Role of Survivin Gene Promoter Polymorphism (−31G>C) in Susceptibility and Survival of Esophageal Cancer in Northern India

Background and Aim

Survivin is an upregulated inhibitor of apoptosis protein in esophageal cancer (EC), and a promoter region polymorphism (?31G>C) in the survivin gene has been reported as a modulator of gene expression. We aim to explore the role of survivin ?31G>C polymorphism in susceptibility and survival of EC patients in northern Indian population.

Materials and Methods

A case–control study was performed in 500 subjects (250 EC patients and 250 controls), and genotyping was done by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP) method.

Results

Survivin CC genotype was found to be significantly associated with EC susceptibility [odds ratio (OR) = 2.29; 95% confidence interval (CI) = 1.27–4.14; P = 0.006], particularly in males (OR = 4.91; 95% CI = 2.19–11.02; P = 0.0001) having squamous cell carcinoma (SCC) histopathology (OR = 2.4; 95% CI = 1.36–4.21; P = 0.002) at middle third esophagus location (OR = 2.60; 95% CI = 1.40–4.82; P = 0.002). Patients carrying CC genotype were found to have higher susceptibility to lymph node metastasis (OR = 2.82; 95% CI = 1.46–5.48; P = 0.002). However, on survival analysis, no prognostic role of survivin ?31G>C polymorphism was detected. In case-only analysis, no gene–environment interaction was observed.

Conclusion

Survivin promoter region polymorphism (?31G>C) is associated with susceptibility and clinical characteristics but not prognosis of esophageal cancer in northern Indian population.     

Complete absence of lateral root of median nerve and communication of musculocutaneous nerve with median nerve--a case report

This is a case of unique variation of median nerve and unusual communication with musculocutaneous nerve. This is found during routine dissection of right axilla of middle aged male cadaver. On dissection it is found that the usual branch like lateral pectoral nerve, musculocutaneous nerve are coming out from lateral cord. But there is no lateral root of median nerve taking origin from lateral cord. Medial root of median nerve originates from medial cord that descends along the medial side of the axillary artery and makes a communication with musculocutaneous nerve infront of the axillary artery. Variations in the formation, arrangements and communication of brachial plexus is very common. The knowledge of this anatomic variation is very valuable and important to surgeon for radical neck surgery, fracture dislocation of shaft of humerus; to anaesthetists for brachial plexus block; to neurologist and anatomist also.     

Comparison of Manning, Rome I, II, and III, and Asian diagnostic criteria: Report of the Multicentric Indian Irritable Bowel Syndrome (MIIBS) study

Background

Attempts to diagnose and subtype irritable bowel syndrome (IBS) by symptom-based criteria have limitations, as these are developed in the West and might not be applicable in other populations.

Objectives

This study aimed to compare different criteria for diagnosing and subtyping of IBS in India.

Method

Manning's and the Rome I, II, and III criteria as well as the Asian criteria were applied to 1,618 patients (from 17 centers in India) with chronic lower gastrointestinal (GI) symptoms with no alarm features and negative investigations.

Results

Of 1,618 patients (aged 37.5 [SD 12.6] years; 71.2 % male), 1,476 (91.2 %), 1,098 (67.9 %), 649 (40.1 %), 849 (52.5 %), and 1,206 (74.5 %) fulfilled Manning's, Rome I, II, and III, and the Asian criteria, respectively. The most common reason for not fulfilling the criteria was absence of the following symptoms: “more frequent stools with onset of pain,” “loose stool with onset of pain,” “relief of pain with passage of stool,” “other abdominal discomfort/bloating,” and, in a minority, not meeting the duration criterion of 3 months/12 weeks. By stool frequency, constipation-predominant IBS (<3 stools/week) was diagnosed in 319 (19.7 %), diarrhea-predominant IBS (>3 stools/day) in 43 (2.7 %), and unclassified in 1,256 (77.6 %). By Bristol stool form, constipation, diarrhea, and unclassified were diagnosed in 655 (40.5 %), 709 (43.8 %), and 254 (15.7 %) patients, respectively. By their own perception, 462 (28.6 %), 541 (33.4 %), and 452 (27.9 %) patients reported constipation-predominant, diarrhea-predominant, and alternating types, respectively.

Conclusion

By Manning's and the Asian criteria, a diagnosis of IBS was made frequently among Indian patients with chronic functional lower GI symptoms with no alarm features; the Rome II criteria gave the lowest yield. By the stool frequency criteria, a majority of patients had unclassified pattern, unlike by the stool form and patients' perception of their symptoms.     

Association of microsomal epoxide hydrolase exon 3 Tyr113His and exon 4 His139Arg polymorphisms with gastric cancer in India

Background

Microsomal epoxide hydrolase, an important phase II xenobiotic enzyme, exhibits polymorphisms at exon 3 (Tyr113His [T/C]) and exon 4 (His139Arg [A/G]), which modulate enzyme activity; this may affect susceptibility to cancers. We studied association between these polymorphisms and gastric cancer (GC).

Methods

In a prospective study, 77 patients with GC, 50 with peptic ulcer, and 160 healthy controls (HC) were genotyped for exon 3 (PCR-RFLP followed by sequencing) and exon 4 (PCR-RFLP). Helicobacter pylori was considered to be present if two of three tests (histology, rapid urease test, and IgG antibody) were positive.

Results

Tyr113His and His139Arg genotypes and haplotypes were comparable among groups. 113His carriers were commoner among H. pylori-negative patients with GC than HC (p-value?=?0.019, odds ratio (OR)?=?2.5, 95 % confidence interval (CI)?=?1.2–5.4). Haplotype combination of exons 3 and 4 113Tyr-139Arg (TA) were associated with higher and reduced risk in patients with GC than HC in presence and absence of H. pylori (25 % vs. 11 %; p-value?=?0.033, OR?=?2.61, 95 % CI?=?1.08–6.3 and 11.6 % vs. 28.7 %; p-value?=?0.004, OR?=?0.33, 95 % CI?=?0.15–0.7, respectively).

Conclusions

Though 113Tyr-139Arg was associated with GC in presence of H. pylori, in its absence, it appeared to be protective. Exon 3, 113His, however, was associated with GC even in absence of H. pylori infection.     

Potential influence of interleukin-1 haplotype IL-1 beta-511*T-IL-1RN*1 in conferring low risk to middle third location of esophageal cancer: a case-control study

Interleukin (IL)-1 gene polymorphisms affect several inflammatory diseases, including cancer. Therefore, we studied genetic association of biallelic (-511C>T) polymorphism of IL-1β and 86-bp VNTR polymorphism of IL-1RN in 159 patients with esophageal cancer (EC) and 194 age- and gender-matched healthy controls. Genetic analysis for IL-1 polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism. The frequencies of IL-1β (-511C>T) and IL-1RN (variable number tandem repeat) genotypes, alleles, and haplotypes did not differ significantly between patients and controls. However, IL-1β -511TT genotype and T1+ haplotype combination illustrated low risk for disease at the middle third location of the tumor (odds ratio [OR] = 0.27; 95% confidence interval [CI] = 0.11–0.62; p = 0.002; OR = 0.462; 95% CI = 0.253–0.845, p = 0.01). In conclusion, subjects with IL-1β -511TT genotype or IL-1β*T-IL-1RN*1 (T1) haplotype had lower risk for middle third tumor location of EC in a northern Indian population.     

Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver

miR-122, an abundant liver-specific microRNA (miRNA), regulates cholesterol metabolism and promotes hepatitis C virus (HCV) replication. Reduced miR-122 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. Nevertheless, the consequences of sustained loss of function of miR-122 in vivo have not been determined. Here, we demonstrate that deletion of mouse Mir122 resulted in hepatosteatosis, hepatitis, and the development of tumors resembling HCC. These pathologic manifestations were associated with hyperactivity of oncogenic pathways and hepatic infiltration of inflammatory cells that produce pro-tumorigenic cytokines, including IL-6 and TNF. Moreover, delivery of miR-122 to a MYC-driven mouse model of HCC strongly inhibited tumorigenesis, further supporting the tumor suppressor activity of this miRNA. These findings reveal critical functions for miR-122 in the maintenance of liver homeostasis and have important therapeutic implications, including the potential utility of miR-122 delivery for selected patients with HCC and the need for careful monitoring of patients receiving miR-122 inhibition therapy for HCV.     

Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.