathogenesis of colorectal cancer (CRC). In this study, we used pyrosequencing of the 16S rRNA gene V3 region to characterize the fecal microbiota of 19 patients with CRC and 20 healthy control subjects. The results revealed striking differences in fecal microbial population patterns between these two groups. Partial least-squares discriminant analysis showed that 17 phylotypes closely related to Bacteroides were enriched in the gut microbiota of CRC patients, whereas nine operational taxonomic units, represented by the butyrate-producing genera Faecalibacterium and Roseburia, were significantly less abundant. A positive correlation was observed between the abundance of Bacteroides species and CRC disease status (R = 0.462, P = 0.046 < 0.5). In addition, 16 genera were significantly more abundant in CRC samples than in controls, including potentially pathogenic Fusobacterium and Campylobacter species at genus level. The dysbiosis of fecal microbiota, characterized by the enrichment of potential pathogens and the decrease in butyrate-producing members, may therefore represent a specific microbial signature of CRC. A greater understanding of the dynamics of the fecal microbiota may assist in the development of novel fecal microbiome-related diagnostic tools for CRC.

Alterations in Faecal and Serum Metabolic Profiles in Patients with Neovascular Age-Related Macular Degeneration.

Neovascular age-related macular degeneration (nAMD) is a common and multifactorial disease in the elderly that may lead to irreversible vision loss; yet the pathogenesis of AMD remains unclear. In this study, nontargeted metabolomics profiling using ultra-performance liquid chromatography coupled with Q-Exactive Orbitrap mass spectrometry was applied to discover the metabolic feature differences in both faeces and serum samples between Chinese nonobese subjects with and without nAMD. In faecal samples, a total of 18 metabolites were significantly altered in nAMD patients, and metabolic dysregulations were prominently involved in glycerolipid metabolism and nicotinate and nicotinamide metabolism. In serum samples, a total of 29 differential metabolites were founded, involved in caffeine metabolism, biosynthesis of unsaturated fatty acids, and purine metabolism. Two faecal metabolites (palmitoyl ethanolamide and uridine) and three serum metabolites (4-hydroxybenzoic acid, adrenic acid, and palmitic acid) were selected as potential biomarkers for nAMD. Additionally, the significant correlations among dysregulated neuroprotective, antineuroinflammatory, or fatty acid metabolites in faecal and serum and IM dysbiosis were found. This comprehensive metabolomics study of faeces and serum samples showed that alterations in IM-mediated neuroprotective metabolites may be involved in the pathophysiology of AMD, offering IM-based nutritional therapeutic targets for nAMD.

Akkermansia muciniphila inhibits nonalcoholic steatohepatitis by orchestrating TLR2-activated γδT17 cell and macrophage polarization.

Current evidence indicates that the next-generation probiotic Akkermansia muciniphila (A. muciniphila) has therapeutic potential for nonalcoholic fatty liver disease (NAFLD), especially its inflammatory stage known as nonalcoholic steatohepatitis (NASH). However, the mechanisms of A. muciniphila in NASH prevention remain unknown. Here, A. muciniphila supplementation prevented hepatic inflammation in high-fat diet-induced NASH mice, characterized by reduced hepatic proinflammatory macrophages (M1) and γδT and γδT17 cells. Consistently, hepatic M1 and γδT cells were enriched in biopsy-proven NASH patients and high-fat/high-carbohydrate diet-induced NASH mice. Antibiotics reduced hepatic M1, γδT and γδT17 cells in NASH mice. Furthermore, A. muciniphila inhibited intestinal barrier disruption and accordingly downregulated hepatic Toll-like receptor 2 (TLR2) expression in NASH mice. The activation of TLR2 by lipoteichoic acid enriched hepatic γδT17 cells (not M1) in normal diet-fed mice and neutralized the γδT cell-lowering and liver inflammation-protecting effects of A. muciniphila in NASH mice. Additionally, activated γδT cells could promote macrophage polarization via IL-17. Our study first supported that A. muciniphila prevented NASH by modulating TLR2-activated γδT17 cells and further macrophage polarization, facilitating clinical therapeutic applications.

Healthy lifestyles in relation to cardiometabolic diseases among schoolteachers: A cross-sectional study.

Background: We aimed to explore the associations of adherence to an overall healthy lifestyle with cardiometabolic diseases (CMDs) among schoolteachers in China. Methods: We conducted a cross-sectional analysis among 2983 teachers (aged 39.8 ± 9.3 years, 73.8% women) in Zhejiang Province, China. A healthy lifestyle score (0-7) was constructed based on seven low-risk factors: healthy diet, noncurrent smoking, noncurrent drinking, regular exercise, normal body mass index (BMI), adequate sleep duration, and limited sedentary behavior. CMDs included self-reported hyperlipidemia, hypertension, diabetes, coronary heart disease, and stroke. Multivariable-adjusted logistic regression models were used to evaluate the associations between healthy lifestyle and CMD. Results: A total of 493 (16.5%) participants had at least one CMD, with hyperlipidemia, hypertension, and diabetes being the three leading CMDs. Each point increment in a healthy lifestyle score was associated with 20% lower odds of having CMD (p-trend < 0.001). Compared with 0-3 low-risk factors, the odds ratios (ORs) and 95% confidence intervals (CIs) were 0.66 (0.50-0.88) for 4 low-risk factors and 0.51 (0.39-0.67) for 5-7 low-risk factors. We observed independent associations for normal BMI (OR = 0.50, 95% CI = 0.40-0.63), noncurrent drinking (OR = 0.53, 95% CI = 0.36-0.77), and limited sedentary behavior (OR = 0.77, 95% CI = 0.62-0.96) in relation to CMD. Healthy diet (OR = 0.75, 95% CI = 0.55-1.01) exhibited marginally significant association with CMD. Conclusions: Our findings suggest that adherence to an overall healthy lifestyle is associated with lower odds of CMD among schoolteachers.

Dynamic Screening of Thyroid Function for the Timely Diagnosis of Congenital Hypothyroidism in Very Preterm Infants: A Prospective Multicenter Cohort Study.

Background: Preterm infants presented a high prevalence of congenital hypothyroidism (CH), while the optimal screening pattern is still under debate. This study aimed at evaluating the characteristics of thyroid function by conducting weekly screening during the first month of life in very preterm infants (VPIs) to achieve timely diagnosis and treatment of CH. Methods: A prospective cohort study was carried out on VPIs born with gestational age (GA) <32 weeks (w) and admitted to the participating institutes from January 1, 2019 to December 31, 2022. Serial serum thyroid hormone levels were measured weekly within the first month after birth, and at 36 w of corrected age, or before discharge. Datasets for serial thyroid hormone levels and general information were obtained. Results: A total of 5992 VPIs were enrolled in this study, of which 456 (7.6%) [95% confidence interval (CI), 6.9-8.3%] were diagnosed with CH. The incidence of CH increased with lower GA, moving from 4.8% [CI, 3.4-6.1%] at GA 31 w to 16.9% [CI, 8.3-25.4%] at GA <26 w. Among the CH subjects, 57.7% [CI, 53.1-62.2%] were identified after the first screening and classified as delayed thyrotropin elevation (dTSH). With the decrease of GA, the proportion of dTSH also increased, moving from 38.1% [CI, 27.5-48.7%] at GA 31 w to 82.6% [CI, 65.8-99.4%] at GA <26 w. Through conducting weekly screening of thyroid function, it was remarkable that only 42.3% [CI, 37.8-46.9%] of CH subjects were diagnosed during the first screening. The cumulative rate of CH identified by rescreening performed at the second, third, and fourth week was 76.1% [CI, 72.2-80.0%], 90.6% [CI, 87.9-93.3%], and 98.9% [CI, 97.9-99.9%], respectively. Conclusion: The incidence of CH and dTSH both increase with lower GA in VPIs. Dynamic screening of thyroid function by weeks within the first month of life is crucial for the timely diagnosis and treatment of CH in VPIs, and it might effectively reduce the implications of missed diagnosis and delayed treatment. Clinical Trials Registration: ChiCTR1900025234 and ChiCTR2000037918 (Registration number).

Metabonomic profiles discriminate hepatocellular carcinoma from liver cirrhosis by ultraperformance liquid chromatography-mass spectrometry.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and usually develops in patients with liver cirrhosis (LC). Biomarkers that discriminate HCC from LC are important but are limited. In the present study, an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS)-based metabonomics approach was used to characterize serum profiles from HCC (n = 82), LC (n = 48), and healthy subjects (n = 90), and the accuracy of UPLC-MS profiles and alpha-fetoprotein (AFP) levels were compared for their use in HCC diagnosis. By multivariate data and receiver operating characteristic curves analysis, metabolic profiles were capable of discriminating not only patients from the controls but also HCC from LC with 100% sensitivity and specificity. Thirteen potential biomarkers were identified and suggested that there were significant disturbances of key metabolic pathways, such as organic acids, phospholipids, fatty acids, bile acids, and gut flora metabolism, in HCC patients. Canavaninosuccinate was first identified as a metabolite that exhibited a significant decrease in LC and an increase in HCC. In addition, glycochenodeoxycholic acid was suggested to be an important indicator for HCC diagnosis and disease prognosis. UPLC-MS signatures, alone or in combination with AFP levels, could be an efficient and convenient tool for early diagnosis and screening of HCC in high-risk populations.

Characterization of fecal microbial communities in patients with liver cirrhosis.

UNLABELLED: Liver cirrhosis is the pathologic end stage of chronic liver disease. Increasing evidence suggests that gut flora is implicated in the pathogenesis of liver cirrhosis complications. The aim of this study was to characterize the fecal microbial community in patients with liver cirrhosis in comparison with healthy individuals. We recruited 36 patients with liver cirrhosis and 24 healthy controls. The fecal microbial communities was analyzed by way of 454 pyrosequencing of the 16S ribosomal RNA V3 region followed by real-time quantitative polymerase chain reaction. Community-wide changes of fecal microbiota in liver cirrhosis were observed compared with healthy controls. The proportion of phylum Bacteroidetes was significantly reduced (P=0.008), whereas Proteobacteria and Fusobacteria were highly enriched in the cirrhosis group (P=0.001 and 0.002, respectively). Enterobacteriaceae (P=0.001), Veillonellaceae (P=0.046), and Streptococcaceae (P=0.001) were prevalent in patients with cirrhosis at the family level. A positive correlation was observed between Child-Turcotte-Pugh (CTP) score and Streptococcaceae (R=0.386, P=0.02). Lachnospiraceae decreased significantly in patients with cirrhosis (P=0.004) and correlated negatively with CTP score (R=-0.49, P=0.002). Using partial least square discriminate analysis, we identified 149 operational taxonomic units (OTUs) as key phylotypes that responded to cirrhosis, most of which were Lachnospiraceae (65 OTUs), Streptococcaceae (23 OTUs), and Veillonellaceae (21 OTUs). CONCLUSION: Fecal microbial communities are distinct in patients with cirrhosis compared with healthy individuals. The prevalence of potentially pathogenic bacteria, such as Enterobacteriaceae and Streptococcaceae, with the reduction of beneficial populations such as Lachnospiraceae in patients with cirrhosis may affect prognosis.

Novel agents-based regimens as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials.

To investigate the effect of novel agents like bortezomib, lenalidomide and thalidomide as part of induction treatment prior to autologous stem-cell transplantation (ASCT) for previously untreated patients with multiple myeloma, we performed a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, the Cochrane controlled trials register and the Science Citation Index were searched for RCTs of novel agents as part of induction therapy before ASCT. Three RCTs of bortezomib, two RCTs of thalidomide and no RCT of lenalidomide were identified, covering a total of 2,316 subjects. Due to different mechanisms of action, we performed a subgroup analysis by type of agent (thalidomide or bortezomib). The weighted risk ratios of a complete response (CR) were 4.25 [95% CI: 2.44-7.41] (p < 0.001) for bortezomib and 1.66 [95% CI: 1.15-2.38] (p = 0.007) for thalidomide, respectively. The summary hazard ratios for progression-free survival (PFS) were 0.73 [95% CI: 0.59-0.89] (p = 0.002) for bortezomib and 0.68 [95% CI: 0.59-0.79] (p < 0.001) for thalidomide, respectively. The corresponding ratios for overall survival (OS) were 0.87 [95% CI: 0.64-1.18] (p = 0.37) and 0.88 [95% CI: 0.73-1.05] (p = 0.14), respectively. Additionally, there was a statistically significant heterogeneity between subgroups (thalidomide and bortezomib) for CR (p = 0.005) but nonsignificant for PFS (p = 0.64) and OS (p = 0.97). In conclusion, our analysis showed novel agents as induction treatment prior to ASCT improved CR and PFS but not OS.

Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus-induced chronic liver disease.

The beneficial effects of Bifidobacteria on health have been widely accepted. Patients with chronic liver disease have varying degrees of intestinal microflora imbalance with a decrease of total Bifidobacterial counts. Since different properties have been attributed to different Bifidobacterium species and there is no information available for the detailed changes in the genus Bifidobacterium in patients with chronic liver disease heretofore, it is meaningful to investigate the structure of this bacterium at the species level in these patients. The aim of this study was to characterize the composition of intestinal Bifidobacterium in patients with hepatitis B virus-induced chronic liver disease. Nested-PCR-based denaturing gradient gel electrophoresis (PCR-DGGE), clone library, and real-time quantitative PCR were performed on the fecal samples of 16 patients with chronic hepatitis B (CHB patients), 16 patients with hepatitis B virus-related cirrhosis (HBV cirrhotics), and 15 healthy subjects (Controls). Though there was no significant difference in the diversity among the three groups (P = 0.196), Bifidobacterium dentium seems to be specifically enhanced in patients as the PCR-DGGE profiles showed, which was further validated by clone library and real-time quantitative PCR. In contrast to the B. dentium, Bifidobacterium catenulatum/Bifidobacterium pseudocatenulatum were detected less frequently in the predominant profile and by quantitative PCR in HBV cirrhotics than in the controls, and the level of this species was also significantly different between these two groups (P = 0.023). Although having no quantitative difference among the three groups, Bifidobacterium longum was less commonly detected in HBV cirrhotics than in CHB patients and Controls by quantitative PCR (P = 0.011). Thus, the composition of intestinal Bifidobacterium was deeply altered in CHB and HBV cirrhotic patients with a shift from beneficial species to opportunistic pathogens. The results provide further insights into the dysbiosis of the intestinal microbiota in patients with hepatitis B virus-induced chronic liver disease and might potentially serve as guidance for the probiotics interventions of these diseases.

Identification of potential immune/diagnosis related gene-immunocyte subtype networks in extracellular immune response to respiratory syncytial virus infection.

INTRODUCTION: Respiratory syncytial virus (RSV) is one of the important pathogenic agents of pediatric respiratory tract infection. Weighted gene co-expression network analysis (WGCNA) is used to study autoimmune diseases, which can find potential hub genes. The diagnostic model based on hub genes and machine learning makes it possible to diagnose the extracellular immune response to RSV infection early. OBJECTIVE: The aim of the present study was to identify potential immune, diagnose and treatment related genes expressed in RSV-infected cells. METHODS: Firstly, gene expression data were downloaded from the Gene Expression Omnibus (GEO) to identify differentially expressed genes (DEGs). Secondly, WGCNA was performed based on DEGs to obtain hub genes related to immunity score. Thirdly, protein-protein interaction (PPI) and the immune infiltration analysis of hub immune related genes were performed. Finally, diagnostic and immune related genes were identified by machine learning, followed by functional analysis. RESULTS: Totally, 2063 DEGs were identified in the extracellular immune response to RSV infection. Among which, 10 key immune and diagnosis related genes were identified, including ITGA2B, GP9, ITGB3, SELP, PPBP, MPL, CXCL8, NFE2, PTGS1 and LY6G6F. Several immune/diagnosis related gene-immunocyte subtype networks were identified, such as CXCL8-Type 17 T helper cell, LY6G6F-CD56 bright natural killer cell, PPBP-activated CD4 T cell/T follicular helper cell, NFE2/PTGS1/SELP-activated dendritic cell, GP9/ITGA2B/MPL-activated CD8 T cell. ITGB3, MPL and PTGS1 could be considered as therapeutic targets. Some significantly enriched signaling pathways were identified, including hematopoietic cell lineage (involving GP9 and ITGA2B), cytokine-cytokine receptor interaction (involving MPL), chemokine signaling pathway (involving PPBP) and arachidonic acid metabolism (involving PTGS1). CONCLUSIONS: The 10-immune related gene signature may be used as potential diagnostic markers for the extracellular immune response to RSV infection, which may provide a new field in searching for diagnostic and therapeutic molecules in the extracellular immune response to RSV infection.