Deficient chaperone-mediated autophagy in macrophage aggravates inflammation of nonalcoholic steatohepatitis by targeting Nup85.

BACKGROUND & AIMS: Nonalcoholic steatohepatitis (NASH), a more severe subtype of nonalcoholic fatty liver disease, can cause cirrhosis and hepatocellular carcinoma. Macrophages play critical roles in initiating and maintaining NASH-induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone-mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage-specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment. METHODS: The CMA function of liver macrophages was detected using Western blot, quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and flow cytometry. By constructing myeloid-specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label-free mass spectrometry was utilized to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, Western blot and RT-qPCR. RESULTS: A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte-derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver-targeted recruitment of monocyte and promoted steatosis and fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA-deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice. CONCLUSIONS: We proposed that the impaired CMA-induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH.

Digital learning in medical education: comparing experiences of Malaysian and Japanese students.

BACKGROUND: Medical education has undergone a transformation from conventional to digital learning, enabling learning without any time and place restrictions. Nevertheless, the actual trends of usage and its impact on learning motivation among medical students between developed and developing nations are yet to be investigated. Hence, this study compares the effect of digital learning on learning motivation among Malaysian and Japanese medical students in Universiti Kebangsaan Malaysia (UKM) and Shiga University of Medical Science (SUMS) respectively. METHODS: A modified Students Motivation towards Science Learning (SMTSL) was used to assess the digital learning usage and learning motivation among 150 UKM and 147 SUMS medical students throughout Year 1 to 5. RESULTS: The frequency of digital learning usage and learning motivation among UKM medical students was significantly higher as compared to SUMS (p < 0.001). Electronic books (e-books) were the most preferred source of digital learning among UKM medical students as compared to SUMS medical students who used research articles, e-books, online courses and videos at similar frequencies. UKM medical students in the clinical phase exhibited a significantly higher learning motivation as compared to preclinical students (p < 0.05) but not among SUMS medical students. CONCLUSION: A suitable learning environment should be developed to encourage digital learning usage among different levels of medical students to enhance its complementary role in medical education and augment the level of motivation among medical students in continuous lifelong learning.

Pure laparoscopic living donor hepatectomy: Focus on 55 donors undergoing right hepatectomy.

Although laparoscopic donor hepatectomy is increasingly common, few centers with substantial experience have reported the results of pure laparoscopic donor right hepatectomy (PLDRH). Here, we report the experiences of 60 consecutive liver donors undergoing pure laparoscopic donor hepatectomy (PLDH), with most undergoing right hepatectomy. None of the 60 donors who underwent PLDH had intraoperative complications and none required transfusions, reoperation, or conversion to open hepatectomy. Forty-five donors who underwent PLDRH between November 2015 and December 2016 were compared with 42 who underwent conventional donor right hepatectomy (CDRH) between May 2013 and February 2014. The total operation time was longer (330.7 vs 280.0 minutes; P < .001) and the percentage with multiple bile duct openings was higher (53.3% vs 26.2%; P = .010) in the PLDRH group. However, the length of postoperative hospital stay (8.4 vs 8.2 days; P = .495) and rate of complications (11.9% vs 8.9%; P = .733) and re-hospitalizations (4.8% vs 4.4%; P = 1.000) were similar in both groups. PLDH, including PLDRH, is feasible when performed by a highly experienced surgeon and transplant team. Further evaluation, including long-term results, may support these preliminary findings of comparative outcomes for donors undergoing PLDRH and CDRH.

Initial experience with purely laparoscopic living-donor right hepatectomy.

BACKGROUND: There may be concerns about purely laparoscopic donor right hepatectomy (PLDRH) compared with open donor right hepatectomy, especially when performed by surgeons accustomed to open surgery. This study aimed to describe technical tips and pitfalls in PLDRH. METHODS: Data from donors who underwent PLDRH at Seoul National University Hospital between December 2015 and July 2017 were analysed retrospectively. Endpoints analysed included intraoperative events and postoperative complications. All operations were performed by a single surgeon with considerable experience in open living donor hepatectomy. RESULTS: A total of 26 donors underwent purely laparoscopic right hepatectomy in the study interval. No donor required transfusion during surgery, whereas two underwent reoperation. In two donors, the dissection plane at the right upper deep portion of the midplane was not correct. One donor experienced portal vein injury during caudate lobe transection, and one developed remnant left hepatic duct stenosis. One donor experienced remnant portal vein angulation owing to a different approach angle, and one experienced arterial damage associated with the use of a laparoscopic energy device. One donor had postoperative bleeding due to masking of potential bleeding foci owing to intra-abdominal pressure during laparoscopy. Two donors experienced right liver surface damage caused by a xiphoid trocar. CONCLUSION: Purely laparoscopic donor hepatectomy differs from open donor hepatectomy in terms of angle and caudal view. Therefore, surgeons experienced in open donor hepatectomy must gain adequate experience in laparoscopic liver surgery and make adjustments when performing PLDRH.

Survival benefit of liver resection for Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma.

BACKGROUND: Although transarterial chemoembolization is recommended as the standard treatment for Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma (BCLC-B HCC), other treatments including liver resection have been used. This study aimed to determine the survival benefit of treatment strategies including resection for BCLC-B HCC compared with non-surgical treatments. METHODS: The nationwide multicentre database of the Korean Liver Cancer Association was reviewed. Patients with BCLC-B HCC who underwent liver resection as a first or second treatment within 2 years of diagnosis and patients who received non-surgical treatment were selected randomly. Survival outcomes of propensity score-matched groups were compared. RESULTS: Among 887 randomly selected patients with BCLC-B HCC, 83 underwent liver resection as first or second treatment and 597 had non-surgical treatment. After propensity score matching, the two groups were well balanced (80 patients in each group). Overall median survival in the resection group was better than that for patients receiving non-surgical treatment (50·9 versus 22·1 months respectively; P < 0·001). The 1-, 2-, 3- and 5-year overall survival rates in the resection group were 90, 88, 75 and 63 per cent, compared with 79, 48, 35 and 22 per cent in the no-surgery group (P < 0·001). In multivariable analysis, non-surgical treatment only (hazard ratio (HR) 3·35, 95 per cent c.i. 2·16 to 5·19; P < 0·001), albumin level below 3·5 g/dl (HR 1·96, 1·22 to 3·15; P = 0·005) and largest tumour size greater than 5·0 cm (HR 1·81, 1·20 to 2·75; P = 0·005) were independent predictors of worse overall survival. CONCLUSION: Treatment strategies that include liver resection offer a survival benefit compared with non-surgical treatments for potentially resectable BCLC-B HCC.

Effects of microencapsulated Lactobacillus plantarum LIP-1 on the gut microbiota of hyperlipidaemic rats.

The in vivo effects of administering free and microencapsulated Lactobacillus plantarum LIP-1 cells (2·0×109 colony-forming units/d) were evaluated in high-fat-diet-induced hyperlipidaemic rats. Results from real-time quantitative PCR targeting to LIP-1 cells showed a higher colon colonisation count of LIP-1 in the rats receiving microencapsulated cells compared with free cells (P<0·05). Moreover, the microencapsulated LIP-1 treatment resulted in a more obvious lipid-lowering effect (P<0·05). Meanwhile, their faecal samples had significantly less lipopolysaccharide-producing bacteria (especially Bilophila, Sutterella and Oscillibacter) and mucosa-damaging bacteria (Bilophila and Akkermansia muciniphila), whereas significantly more SCFA-producing bacteria (P<0·05) (namely Lactobacillus, Alloprevotella, Coprococcus, Eubacterium and Ruminococcus) and bacteria that potentially possessed bile salt hydrolase activity (Bacteroides, Clostridium, Eubacterium and Lactobacillus), and other beneficial bacteria (Alistipes and Turicibacter). Further, Spearman's correlation analysis showed significant correlations between some of the modulated gut bacteria and the serum lipid levels. These results together confirm that microcapsulation enhanced the colon colonisation of LIP-1 cells, which subsequently exhibited more pronounced effects in improving the gut microbiota composition of hyperlipidaemic rats and lipid reduction.

Early Secreted Antigenic Target of 6 kDa of Mycobacterium tuberculosis Stimulates Macrophage Chemoattractant Protein-1 Production by Macrophages and Its Regulation by p38 Mitogen-Activated Protein Kinases and Interleukin-4.

Early secreted antigenic target of 6 kDa (ESAT-6), the major virulence factor of Mycobacterium tuberculosis, affects host immunity and the formation of granulomas likely through inflammatory cytokines. To understand its role in this regard further, we investigated the effect of ESAT-6 on macrophages by determining the production of macrophage chemoattractant protein (MCP)-1, a major chemokine associated with tuberculosis pathogenesis, by murine bone marrow-derived macrophages (BMDMs) and its regulation by protein kinases and cytokines. The results revealed that ESAT-6, but not Ag85A and culture filtrate protein 10 kDa (CFP10), induced MCP-1 production by BMDMs dose and time dependently. Inhibition of p38 but not other mitogen-activated protein kinases (MAPK) and PI3K further enhanced ESAT-6-induced MCP-1 production by BMDMs. Inhibition of p38 MAPK enhanced ESAT-6-induced MCP-1 mRNA accumulation without affecting mRNA stability. ESAT-6 also induced TNF-α from BMDMs and MCP-1 from mouse lung epithelial cells, and these were suppressed by p38 MAPK inhibition, implying cytokine- and cell-specific effect of p38 MAPK inhibition on ESAT-6-induced MCP-1 by macrophages. Pretreatment of BMDMs with IL-4, but not other cytokines (IL-2, IL-10, TNF-α, IFN-γ and IL-1α) further elevated ESAT-6-stimulated MCP-1 production although IL-4 did not induce MCP-1 without ESAT-6. Both p38 MAPK inhibitor and IL-4 did not show additive effect on ESAT-6-induced MCP-1 protein level despite such effect on MCP-1 mRNA level was evident. In conclusion, these results indicate a specific role for both p38 MAPK and IL-4 in ESAT-6-induced MCP-1 production by macrophages and suggest a pathway with significance in tuberculosis pathogenesis.

Carbon dioxide capture and utilization: using dinuclear catalysts to prepare polycarbonates.

The copolymerization of epoxides, including cyclohexene oxide and vinyl-cyclohexene oxide with carbon dioxide are presented. These processes are catalyzed using a homogeneous di-zinc complex that shows good activity and very high selectivities for polycarbonate polyol formation. The polymerizations are investigated in the presence of different amounts of exogenous reagents, including water, diols and diamines, as models for common contaminants in any carbon dioxide capture and utilization scenario.

Effect of exposure routes on the relationships of lethal toxicity to rats from oral, intravenous, intraperitoneal and intramuscular routes.

The lethal toxicity values (log 1/LD(50)) of 527 aliphatic and aromatic compounds in oral, intravenous, intramuscular and intraperitoneal routes were used to investigate the relationships of log 1/LD(50) from different exposure routes. Regression analysis shows that the log 1/LD(50) values are well correlated between intravenous and intraperitoneal or intramuscular injections. However, the correlations between oral and intravenous or intraperitoneal routes are relatively poor. Comparison of the average residuals indicates that intravenous injection is the most sensitive exposure route and oral administration is the least sensitive exposure route. This is attributed to the difference in kinetic process of toxicity testing. The toxic effect of a chemical can be similar or significantly different between exposure routes, depending on the absorption rates of chemicals into blood. Inclusion of hydrophobic parameter and fractions of ionic forms can improve the correlations between intravenous and intraperitoneal or oral routes, but not between intraperitoneal and oral routes. This is due to the differences of absorption rate in different exposure environments from different routes. Several factors, such as experimental uncertainty, metabolism and toxic kinetics, can affect the correlations between intravenous and intraperitoneal or oral routes.

Genetic association analysis of 30 genes related to obesity in a European American population.

OBJECTIVE: Obesity, which is frequently associated with diabetes, hypertension and cardiovascular diseases, is primarily the result of a net excess of caloric intake over energy expenditure. Human obesity is highly heritable, but the specific genes mediating susceptibility in non-syndromic obesity remain unclear. We tested candidate genes in pathways related to food intake and energy expenditure for association with body mass index (BMI). METHODS: We reanalyzed 355 common genetic variants of 30 candidate genes in seven molecular pathways related to obesity in 1982 unrelated European Americans from the New York Cancer Project. Data were analyzed by using a Bayesian hierarchical generalized linear model. The BMIs were log-transformed and then adjusted for covariates, including age, age(2), gender and diabetes status. The single-nucleotide polymorphisms (SNPs) were modeled as additive effects. RESULTS: With the stipulated adjustments, nine SNPs in eight genes were significantly associated with BMI: ghrelin (GHRL; rs35683), agouti-related peptide (AGRP; rs5030980), carboxypeptidase E (CPE; rs1946816 and rs4481204), glucagon-like peptide-1 receptor (GLP1R; rs2268641), serotonin receptors (HTR2A; rs912127), neuropeptide Y receptor (NPY5R;Y5R1c52), suppressor of cytokine signaling 3 (SOCS3; rs4969170) and signal transducer and activator of transcription 3 (STAT3; rs4796793). We also found a gender-by-SNP interaction (rs1745837 in HTR2A), which indicated that variants in the gene HTR2A had a stronger association with BMI in males. In addition, NPY1R was detected as having a significant gene effect even though none of the SNPs in this gene was significant. CONCLUSION: Variations in genes AGRP, CPE, GHRL, GLP1R, HTR2A, NPY1R, NPY5R, SOCS3 and STAT3 showed modest associations with BMI in European Americans. The pathways in which these genes participate regulate energy intake, and thus these associations are mechanistically plausible in this context.

Clinical and genetic predictors of weight gain in patients diagnosed with breast cancer.

BACKGROUND: Post-diagnosis weight gain in breast cancer patients has been associated with increased cancer recurrence and mortality. Our study was designed to identify risk factors for this weight gain and create a predictive model to identify a high-risk population for targeted interventions. METHODS: Chart review was conducted on 459 breast cancer patients from Northwestern Robert H. Lurie Cancer Centre to obtain weights and body mass indices (BMIs) over an 18-month period from diagnosis. We also recorded tumour characteristics, demographics, clinical factors, and treatment regimens. Blood samples were genotyped for 14 single-nucleotide polymorphisms (SNPs) in fat mass and obesity-associated protein (FTO) and adiponectin pathway genes (ADIPOQ and ADIPOR1). RESULTS: In all, 56% of patients had >0.5 kg m(-2) increase in BMI from diagnosis to 18 months, with average BMI and weight gain of 1.9 kg m(-2) and 5.1 kg, respectively. Our best predictive model was a primarily SNP-based model incorporating all 14 FTO and adiponectin pathway SNPs studied, their epistatic interactions, and age and BMI at diagnosis, with area under receiver operating characteristic curve of 0.85 for 18-month weight gain. CONCLUSION: We created a powerful risk prediction model that can identify breast cancer patients at high risk for weight gain.

Influences of adding easily degradable organic waste on the minimization and humification of organic matter during straw composting.

To find a better composting process with low greenhouse gas emission and high humus production, the effect of adding kitchen waste on reduction and humification of organic matter during straw composting was studied. Three processes were compared, consisting of different ratios of straw and kitchen waste (1:2, 1:1, and 2:1). At four time points over a 62-d incubation, the reduction and humification of compost was evaluated by measuring the total mass, carbon content, and humic material content of the compost. Treatment 1 (straw/kitchen waste ratio of 1:2) reduced the total mass of compost the most. Treatment 2 (straw/kitchen waste ratio of 1:1) reduced the total carbon content the most, reflecting the highest emission of greenhouse gas. Treatment 3 produced the most humic acid material and released the lowest amount of carbon. Hence, from the point of view of reducing greenhouse gas emissions and increasing stable organic matter such as humus and humic acid during composting, treatment #3 was optimal. The three treatments resulted in significant differences in microbial biomass and enzyme activity during composting. The highest amount of active microbial biomass was associated with the largest reduction in compost mass (treatment 1). Higher proportions of straw (treatments 2 and 3), which contains more lignin, were associated with greater ß-glycosidase activity, which may generate more humus that can improve soil quality. Dehydrogenase activity seemed to be the most important microbial factor in organic carbon catabolism or humification.

Cancer cell proliferation is inhibited by specific modulation frequencies.

BACKGROUND: There is clinical evidence that very low and safe levels of amplitude-modulated electromagnetic fields administered via an intrabuccal spoon-shaped probe may elicit therapeutic responses in patients with cancer. However, there is no known mechanism explaining the anti-proliferative effect of very low intensity electromagnetic fields. METHODS: To understand the mechanism of this novel approach, hepatocellular carcinoma (HCC) cells were exposed to 27.12 MHz radiofrequency electromagnetic fields using in vitro exposure systems designed to replicate in vivo conditions. Cancer cells were exposed to tumour-specific modulation frequencies, previously identified by biofeedback methods in patients with a diagnosis of cancer. Control modulation frequencies consisted of randomly chosen modulation frequencies within the same 100 Hz-21 kHz range as cancer-specific frequencies. RESULTS: The growth of HCC and breast cancer cells was significantly decreased by HCC-specific and breast cancer-specific modulation frequencies, respectively. However, the same frequencies did not affect proliferation of nonmalignant hepatocytes or breast epithelial cells. Inhibition of HCC cell proliferation was associated with downregulation of XCL2 and PLP2. Furthermore, HCC-specific modulation frequencies disrupted the mitotic spindle. CONCLUSION: These findings uncover a novel mechanism controlling the growth of cancer cells at specific modulation frequencies without affecting normal tissues, which may have broad implications in oncology.

A systematic review and meta-analysis on the efficacy of probiotics for bacterial vaginosis.

OBJECTIVE: The current study aimed at assessing the overall efficacy of probiotics for the treatment of bacterial vaginosis (BV) through the review of relevant studies. MATERIALS AND METHODS: A systematic literature review was conducted based largely on the following electronic databases updated to May 2021: Embase, the Cochrane Library, and PubMed, with the use of keywords. The investigators also thoroughly reviewed key pertinent sources in the literature for further inclusion. RESULTS: Eighteen studies including 1651 patients were selected in the present meta-analysis. In comparison with antibiotics, antibiotics plus probiotics significantly decreased the recurrence rate of BV (at 1-3 months and overall analysis) and increased the cure/remission rate of BV (at 1-3 months and overall analysis). Compared with placebo, probiotics decreased the recurrence rate of BV (at 1-3 months and overall analysis) and increased the cure/remission rate of BV (at 1-3 months). Compared with antibiotics, probiotics significantly decreased the recurrence rate of BV (at <1 month, 1-3 months and overall analysis) as well as the incidence of adverse events (AEs) (at less than 1 month) and increased the cure/remission rate of BV (at 1-3 months). CONCLUSIONS: In comparison with short-term probiotics treatment (<1 month), long-term probiotics treatment (1-3 months) yields superior beneficial outcomes and efficacy in the treatment of BV.

[A protein complex recognition method based on spatial-temporal graph convolution neural network].

OBJECTIVE: To propose a new method for mining complexes in dynamic protein network using spatiotemporal convolution neural network. METHODS: The edge strength, node strength and edge existence probability are defined for modeling of the dynamic protein network. Based on the time series information and structure information on the graph, two convolution operators were designed using Hilbert-Huang transform, attention mechanism and residual connection technology to represent and learn the characteristics of the proteins in the network, and the dynamic protein network characteristic map was constructed. Finally, spectral clustering was used to identify the protein complexes. RESULTS: The simulation results on several public biological datasets showed that the F value of the proposed algorithm exceeded 90% on DIP dataset and MIPS dataset. Compared with 4 other recognition algorithms (DPCMNE, GE-CFI, VGAE and NOCD), the proposed algorithm improved the recognition efficiency by 34.5%, 28.7%, 25.4% and 17.6%, respectively. CONCLUSION: The application of deep learning technology can improve the efficiency in analysis of dynamic protein networks.

Mucoadhesive Low Molecular Chitosan Complexes to Protect rHuKGF from Proteolysis: In-vitro Characterization and FHs 74 Int Cell Proliferation Studies.

BACKGROUND: Recombinant Keratinocyte Growth Factor (rHuKGF) is a therapeutic protein used widely in oral mucositis after chemotherapy in various cancers, stimulating lung morphogenesis and gastrointestinal tract cell proliferation. In this research study, chitosan-rHuKGF polymeric complex was implemented to improve the stability of rHuKGF and used as rejuvenation therapy for the treatment of oral mucositis in cancer patients. OBJECTIVE: Complexation of rHuKGF with mucoadhesive low molecular weight chitosan to protect rHuKGF from proteolysis and investigate the effect of chitosan-rHuKGF complex on the proliferation rate of FHs 74 Int cells. METHODS: The interaction between chitosan and rHuKGF was studied by molecular docking. Malvern ZetaSizer Nano Zs and Fourier-Transform Infrared spectroscopy (FTIR) tests were carried out to characterize the chitosan-rHuKGF complex. In addition, SDS-PAGE was performed to investigate the interaction between chitosan-rHuKGF complex and pepsin. The effect of chitosan-rHuKGF complex on the proliferation rate of FHs 74 Int cells was studied by MTT assay. RESULTS: Chitosan-rHuKGF complex was formed through the hydrogen bonding proven by the docking studies. A stable chitosan-rHuKGF complex was formed at pH 4.5 and was protected from proteolysis and assessed by SDS PAGE. According to the MTT assay results, chitosan-rHuKGF complex increased the cell proliferation rate of FHs 74 Int cells. CONCLUSION: The developed complex improved the stability and the biological function of rHuKGF.

LC/MS-Based Global Metabolomic Identification of Serum Biomarkers Differentiating Hepatocellular Carcinoma from Chronic Hepatitis B and Liver Cirrhosis.

Chronic hepatitis B virus (CHB) infection is one of the primary risk factors associated with the development of hepatocellular carcinoma (HCC). Despite having been extensively studied, diagnosing early-stage HCC remains challenging, and diagnosed patients have a poor (3-5%) survival rate. Identifying new approaches to detect changes in the serum metabolic profiles of patients with CHB and liver cirrhosis (LC) may provide a valuable approach to better detect HCC at an early stage when it is still amenable to treatment, thereby improving patient prognosis and survival. In the present study, we, therefore, employed a liquid chromatography-mass spectrometry (LC-MS)-based approach to evaluate the serum metabolic profiles of 30 CHB patients, 29 LC patients, and 30 HCC patients. We then employed appropriate statistical methods to identify those metabolites that were best able to distinguish HCC cases from LC and CHB controls. A mass-based database was then used to putatively identify these metabolites. We then confirmed the identities of a subset of these metabolites through comparisons with the MS/MS fragmentation patterns and retention times of reference standards. The serum samples were then reanalyzed to quantify the levels of these selected metabolites and of other metabolites that have previously been identified as potential HCC biomarkers. Through this approach, we observed clear differences in the metabolite profiles of the CHB, LC, and HCC patient groups in both positive- and negative-ion modes. We found that the levels of taurodeoxy cholic acid (TCA) and 1,2-diacyl-3-ß-d-galactosyl-sn-glycerol rose with the progression from CHB to LC to HCC, whereas levels of 5-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid, and glycyrrhizic acid were gradually reduced with liver disease progression in these groups. The ROC analysis showed that taurodeoxy cholic acid (TCA), 1,2-diacyl-3-ß-d-galactosyl-sn-glycerol, 5-hydroxy-6E,8Z,11Z,14Z,17Z-eicosapentaenoic acid, and glycyrrhizic acid had a diagnosis performance with liver disease progression. These four metabolites have a significant correlation with alpha fetal protein (AFP) level and age. Our results highlight novel metabolic biomarkers that have the potential to be used for differentiating between CHB, LC, and HCC patients, thereby facilitating the identification and treatment of patients with early-stage HCC.

Genetic association of htSNPs across the major histocompatibility complex with rheumatoid arthritis in an African-American population.

Notwithstanding the well-established association of HLA-DRB1 shared epitope alleles, interest remains in identifying additional major histocompatibility complex (MHC) region variants associated with rheumatoid arthritis (RA). We used a panel of 1201 haplotype-tagging single nucleotide polymorphisms (SNPs) designed for African Americans to find genetic variants associated with RA in a 3.8-Mb region encompassing the MHC. Conditioning on seven covariates, including HLA-DRB1 risk alleles and population structure, we identified an SNP in HLA-DOA (rs9276977) significantly associated with RA; minor allele frequency (MAF) 0.27 in cases versus 0.21 in controls, odds ratio (+/-95% confidence interval)=2.86 (1.61, 5.31). Genotyping of rs9276977 in an independent sample of African-American RA patients and controls did not replicate the association (MAF 0.28 in cases versus 0.27 in controls). This study points to the potential association of a SNP in the HLA-DOA gene with RA in African Americans, but also underscores the importance of replication of findings in larger patient cohorts.

High viremia, prolonged Lamivudine therapy and recurrent hepatocellular carcinoma predict posttransplant hepatitis B recurrence.

Hepatitis B virus (HBV) recurrence following orthotopic liver transplantation (OLT) is generally preventable by prophylaxis with hepatitis B immunoglobulin (HBIG) and lamivudine (LAM). However, HBV recurrence sometimes develops despite prophylaxis. This study assessed posttransplant outcomes and identified predictors of HBV recurrence. We analyzed the outcomes of 209 consecutive patients positive for hepatitis B surface antigen who underwent OLT, who received either combination prophylaxis with HBIG and LAM (89.0%) or HBIG monoprophylaxis (11.0%). The median follow-up was 36.8 months (range, 1.0-84.4). Posttransplant HBV recurrence occurred in 22 patients (10.5%), including 13 patients with drug-resistant mutations. HBV recurrence was observed in six patients after hepatocellular carcinoma (HCC) recurrence. Independent predictors of HBV recurrence were recurrent HCC (p < 0.001), LAM therapy >1.5 years (p = 0.001) and high HBV DNA titers (> or =10(5) copies/mL) at OLT (p = 0.036). In conclusion, high viremia at OLT and prolonged exposure to LAM should be further stressed as main predictors of HBV recurrence.