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To date, over 100 small-molecule oncology drugs have been approved by the FDA. Because of the inherent heterogeneity of tumors, these small molecules are often administered in combination to prevent emergence of resistant cell subpopulations. Therefore, new combination strategies to overcome drug resistance in patients with advanced cancer are needed. In this study, we performed a systematic evaluation of the therapeutic activity of over 5,000 pairs of FDA-approved cancer drugs against a panel of 60 well-characterized human tumor cell lines (NCI-60) to uncover combinations with greater than additive growth-inhibitory activity. Screening results were compiled into a database, termed the NCI-ALMANAC (A Large Matrix of Anti-Neoplastic Agent Combinations), publicly available at https://dtp.cancer.gov/ncialmanac. Subsequent in vivo experiments in mouse xenograft models of human cancer confirmed combinations with greater than single-agent efficacy. Concomitant detection of mechanistic biomarkers for these combinations in vivo supported the initiation of two phase I clinical trials at the NCI to evaluate clofarabine with bortezomib and nilotinib with paclitaxel in patients with advanced cancer. Consequently, the hypothesis-generating NCI-ALMANAC web-based resource has demonstrated value in identifying promising combinations of approved drugs with potent anticancer activity for further mechanistic study and translation to clinical trials. Cancer Res; 77(13); 3564–76. ©2017 AACR.

This file contains: Supplementary Methods for pharmacodynamic biomarker analyses, clinicaltrials.gov searches, and molecular correlation analyses; Supplementary Figures S1 (overview of the NCI-ALMANAC web resource), S2 (apoptotic biomarker response to bortezomib-clofarabine), and S3 (associations between ABC transporter activity and nilotinib-paclitaxel combination activity); and Supplementary Tables S1 (FDA-approved agents used in the NCI-ALMANAC screen), S2 (tumor doubling time analysis of xenograft experiments with clinically tested NCI-ALMANAC-derived combinations), S3 (in vitro, in vivo, and clinical activity of NCI-ALMANAC-derived combinations), and S4 (tumor doubling time analysis of xenograft experiments with novel NCI-ALMANAC-derived combinations).

Background: Triple-Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with few targeted therapies, limiting patients to harsh systemic treatments and resulting in the lowest 5-year survival rate of all breast cancer subtypes. This survival rate plummets after metastasis to another site, making it crucial to identify new therapeutic options for TNBC patients to prevent recurrence and metastasis. The small molecule therapy birinapant, a secondary mitochondrial activator of caspases (SMAC) mimetic, represents a potential new avenue for TNBC treatment. Birinapant initiates apoptotic signaling through targeting of Inhibitor of Apoptosis (IAP) proteins in the Tumor Necrosis Factor Receptor (TNFR) extrinsic apoptosis signaling pathway, leading to the formation of a death complex, caspase activity, and apoptosis. We have found that approximately 25% of TNBC patient-derived xenograft (PDX) and xenograft-derived organoid (PDxO) models are exquisitely sensitive to birinapant treatment. However, the majority of our TNBC patient-derived lines remain resistant through unknown means. We seek to understand the parameters for birinapant response and the mechanism of inherent resistance in TNBC using our patient-derived TNBC models. Approach and Results: Preliminary Western blot experiments revealed that treatment of birinapant-sensitive and resistant PDX tumors in vivo and PDxOs in vitro with birinapant causes degradation of cIAP1 and cIAP2, but only causes apoptosis in birinapant-sensitive lines. Therefore, there may be a disruption of necessary downstream apoptotic signaling in the birinapant-resistant lines. Through follow-up Western blot experiments we determined that at baseline, birinapant-resistant PDxOs do not lack the TNFR extrinsic apoptosis proteins required for apoptosis signaling after IAP degradation, nor is there an abundance of these proteins in the birinapant-sensitive PDxOs. Furthermore, to determine if TNFR extrinsic apoptosis signaling is impaired in birinapant-resistant PDxOs, we treated birinapant-resistant and -sensitive PDxOs with the TNF-a cytokine, which is known to enhance extrinsic apoptosis signaling in the presence of birinapant. Treatment with TNF-a and birinapant did not induce apoptosis in the birinapant-resistant PDxOs, suggesting that the extrinsic apoptosis signaling pathway may be the culprit of resistance in these patient-derived lines. Discussion: Follow-up experiments will address whether an inability to execute extrinsic apoptosis through other death receptor pathways explains birinapant resistance in these models. This work will allow us to uncover what predisposes TNBC patients to be resistant or sensitive to birinapant, and determine how this may be harnessed therapeutically to improve outcomes for TNBC patients. This project was funded in part with federal funds under HHSN261201500003I and U54CA224076. Citation Format: Elisabeth A. Brown, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Zhengtao Chu, Jeevan Govindharajulu, Ralph Parchment, James Doroshow, Apurva Srivastava, Alana Welm. Determinants of birinapant efficacy in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 393.

A 50-year-old male diabetic, hypertensive and chronic smoker presented with complex aortic, splanchnic aneurysms with impending rupture of iliac artery aneurysm, underwent coiling of celiac artery, internal iliac artery, and fenestrated/chimney endovascular aortic repair. One month later, the patient landed in an emergency due to bleeding complications of common hepatic artery and gastroduodenal artery aneurysms, which were managed successfully using endovascular techniques. The mayhem of progressive nature of the disease in the patient continued as he had left lower limb ischemia due to occlusion of the iliac artery and iliac limb of the aortic graft device as he continued to smoke. All of the above sequences of events occurred over a period of 5 years. He also developed a giant aneurysm of left anterior descending of 6.8 cm diameter, which had to be repaired by open surgical technique. The patient has been followed up for 6 years since his first presentation, and he was managed successfully from all the catastrophe of events using endovascular techniques. Giant coronary artery aneurysm with previous aneurysms at multiple sites is quite unusual and rare. Currently, there is no consensus regarding the clinical characteristics, diagnostic method, and the treatment of these cases.

Aim: The study was aimed to evaluate the role of two-dimensional (2D) perfusion angiography (PA) as a predictor in wound healing outcomes in patients of critical limb ischemia. Subject and Methods: It was a pilot study conducted over a period of 16 months after taking informed consent and institutional ethical clearance. The study included 40 patients of which 8 were lost to follow-up, hence the prospective data of 32 patients was collected and analyzed. Patients were subjected to endovascular intervention and 2D perfusion software was applied to the digital subtraction angiography images and its parameters were assessed. Transcutaneous oxygen tension (TcPO2) was measured pre- and postintervention and patients were closely followed up for the time taken for wound healing. Results: The median age was 62 years ranging from 30 to 85 years. Most common comorbidity was diabetes (21/32 patients). The mean Ankle–Brachial Index in the study was 0.55 and mean TcPO2 at admission was 26.5 mm of Hg. Most common involved angiosome was percutaneous transluminal angioplasty angiosome. Fifteen patients underwent direct, 9 indirect, and remaining 8 patients underwent revascularization in both territories. The mean percent improvement in TcPO2 was higher in indirect when compared to direct revascularization but it was not statistically significant. The time taken in wound healing was significantly higher in diabetics when compared to nondiabetics with P = 0.03. Most reliable parameter in 2D PA was area under the curve (AUC) which correlated with increase in volume of tissue perfusion. Patients with >100% improvement in AUC showed significantly better wound healing rates when compared to patients with

Background: Previous studies on sternocleidomastoid flaps, have defined the importance of preserving sternocleidomastoid (SCM) branch of superior thyroid artery (STA). This theory drew criticism, as this muscle is known to be a type II muscle, i.e., the muscle has one dominant pedicle (branches from the occipital artery at the superior pole) and smaller vascular pedicles entering the belly of muscle (branches from STA and thyrocervical trunk) at the middle and lower pole respectively. It was unlikely for the SCM branch of STA to supply the upper and lower thirds of the muscle. We undertook a cadaveric angiographic study to investigate distribution of STA supply to SCM muscle.Methods: It is a prospective study on 10 cadaveric SCM muscles along with ipsilateral STA which were evaluated with angiography using diatrizoate (urograffin) dye. Radiographic films were interpreted looking at the opacification of the muscle. Results were analyzed using frequency distribution and percentage. Results:Out of ten specimens, near complete opacification was observed in eight SCM muscle specimens. While one showed poor uptake in the lower third of the muscle, the other showed poor uptake in the upper third segment of muscle. Conclusion: Based on the above findings we propose to re-classify sternocleidomastoid flap as a type III flap as the STA branch also supplies the whole muscle along with previously described pedicle from occipital artery. However, this needs to be further corroborated intra-operatively using scanning laser doppler.

Background: Vascular injury in extremity is a complication of both blunt and penetrating trauma. In Indian scenario, patients generally present late to the tertiary care center with mangled extremity for treatment. The aim of the study is to assess the risk factors affecting the outcome in the management of patients with lower extremity arterial trauma. Materials and Methods: A single-center, observational study was conducted at Sir Ganga Ram Hospital, New Delhi, from January 2013 to June 2017. Sixty patients of lower extremity arterial trauma who underwent revascularization were included and followed up for 6 months. All the risk factors (mode/mechanism of injury, time since injury, compartment syndrome, mangled extremity severity score [MESS], etc.,) and limb salvage were assessed at 6 months. Statistical analysis was performed using Chi-square test and Fisher's exact test. Results: Majority of the patients presented late (6–24 h) of injury and had high mean MESS (7.85). The most common mechanism of injury was blunt trauma (83.3%), and popliteal artery (72%) was the most commonly injured artery. Limb salvage was achieved in 75% of the patients. Time since injury and MESS score affected the limb salvage significantly. On multivariate analysis, MESS score was the single independent factor which affected the limb salvage (95% confidence interval, 0.231–0.769, P = 0.005). Conclusions: MESS is the most important predictors for limb salvage. Multidisciplinary team approach with timely diagnosis and immediate repair is the key to the ultimate goal of functional limb salvage.

Persistent left superior vena cava is an extremely rare venous anomaly affecting 0.5% to 2% of the general population. Persistent left superior vena cava with absent right superior vena cava, also termed as “isolated persistent left superior vena cava.” Persistent left superior vena cava, without associated cardiac anomalies, is usually innocuous. Its discovery, however, has important clinical implications. It can pose clinical difficulties with central venous access, hemodialysis catheter placement, and pacemaker implantation. We hereby present a case of persistent left superior vena cava that was incidentally encountered after the placement of a hemodialysis catheter through the left internal jugular vein. This case highlights the pertinent radiologic findings and emphasizes the importance of familiarity to such an anatomic anomaly.

Polymers are being used extensively in drug delivery due to their surface and bulk properties. They are being used in drug formulations and in drug delivery devices. These drug delivery devices may be in the form of implants for controlled drug delivery. Polymers used in colloidal drug carrier systems, consisting of small particles, show great advantage in drug delivery systems because of optimized drug loading and releasing property. Polymeric nano particulate systems are available in wide variety and have established chemistry. Non toxic, biodegradable and biocompatible polymers are available. Some nano particulate polymeric systems possess ability to cross blood brain barrier. They offer protection against chemical degradation. Smart polymers are responsive to atmospheric stimulus like change in temperature; pressure, pH etc. thus are extremely beneficial for targeted drug delivery. Some polymeric systems conjugated with antibodies/specific biomarkers help in detecting molecular targets specifically in cancers. Surface coating with thiolated PEG, Silica-PEG improves water solubility and photo stability. Surface modification of drug carriers e.g. attachment with PEG or dextran to the lipid bilayer increases their blood circulation time. Polymer drug conjugates such as Zoladex, Lupron Depot, On Caspar PEG intron are used in treatment of prostate cancer and lymphoblastic leukemia. Polymeric Drug Delivery systems are being utilized for controlled drug delivery assuring patient compliance.

Obesity is an increasingly important health problem worldwide as well as in developing countries like India. Recent genetic studies suggest that obesity associated FTO and IRX3 are functionally linked and many effects due to genetic variants in FTO gene act through IRX3.To evaluate the association of FTO and IRX3 genetic variants towards obesity risk.North Indian individuals categorised as non-obese (BMI 30 kg/m(2)) and obese (BMI ≥ 30 kg/m(2)) were selected. FTO rs8050136, rs1421085, rs9939609, rs17817449 and IRX3 rs3751723 were genotyped by means of validated Taqman® allelic discrimination to evaluate their association with obesity by means of single locus logistic regression by SPSS ver. 19 and multi-locus linkage and haplotype analysis by SNPStats and gene-gene interaction with Generalised Multifactor Dimensionality Reduction (GMDR) ver.6.In single locus analysis, FTO rs8050136 CA (p = 0.0001; OR (95% CI) = 2.4 (1.7-3.4) and AA (p = 0.0001; OR (95% CI) = 3.1 (1.9-5.2); FTO rs1421085 TA (p = 0.0001; OR (95% CI) = 2.1 (1.4-3.0) and AA (p = 0.0001; OR (95% CI) = 3.0 (1.8-5.0); FTO rs9939609 TC (p = 0.0001; OR (95% CI) = 2.1 (1.5-3.1) and CC (p = 0.0001; OR (95% CI) = 4.2 (2.5-7.3) along with TG (p = 0.001; OR (95% CI) = 2.1 (1.3-3.2) and GG (p = 0.021; OR (95% CI) = 3.8 (1.2-11.8) genotypes of FTO rs17817449 with GT (p = 0.0001; OR (95% CI) = 2.1 (1.5-3.1) and TT (p = 0.012; OR (95% CI) = 3.3 (1.8-3.6) genotypes of IRX3 rs3751723 were significantly associated with obesity. In multi-locus analysis, SNPs of FTO and IRX3 were in strong linkage disequilibrium and in haplotype and GMDR analysis the SNPs were significantly associated with obesity risk (p 0.05).This is the first study to reveal that genetic variants of both FTO and IRX3 genes are in high linkage disequilibrium (LD) and are associated with obesity risk in North Indians.

Introduction Therapeutic misadventure is defined as an injury or an adverse event caused by medical management rather than by an underlying disease. Femoro-popliteal bypass is the standard of care in a long segment femoral-popliteal occlusive lesion. Misadventure in the femoral-popliteal bypass in the form of distal anastomosis to the popliteal vein is a serious limb threatening event and is not reported by surgeons to the best of our knowledge. Case summary A 63 years old gentleman who had undergone femoro-popliteal bypass for disabling claudication presented with rest pain. The patient was suspected to have graft to vein anastomosis instead of graft to distal artery anastomosis on duplex examination. The patient underwent total endovascular management of the disease with endoluminal bypass and coil angio-embolization of the vein graft. The condition of the patient improved dramatically with relief of symptoms and improvement in his walking distance. Conclusion Glaring therapeutic misadventures of this kind must be averted. Evidence based medicine with protocol based surgery should be performed after acquiring a reasonable amount of structured training to eliminate medical and surgical disasters.

Introduction: Assessment of carbon dioxide (CO2) angiography for its efficacy and limitations in lower limb angioplasties for chronic limb-threatening limb ischemia needs to be evaluated in detail, as the use of CO2 as a contrast agent has a distinct advantage over conventional iodinated contrast medium (ICM) in patients with borderline chronic kidney disease (CKD), with respect to nephrotoxicity caused by the later. Aims and Objectives: To study the quality of angiography images obtained with CO2 as a contrast agent and the efficacy of CO2 angiography in guiding lower limb angioplasties for critical limb ischemia. Design: This was a prospective, observational, comparative, cohort study. Study Period: September 2017–December 2018. Materials and Methods: Patients of critical limb ischemia with raised serum creatinine level (>1.49 mg/dL) who were not on the dialysis and undergoing endovascular revascularization were enrolled in the study. Hand injections were made using CO2 Angioset. Intraoperative evaluation of image quality obtained using CO2 was done by two vascular surgeons and compared with conventional contrast medium. Necessary therapeutic intervention was performed using CO2 angiography image if reliable image was acquired using the same. Results: A total of 100 patients were evaluated consisting of 176 arterial segments, out of which 145 segments required use of ICM and 31 segments were intervened using CO2 only as a contrast agent (19 superficial femoral artery, 6 common iliac artery, 2 pop artery, 3 external iliac artery, and 1 anterior tibial artery). Assessment of scores given by the observer 1 and observer 2 was performed by their comparison for the statistical significance using McNemar–Bowker test and was found to be statistically significant with P = 0.02. Kendall's Tau b coefficient is 0.74 (significant) and Cohen's kappa is 0.63 (significant). Good-quality images were seen in above the knee (ATK) segment in 39.3% and moderate in 57.8%. However, below the knee (BTK) segments received poor image quality score in majority, i.e., 82.6%. There was significant reduction observed in the total volume of ICM. No major adverse reaction/complication encountered during the procedures was observed, except pain being the most common and distressing complication. Conclusions: CO2 angiography is a very useful tool in the armamentarium of vascular surgeon, especially while performing angioplasties for peripheral arterial disease in borderline CKD patients, not on dialysis, because it not only reduces the amount of iodinated contrast used but also has good imaging ability in ATK vessels. It was fought with multiple issues while imaging BTK vessels, leading to reduction in its reliability and feasibility in that segment.

Obesity is a multi-factorial disorder influenced by genetic and environmental factors. The physiological pathways associated with obesity are complex and involve several genes.The aim of this survey is to evaluate the association of genetic variants of melanocortin-4-receptor (MC4R), pro-opiomelanocortin (POMC), apolipoprotein E (APOE) and agouti-related protein (AGRP) with obesity in the North Indian population.MC4R rs17782313, POMC rs1042571, APOE-Hha1 and AGRP rs3412352 polymorphisms were investigated for their association in 396 obese individuals with BMI ≥ 30 kg/m(2) and 300 healthy non-obese individuals with BMI 30 kg/m(2). Genotyping was performed using Taqman probes and PCR-RFLP methods. Single locus logistic regression analysis was conducted using (SPSS), ver.19 and PLINK software Version 1.01 and high order genetic interactions associated with obesity risk were analysed using MDR software (version 2.3.0.2).The genotypes of MC4R rs17782313, POMC rs1042571 and APOE-Hha1 were significantly associated with obese individuals (BMI ≥ 30 kg/m(2)) when compared with non-obese individuals (BMI 30 kg/m(2)). No association of AGRP rs34123523 was seen with obesity.The best interaction model for predicting obesity risk by MDR analysis was the three factor model including POMC (C T), MC4R (T C) and APOE (Hha1) polymorphisms. Genetic variants in MC4R, POMC and APOE genes might play significant roles in predisposing obesity (BMI ≥ 30 kg/m(2)) in the North Indian population.

Introduction: Postthrombotic syndrome (PTS) occurs in 20%–60% of patients after acute deep-vein thrombosis (DVT) treated with anticoagulation alone. Residual thrombus after DVT leads to ambulatory venous hypertension which consequently causes PTS. Thus, evacuating the clot during DVT itself might prevent PTS – the “Open Vein Hypothesis.” Pharmacomechanical catheter-directed thrombolysis (PCDT) evacuates the thrombus working on this very hypothesis. PCDT is usually performed using specialized devices which are expensive and not easily available in our country. In this study, we describe a method to perform PCDT using a commonly available and inexpensive guiding catheter in an aim to prevent PTS after DVT. Aims and Objectives: This study aimed to evaluate if in acute DVT, our method of PCDT reduces the occurrence of PTS, as compared to anticoagulation alone. Design: This is a prospective, randomized, comparative, cohort study. Study Period: The study was conducted from June 2016 to May 2017 with 1-year follow-up. Materials and Methods: Patients presenting with acute DVT of

The aim of the study was to investigate the association of 55 SNPs in 28 genes with obesity risk in a North Indian population using a multianalytical approach.Overall, 480 subjects from the North Indian population were studied using strict inclusion/exclusion criteria. SNP Genotyping was carried out by Sequenom Mass ARRAY platform (Sequenom, San Diego, CA) and validated TaqmanLogistic regression analysis of 55 SNPs revealed significant associations (P .05) of 49 SNPs with BMI linked obesity risk whereas the remaining 6 SNPs revealed no association (P .05). The pathway-wise G-score revealed the significant role (P = .0001) of food intake-energy expenditure pathway genes. In CART analysis, the combined genotypes of FTO rs9939609 and TCF7L2 rs7903146 revealed the highest risk for BMI linked obesity. The analysis of the FTO-IRX3 locus revealed high LD and high order gene-gene interactions for BMI linked obesity. The interaction network of all of the associated genes in the present study generated by GENEMANIA revealed direct and indirect connections. In addition, the analysis with centralized obesity revealed that none of the SNPs except for FTO rs17818902 were significantly associated (P .05).In this multi-analytical approach, FTO rs9939609 and IRX3 rs3751723, along with TCF7L2 rs7903146 and TMEM18 rs6548238, emerged as the major SNPs contributing to BMI linked obesity risk in the North Indian population.

Numerous classical genetic studies have proved that genes are contributory factors for obesity. Genes are directly responsible for obesity associated disorders such as Bardet-Biedl and Prader-Willi syndromes. However, both genes as well as environment are associated with obesity in the general population. Genetic epidemiological approaches, particularly genome-wide association studies, have unraveled many genes which play important roles in human obesity. Elucidation of their biological functions can be very useful for understanding pathobiology of obesity. In the near future, further exploration of obesity genetics may help to develop useful diagnostic and predictive tests for obesity treatment.

Background: Bleeding and vascular complications following retrograde common femoral artery access are studied. Access site complications, their incidence, and risk factors following antegrade access remain unclear. Materials and Methods: We retrospectively analyzed 189 patients from our prospectively collected database at Jain Institute of Vascular Sciences, Bengaluru, India. All patients had antegrade femoral access and underwent femoral and popliteal artery interventions from January 2013 to December 2014. We aimed to study incidence, risk factors, length of postintervention hospital stay, and early morbidity following antegrade femoral access. Antegrade direct arterial punctures resulted in a complication rate of 14.28%, which comprised 20 ecchymosis (74.07%), 5 groin hematoma (18.51%), and 2 pseudoaneurysm (0.07%). Two patients required blood transfusion. Groin hematoma was common in females (3 vs. 2 patients) than males but had less ecchymosis (7 vs. 13 patients). Age more than 69 years, female sex, 7 Fr sheath size, direct arterial puncture by palpation, and manual compression were associated with higher incidence of complications. Complicated patients had longer hospital stay (3.52 ± 1.19 days vs 1.34 ± 0.59; range 1–7 days; P = 0.0001). Conclusion: Several factors predict access site-related complications following antegrade femoral access, notably gender, age, ultrasound guidance, sheath size, and closure device. Knowledge of these findings could be useful to determine strategies to reduce access site vascular and bleeding risk and improve outcomes.

Rheumatic heart disease (RHD) is the most serious complication of heart that comprises inflammatory reactions in heart valves. Cytokines play a critical role in triggering inflammatory reactions and they activate the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway. Altered signals of STATs play important roles in the balance between proinflammatory and anti-inflammatory cytokines in inflammatory diseases. The aim of the present study was to investigate for the association of polymorphisms related with STAT genes, i.e. STAT3 (rs4796793 C/G) and STAT5b (rs6503691 C/T) with the pathogenesis of RHD. This case-control association study involved 300 healthy controls and 400 RHD patients from North Indian Population. We categorized RHD patients into two subgroups based on involvement of heart valves, mitral valve lesion alone (MVL), and combined valve lesions including mitral valve (CVL). Genotyping was done by RFLP/Taqman probes. We observed that STAT3 CG and GG genotypes were significantly associated with RHD (p=0.030 and p=0.014 respectively), STAT5b CT and TT genotypes were also significantly associated with RHD (p≤0.001). Haplotype analysis revealed that minor alleles of both the variants (Grs4796793Trs6503691) were significantly associated (p

OBJECTIVE: Genetic variants of the melanocortin-4 receptor gene (MC4R), agouti related protein (AGRP) and proopiomelanocortin (POMC) are reported to be associated with obesity. Therefore, the aim of this study is to examine MC4R rs17782313, MC4R rs17700633, AGRP rs3412352 and POMCrs1042571 for any association with obesity in North Indian subjects. METHODS: The variants were investigated for association in 300 individuals with BMI ≥30 kg/m(2) and 300 healthy non-obese individuals BMI

Objectives The aim of the study was to investigate the association of 55 SNPs in 28 genes with obesity risk in a North Indian population using a multianalytical approach. Methods Overall, 480 subjects from the North Indian population were studied using strict inclusion/exclusion criteria. SNP Genotyping was carried out by Sequenom Mass ARRAY platform (Sequenom, San Diego, CA) and validated Taqman® allelic discrimination (Applied Biosystems®). Statistical analyses were performed using SPSS software version 19.0, SNPStats, GMDR software (version 6) and GENEMANIA. Results Logistic regression analysis of 55 SNPs revealed significant associations (P .05). The pathway-wise G-score revealed the significant role (P = .0001) of food intake-energy expenditure pathway genes. In CART analysis, the combined genotypes of FTO rs9939609 and TCF7L2 rs7903146 revealed the highest risk for BMI linked obesity. The analysis of the FTO-IRX3 locus revealed high LD and high order gene-gene interactions for BMI linked obesity. The interaction network of all of the associated genes in the present study generated by GENEMANIA revealed direct and indirect connections. In addition, the analysis with centralized obesity revealed that none of the SNPs except for FTO rs17818902 were significantly associated (P

Obesity is a major health problem worldwide and is associated with a risk of many chronic diseases like type 2 diabetes, cardiovascular disease and cancer1. The aetiology of obesity is multi-factorial and any combination of environmental and lifestyle factors may possibly interact with multiple genetic variants to result in obesity2. In such multifactorial disorders, genome-wide association study (GWAS) is used to discover genetic variants associated with diseases. In 2007, using GWAS, a UK research team led by Dr Andrew Hattersley of Peninsula Medical School in Exeter discovered a gene variant that showed strong link with body mass index (BMI)3. The gene harbouring the variant was named as fat mass and obesity-associated (FTO). Further studies on 13 cohorts of 38,759 Britons, Finns and Italians also showed similar link between the FTO variant and body weight. Subsequently, several other genetic variants of FTO such as rs99396094, rs99305065, rs1421085, rs17817449, and rs11219806 have also been shown to confer very significant risk for obesity.

BACKGROUND: Over the last few decades, obesity, diabetes, and hypertension have become main health evils. The health problems of obesity are well-recognized. However, the fact that all obese individuals are not at the same risk of developing a disease is also recognized. The apolipoprotein B (APOB) plays a central role in lipid metabolism. So we compare the association of APOB XbaI gene polymorphism and lipid profile total in obese north Indian population. MATERIALS AND METHODS: A total of 132 obese (body mass index [BMI] >25 kg/m2) and 132 age matched non-obese (BMI ≤ 25 kg/m2) subjects were studied after taking detailed clinical profile. Lipid profile in serum/plasma was done using commercial kits. Genetic analysis of APOB XbaI was done using Polymerase Chain Reaction-Restriction Fragment Leanth polymorphism (PCR-RFLP). STATISTICAL ANALYSIS: Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) (version 11.5) software (IBM Corporation). All continuous variables were expressed as mean ± SD and tested by analysis of variance test. Comparisons of categorical variables were assessed using χ2 tests or Fisher's exact test. P < 0.05 was considered as significant. RESULTS: Analysis showed that obese subjects had significantly higher value of the waist-to-hip ratio, blood pressure (systolic and diastolic), and lipid profile. In APOB XbaI gene polymorphism, we did not find significant differences in genotype or allele frequencies. Moreover, none of the studied metabolic parameters (lipid profile) showed any association with the gene polymorphism. CONCLUSIONS: Study reveals no considerable association of APOB XbaI gene polymorphism with obesity and lipid profile in north Indians.