Rescue of DNA damage after constricted migration reveals a mechano-regulated threshold for cell cycle.

Migration through 3D constrictions can cause nuclear rupture and mislocalization of nuclear proteins, but damage to DNA remains uncertain, as does any effect on cell cycle. Here, myosin II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent block in cell cycle appears unaffected. Co-overexpression of multiple DNA repair factors or antioxidant inhibition of break formation also exert partial effects, independently of rupture. Combined treatments completely rescue cell cycle suppression by DNA damage, revealing a sigmoidal dependence of cell cycle on excess DNA damage. Migration through custom-etched pores yields the same damage threshold, with ∼4-µm pores causing intermediate levels of both damage and cell cycle suppression. High curvature imposed rapidly by pores or probes or else by small micronuclei consistently associates nuclear rupture with dilution of stiff lamin-B filaments, loss of repair factors, and entry from cytoplasm of chromatin-binding cGAS (cyclic GMP-AMP synthase). The cell cycle block caused by constricted migration is nonetheless reversible, with a potential for DNA misrepair and genome variation

A preliminary randomized double blind placebo-controlled trial of intravenous immunoglobulin for Japanese encephalitis in Nepal

BACKGROUND: Japanese encephalitis (JE) virus (JEV) is a mosquito-borne flavivirus found across Asia that is closely related to West Nile virus. There is no known antiviral treatment for any flavivirus. Results from in vitro studies and animal models suggest intravenous immunoglobulin (IVIG) containing virus-specific neutralizing antibody may be effective in improving outcome in viral encephalitis. IVIG's anti-inflammatory properties may also be beneficial. METHODOLOGY/PRINCIPAL FINDINGS: We performed a pilot feasibility randomized double-blind placebo-controlled trial of IVIG containing anti-JEV neutralizing antibody (ImmunoRel, 400mg/kg/day for 5 days) in children with suspected JE at two sites in Nepal; we also examined the effect on serum neutralizing antibody titre and cytokine profiles. 22 children were recruited, 13 of whom had confirmed JE; 11 received IVIG and 11 placebo, with no protocol violations. One child (IVIG group) died during treatment and two (placebo) subsequently following hospital discharge. Overall, there was no difference in outcome between treatment groups at discharge or follow up. Passive transfer of anti-JEV antibody was seen in JEV negative children. JEV positive children treated with IVIG had JEV-specific neutralizing antibody titres approximately 16 times higher than those treated with placebo (p=0.2), which was more than could be explained by passive transfer alone. IL-4 and IL-6 were higher in the IVIG group. CONCLUSIONS/SIGNIFICANCE: A trial of IVIG for JE in Nepal is feasible. IVIG may augment the development of neutralizing antibodies in JEV positive patients. IVIG appears an appealing option for JE treatment that warrants further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01856205

A Study of Salty Processed Food Consumption Pattern among Different Ethnic Group in Patient with Gastric Cancer

Gastric cancer is the fourth most frequently occurring malignancy, after lung, breast and colorectal cancer, and the second most common cause of death from cancer worldwide. The global incidence of gastric cancer shows wide geographic variation with a 15-20 fold difference between high and low incidence region. Therefore the prevention of gastric cancer represents one of the most important aspects of any cancer control strategy around the world. From the hospital based data in Nepal gastric cancer is the third most common cancer in males and the sixth common cancer in females. An observational hospital based descriptive study was carried out in the Oncology Unit of (NMCTH) from 2013-2018 on relationship between salty processed food consumption and increased possibility of development of gastric cancer in different ethnic groups of Nepal. Fifty-four diagnosed gastric cancer patients were enrolled and their dietary habits were extensively looked into. Of these 55.6% (30) were males and 44.4% (24) were females. The patient’s age ranged between 25-75 years and the peak incidence was in age group 41-60 years. The habit of consumption of smoked meat was higher (77.8%) than the consumption of packed food and fermented food. Tibeto-mongoloid ethnicity was found to have more prevalence (64.8%) to gastric cancer. The common site of presentation of gastric cancer was at the antrum (44.4%) and tubular adenocarcinoma was the most common type. It was the Tibeto-mongoloids whose food habit pattern comprised of major consumption of salty processed food and having more preference for salty processed food in daily life had increased high risk of gastric cancer than the other ethnic groups. This concludes that food consumption pattern play a critical role in the incidence of gastric cancer and dietary modification to reduce salt and salted food is a practical strategy with which gastric cancer risk can be prevented in these high risk ethnic group of Nepal.</jats:p

Measurement of magnetic susceptibility of Rajmahal traps

Necessary apparatus for the measurement or magnetic susceptibility was built up The average magnetic suceptibility or the Rajmahal traps in eastern India is estimated to be 0.554 x 10-3 emu/ce and is thus low compared to basalt from over areas of the world such. as Japan and Great Britain. Heating effect on magnetic susceptibility has been studied. Generally the susceptibility Increases with the increase or temperature.</jats:p

Idiotype vaccine strategies for treatment of follicular lymphoma

Follicular lymphoma is an indolent lymphoma associated with a relapsing course. Immunization with tumor B cell idiotype (Id; a unique variable region of surface B cell immunoglobulin) may induce humoral and cellular immune response against the tumor. Based on promising results from early phase clinical trials with Id vaccine, three Phase III trials were initiated, which, despite failing to meet their primary end points, still provided a glimmer of optimism. This article describes the clinical development of the Id vaccine against follicular lymphoma, outlines the outcomes of clinical trials and delineates the future prospects for the integration of the idiotype vaccine into follicular lymphoma treatment. </jats:p

Polynitroxyl Albumin Prevents Vaso-Occlusion in Transgenic Sickle Mice.

Abstract Sickle cell disease is characterized by excessive oxidative stress. Sickle patients have enhanced rates of endogenous reactive oxygen species (ROS) production and impaired antioxidant defense mechanisms. We hypothesize that excessive production of ROS promotes activation of vascular endothelium and vaso-occlusion in sickle cell disease. Intravascular ROS production has been shown to trigger the activation of vascular endothelium and increase leukocyte-endothelium interactions. We investigated whether inhibition of intravascular ROS production by treatment with polynitroxyl albumin (PNA), a superoxide dismutase and catalase mimetic agent, could modulate endothelial cell activation and vaso-occlusion in S+S Antilles transgenic sickle mice after hypoxia-reoxygenation. Nuclear factor-kappa B (NF-kB), an oxidant sensitive transcription factor critical for endothelial cell activation, was elevated in lungs and livers of sickle mice and was reduced 2.5 (p=0.043) and 1.5 (p=0.043) fold respectively, by treatment with PNA after hypoxia-reoxygenation. Similarly, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were elevated 3 to 4.7 fold in the same organs (p&lt;0.05). After treatment with PNA, VCAM-1 expression was reduced 2.3 fold in lungs (p=0.014) and 1.5 fold in livers (p=0.006), ICAM-1 expression decreased 1.7 fold in lungs (p=0.014) and 2 fold in livers (p=0.007). Control studies using human serum albumin had no effect on NF-kB activation or adhesion molecule expression in sickle mice. These anti-inflammatory effects of PNA on endothelium corresponded with changes in blood flow in dorsal skin venules. Intravital microscopy revealed that PNA significantly inhibited hypoxia-reoxygenation-induced leukocyte rolling (3.8 fold inhibition, p&lt;0.001) and completely inhibited vaso-occlusion (p&lt;0.001) in venules in the dorsal skin of transgenic sickle mice. We speculate that therapies that reduce ROS will result in improved organ perfusion in sickle cell disease.</jats:p