Mitochondrial DNA Copy Number and Risk of Oral Cancer: A Report from Northeast India

Background

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer globally. Tobacco consumption and HPV infection, both are the major risk factor for the development of oral cancer and causes mitochondrial dysfunction. Genetic polymorphisms in xenobiotic-metabolizing enzymes modify the effect of environmental exposures, thereby playing a significant role in gene–environment interactions and hence contributing to the individual susceptibility to cancer. Here, we have investigated the association of tobacco - betel quid chewing, HPV infection, GSTM1-GSTT1 null genotypes, and tumour stages with mitochondrial DNA (mtDNA) content variation in oral cancer patients.

Methodology/Principal Findings

The study comprised of 124 cases of OSCC and 140 control subjects to PCR based detection was done for high-risk HPV using a consensus primer and multiplex PCR was done for detection of GSTM1-GSTT1 polymorphism. A comparative ΔCt method was used for determination of mtDNA content. The risk of OSCC increased with the ceased mtDNA copy number (P_trend = 0.003). The association between mtDNA copy number and OSCC risk was evident among tobacco – betel quid chewers rather than tobacco – betel quid non chewers; the interaction between mtDNA copy number and tobacco – betel quid was significant (P = 0.0005). Significant difference was observed between GSTM1 - GSTT1 null genotypes (P = 0.04, P = 0.001 respectively) and HPV infection (P<0.001) with mtDNA content variation in cases and controls. Positive correlation was found with decrease in mtDNA content with the increase in tumour stages (P<0.001). We are reporting for the first time the association of HPV infection and GSTM1-GSTT1 null genotypes with mtDNA content in OSCC.

Conclusion

Our results indicate that the mtDNA content in tumour tissues changes with tumour stage and tobacco-betel quid chewing habits while low levels of mtDNA content suggests invasive thereby serving as a biomarker in detection of OSCC.     

Off‐Shoring Clinical Research: Exploitation and the Reciprocity Constraint

The last 20 years have seen a staggering growth in the practice of off‐shoring clinical research to low‐and middle‐income countries (LICs and MICs), a growth that has been matched by the neoliberal policies adopted by host countries towards attracting trials to their shores. A recurring concern in this context is the charge of exploitation, linked to various aspects of off‐shoring. In this paper, I examine Alan Wertheimer's approach and offer an alternative view of understanding exploitation in this context. I will suggest that the justification for the enterprise of research is largely dependent on its integration within a health system from which participants regularly benefit and I argue that an attention to a principle of reciprocity will enable us to better recognize and address exploitation in international research.     

A Mycobacterial Phosphoribosyltransferase Promotes Bacillary Survival by Inhibiting Oxidative Stress and Autophagy Pathways in Macrophages and Zebrafish

Mycobacterium tuberculosis employs various strategies to modulate host immune responses to facilitate its persistence in macrophages. The M. tuberculosis cell wall contains numerous glycoproteins with unknown roles in pathogenesis. Here, by using Concanavalin A and LC-MS analysis, we identified a novel mannosylated glycoprotein phosphoribosyltransferase, encoded by Rv3242c from M. tuberculosis cell walls. Homology modeling, bioinformatic analyses, and an assay of phosphoribosyltransferase activity in Mycobacterium smegmatis expressing recombinant Rv3242c (MsmRv3242c) confirmed the mass spectrometry data. Using Mycobacterium marinum-zebrafish and the surrogate MsmRv3242c infection models, we proved that phosphoribosyltransferase is involved in mycobacterial virulence. Histological and infection assays showed that the M. marinum mimG mutant, an Rv3242c orthologue in a pathogenic M. marinum strain, was strongly attenuated in adult zebrafish and also survived less in macrophages. In contrast, infection with wild type and the complemented ΔmimG:Rv3242c M. marinum strains showed prominent pathological features, such as severe emaciation, skin lesions, hemorrhaging, and more zebrafish death. Similarly, recombinant MsmRv3242c bacteria showed increased invasion in non-phagocytic epithelial cells and longer intracellular survival in macrophages as compared with wild type and vector control M. smegmatis strains. Further mechanistic studies revealed that the Rv3242c- and mimG-mediated enhancement of intramacrophagic survival was due to inhibition of autophagy, reactive oxygen species, and reduced activities of superoxide dismutase and catalase enzymes. Infection with MsmRv3242c also activated the MAPK pathway, NF-κB, and inflammatory cytokines. In summary, we show that a novel mycobacterial mannosylated phosphoribosyltransferase acts as a virulence and immunomodulatory factor, suggesting that it may constitute a novel target for antimycobacterial drugs.     

The importance of an inter-compartmental delay in a model for human gastric acid secretion

In this work we re-examine an existing model of gastric acid secretion. The model is a 2-compartment model of the human stomach accounting for regions where relevant cells (D, G, ECL and parietal cells) and proteins and acid they secrete (somatostatin, gastrin, histamine, and gastric acid, respectively) are found. These proteins compose a positive and negative feedback system that controls the secretion of gastric acid by parietal cells. The original model consists of 18 ordinary differential equations and yields a stable 3-period limit cycle solution. We modify the existing model by introducing a delay into the system and assuming that the cell populations are in steady state over a short-time window (<300 h) and are able to reduce the system to an 8-equation delay differential equation model. In addition to demonstrating congruency between the two models, we also show that a similar stability is only reproducible when the delay in gastrin transport is approximately 30 min. This suggests that gastric acid secretion homeostasis likely depends strongly on the delay in gastrin transport from the antrum to the corpus. Equal contribution.     

MDM2 induces hyperplasia and premalignant lesions when expressed in the basal layer of the epidermis

The MDM2 oncogene is overexpressed in 5-10% of human tumours. Its major physiological role is to inhibit the tumour suppressor p53. However, MDM2 has p53-independent effects on differentiation and does not predispose to tumorigenesis when it is expressed in the granular layer of the epidermis. These unexpected properties of MDM2 could be tissue specific or could depend on the differentiation state of the cells. Strikingly, we found that MDM2 has p53-dependent effects on differentiation, proliferation and apoptosis when it is expressed in the less differentiated basal layer cells. MDM2 inhibits UV induction of p53, the cell cycle inhibitor p21(WAF1/CIP1) and apoptosis ('sunburn cells'). Importantly, MDM2 increases papilloma formation induced by chemical carcinogenesis and predisposes to the appearance of premalignant lesions and squamous cell carcinomas. p53 has a natural role in the protection against UV damage in the basal layer of the epidermis. Our results show that MDM2 predisposes to tumorigenesis when expressed at an early stage of differentiation, and provide a mouse model of MDM2 tumorigenesis relevant to p53's tumour suppressor functions.     

Heavy Metals in Indigenous Preparations Used for Sex Selection During Pregnancy in India

Biological Trace Element Research - Indigenous preparations (IPs) have evoked a considerable interest in alleviating infections and chronic diseases and improving wellbeing. While such formulations...     

A comparison of VO2max and metabolic variables between treadmill running and treadmill skating

The purpose of this study was to determine differences in VO2max and metabolic variables between treadmill running and treadmill skating. This study also examined VO2max responses during a continuous skating treadmill protocol and a discontinuous skating treadmill protocol. Sixteen male high school hockey players, who had a mean age of 16 +/- 1 years and were of an above-average fitness level, participated in this study. All subjects completed 4 exercise trials: a 1-hour skating treadmill familiarization trial, a treadmill running trial, and 2 randomized skating treadmill trials. Minute ventilation (VE), oxygen consumption VO2), carbon dioxide production VCO2), respiratory exchange ratio (RER), and heart rate were averaged every 15 seconds up to VO2max for each exercise test. The results showed that there was a significant difference (P < 0.05) for VO2max (mL.kg.min) and maximal VCO2 (L.min) between the running treadmill protocol and discontinuous skating treadmill protocol. There was also a significant difference for maximal RER between the discontinuous and continuous skating treadmill protocol and between the discontinuous skating treadmill protocol and running treadmill protocol. In conclusion, the running treadmill elicited a greater VO2max (mL.kg.min) than the skating treadmill did, but when it comes to specificity of ice skating, the skating treadmill may be ideal. Also, there was no significant difference between the discontinuous and continuous skating treadmill protocols. Therefore, a continuous protocol is possible on the skating treadmill without compromising correct skating position and physiologic responses. However, the continuous skating treadmill protocol should undergo validation before other scientists, coaches, and strength and conditioning professionals can apply it correctly.