Hypoxia drives transient site-specific copy gain and drug-resistant gene expression

Copy number heterogeneity is a prominent feature within tumors. The molecular basis for this heterogeneity remains poorly characterized. Here, we demonstrate that hypoxia induces transient site-specific copy gains (TSSGs) in primary, nontransformed, and transformed human cells. Hypoxia-driven copy gains are not dependent on HIF1α or HIF2α; however, they are dependent on the KDM4A histone demethylase and are blocked by inhibition of KDM4A with a small molecule or the natural metabolite succinate. Furthermore, this response is conserved at a syntenic region in zebrafish cells. Regions with site-specific copy gain are also enriched for amplifications in hypoxic primary tumors. These tumors exhibited amplification and overexpression of the drug resistance gene CKS1B, which we recapitulated in hypoxic breast cancer cells. Our results demonstrate that hypoxia provides a biological stimulus to create transient site-specific copy alterations that could result in heterogeneity within tumors and cell populations. These findings have major implications in our understanding of copy number heterogeneity and the emergence of drug resistance genes in cancer.     

Sterility in Zambia

Background : Several regions such as Zambia in sub-Saharan Africa experience very high levels of sterility. Current explanations for high levels of sterility in Zambia have focused on biological determinants and have paid little attention to the plausible effects of social determinants of sterility. Aim : This study has two objectives. The first objective is to examine the extent of sterility in Zambia during 1980 and 1990. The second objective is to assess the contribution of selected social determinants to the current levels of sterility in Zambia. Subjects and methods : Sterility among women in Zambia is calculated for two periods in 1980 and 1990 using census data. The study used parity progression ratios for the calculation of sterility rates. Selected social determinants of Zambian sterility were obtained from the Demographic Health Survey (ZDHS). Net effects of selected social determinants were examined using logistic regression. Results : High sterility levels were found in a few Zambian Provinces. During 1980 and 1990, the rates for North Western, Eastern and Western provinces remained considerably higher than for other Zambian provinces. It was found that social level variables remained strong and significant even after controlling for the effects of incidence of biological factors such as sexually transmitted diseases (STDs). Conclusions : The findings of the study support the importance of developing social policies for eradicating sterility. The argument that sterility is biological and that it is not amenable to social interventions perhaps needs revision in the light of the findings of this study.     

Three-dimensional directional nerve guide conduits fabricated by dopamine-functionalized conductive carbon nanofibre-based nanocomposite ink printing

A potential issue in current nerve guides is that they do not transmit electrical nerve impulses between the distal and proximal end of an injured nerve, i.e. a synapse. Conductivity is a desirable property of an ideal nerve guide that is being considered for peripheral nerve regeneration. Most conductive polymers reported for the fabrication of tissue engineering scaffolds, such as polypyrrole and polyaniline, are non-biodegradable and possess weak mechanical properties, and thus cannot be fabricated into 3D structures. Herein, we have designed a new nanocomposite material composed of dopamine, carbon nanofibers (CNF) and polycaprolactone (PCL) for the fabrication of nerve conduits, which facilitates the growth and migration of neurons toward the targeted end of an injured nerve. This support and navigation of the scaffold leads to better sensory and motor function. The results showed that the mechanical properties of the printed PCL increased by 30% in comparison with the pure PCL film, which is comparable with human nerves. The in vitro cell study of human glioma cells showed that the printed lines provided support for neural cell attachment, migration and differentiation toward the targeted end. In contrast, in the absence of printed lines in the scaffold, the cells attach and grow in random directions, forming a flower shape (cell cluster) on the surface of PCL. Thus, the proposed scaffold is a promising candidate for nerve guide application based on its signal transmission and navigating neurons in a correct pathway towards the targeted end.

Directional growth induced by dopamine-functionalized CNF-based nanocomposite ink printing.     

Isolated noncompaction of right ventricle--a case report

Isolated noncompaction of ventricular myocardium (INVM) is a genetic cardiomyopathy due to abnormal arrest in endomyocardial embryogenesis between fetal 5th and 8th week. Noncompaction of right ventricle alone is rare. Here we present one such case where a young man presented with progressive right heart failure and atrial fibrillation. Subsequent evaluation by echo and cardiac magnetic resonance imaging confirmed our diagnosis. The cardinal manifestations of INVM are heart failure, arrhythmia, and embolic events and our case presented with former two manifestations. Echocardiographic criteria for diagnosing INVM are discussed.     

Strategies for Molecular Classification of Asthma Using Bipartite Network Analysis of Cytokine Expression

Asthma is a chronic inflammatory disease of the airways that leads to various degrees of recurrent respiratory symptoms affecting patients globally. Specific subgroups of asthma patients have severe disease leading to increased healthcare costs and socioeconomic burden. Despite the overwhelming prevalence of the asthma, there are limitations in predicting response to therapy and identifying patients who are at increased risk of morbidity. This syndrome presents with common clinical signs and symptoms; however, awareness of subgroups of asthma patients with distinct characteristics has surfaced in recent years. Investigators attempt to describe the phenotypes of asthma to ultimately assist with diagnostic and therapeutic applications. Approaches to asthma phenotyping are multifold; however, it can be partitioned into 2 essential groups, clinical phenotyping and molecular phenotyping. Innovative techniques such as bipartite network analysis and visual analytics introduce a new dimension of data analysis to identify underlying mechanistic pathways.