Subgroup analysis based on prognostic and predictive gene signatures for adjuvant chemotherapy in early-stage non-small-cell lung cancer patients

In treating patients diagnosed with early Stage I non-small-cell lung cancer (NSCLC), doctors must choose surgery alone, Adjuvant Cisplatin-Based Chemotherapy (ACT) alone or both. For patients with resected stages IB to IIIA, clinical trials have shown a survival advantage from 4–15% with the adoption of ACT. However, due to the inherent toxicity of chemotherapy, it is necessary for doctors to identify patients whose chance of success with ACT is sufficient to justify the risks. This research seeks to use gene expression profiling in the development of a statistical decision-making algorithm to identify patients whose survival rates will improve from ACT treatment. Using the data from the National Cancer Institute, the lasso method in the Cox-Proportional-Hazards regression model is used as the main method to determine a feasible number of genes that are strongly associated with the treatment-related patient survival. Considering treatment groups separately, the patients are assigned a risk category based on the estimation of survival times. These risk categories are used to develop a Random Forests classification model to identify patients who are likely to benefit from chemotherapy treatment. This model allows the prediction of a new patient’s prognosis and the likelihood of survival benefit from ACT treatment based on a feasible number of genomic biomarkers. The proposed methods are evaluated using a simulation study.     

Cationic liposome co-encapsulation of SMAC mimetic and zVAD using a novel lipid bilayer fusion loaded with MLKL-pDNA for tumour inhibition in vivo

The increase in multidrug resistance among colon cancer cells presents a challenge for the development of effective therapies. Small-molecule analogues of second mitochondria-derived activator of caspase (SMAC) mimetic in association with mixed lineage kinase domain-like protein (MLKL)-pDNA and z-VAD-fmk have shown ideal antitumor effects in colon cancer cells in vitro via induction of RIP3-dependent necroptosis. To achieve synergistic antitumor effects in vivo, liposomes loaded with SMAC mimetic, MLKL-pDNA and z-VAD-fmk have been developed using novel lipid fusion methods to co-localise the molecules of interest within the tumour cells. The co-encapsulation liposome (MLKL-zVAD-BV6-LP) had a high entrapment efficiency of approximately 95% for both zVAD and BV6 and was able to condense MLKL-pDNA very well. The vectors showed good biocompatibility, tumour targeting and small-molecule co-localisation. In a CT26 mouse model, the MLKL-zVAD-BV6-LP exhibited a tumour-suppression rate of over 60% in vivo, which was significantly higher than that of both the null-liposome and coadministration groups. Above all, the co-encapsulation system provided a novel approach to combination tumour therapy.     

ARL4C stabilized by AKT/mTOR pathway promotes the invasion of PTEN-deficient primary human glioblastoma

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deficiency in primary human glioblastoma (GBM) is associated with increased invasiveness and poor prognosis with unknown mechanisms. Therefore, how loss of PTEN promotes GBM progression remains to be elucidated. Herein, we identified that ADP-ribosylation factor like-4C (ARL4C) was highly expressed in PTEN-deficient human GBM cells and tissues. Mechanistically, loss of PTEN stabilized ARL4C protein due to AKT/mTOR pathway-mediated inhibition of ARL4C ubiquitination. Functionally, ARL4C enhanced the progression of GBM cells in vitro and in vivo. Moreover, microarray profiling and GST pull-down assay identified that ARL4C accelerated tumor progression via RAC1-mediated filopodium formation. Importantly, targeting PTEN potently inhibited GBM tumor progression in vitro and in vivo, whereas overexpression of ARL4C reversed the tumor progression impaired by PTEN overexpression. Clinically, analyses with patients' specimens validated a negative correlation between PTEN and ARL4C expression. Elevated ARL4C expression but PTEN deficiency in tumor was associated with poorer disease-free survival and overall survival of GBM patients. Taken together, ARL4C is critical for PTEN-deficient GBM progression and acts as a novel prognostic biomarker and a potential therapeutic candidate. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Molecular characterization of Coxsackievirus A16 strains isolated from children with severe hand,foot, and mouth disease in Yunnan,Southwest China,during 2009-2015

Coxsackievirus A16 (CV-A16) commonly causes mild symptoms, but severe diseases, such as aseptic meningitis, encephalitis, and even fatal cases, have been reported. Thirteen CV-A16 strains were isolated from patients with severe hand, foot, and mouth disease in Yunnan, Southwest China, from 2009 to 2015. Subgenotype B1a and B1b of CV-A16 were predominantly circulating the region with B1b the predominant strain in recent years. The mean rate of nucleotide substitution based on the VP1 gene sequence was 4.545 × 10 ⁻³ substitution per site per year from 2009 to 2015. These results may help in understanding the genetic diversity of CV-A16 and develop a CV-A16 vaccine.     

A cross-sectional serum investigation of a clustering hepatitis C virus infection in Southwest China

Serum samples were collected in a village with a clustering hepatitis C virus (HCV) infection. HCV antibody, HCV RNA loads, liver function indexes, HCV envelope antibody, and neutralizing activity were assessed. Among 851 adult sera, 342 samples were positive for anti-HCV. Of these positive samples, 254 (74.3%) were HCV RNA positive (≥800 copies/mL). None of the 69 children's sera were positive for HCV antibody or RNA. Among the HCV antibody positive sera, alanine aminotransferase, and aspartate aminotransferase levels increased with the higher virus loads, but decreased when virus loads were higher than 1 × 10 ⁶ copies/mL. HCV envelope antibody and neutralizing antibody levels increased with viral load.     

Epidemiology of human adenovirus infection in children hospitalized with lower respiratory tract infections in Hunan,China

To investigate the current genotypes of circulating human adenovirus (HAdV) strains, we molecularly genotyped HAdV in the nasopharyngeal aspirates (NPAs) of patients with acute lower respiratory tract infections (ALRTIs) and attempted to determine their associations with clinical symptoms. A total of 4751 NPA samples were collected from 4751 patients admitted to Hunan Provincial People's Hospital from September 2007 to March 2014, of which 447 (9.4%) samples were HAdV positive. Fourteen different HAdV types were identified; HAdV types 1 to 7 (HAdV 1-7) were identified in 95.7% of the 447 NPA samples with HAdV-7 and HAdV-3 being the most prevalent. In addition, 93.3% (417 of 447) of patients were younger than 5 years. The incidence of HAdV infection peaked in summer. Different HAdV types showed a predilection for different age groups and different seasonal distribution patterns. Coinfection of HAdVs and other respiratory viruses was detected in 63.3% (283 of 447) of the HAdV-positive samples. The most common clinical diagnosis was pneumonia and the most common symptoms were fever and cough. In comparison with children infected with HAdV-3 alone, those infected with HAdV-7 alone had an increased frequency of severe pneumonia involvement (11.6% vs 32.4%; P = 0.031), higher intensive care unit admission rates (7.0% vs 26.5%; P = 0.019), and a longer length of hospital stay (P = 0.03). Mixed infections in younger children were associated with a longer hospital stay (P = 0.023). Our results demonstrate the recent changes in the trends of circulating HAdV genotypes associated with ALRTIs in Hunan China.