Rural-urban differentials of premature mortality burden in south-west China

BACKGROUND: Yunnan province is located in south western China and is one of the poorest provinces of the country. This study examines the premature mortality burden from common causes of deaths among an urban region, suburban region and rural region of Kunming, the capital of Yunnan. METHODS: Years of life lost (YLL) rate per 1,000 and mortality rate per 100,000 were calculated from medical death certificates in 2003 and broken down by cause of death, age and gender among urban, suburban and rural regions. YLL was calculated without age-weighting and discounting rate. Rates were age-adjusted to the combined population of three regions. However, 3% discounting rate and a standard age-weighting function were included in the sensitivity analysis. RESULTS: Non-communicable diseases contributed the most YLL in all three regions. The rural region had about 50% higher premature mortality burden compared to the other two regions. YLL from infectious diseases and perinatal problems was still a major problem in the rural region. Among non-communicable diseases, YLL from stroke was the highest in the urban/suburban regions; COPD followed as the second and was the highest in the rural region. Mortality burden from injuries was however higher in the rural region than the other two regions, especially for men. Self-inflicted injuries were between 2–8 times more serious among women. The use of either mortality rate or YLL gives a similar conclusion regarding the order of priority. Reanalysis with age-weighting and 3% discounting rate gave similar results. CONCLUSION: Urban south western China has already engaged in epidemiological pattern of developed countries. The rural region is additionally burdened by diseases of poverty and injury on top of the non-communicable diseases

Fine mapping of qSTV11KAS, a major QTL for rice stripe disease resistance

Rice stripe disease, caused by rice stripe virus (RSV), is one of the most serious diseases in temperate rice-growing areas. In the present study, we performed quantitative trait locus (QTL) analysis for RSV resistance using 98 backcross inbred lines derived from the cross between the highly resistant variety, Kasalath, and the highly susceptible variety, Nipponbare. Under artificial inoculation in the greenhouse, two QTLs for RSV resistance, designated qSTV7 and qSTV11KAS, were detected on chromosomes 7 and 11 respectively, whereas only one QTL was detected in the same location of chromosome 11 under natural inoculation in the field. The stability of qSTV11KAS was validated using 39 established chromosome segment substitution lines. Fine mapping of qSTV11KAS was carried out using 372 BC3F2:3 recombinants and 399 BC3F3:4 lines selected from 7,018 BC3F2 plants of the cross SL-234/Koshihikari. The qSTV11KAS was localized to a 39.2 kb region containing seven annotated genes. The most likely candidate gene, LOC_Os11g30910, is predicted to encode a sulfotransferase domain-containing protein. The predicted protein encoded by the Kasalath allele differs from Nipponbare by a single amino acid substitution and the deletion of two amino acids within the sulfotransferase domain. Marker-resistance association analysis revealed that the markers L104-155 bp and R48-194 bp were highly correlated with RSV resistance in the 148 landrace varieties. These results provide a basis for the cloning of qSTV11KAS, and the markers may be used for molecular breeding of RSV resistant rice varieties

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

The effects of sorafenib – an oral multikinase inhibitor targeting the tumour and tumour vasculature – were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements <25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with ⩾25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with ⩾25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had ⩾25% tumour shrinkage and remained on open-label sorafenib; six (16%) had <25% tumour growth and were randomised (placebo, n=3; sorafenib, n=3); and 27 had ⩾25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n=1 open-label; n=6 randomised), 62% (n=23) progressive disease (PD) and 19% (n=7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n=4 had PD; n=1 had SD; n=1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n=9 PD; n=1 SD; n=1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies

Myosin Light-Chain Kinase Is Necessary for Membrane Homeostasis in Cochlear Inner Hair Cells

The structural homeostasis of the cochlear hair cell membrane is critical for all aspects of sensory transduction, but the regulation of its maintenance is not well understood. In this report, we analyzed the cochlear hair cells of mice with specific deletion of myosin light chain kinase (MLCK) in inner hair cells. MLCK-deficient mice showed impaired hearing, with a 5- to 14-dB rise in the auditory brainstem response (ABR) thresholds to clicks and tones of different frequencies and a significant decrease in the amplitude of the ABR waves. The mutant inner hair cells produced several ball-like structures around the hair bundles in vivo, indicating impaired membrane stability. Inner hair cells isolated from the knockout mice consistently displayed less resistance to hypoosmotic solution and less membrane F-actin. Myosin light-chain phosphorylation was also reduced in the mutated inner hair cells. Our results suggest that MLCK is necessary for maintaining the membrane stability of inner hair cells

Histone deacetylase inhibitors: potential targets responsible for their anti-cancer effect

The histone deacetylase inhibitors (HDACi) have demonstrated anticancer efficacy across a range of malignancies, most impressively in the hematological cancers. It is uncertain whether this clinical efficacy is attributable predominantly to their ability to induce apoptosis and differentiation in the cancer cell, or to their ability to prime the cell to other pro-death stimuli such as those from the immune system. HDACi-induced apoptosis occurs through altered expression of genes encoding proteins in both intrinsic and extrinsic apoptotic pathways; through effects on the proteasome/aggresome systems; through the production of reactive oxygen species, possibly by directly inducing DNA damage; and through alterations in the tumor microenvironment. In addition HDACi increase the immunogenicity of tumor cells and modulate cytokine signaling and potentially T-cell polarization in ways that may contribute the anti-cancer effect in vivo. Here, we provide an overview of current thinking on the mechanisms of HDACi activity, with attention given to the hematological malignancies as well as scientific observations arising from the clinical trials. We also focus on the immune effects of these agents

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe