SEU2-Net: multi-scale U2-Net with SE attention mechanism for liver occupying lesion CT image segmentation.

Liver occupying lesions can profoundly impact an individual's health and well-being. To assist physicians in the diagnosis and treatment of abnormal areas in the liver, we propose a novel network named SEU2-Net by introducing the channel attention mechanism into U2-Net for accurate and automatic liver occupying lesion segmentation. We design the Residual U-block with Squeeze-and-Excitation (SE-RSU), which is to add the Squeeze-and-Excitation (SE) attention mechanism at the residual connections of the Residual U-blocks (RSU, the component unit of U2-Net). SEU2-Net not only retains the advantages of U2-Net in capturing contextual information at multiple scales, but can also adaptively recalibrate channel feature responses to emphasize useful feature information according to the channel attention mechanism. In addition, we present a new abdominal CT dataset for liver occupying lesion segmentation from Peking University First Hospital's clinical data (PUFH dataset). We evaluate the proposed method and compare it with eight deep learning networks on the PUFH and the Liver Tumor Segmentation Challenge (LiTS) datasets. The experimental results show that SEU2-Net has state-of-the-art performance and good robustness in liver occupying lesions segmentation.

T-Cell Receptor ß Chain and B-Cell Receptor Repertoires in Chronic Hepatitis B Patients with Coexisting HBsAg and Anti-HBs.

Antibodies in response to antigens are related to the immune repertoire of T- and B-cell receptors. However, some patients with chronic hepatitis B (CHB) have coexisting HBsAg and anti-HBsAg antibodies (anti-HBs) that cannot neutralize HBV. We attempted to investigate the repertoires that produce this response in CHB patients. The T-cell receptor ß chain (TRB) and B-cell receptor (BCR) repertoires of peripheral blood genomic DNA were analyzed using MiXCR. T-cell receptor (TCR) cluster analysis was carried out by clusTCR, and motifs prediction was selected by Multiple Em for Motif Elicitation (MEME). A total of 76 subjects were enrolled, including 26 HBsAg and anti-HBs coexisting patients with CHB (DP group), 25 anti-HBs single-positive healthy people (SP group), and 25 CHB patients (CHB group). The clone length of BCR in 39, 90 was significantly different among these groups (p = 0.005, 0.036). The motif "CASSLG" in the DP group was significantly higher than SP and CHB groups and may relate to coexistence, and the motif "GAGPLT" was only shown in the SP group and may relate to anti-HB expression. These provide important insights into vaccine development and CHB treatment.

The Emerging Role of Branched-Chain Amino Acids in Liver Diseases.

Chronic liver diseases pose a substantial health burden worldwide, with approximately two million deaths each year. Branched-chain amino acids (BCAAs)-valine, leucine, and isoleucine-are a group of essential amino acids that are essential for human health. Despite the necessity of a dietary intake of BCAA, emerging data indicate the undeniable correlation between elevated circulating BCAA levels and chronic liver diseases, including non-alcoholic fatty liver diseases (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC). Moreover, circulatory BCAAs were positively associated with a higher cholesterol level, liver fat content, and insulin resistance (IR). However, BCAA supplementation was found to provide positive outcomes in cirrhosis and HCC patients. This review will attempt to address the contradictory claims found in the literature, with a special focus on BCAAs' distribution, key signaling pathways, and the modulation of gut microbiota. This should provide a better understanding of BCAAs' possible contribution to liver health.

Human immune repertoire in hepatitis B virus infection.

Hepatitis B virus (HBV) infection is a public health threat that affects 257 million people worldwide and can progress to liver cirrhosis, liver failure, and hepatocellular carcinoma. The HBV antigen- induced adaptive immune response plays an important role in HBV clearance. Immune repertoire sequencing (IRS) has been used to investigate the molecular mechanisms behind the immune system, find novel ways to treat HBV infection, and evaluate the genetic responses and immune characteristics of individuals infected by HBV or immunized by HBV vaccine. This review summarizes the human immune repertoire analysis methodology, and the application of the IRS in the prediction of HBV infection progression, treatment, and vaccination.

Clinical Aspects of Gut Microbiota in Hepatocellular Carcinoma Management.

Liver cancer, predominantly hepatocellular carcinoma (HCC), is the third leading cause of cancer-related deaths worldwide. Emerging data highlight the importance of gut homeostasis in the pathogenesis of HCC. Clinical and translational studies revealed the patterns of dysbiosis in HCC patients and their potential role for HCC diagnosis. Research on underlying mechanisms of dysbiosis in HCC development pointed out the direction for improving the treatment and prevention. Despite missing clinical studies, animal models showed that modulation of the gut microbiota by probiotics may become a new way to treat or prevent HCC development.

Human genetic susceptibility to hepatitis B virus infection.

Hepatitis B virus (HBV) infection is still a serious health threat worldwide. The outcomes of HBV infection consist of spontaneous HBV clearance and chronic HBV infection. Multiple factors contribute to the disparity of HBV infection outcomes, including host factors, viral factors and environmental factors. The present review comprehends the current researches mainly focusing on the relationships between genetic determinants, including single nucleotide polymorphisms (SNPs) and haplotypes, and susceptibility of HBV infection, namely chronic (persistent) HBV infection and HBV clearance. A number of determinants in the chromosomes, including mutations in human leukocyte antigens (HLAs), cytokines genes, toll-like receptors (TLRs), and other genes are related to the human susceptibility to HBV infection. Among the above variants, some of those in HLAs have been studied and replicated in multiple-ethnic populations and came to consistent conclusions, while some others are novel and need to be evaluated further.

Efficacy of serum miRNA test as a non-invasive method to diagnose nonalcoholic steatohepatitis: a systematic review and meta-analysis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a key turning point during the progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have shown that serum miRNA tests may be effective in the diagnosis of NAFLD. We conducted a meta-analysis to assess the evidence for the diagnostic efficacy of serum miRNAs in patients with NAFLD and its subtype, NASH, in particular. METHODS: After a systematic review, sensitivity, specificity, and area under the receiver operating characteristics curve (AUROC) were pooled to determine the efficacy of serum miRNA test for the diagnosis of NAFLD and NASH. Clinical utility was evaluated by Fagan's nomogram and likelihood ratio scattergram. Heterogeneity was evaluated by subgroup analysis and meta-regression. Publication bias was detected by Deeks' funnel plot. RESULTS: We included 27 trials containing 1775 NAFLD patients (including simple steatosis and NASH) and 586 NASH patients. For NAFLD vs NASH, the pooled sensitivity, specificity, and AUROC were (0.71 vs. 0.74), (0.76 vs. 0.85) and (0.80 vs. 0.86), respectively. Serum miRNA had high accuracy for distinguishing NASH from simple steatosis, with an AUROC of 0.91. Among the most commonly studied serum miRNAs, miRNA-34a showed moderate diagnostic accuracy for NAFLD and the lowest heterogeneity (sensitivity I2 = 5.73%, specificity I2 = 33.16%, AUROC = 0.85). According to subgroup analysis and meta-regression, a lower BMI (< 30 kg/m2) might be a crucial source of heterogeneity. CONCLUSIONS: As a novel non-invasive method, serum miRNA test exhibited robust diagnostic efficacy for NASH. Among these well-studied miRNAs, miRNA-34a was more available for diagnosis. Diagnosis of NAFLD by serum miRNA is more likely to be accurate in patients with BMI ≥ 30 kg/m2.

Survival and time to initiation of adjuvant chemotherapy among breast cancer patients: a systematic review and meta-analysis.

The relationship between survival and time to the start of adjuvant chemotherapy (AC) among breast cancer patients is unclear. In order to illustrate the effect of delaying the initiation of AC on survival we have undertaken a systematic review and meta-analysis. We identified 12 available studies in the meta-analysis including 15 independent analytical groups. This meta-analysis showed that a 4-week delay before AC was associated with a significantly worse overall survival (OS)(HR=1.13; 95% confidence interval [CI], 1.08-1.19) and disease free survival (DFS)(HR=1.14; 95%CI, 1.05-1.24). Two studies categorized patients into hormone receptor-positive, ERBB2-positive, and triple-negative breast cancer (TNBC) patients according to the clinicopathological features of breast cancer. The HRs for OS between waiting time (WT) ≤30 days and 31-60 days in the subgroups were extracted and analyzed. The analysis demonstrated that a WT of 31-60 days was related to worse OS among patients with TNBC (HR, 1.26; 95% CI, 1.08-1.48), but had no significant effect on OS among those with hormone receptor-positive (HR, 1.02; 95% CI, 0.89-1.15) or ERBB2-postive (HR, 0.95; 95%CI, 0.79-1.14) tumors. In this meta-analysis of the eligible literatures reviewing the time to AC, a longer waiting time to adjuvant chemotherapy may lead to worse survival in breast cancer patients, especially in TNBC patients.

Pharmacokinetics of surotomycin from phase 1 single and multiple ascending dose studies in healthy volunteers.

BACKGROUND: Surotomycin, a novel, orally administered, cyclic, lipopeptide antibacterial in development for the treatment of Clostridium difficile-associated diarrhea, has demonstrated minimal intestinal absorption in animal models. METHODS: Safety, tolerability, and plasma pharmacokinetics of single and multiple ascending oral doses (SAD/MAD) of surotomycin in healthy volunteers were characterized in two randomized, double-blind, placebo-controlled, phase 1 studies. RESULTS: Participants were sequentially enrolled into one of four SAD (500, 1000, 2000, 4000 mg surotomycin) or three MAD (250, 500, 1000 mg surotomycin twice/day for 14 days) cohorts. Ten subjects were randomized 4:1 into each cohort to receive surotomycin or placebo. Surotomycin plasma concentrations rose as dose increased (maximum plasma concentration [Cmax]: 10.5, 21.5, 66.6, and 86.7 ng/mL). Systemic levels were generally low, with peak median surotomycin plasma concentrations observed 6-12 h after the first dose. In the MAD study, surotomycin plasma concentrations were higher on day 14 (Cmax: 25.5, 37.6, and 93.5 ng/mL) than on day 1 (Cmax: 6.8, 11.0, and 21.1 ng/mL for increasing doses), indicating accumulation. In the SAD study, <0.01% of the administered dose was recovered in urine. Mean surotomycin stool concentration from the 1000 mg MAD cohort was 6394 µg/g on day 5. Both cohorts were well tolerated with all adverse events reported as mild to moderate. CONCLUSION: Both SAD and MAD studies of surotomycin demonstrated minimal systemic exposure, with feces the primary route of elimination following oral administration; consistent with observations with similar compounds, such as fidaxomicin. Results of these phase 1 studies support the continued clinical development of surotomycin for the treatment of Clostridium difficile-associated diarrhea. TRIAL REGISTRATION: NCT02835118 and NCT02835105 . Retrospectively registered, July 13 2016.

Metabolism and disposition of 2-methoxy-4-nitroaniline in male and female Harlan Sprague Dawley rats and B6C3F1/N mice.

The disposition of 2-Methoxy-4-nitroaniline (MNA) was investigated in male and female Harlan Sprague Dawley rats and B6C3F(1)/N mice following oral, intravenous, and dermal exposure to [(14)C]MNA at 2, 15, or 150 mg/kg. Clearance of MNA was investigated in male and female rat, mouse, and human hepatocytes. MNA was cleared slowly in hepatocytes from rat (t(1/2) = 152-424 min) and human (t(1/2) = 118-403 min) but faster in mouse (t(1/2)= 70-106 min). MNA was well-absorbed in rats and mice following oral administration and eliminated chiefly in urine (rats, 75-79%; mice, 55-68%) 72 h post dosing. Less than 1% of the radioactivity remained in tissues at 72 h. MNA was poorly absorbed following dermal application in rats (5.5%) and mice (10%) over 24 h. The major pathway of metabolism of MNA was via hydroxylation of the phenyl ring to form 6-hydroxy MNA; major metabolites detected were sulfate and glucuronide conjugates of 6-hydroxy MNA. Following oral administration, the percent of total radioactivity bound in tissues bound was highest in liver (43%) and red blood cells (30%), whereas the radioactivity bound to DNA was highest in cecum (160 pmol/mg DNA).

Identification of [14C]fluasterone metabolites in urine and feces collected from dogs after subcutaneous and oral administration of [14C]fluasterone.

The objective of this research was the identification of the metabolic profile of fluasterone, a synthetic derivative of dehydroepiandrosterone, in dogs treated orally or subcutaneously with [4-(14)C]fluasterone. Separation and characterization techniques used to identify the principal metabolites of fluasterone in urine and feces included high-performance liquid chromatography (HPLC), liquid scintillation spectrometry, HPLC/tandem mass spectrometry, and NMR. In urine, the majority of the radioactivity was present as two components that had apparent molecular weights consistent with their tentative identification as monoglucuronide conjugates of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol and X(alpha or beta)-4alpha-dihydroxy-16alpha-fluoro-5-androsten-17beta-ol. The identification of the monoglucuronide conjugate of 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol was also supported by NMR data. In support of this identification, these metabolites were cleaved with glucuronidase enzyme treatment, which gave rise to components with molecular weights again consistent with the aglycones of a monohydroxylated, 17-keto reduced (dihydroxy) fluasterone metabolite and a dihydroxylated, 17-keto reduced (trihydroxy) fluasterone metabolite. In feces, nonconjugated material predominated. The primary metabolites eliminated in feces were the two hydroxy fluasterone metabolites arising from 17-reduction (16alpha-fluoro-5-androsten-17beta-ol and 16alpha-fluoro-5-androsten-17alpha-ol) and 4alpha-hydroxy-16alpha-fluoro-5-androsten-17beta-ol that was present in urine in glucuronide form.