Functional Blockade of Small GTPase RAN Inhibits Glioblastoma Cell Viability

Glioblastoma, the most common malignant tumor in the brain, lacks effective treatments and is currently incurable. To identify novel drug targets for this deadly cancer, the publicly available results of RNA interference screens from the Project Achilles database were analyzed. Ten candidate genes were identified as survival genes in 15 glioblastoma cell lines. RAN, member RAS oncogene family (RAN) was expressed in glioblastoma at the highest level among all candidates based upon cDNA microarray data. However, Kaplan-Meier survival analysis did not show any correlation between RAN mRNA levels and patient survival. Because RAN is a small GTPase that regulates nuclear transport controlled by karyopherin subunit beta 1 (KPNB1), RAN was further analyzed together with KPNB1. Indeed, GBM patients with high levels of RAN also had more KPNB1 and levels of KPNB1 alone did not relate to patient prognosis. Through a Cox multivariate analysis, GBM patients with high levels of RAN and KPNB1 showed significantly shorter life expectancy when temozolomide and promoter methylation of O6-methylguanine DNA methyltransferase were used as covariates. These results indicate that RAN and KPNB1 together are associated with drug resistance and GBM poor prognosis. Furthermore, the functional blockade of RAN and KPNB1 by importazole remarkably suppressed cell viability and activated apoptosis in GBM cells expressing high levels of RAN, while having a limited effect on astrocytes and GBM cells with undetectable RAN. Together, our results demonstrate that RAN activity is important for GBM survival and the functional blockade of RAN/KPNB1 is an appealing therapeutic approach

Deep resequencing reveals excess rare recent variants consistent with explosive population growth

Accurately determining the distribution of rare variants is an important goal of human genetics, but resequencing of a sample large enough for this purpose has been unfeasible until now. Here, we applied Sanger sequencing of genomic PCR amplicons to resequence the diabetes-associated genes KCNJ11 and HHEX in 13,715 people (10,422 European Americans and 3,293 African Americans) and validated amplicons potentially harbouring rare variants using 454 pyrosequencing. We observed far more variation (expected variant-site count ∼578) than would have been predicted on the basis of earlier surveys, which could only capture the distribution of common variants. By comparison with earlier estimates based on common variants, our model shows a clear genetic signal of accelerating population growth, suggesting that humanity harbours a myriad of rare, deleterious variants, and that disease risk and the burden of disease in contemporary populations may be heavily influenced by the distribution of rare variants

World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions

BACKGROUND: To help adapt cardiovascular disease risk prediction approaches to low-income and middle-income countries, WHO has convened an effort to develop, evaluate, and illustrate revised risk models. Here, we report the derivation, validation, and illustration of the revised WHO cardiovascular disease risk prediction charts that have been adapted to the circumstances of 21 global regions. METHODS: In this model revision initiative, we derived 10-year risk prediction models for fatal and non-fatal cardiovascular disease (ie, myocardial infarction and stroke) using individual participant data from the Emerging Risk Factors Collaboration. Models included information on age, smoking status, systolic blood pressure, history of diabetes, and total cholesterol. For derivation, we included participants aged 40-80 years without a known baseline history of cardiovascular disease, who were followed up until the first myocardial infarction, fatal coronary heart disease, or stroke event. We recalibrated models using age-specific and sex-specific incidences and risk factor values available from 21 global regions. For external validation, we analysed individual participant data from studies distinct from those used in model derivation. We illustrated models by analysing data on a further 123 743 individuals from surveys in 79 countries collected with the WHO STEPwise Approach to Surveillance. FINDINGS: Our risk model derivation involved 376 177 individuals from 85 cohorts, and 19 333 incident cardiovascular events recorded during 10 years of follow-up. The derived risk prediction models discriminated well in external validation cohorts (19 cohorts, 1 096 061 individuals, 25 950 cardiovascular disease events), with Harrell's C indices ranging from 0·685 (95% CI 0·629-0·741) to 0·833 (0·783-0·882). For a given risk factor profile, we found substantial variation across global regions in the estimated 10-year predicted risk. For example, estimated cardiovascular disease risk for a 60-year-old male smoker without diabetes and with systolic blood pressure of 140 mm Hg and total cholesterol of 5 mmol/L ranged from 11% in Andean Latin America to 30% in central Asia. When applied to data from 79 countries (mostly low-income and middle-income countries), the proportion of individuals aged 40-64 years estimated to be at greater than 20% risk ranged from less than 1% in Uganda to more than 16% in Egypt. INTERPRETATION: We have derived, calibrated, and validated new WHO risk prediction models to estimate cardiovascular disease risk in 21 Global Burden of Disease regions. The widespread use of these models could enhance the accuracy, practicability, and sustainability of efforts to reduce the burden of cardiovascular disease worldwide. FUNDING: World Health Organization, British Heart Foundation (BHF), BHF Cambridge Centre for Research Excellence, UK Medical Research Council, and National Institute for Health Research

Effective management of Colles fracture using Murivenna and Abha Guggulu – A case report

Colles fracture is the commonest fracture encountered in orthopedic practice that demands prompt therapeutic intervention, and adequate follow-up to ensure complete healing. Various types of fractures, methods of reduction, and healing have been explained in the classical Ayurveda texts. These techniques are scientific and time-tested. This paper aims to report the successful management of Colles fracture case using Ayurveda and modern techniques with the use of Murivenna (an oil-based herbal formulation mentioned in the contemporary texts of Ayurveda), half-cast POP, and aluminum splinted bandage along with the internal medicine Abha Guggulu. A 75-year-old moderately built woman diagnosed with Colles fracture was treated with a closed manipulative reduction technique followed by a below-elbow half-cast POP and an aluminum splint. Murivenna was poured anteriorly to the fractured site and Abha Guggulu was administered internally. Re-bandaging was done on the 7th day and 21st day. The bandage was removed on the 35th day. The patient's condition improved considerably with a good range of wrist movements and then she was advised to commence rehabilitation. This integrative method, adhering to Ayurvedic principles and modern techniques is unique, patient-friendly, and without adverse events

OfftargetFinder: a web tool for species-specific RNAi design

MOTIVATION: RNA interference (RNAi) technology is being developed as a weapon for pest insect control. To maximize the specificity that such an approach affords we have developed a bioinformatic web tool that searches the ever-growing arthropod transcriptome databases so that pest-specific RNAi sequences can be identified. This will help technology developers finesse the design of RNAi sequences and suggests which non-target species should be assessed in the risk assessment process. AVAILABILITY AND IMPLEMENTATION: http://rnai.specifly.org CONTACT: [email protected]

The Role of Class IA Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunits in Glioblastoma

Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) plays a critical role in the pathogenesis of cancer including glioblastoma, the most common and aggressive form of brain cancer. Targeting the PI3K pathway to treat glioblastoma has been tested in the clinic with modest effect. In light of the recent finding that PI3K catalytic subunits (PIK3CA/p110α, PIK3CB/p110β, PIK3CD/p110δ, and PIK3CG/p110γ) are not functionally redundant, it is imperative to determine whether these subunits play divergent roles in glioblastoma and whether selectively targeting PI3K catalytic subunits represents a novel and effective strategy to tackle PI3K signaling. This article summarizes recent advances in understanding the role of PI3K catalytic subunits in glioblastoma and discusses the possibility of selective blockade of one PI3K catalytic subunit as a treatment option for glioblastoma