Inhibition of Amyloid ß Aggregation and Cytotoxicity by Berbamine Hydrochloride.

Alzheimer's disease (AD) continues to be a major global health challenge, and the recent approval of Aduhelm and Leqembi has opened new avenues for its treatment. Small-molecule inhibitors targeting Aß aggregation hold promise as an alternative to monoclonal antibodies. In this study, we evaluated the ability of berbamine hydrochloride (BBMH), a member of the bisbenzylisoquinoline alkaloids, to reduce Aß aggregation and cytotoxicity. Thioflavin T kinetics, circular dichroism spectroscopy, and atomic force microscopy results indicated that BBMH effectively inhibited Aß aggregation. Surface plasmon resonance and molecular docking results further revealed that BBMH could bind to Aß fibrils, thereby hindering the aggregation process. This physical picture has been confirmed in a quantitative way by chemical kinetics analysis, which showed BBMH tends to bind with the fibril ends and thus prevents the transition from protofibrils to mature fibrils as well as the elongation process. Additionally, our MTT results showed that BBMH was able to reduce the cytotoxicity of Aß40 on N2a cells. Our results demonstrate, for the first time, the potential of BBMH to inhibit Aß aggregation and cytotoxicity, offering a promising direction for further research and drug development efforts in the fight against Alzheimer's disease.

Toxic effects of bisphenol AF on the embryonic development of marine medaka (Oryzias melastigma).

Bisphenol AF (BPAF), an emerging environmental endocrine disruptor, has been detected in surface waters worldwide and has adverse effects on aquatic organisms. The accumulation of BPAF in oceans and its potential toxic effect on marine organisms are important concerns. In this study, the effects of BPAF (10, 100, 1, and 5 mg/L) on marine medaka (Oryzias melastigma) were evaluated, including effects on the survival rate, heart rate, hatchability, morphology, and gene expression in embryos. The survival rate of marine medaka embryos was significantly lower after treatment with 5 mg/L BPAF than in the solvent control group. Exposure to 1 mg/L and 5 mg/L BPAF significantly reduced hatchability. Low-dose BPAF (10 µg/L) significantly accelerated the heart rate of embryos, while high-dose BPAF (5 mg/L) significantly decreased the heart rate. BPAF exposure also resulted in notochord curvature, pericardial edema, yolk sac cysts, cardiovascular bleeding, and caudal curvature in marine medaka. At the molecular level, BPAF exposure affected the transcript levels of genes involved in the thyroid system (dio1, dio3a, trhr2, tg, and thra), cardiovascular system (gata4, atp2a1, and cacna1da), nervous system (elavl3 and gap43), and antioxidant and inflammatory systems (sod, pparß, and il-8) in embryos. These results indicate that BPAF exposure can alter the expression of functional genes, induce abnormal development, and reduce the hatching and survival rates in marine medaka embryos. Overall, BPAF can adversely affect the survival and development of marine medaka embryos, and BPAF may not be an ideal substitute for BPA.

Discovery of novel tubulin inhibitors targeting taxanes site by virtual screening, molecular dynamic simulation, and biological evaluation.

Microtubules play crucial role in process of mitosis and cell proliferation, which have been considered as attractive drug targets for anticancer therapy. The aim of this study was to discover novel and chemically diverse tubulin inhibitors for treatment of cancer. In this investigation, the multilayer virtual screening methods, including common feature pharmacophore model, structure-based pharmacophore model and molecular docking, were developed to screen BioDiversity database with 30,000 compounds. A total of 102 compounds were obtained by the virtual screening, and further filtered by diverse chemical clusters with desired properties and PAINS analysis. Finally, 50 compounds were selected and submitted to the biological evaluation. Among these hits, hits 8 and 30 with novel scaffolds displayed stronger antiproliferative activity on four human tumor cells including Hela, A549, MCF-7, and HepG2. Moreover, the two hits were subsequently submitted to molecular dynamic simulations of 90 ns with the aim of exploring the stability of ligand-protein interactions into the binding pocket, and further probing the mechanism of the interaction between tubulin and hits. The molecular dynamic simulation results revealed there had stronger interactions between tubulin and hits in equilibrium state. Therefore, the hits 8 and 30 have been well characterized as lead compounds for developing new tubulin inhibitors with potential anticancer activity.

lncRNA MIR155HG Alleviates Depression-Like Behaviors in Mice by Regulating the miR-155/BDNF Axis.

Depression is one of most common psychiatric disorders, and the detailed molecular mechanism remains to be fully elucidated. Brain-derived neurotrophic factor (BDNF) is a critical neurotrophic factor that is decreased and closely involved in the development of depression. Noncoding RNAs are central regulators of cellular activities that modulate target genes. However, the roles of long noncoding RNA (lncRNA) MIR155HG and miRNA-155 (miR-155) in the pathophysiology of depression are unclear. In the present study, we aimed to explore the effects of lncRNA MIR155HG and miR-155 on the development of depression and uncover the underlying molecular mechanism. Real-time quantitative polymerase chain reaction was used to examine the expression of MIR155HG and miR-155. Western blotting was applied to measure the expression of BDNF. A luciferase reporter assay was utilized to determine the regulatory relationship between MIR155HG and miR-155. Our current work found that lncRNA MIR155HG and BDNF levels decreased while miR-155 levels increased in the hippocampal region of CUMS (chronic unpredictable mild stress) mice, a well-accepted mouse model of depression. Moreover, MIR155HG rescued while miR-155 exacerbated the depression-like behaviors of CUMS mice. Through bioinformatics analysis and luciferase reporter assays, we found that MIR155HG directly bound to and negatively modulated the expression of miR-155. Moreover, increased miR-155 was found to repress the expression of BDNF, a critical neurotrophic factor that has been reported to alleviate the depression-like behaviors of CUMS mice. Our present study revealed that lncRNA MIR155HG protected CUMS mice by regulating the miR-155/BDNF axis. Our study aimed to understand the pathophysiology of depression and provided potential therapeutic targets to diagnose and treat depression.

A review of the association between oral bacterial flora and obstructive sleep apnea-hypopnea syndrome comorbid with cardiovascular disease.

PURPOSE: Obstructive sleep apnea-hypopnea syndrome (OSAHS), a common sleep disorder, has been shown to be an independent risk factor for cardiovascular disease (CVD). Recent studies have focused on the important roles of microorganisms in human health; for example, microorganisms are reportedly associated with obesity, metabolic disorders, and CVD. The number of oral bacteria in patients with OSAHS is considerably higher than that in healthy individuals, and infection with oral bacterial pathogens is associated with the development of CVD. However, whether changes in the oral microbiota mediate the development of OSAHS and CVD remains unknown. METHODS: Therefore, we attempted to review the association between changes in oral microbiota in patients with OSAHS and the development of CVD. RESULTS: Oral microbiota possibly acts via multiple pathways including direct invasion, platelet aggregation, immune response, inflammatory response, and oxidative stress response, leading to the development of CVD in patients with OSAHS. In particular, the strains Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia have demonstrated profound effects. OSAHS leads to changes in the oral bacterial flora and thus may facilitate the occurrence and development of CVD. CONCLUSION: We propose that the underlying mechanism of CVDs resulting from oral microbiota in patients with OSAHS should be elucidated in further studies.

Gut microbiota in obstructive sleep apnea-hypopnea syndrome: disease-related dysbiosis and metabolic comorbidities.

Gut microbiota alterations manifest as intermittent hypoxia and fragmented sleep, thereby mimicking obstructive sleep apnea-hypopnea syndrome (OSAHS). Here, we sought to perform the first direct survey of gut microbial dysbiosis over a range of apnea-hypopnea indices (AHI) among patients with OSAHS. We obtained fecal samples from 93 patients with OSAHS [5 < AHI ≤ 15 (n=40), 15 < AHI ≤ 30 (n=23), and AHI ≥ 30 (n=30)] and 20 controls (AHI ≤ 5) and determined the microbiome composition via 16S rRNA pyrosequencing and bioinformatics analysis of variable regions 3-4. We measured fasting levels of homocysteine (HCY), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). Results revealed gut microbial dysbiosis in several patients with varying severities of OSAHS, reliably separating them from controls with a receiver operating characteristic-area under the curve (ROC-AUC) of 0.789. Functional analysis in the microbiomes of patients revealed alterations; additionally, decreased in short-chain fatty acid (SCFA)-producing bacteria and increased pathogens, accompanied by elevated levels of IL-6. Lactobacillus levels correlated with HCY levels. Stratification analysis revealed that the Ruminococcus enterotype posed the highest risk for patients with OSAHS. Our results show that the presence of an altered microbiome is associated with HCY among OSAHS patients. These changes in the levels of SCFA affect the levels of pathogens that play a pathophysiological role in OSAHS and related metabolic comorbidities.

Extensive disseminated cysticercosis: a case report in Yunnan province, China.

BACKGROUND: Cysticercosis is spreading all over the world and it is a major health problem in most countries of Latin America, Africa, and Asia. Extensive disseminated cysticercosis is relatively rare and fewer than 120 case have been reported in the worldwide. We reported a rare case of extensive disseminated cysticercosis in Yunan province, China. CASE PRESENTATION: A rare case of extensive disseminated cysticercosis, in a 61-year-old male Chinese was detected from Yunnan province in 2018. Clinical and etiological examination was performed, as well as the epidemiological investigation. CONCLUSION: The life cycle of T. solium in the area where the case came from is complete. We expect this case could raise the attentions to the control of Taenia solium infection and subsequent cysticercosis there.

Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4+ T Cells.

HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1 gag mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4+ T cells. Furthermore, Naf1 knockdown in resting CD4+ T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency in vivo Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy. IMPORTANCE: HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.

Crystal structure of Psb27 from Arabidopsis thaliana determined at a resolution of 1.85 Å.

Proper biogenesis and maintenance of photosynthetic thylakoid membrane complexes are essential for the photosynthetic light reactions. A thylakoid lumenal protein, Psb27, plays a vital role in assembly or/and maintenance of photosystem II (PSII). In cyanobacteria, it is a small lipoprotein docked to the lumenal side of PSII, and functions in the assembly of the Mn4Ca cluster and in the PSII repair cycle. However, Psb27 from Arabidopsis thaliana is not a lipoprotein, and it is involved in PSII repair and acclimation to fluctuating light stress, suggesting a functional divergence between Arabidopsis Psb27 and cyanobacterial Psb27s. To gain a better understanding of Psb27 from higher plants, we determined the crystal structure of Arabidopsis Psb27 by X-ray crystallography at a resolution of 1.85 Å. The structure of Arabidopsis Psb27 is a four-helix bundle, similar to its orthologues from cyanobacteria. However, there are several structural differences between Arabidopsis Psb27 and cyanobacterial Psb27s concerning the overall molecular shape, the N- and C-terminal structures, and the surface charge. These differences suggest that Psb27 from higher plants and cyanobacteria may function differently.

Single-stage posterior vertebral column resection and internal fixation for old fracture-dislocations of thoracolumbar spine: a case series and systematic review.

PURPOSE: To evaluate the efficacy of single-stage posterior vertebral column resection for old thoracolumbar fracture-dislocations with spinal cord injury. METHODS: From January 2007 to June 2013, twelve male patients (average age, 32.6 years; range 19-57 years) with old fracture-dislocations of the thoracolumbar spine and spinal cord injury underwent single-stage posterior vertebral column resection and internal fixation. All patients were assessed for relief of the pain and restoration of neurologic function. Postoperative Cobb angle was measured and bone graft fusion was evaluated by X-ray. A systematic review of 25 studies evaluating surgical management of thoracolumbar fractures with spinal cord injuries was also performed. RESULTS: From our case series, six of the nine patients with Frankel grade A had significant improvement in urination and defecation after surgery. The three patients with Frankel grades B and C had progression of 1-2 grades after surgery. Bony fusion was achieved and local back pain was relieved in all patients after surgery. From our systematic review of 25 studies, the majority of patients had improved back pain, the postoperative kyphotic angle was significantly reduced compared with pre-operative kyphotic angle. CONCLUSION: Single-stage posterior vertebral column resection and internal fixation for old thoracolumbar fracture-dislocations is an ideal treatment allowing for thorough decompression, relief of pain, correction of deformities, and restoration of spinal stability. LEVEL OF EVIDENCE: IV.

Higher antiviral response of RIG-I through enhancing RIG-I/MAVS-mediated signaling by its long insertion variant in zebrafish.

As an intracellular pattern recognition receptor (PRR), the retinoic acid-inducible gene-I (RIG-I) is responsible for the recognition of cytosolic viral nucleic acids and the production of type I interferons (IFNs). In the present study, an insertion variant of RIG-I with 38 amino acids inserted in the N-terminal CARD2 domain, as well as the typical type, named as RIG-Ia and RIG-Ib respectively were identified in zebrafish. RIG-Ia and RIG-Ib were all up-regulated following the infection of a negative ssRNA virus, the Spring Viremia of Carp Virus (SVCV), and an intracellular Gram-negative bacterial pathogen Edwardsiella tarda, indicating the RLR may have a role in the recognition of both viruses and bacteria. The over-expression of RIG-Ib in cultured fish cells resulted in significant increase in type I IFN promoter activity, and in protection against SVCV infection, whereas the over-expression of RIG-Ia had no direct effect on IFN activation nor antiviral response. Furthermore, it was revealed that both RIG-Ia and RIG-Ib were associated with the downstream molecular mitochondrial antiviral signaling protein, MAVS, and interestingly RIG-Ia when co-transfected with RIG-Ib or MAVS, induced a significantly higher level of type I IFN promoter activity and the expression level of Mx and IRF7, implying that the RIG-Ia may function as an enhancer in the RIG-Ib/MAVS-mediated signaling pathway.

A screening strategy for phenotypic detection of carbapenemase in the clinical laboratory.

Nosocomial infections caused by carbapenemase-producing Enterobacteriaceae have emerged as an important challenge worldwide and represent a great limitation for antimicrobial therapy. Detection of carbapenemase in Enterobacteriaceae species also remains challenging. Although the modified Hodge test is recommended, it lacks specificity and is unable to distinguish between carbapenemase types. Here, we demonstrated a screening strategy for the phenotypic detection of carbapenemases among Enterobacteriaceae isolates in the clinical laboratory by using ethylenediaminetetraacetic acid and phenylboronic acid. This strategy displayed an overall 100% sensitivity and 98.6% specificity for carbapenemase detection in Enterobacteriaceae, which was superior to that of the modified Hodge test (98.0% sensitivity and 84.3% specificity), and it also discriminated the carbapenemase phenotypes of KPC-2, VIM-1, and OXA-48.

Serum metabolomics analysis of patients with chronic obstructive pulmonary disease and 'frequent exacerbator' phenotype.

Chronic obstructive pulmonary disease (COPD) exacerbations accelerate loss of lung function and increased mortality. The complex nature of COPD presents challenges in accurately predicting and understanding frequent exacerbations. The present study aimed to assess the metabolic characteristics of the frequent exacerbation of COPD (COPD­FE) phenotype, identify potential metabolic biomarkers associated with COPD­FE risk and evaluate the underlying pathogenic mechanisms. An internal cohort of 30 stable patients with COPD was recruited. A widely targeted metabolomics approach was used to detect and compare serum metabolite expression profiles between patients with COPD­FE and patients with non­frequent exacerbation of COPD (COPD­NE). Bioinformatics analysis was used for pathway enrichment analysis of the identified metabolites. Spearman's correlation analysis assessed the associations between metabolites and clinical indicators, while receiver operating characteristic (ROC) analysis evaluated the ability of metabolites to distinguish between two groups. An external cohort of 20 patients with COPD validated findings from the internal cohort. Out of the 484 detected metabolites, 25 exhibited significant differences between COPD­FE and COPD­NE. Metabolomic analysis revealed differences in lipid, energy, amino acid and immunity pathways. Spearman's correlation analysis demonstrated associations between metabolites and clinical indicators of acute exacerbation risk. ROC analysis demonstrated that the area under the curve (AUC) values for D­fructose 1,6­bisphosphate (AUC=0.871), arginine (AUC=0.836), L­2­hydroxyglutarate (L­2HG; AUC=0.849), diacylglycerol (DG) (16:0/20:5) (AUC=0.827), DG (16:0/20:4) (AUC=0.818) and carnitine­C18:2 (AUC=0.804) were >0.8, highlighting their discriminative capacity between the two groups. External validation results demonstrated that DG (16:0/20:5), DG (16:0/20:4), carnitine­C18:2 and L­2HG were significantly different between patients with COPD­FE and those with COPD­NE. In conclusion, the present study offers insights into early identification, mechanistic understanding and personalized management of the COPD­FE phenotype.

Tumour response following preoperative chemotherapy is affected by body mass index in patients with colorectal liver metastases.

BACKGROUND: Colorectal cancer is the third most prevalent malignancy globally and ranks second in cancer-related mortality, with the liver being the primary organ of metastasis. Preoperative chemotherapy is widely recommended for initially or potentially resectable colorectal liver metastases (CRLMs). Tumour pathological response serves as the most important and intuitive indicator for assessing the efficacy of chemotherapy. However, the postoperative pathological results reveal that a considerable number of patients exhibit a poor response to preoperative chemotherapy. Body mass index (BMI) is one of the factors affecting the tumorigenesis and progression of colorectal cancer as well as prognosis after various antitumour therapies. Several studies have indicated that overweight and obese patients with metastatic colorectal cancer experience worse prognoses than those with normal weight, particularly when receiving first-line chemotherapy regimens in combination with bevacizumab. AIM: To explore the predictive value of BMI regarding the pathologic response following preoperative chemotherapy for CRLMs. METHODS: A retrospective analysis was performed in 126 consecutive patients with CRLM who underwent hepatectomy following preoperative chemotherapy at four different hospitals from October 2019 to July 2023. Univariate and multivariate logistic regression models were applied to analyse potential predictors of tumour pathological response. The Kaplan-Meier method with log rank test was used to compare progression-free survival (PFS) between patients with high and low BMI. BMI < 24.0 kg/m2 was defined as low BMI, and tumour regression grade 1-2 was defined as complete tumour response. RESULTS: Low BMI was observed in 74 (58.7%) patients and complete tumour response was found in 27 (21.4%) patients. The rate of complete tumour response was significantly higher in patients with low BMI (29.7% vs 9.6%, P = 0.007). Multivariate analysis revealed that low BMI [odds ratio (OR) = 4.56, 95% confidence interval (CI): 1.42-14.63, P = 0.011], targeted therapy with bevacizumab (OR = 3.02, 95%CI: 1.10-8.33, P = 0.033), preoperative carcinoembryonic antigen level < 10 ng/mL (OR = 3.84, 95%CI: 1.19-12.44, P = 0.025) and severe sinusoidal dilatation (OR = 0.17, 95%CI: 0.03-0.90, P = 0.037) were independent predictive factors for complete tumour response. The low BMI group exhibited a significantly longer median PFS than the high BMI group (10.7 mo vs 4.7 mo, P = 0.011). CONCLUSION: In CRLM patients receiving preoperative chemotherapy, a low BMI may be associated with better tumour response and longer PFS.

Diagnostic value of carbohydrate antigen 50 in biliary tract cancer: A large-scale multicenter study.

BACKGROUND: To date, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) have been widely used for the screening, diagnosis and prediction of biliary tract cancer (BTC) patients. However, few studies with large sample sizes of carbohydrate antigen 50 (CA50) were reported in BTC patients. METHODS: A total of 1121 patients from the Liver Cancer Clin-Bio Databank of Anhui Hepatobiliary Surgery Union between January 2017 and December 2022 were included in this study (673 in the training cohort and 448 in the validation cohort): among them, 458 with BTC, 178 with hepatocellular carcinoma (HCC), 23 with combined hepatocellular-cholangiocarcinoma, and 462 with nontumor patients. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the diagnostic efficacy and clinical usefulness. RESULTS: ROC curves obtained by combining CA50, CA19-9, and AFP showed that the AUC value of the diagnostic MODEL 1 was 0.885 (95% CI 0.856-0.885, specificity 70.3%, and sensitivity 84.0%) in the training cohort and 0.879 (0.841-0.917, 76.7%, and 84.3%) in the validation cohort. In addition, comparing iCCA and HCC (235 in the training cohort, 157 in the validation cohort), the AUC values of the diagnostic MODEL 2 were 0.893 (95% CI 0.853-0.933, specificity 96%, and sensitivity 68.6%) in the training cohort and 0.872 (95% CI 0.818-0.927, 94.2%, and 64.6%) in the validation cohort. CONCLUSION: The model combining CA50, CA19-9, and AFP not only has good diagnostic value for BTC but also has good diagnostic value for distinguishing iCCA and HCC.

Screening of potential pseudo att sites of Streptomyces phage ΦC31 integrase in the human genome.

AIM: ΦC31 integrase mediates site-specific recombination between two short sequences, attP and attB, in phage and bacterial genomes, which is a promising tool in gene regulation-based therapy since the zinc finger structure is probably the DNA recognizing domain that can further be engineered. The aim of this study was to screen potential pseudo att sites of ΦC31 integrase in the human genome, and evaluate the risks of its application in human gene therapy. METHODS: TFBS (transcription factor binding sites) were found on the basis of reported pseudo att sites using multiple motif-finding tools, including AlignACE, BioProspector, Consensus, MEME, and Weeder. The human genome with the proposed motif was scanned to find the potential pseudo att sites of ΦC31 integrase. RESULTS: The possible recognition motif of ΦC31 integrase was identified, which was composed of two co-occurrence conserved elements that were reverse complement to each other flanking the core sequence TTG. In the human genome, a total of 27924 potential pseudo att sites of ΦC31 integrase were found, which were distributed in each human chromosome with high-risk specificity values in the chromosomes 16, 17, and 19. When the risks of the sites were evaluate more rigorously, 53 hits were discovered, and some of them were just the vital functional genes or regulatory regions, such as ACYP2, AKR1B1, DUSP4, etc. CONCLUSION: The results provide clues for more comprehensive evaluation of the risks of using ΦC31 integrase in human gene therapy and for drug discovery.

Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001).

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4-11.0) versus 8.0 months (95% CI, 6.6-9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1-27.3] vs. 15.7 months [13.0-20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.

Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia.

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

Phylogenetic and molecular characterization of coxsackievirus A24 variant isolates from a 2010 acute hemorrhagic conjunctivitis outbreak in Guangdong, China.

BACKGROUND: Acute hemorrhagic conjunctivitis is a common disease in China. As a notifiable disease, cases are registered by ophthalmologists on the AHC surveillance system. An AHC outbreak caused by CA24v was observed in Guangdong Province in 2007 by the National Disease Supervision Information Management System. Three years later, a larger outbreak occurred in Guangdong during the August-October period (2010). To characterize the outbreak and compare the genetic diversity of CA24v, which was determined to be the cause of the outbreak, the epidemiology and the molecular characterization of CA24v were analyzed in this study. RESULTS: A total of 69,635 cases were reported in the outbreak. 73.5% of index cases originated from students, children in kindergarten and factory workers, with the ≦ 9 age group at the highest risk. The male to female ratio was 1.84:1 among 0-19 years. 56 conjunctival swabs were collected to identify the causative agent from five cities with the AHC outbreak. 30 virus strains were isolated, and two of the genomes had the highest identity values (95.8%) with CA24v genomes. Four CA24v genotypes were identified by phylogenetic analysis for the VP1 and 3C regions. CA24v which caused the outbreak belonged to genotype IV. Furthermore, full nucleotide sequences for four representative isolates in 2010 and 2007 were determined and compared. 20 aa mutations, two nt insertions and one nt deletion were observed in the open reading frame, with 5'- and 3'- UTR respectively between them. CONCLUSIONS: CA24v was determined to be the pathogen causing the outbreak and belongs to genotype IV. VP1 is more informative than 3C(Pro) for describing molecular epidemiology and we hypothesize that accumulative mutations may have promoted the outbreak.