Characterization of the CXCR4 Signaling in Pancreatic Cancer Cells

CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1α, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.     

Polyhalide derivatives of poly[N-(2-aminoethyl)-acrylamido]triethylammonium resins as iodinating reagents

Poly[N-(2-aminoethyl)acrylamido]triethylammonium dichloroiodate, tetrachloroiodate and dibromoiodate resins have been developed as a new class of heterogeneous reagents. The use of the polyhalide derivatives for the selective iodination of aromatic amines and phenols is described. The influence of the various reaction parameters including nature of the solvent, effective molar concentration of the reagent and temperature were investigated to find out the optimum reaction conditions for achiveing selectivity for monoiodination.     

Zinc-mediated carboxylations of allylic and propargylic halides in flow: synthesis of β-lactones via subsequent bromolactonization

Zinc-mediated carboxylation of allylic halides under flow conditions delivered β,γ-unsaturated carboxylic acids and subsequent bromolactonization provides a streamlined process for the synthesis of γ-bromo-β-lactones. The described process further demonstrates the utility of organozinc reagents prepared by passage of allylic halides through a metallic zinc column integrated into a flow process. Use of a tube-in-tube reactor for efficient CO₂ introduction led to improvements in conversion compared to a batch process and improved overall yields of β-lactones. The described flow process was also applied to propargylic bromides for the synthesis of allenic and propargylic acids.

Zinc-mediated carboxylation of allylic halides under flow conditions delivered β,γ-unsaturated carboxylic acids and subsequent bromolactonization provides a streamlined process for the synthesis of γ-bromo-β-lactones.     

Association between the Dietary Inflammatory Index and Gastric Disease Risk: Findings from a Korean Population-Based Cohort Study

Evidence suggests that diets with high pro-inflammatory potential may play a substantial role in the origin of gastric inflammation. This study aimed to examine the association between the energy-adjusted dietary inflammatory index (E-DII^TM) and gastric diseases at baseline and after a mean follow-up of 7.4 years in a Korean population. A total of 144,196 participants from the Korean Genome and Epidemiology Study_Health Examination (KoGES_HEXA) cohort were included. E-DII scores were computed using a validated semi-quantitative food frequency questionnaire. Multivariate logistic regression and Cox proportional hazards regression were used to assess the association between the E-DII and gastric disease risk. In the prospective analysis, the risk of developing gastric disease was significantly increased among individuals in the highest quartile of E-DII compared to those in the lowest quartile (HR_quartile4vs1 = 1.22; 95% CI = 1.08–1.38). Prospective analysis also showed an increased risk in the incidence of gastritis (HR_quartile4vs1 = 1.19; 95% CI = 1.04–1.37), gastric ulcers (HR_quartile4vs1 = 1.47; 95% CI = 1.16–1.85), and gastric and duodenal ulcers (HR_quartile4vs1 = 1.46; 95% CI = 1.17–1.81) in the highest E-DII quartile compared to the lowest quartile. In the cross-sectional analysis, the E-DII score was not associated with the risk of gastric disease. Our results suggest that a pro-inflammatory diet, indicated by high E-DII scores, is prospectively associated with an increased risk of gastric diseases. These results highlight the significance of an anti-inflammatory diet in lowering the risk of gastric disease risk in the general population.     

A novel approach to control brown dog tick,Rhipicephalus sanguineus using sustained release poly-ɛ-caprolactone-pheromone microspheres

Control of brown dog tick, Rhipicephalus sanguineus was attempted by utilizing sustained release preparations of synthetic analogues of assembly pheromones. The assembly pheromone, in defined ratio, was encapsulated using poly-?-caprolactone by water-in-oil-in-water double emulsion solvent evaporation technique. In the in vitro bioassay, percent mortality with test microspheres was 95.6, 64 and 44 among the unfed larvae, unfed nymph and unfed adults respectively, 24 hours post-exposure. Field trials were carried out to evaluate the efficacy of microspheres in luring and killing environmental stages of R. sanguineus in dog houses/kennels. Engorged and unfed stages in the environment were found adhered and dead on the specially designed lure.     

Prognostic importance of DNA repair gene polymorphisms of <Emphasis Type="Italic">XRCC1</Emphasis> Arg399Gln and <Emphasis Type="Italic">XPD</Emphasis> Lys751Gln in lung cancer patients from India

Purpose Inter individual variation in lung cancer susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the Base Excision Repair (BER) and nucleotide excision repair (NER) pathway. Two of the genetic polymorphisms, XRCC1Arg399Gln and XPD Lys751Gln have been extensively studied in the association with lung cancer risk, although published studies have been inconclusive. Methods In order to verify the role of the common variant alleles in the XPD gene, we have genotyped 211 lung cancer patients and 211 healthy controls using PCR-RFLP assays in a hospital based, case-control study in an Indian population. Logistic regression models were fit to examine the relationship between the log odds of lung cancer and each covariate. Overall Survival in relation to various genotypes and clinicopathological factors were analyzed using Kaplan Meier estimates and hazard ratios were calculated using Cox Regression analysis. Results The carriers of XRCC1 399 AA genotypes were at higher risk of lung cancer (OR = 2.1, 95% CI:1.224–3.669, P = 0.007) than carriers of GG genotype. Subjects carrying 751 AC genotype were at an increased risk of carcinoma of the lung (OR = 1.8; 95% CI:1.233–2.807, P = 0.003) than subjects with AA genotypes. Compared to the XRCC1 399 GG/ XPD 751 AA reference genotype, the combined variants, XRCC1 399 GG/ XPD 751 AC+CC (OR = 1.9, 95% CI: 1.037–3.481), P = 0.03), XRCC1 399 GA+AA/ XPD 751 AA (OR = 1.7, 95% CI: 1.020–2.833, P = 0.04), XRCC1 399 GA+AA/XPD 751 AC+CC (OR = 2.7, 95% CI: 1.582–4.864, P = 0.01), had significantly higher odds ratios. Increasing numbers of either XPD or XRCC1 variant alleles were associated with shorter overall survival, the risk being significant for the XRCC1 gene polymorphism (P = 0.01 by log-rank test). The hazard of dying was significant for the XRCC1 399 AA genotype (HR = 3.04, 95%CI: 1.393–6.670, P = 0.005). Higher tumour stage also came out as significant predictors of patient death. Conclusions These findings suggest that genetic polymorphisms in the DNA repair genes may modulate overall lung cancer susceptibility and that pathological stage and XRCC1 Arg399Gln independently predicted overall survival among Indian lung cancer patients.     

Global Supply and Demand of Opioids for Pain Management

Purpose of Review

The goal of this review is to evaluate the global supply and demand of opioids used for pain management and discuss how it relates to the utilization of opioids around the world. The purpose of the review is also to determine the factors that contribute to inappropriate pain management.

Recent Findings

The total global production of opium for opioid manufacturing is enough to supply the growing global demands. However, licit opioids are only consumed by 20% of the world population. Most people throughout the world had no access to opioid analgesics for pain relief in case of need. Opioid misuse and abuse is not only a phenomena plague by the USA but globally across many countries.

Summary

Many countries have a lack of availability of opioids, contributing factors being strict government regulations limiting access, lack of knowledge of the efficacy of opioid analgesics in treating acute and chronic pain and palliative care, and the stigma that opioids are highly addictive. For the countries in which opioids are readily available and prescribed heavily, diversion, misuse, abuse, and the resurgence of heroin have become problems leading to morbidity and mortality. It is pertinent to find a balance between having opioids accessible to patients in need, with ensuring that opioids are regulated along with other illicit drugs to decrease abuse potential.