Epidermal growth factor receptor and integrins meet redox signaling through P66shc and Rac1.

This review examines the concerted role of Epidermal Growth Factor Receptor (EGFR) and integrins in regulating Reactive oxygen species (ROS) production through different signaling pathways. ROS as such are not always deleterious to the cells but they also act as signaling molecules, that regulates numerous indespensible physiological fuctions of life. Many adaptor proteins, particularly Shc and Grb2, are involved in mediating the downstream signaling pathways stimulated by EGFR and integrins. Integrin-induced activation of EGFR and subsequent tyrosine phosphorylation of a class of acceptor sites on EGFR leads to alignment and tyrosine phosphorylation of Shc, PLCγ, the p85 subunit of PI-3 K, and Cbl, followed by activation of the downstream targets Erk and Akt/PKB. Functional interactions between these receptors result in the activation of Rac1 via these adaptor proteins, thereby leading to Reactive Oxygen Species. Both GF and integrin activation can produce oxidants independently, however synergistically there is increased ROS generation, suggesting a mutual cooperation between integrins and GFRs for redox signalling. The ROS produced further promotes feed-forward stimulation of redox signaling events such as MAPK activation and gene expression. This relationship has not been reviewed previously. The literature presented here can have multiple implications, ranging from looking at synergistic effects of integrin and EGFR mediated signaling mechanisms of different proteins to possible therapeutic interventions operated by these two receptors. Furthermore, such mutual redox regulation of crosstalk between EGFR and integrins not only add to the established models of pathological oxidative stress, but also can impart new avenues and opportunities for targeted antioxidant based therapeutics.

A simple, economical and environmental-friendly method for staining protein gels using an extract from walnut-husk.

We wish to present a simple, rapid, cost-effective and environmentally safe method for staining proteins in polyacrylamide gels, using aqueous-based natural extracts from fresh green walnut (Juglans regia) hulls/husks. The technique takes not more than 10 min for staining and is comparable in sensitivity to the most commonly used Coomassie R-250 staining method when applied to different concentrations of Bovine Serum Albumin (BSA) and various amounts of E. coli extracts. The protein (BSA) band (~0.5 µg) and E. coli extract comprising ~25 µg total protein can be visualized on polyacrylamide gels. Compared to both Coomassie and Ponceau S staining, the current method displayed more intense bands when proteins are transferred to polyvinylidene fluoride (PVDF) membrane. Although the walnut-dye (WD) method does not require a time-consuming destaining step, excess background stain can simply be removed by washing in water. Extract from old dried black husks and extract from fresh green husks kept for a year was also effective. Using LC-MS, Myricetin and/or Kaempferol were found to be active compounds responsible for staining proteins. Compared to traditional Coomassie method, the inclusion of expensive and toxic solvents (methanol and acetic acid) is completely avoided resulting in positive health, environmental and economic benefits. In view of all these advantages, the WD method has immense potential to replace currently used protein staining techniques.

Association of Activity Altering Genotypes - Tyr113His and His139Arg in Microsomal Epoxide Hydrolase Enzyme with Esophageal Squamous Cell Carcinoma.

The study aimed to explore the relationship of microsomal epoxide hydrolase (mEH) exon 3 (Tyr113His) and exon 4 (His139Arg) polymorphisms and predicted mEH activity with esophageal squamous cell carcinoma (ESCC) risk. 482 histologically confirmed cases and equal number of matched controls were analyzed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). Conditional logistic regression models were used to examine the association of polymorphisms with ESCC. We noted exon 3 slow genotype (OR = 6.57; CI 3.43-12.57) as well as predicted low mEH activity (OR = 3.99; CI 2.32-6.85) was associated with the ESCC risk. Elevated ESCC risk estimates were seen in smokers independent of genotypes but the association was stronger among smokers with exon 3 variant (OR = 6.67; 3.29-13.53) and low activity (OR = 7.52; CI 3.46-16.37) genotypes. Positive family history of cancer synergistically increased ESCC risk in the individuals who harbored exon 3 (OR = 13.59; CI 5.63-32.81) or altered mEH activity genotypes (OR = 13.35; CI 5.10-34.94). Significant interaction was seen between mEH exon 3 and exon 4 genotypes (P = 0.006) and between predicted mEH activity and positive family history of cancer (P = 0.018). These findings suggest association of ESCC risk with mEH polymorphisms which get modified by tobacco smoking and positive family history of cancer.

Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study.

BACKGROUND/AIMS: Acute liver failure (ALF) is a rare but severe medical emergency. To date, there is no established treatment for non-acetaminophen-induced acute liver failure (NAI-ALF) other than liver transplantation, and little is known about the use of N-acetylcysteine (NAC) in NAI-ALF. A randomized case control study was conducted with the aim to determine the effect of NAC on the mortality of NAI-ALF patients, as well as to evaluate the safety and efficacy of NAC use. PATIENTS AND METHODS: A total of 80 patients diagnosed with NAI-ALF were included in the study. Forty patients received NAC infusion for 72 h whereas the control group received placebo. The variables evaluated were demographic characteristics, signs and symptoms, biochemical parameters, and clinical course during hospitalization. RESULTS: The two groups (NAC and control) were comparable for various baseline characteristics (such as etiology of ALF, INR, alanine aminotransferase, creatinine, albumin, and grade of encephalopathy), except for age. Although majority of patients had undetermined etiology (32.5% in NAC group and 42.5% in control group), the second main cause was acute hepatitis E and drug or toxin-induced ALF. The mortality decreased to 28% with the use of NAC versus 53% in the control group (P = 0.023). The use of NAC was associated with shorter length of hospital stay in survived patients (P = 0.002). Moreover, the survival of patients was improved by NAC (P = 0.025). Also, drug-induced ALF showed improved outcome compared to other etiologies. CONCLUSION: The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe.

Impediments in foreign collaboration and conducting a high throughput molecular epidemiology research in India, an assessment from a feasibility study.

BACKGROUND: Esophageal cancer is one of the world's top ten cancers. Its incidence, especially in the form of squamous cell carcinoma, is very high in some Asian regions including Kashmir. Jammu Kashmir and Ladakh are three provinces of Jammu and Kashmir, the northern most state of India. The three regions represent ethnically diverse socio-cultural populations with different incidences of esophageal squamous cell carcinoma (ESCC), a suitable setting for epidemiological studies. Hence, comparing the lifestyle, dietary habits and gene pools between the three regions will help in elucidation of ESCC etiology further. Therefore, to assess the possibility of conducting a larger case control study, we carried out a feasibility study to identify the collaborators as well as to explore patient referral systems and available research facilities in the state. FINDINGS: We found conducting good cancer molecular epidemiology studies is difficult due to lack of proper research facilities and favourable administrative guidelines. The appropriate storage, transportation and analyses facilities of biological specimens for genome-wide association study and assessment of nutrition and exposure markers are unavailable or not sufficiently developed. Guidelines that can encourage scientific collaborations within the country seem unavailable. However, the administrative guidelines available under which the export of biological specimens out of India for analysis seems impossible. Consequently, Indian researchers are unable to collaborate with foreign scientists and render state of art research facilities inaccessible to them. Scientists in other parts of India may also confront with most of these impediments. CONCLUSION: The study found that for conducting conclusive molecular epidemiological studies in India, referral system in hospitals is not systematic, scientific research facilities are inadequate as well as the guidelines for foreign collaboration  are not favourable.

Salt tea consumption and esophageal cancer: a possible role of alkaline beverages in esophageal carcinogenesis.

Salt tea is the most commonly used beverage in Kashmir, India, where esophageal squamous cell carcinoma (ESCC) is the most common cancer. Salt tea is brewed in a unique way in Kashmir, usually with addition of sodium bicarbonate, which makes salt tea alkaline. As little information about the association between salt tea drinking and ESCC was available, we conducted a large-scale case-control study to investigate this association in Kashmir. We recruited 703 histologically confirmed cases of ESCC and 1664 controls individually matched to cases for age, sex, and district of residence. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Participants who consumed >1,250 ml day(-1) showed an increased risk of ESCC (OR = 2.60, 95% CIs = 1.68-4.02). Samovar (a special vessel for the beverage preparation) users (OR = 1.77, 95% CIs 1.25-2.50) and those who ate cereal paste with salt tea (OR = 2.14, 95% CIs = 1.55-2.94) or added bicarbonate sodium to salt tea (OR = 2.12, 95% CIs = 1.33-3.39) were at higher risk of ESCC than others. When analysis was limited to alkaline tea drinkers only, those who both consumed cereal paste with salt tea and used samovar vessel were at the highest risk (OR = 4.58, 95% CIs = 2.04-10.28). This study shows significant associations of salt tea drinking and some related habits with ESCC risk.

CYP1A1 and CYP2E1 genotypes and risk of esophageal squamous cell carcinoma in a high-incidence region, Kashmir.

The study analyzed the relationship between genetic polymorphisms of phase I xenobiotic metabolizing enzymes, cytochromes P450 (CYP) 1A1 and CYP2E1 and esophageal squamous cell carcinoma (ESCC) in Kashmir, India. The different genotypes of CYP1A1 and CYP2E1 were analyzed by polymerase chain reaction and restriction fragment length polymorphism in 526 ESCC cases and equal number of matched controls. Conditional logistic regression models were used to assess the association of various genotypes with ESCC, gene-gene, and gene-environment interactions. High risk of ESCC was found in participants who carried CYP1A1 Val/Val genotype (OR=2.87; 95 % CI=1.00-8.44) and the risk increased in such individuals when c1/c1 of CYP2E1 genotype was also present (OR=5.68; 95 % CI=1.09-29.52). Risk due to CYP1A1 Val/Val genotype was further enhanced (OR=8.55; 95 % CI=1.86-42.20) when the analysis was limited to ever smokers. Participants who carried CYP2E1 c1/c2 genotype showed an inverse relation (OR=0.27; 95 % CI=0.17-0.43) with ESCC. The inverse association of CYP2E1 c1/c2 genotype was retained when CYP1A1 Ile/Ile was also present (OR=0.18; 95 % CI=0.09-0.32), as well as when analysis was limited to ever smokers (OR=0.45; 95 % CI=0.23-0.90). Significant interaction was found between CYP1A1 (Val/Val) and CYP2E1 (c1/c1) genotypes (OR=1.30; 95 % CI=1.12-1.51; P=0.001) and between CYP1A1 (Val/Val) and smoking (OR=1.31; 95 % CI=1.01-1.69; P=0.043). The study suggests CYP1A1 Val/Val and CYP2E1 c1/c1 genotypes are significantly associated with ESCC risk.

Socioeconomic status and esophageal squamous cell carcinoma risk in Kashmir, India.

Studies have persistently associated esophageal squamous cell carcinoma (ESCC) risk with low socioeconomic status (SES), but this association is unexplored in Kashmir, an area with a high incidence of ESCC in the northernmost part of India. We carried out a case-control study to assess the association of multiple indicators of SES and ESCC risk in the Kashmir valley. A total number of 703 histologically confirmed ESCC cases and 1664 controls matched to the cases for age, sex, and district of residence were recruited from October 2008 to January 2012. Conditional logistic regression models were used to calculate unadjusted and adjusted odds ratios and 95% confidence intervals. Composite wealth scores were constructed based on the ownership of several appliances using multiple correspondence analyses. Higher education, living in a kiln brick or concrete house, use of liquefied petroleum gas and electricity for cooking, and higher wealth scores all showed an inverse association with ESCC risk. Compared to farmers, individuals who had government jobs or worked in the business sector were at lower risk of ESCC, but this association disappeared in fully adjusted models. Occupational strenuous physical activity was strongly associated with ESCC risk. In summary, we found a strong relationship of low SES and ESCC in Kashmir. The findings need to be studied further to understand the mechanisms through which such SES parameters increase ESCC risk.