Cytokine gene polymorphisms and their association with cervical cancer: A North Indian study

Introduction: The production of cytokines, growth factors and adhesion molecules promotes tumor progression and involves inflammation, angiogenesis and thrombosis, thus providing optimal conditions for cancer development.Materials and methods: The present study was undertaken to evaluate association of cytokine gene polymorphisms with cervical cancer in a north Indian population. Genotyping of single nucleotide polymorphisms (SNPs) viz. IL 6-597G/A (rs1800797), IL-1b-511C/T (rs16944) and TNF-a-308G/A (rs1800629) was carried out in 100 each of cases and healthy age matched controls by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Genotype and allele frequencies were calculated by SPSS (ver.16) and gene–gene interaction was analyzed using SHEsis (ver. Online).Results: Epidemiological studies showed that women >40 years have higher risk of cervical cancer due to early pregnancies. IL-6 and TNF-a promoter polymorphisms showed significant association (P < 0.001) while the SNP combinations G A T* and G G T* of IL-6-597A/G, TNF-a-308G/A and IL-1b-511C/T polymorphisms showed increased risk up to 9.0 and 3.30 times respectively.Conclusion: Therefore, the promoter polymorphisms in cytokine genes can be used as biomarkers to predict cervical cancer susceptibility in a north Indian population. However, such studies need to be carried out in different ethnic populations in order to discover the specific risk alleles, genotypes and combinations for disease prediction.Keywords: Cervical cancer; SNP; Association; IL-6; IL-1b; TNF-

Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D

Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis

A recent Genome-wide Association Study (GWAS) identified association with variants in X-linked CLDN2 and MORC4 and PRSS1-PRSS2 loci with Chronic Pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients

Multiple Approaches to the Restoration of Disturbed Desert Land

Three experiments were conducted to examine restoration of disturbed land in Arizona. The first experiment attempted to revegetate abandoned farmland by direct seeding native seeds and using various soil preparation techniques, amendments, and weeding of Salsola iberica. Only irrigation and weeding had a significant effect on seed germination and canopy cover. Irrigation increased plant cover on plots, but weeds dominated the cover. A seedbank study conducted near the end of the second growing season found the soil was dominated by weeds and contained few viable native seeds. The results illustrate the difficulty of establishing native plants on abandoned desert farmland due to the dominance of weedy species, the presence of salts in the soil, and the lack of adequate soil moisture.The second experiment, a lysimeter study, tested the efficacy of different evapotranspiration (ET) soil cover designs for stabilization of acidic copper mine tailing piles. The study evaluated the effectiveness of capillary barriers (CB) to contain the waste found in tailings and different plants to revegetate the piles. The ET covers reduced infiltration of water into tailings. Copper concentrations increased significantly in plant tissue grown on the ET covers compared to plants grown in the greenhouse. Plants did not exhibit signs of phytotoxicity and concentrations were below levels toxic to all domestic animals except sheep. The CB did not reduce water infiltration into the tailings or upward migration of copper into the soil cover. Vegetation is vital to an effective ET cover. A mix of transplanted shrubs and seeded grasses and forbs establish long-term, sustainable vegetation.The third experiment examined the influence of biosolids on the bacterial communities within mine tailings by bacterial counts and bacterial diversity. The diversity of neutral copper mine tailings two weeks after biosolid application was compared with that of desert soil via cloning and sequencing of PCR amplified community 16S rRNA. Culturable heterotrophic plate counts (HPC) increased following biosolid addition. Total direct counts exceeded HPC by approximately two orders of magnitude. Overall, biosolid-amended tailings contained large numbers of bacteria diverse in nature and with many of the traits of normal desert soil bacterial communities

An investigation into the biological role of Pak1 phosphorylation by Cdks in neurones and mitotic cells

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Cyclooxygenase 1 (COX1) expression in Type 2 diabetes mellitus: A preliminary study from north India

Background and purpose: The 6th edition of International Diabetes Federation, 2014 shows an estimate of 387 million people with Type 2 diabetes mellitus (T2DM) worldwide, expected to rise to 592 million by 2035. T2DM is a metabolic disorder, one of the reasons being oxidative stress due to impairment in antioxidant enzymes. It leads to several complications such as micro and macrovascular diseases. Cyclooxygenase1 (COX1) enzyme is the rate limiting factor for the arachidonic pathway leading to vascular wall contraction with angiotensin II occurring in heart diseases resulting from T2DM. COX1 determines 6-Keto Prostaglandin F1α (6-k-PGF1α) level, plays a major role in vasodilation and restricts macrophage platelet aggregation. The aim of the present study was to compare the COX1 expression and level of reactive oxygen species (ROS) in T2DM patients and controls at different time periods in human macrophages in order to find a biomarker or drug target. Subjects and methods: The study subjects consisted of 100 individuals, 50 each from T2DM patients and healthy sex/age matched controls. Cell proliferation by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and ROS measurement by 2′,7′-dichlorofluorescein diacetate (DCFDA) staining were performed at different time periods (24, 48, 72 h). COX1 mRNA expression was checked by relative quantification method after real-time polymerase chain reaction (RT-PCR). Results: The MTT assay showed that cell viability was significantly higher at 48 h (P  0.05). Conclusion: Although COX1 is known to be a “housekeeping” gene, our study showed that its expression can be correlated with the disease condition and be used as a marker. However, further studies are required in more number of samples from other ethnic populations to confirm the findings

Association of IL-4 and IL-1RN (receptor antagonist) gene variants and the risk of type 2 diabetes mellitus: A study in the north Indian population

Background: Inflammation is a key event closely associated with the pathophysiology of type 2 diabetes mellitus (T2DM). Association of genetic polymorphisms of inflammatory cytokines with T2DM is largely unknown. Our objective was to investigate the relationship of polymorphism of IL-1RN and IL-4, two important biomarkers of inflammation, with the risk of T2DM. Setting and Design: We recruited 120 clinically diagnosed T2DM patients and 150 normal healthy controls for this study in order to evaluate the nature of polymorphisms of IL-1RN and IL-4. Materials and Methods: Genomic DNA was isolated from the blood of all subjects, and the variable number of tandem repeat (VNTR) polymorphisms of IL-1RN and IL-4 genes was identified by polymerase chain reaction. Statistical Analysis Used: Genotype distribution and allelic frequencies were compared between patients and control group. Means, as well as odds ratios (ORs) with 95% confidence intervals (CI), were calculated using SPSS software (version 11.5). Results: Our study revealed that distribution of both IL-4 and IL-1RN (VNTR) gene polymorphisms were significantly associated with T2DM subjects. We, however, failed to find any association of gene-gene (IL-4 and IL-1RN) interaction with T2DM. Conclusions: Both IL-4 and IL-1RN (VNTR) gene polymorphisms were significantly associated with T2DM subjects. This may suggest that the genetic polymorphisms of IL-4 and IL-1RN genes could serve as susceptibility indicators for T2DM in the Indian population, but the actual mechanism of these associations will require more elaborate investigations. Lack of association of gene-gene (IL-4 and IL-1RN) interaction with T2DM may indicate the independent nature of influence of both these genes on the risk of T2DM

Clinical Studies of Cell Therapy in Cardiovascular Medicine: Recent Developments and Future Directions

Given the rising prevalence of cardiovascular disease worldwide and the limited therapeutic options for severe heart failure, novel technologies that harness the regenerative capacity of the heart are sorely needed. The therapeutic use of stem cells has the potential to reverse myocardial injury and improve cardiac function, in contrast to most current medical therapies that only mitigate heart failure symptoms. Nearly 2 decades and >200 trials for cardiovascular disease have revealed that most cell types are safe; however, their efficacy remains controversial, limiting the transition of this therapy from investigation to practice. Lessons learned from these initial studies are driving the design of new clinical trials; higher fidelity of cell isolation techniques, standardization of conditions, more consistent use of state of the art measurement techniques, and assessment of multiple end points to garner insights into the efficacy of stem cells. Translation to clinical trials has almost outpaced our mechanistic understanding, and individual patient factors likely play a large role in stem cell efficacy. Therefore, careful analysis of dosing, delivery methods, and the ideal patient populations is necessary to translate cell therapy from research to practice. We are at a pivotal stage in the field in which information from many relatively small clinical trials must guide carefully executed efficacy trials. Larger efficacy trials are being launched to answer questions about older, first-generation stem cell therapeutics, while novel, second-generation products are being introduced into the clinical realm. This review critically examines the current state of clinical research on cell-based therapies for cardiovascular disease, highlighting the controversies in the field, improvements in clinical trial design, and the application of exciting new cell products