Acid suppressive drugs and gastric cancer: a meta-analysis of observational studies.

AIM: To evaluate the association between acid suppressive drug use and the development of gastric cancer. METHODS: A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H2RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached. RESULTS: Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I² = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H2RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I² = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19-1.64, I² = 0.0%, P = 0.377). CONCLUSION: Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.

Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials.

PURPOSE: This study aimed to investigate the neuroprotective effects of vitamin E for preventing chemotherapy-induced peripheral neuropathy (CIPN). METHODS: A comprehensive search from 1973 through July 2011 identified randomized controlled trials (RCTs) that reported the preventive effects of vitamin E on CIPN. The relative risk (RR) of CIPN with vitamin E supplementation, compared with placebo, was assessed with the Bayesian random effect model and expressed as RR with a 95 % credible-interval (CrI). Bayesian outcome probabilities were calculated as the probability (P) of RR < 1. RESULTS: Five RCTs, involving 319 patients, were identified. Upon pooling these RCTs, vitamin E supplementation (300 - 600 mg/day) had a significant effect on CIPN prevention (RR 0.43; 95 % CrI 0.10 - 1.00, P = 97.5 %). Subgroup analysis by chemotherapeutic agent type was only available for cisplatin and showed that vitamin E supplementation significantly reduced the incidence of CIPN (RR 0.26; 95 % CrI 0.06 - 0.89, P = 98.1 %). Furthermore, there were no adverse effects caused by vitamin E supplementation in any of the RCTs. CONCLUSION: Available data included in this meta-analysis show that vitamin E supplementation might significantly prevent CIPN. Currently, however, the data are insufficient to confidently conclude the true value. Large-scale, rigorously designed RCTs are needed to confirm the role of vitamin E supplementation in CIPN prevention.

Use of Proton Pump Inhibitor and Risk of Colorectal Cancer: A Meta-analysis of Observational Studies.

BACKGROUND: Previous case-control studies have reported inconsistent findings regarding the association between proton pump inhibitor (PPI) use and colorectal cancer (CRC) risk. We investigated these associations using meta-analysis. METHODS: We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library in April 2011. Two evaluators independently reviewed and selected articles, based on pre-determined selection criteria. RESULTS: Out of 737 articles meeting our initial criteria, 5 case-control studies, which involved 120,091 participants (9,514 cases and 110,577 controls), were included in the final analyses. The overall use of PPI (used vs. never or rarely used) was not significantly associated with the risk of CRC in a fixed-effects model meta-analysis of all 5 case-control studies (odds ratio [OR], 1.08; 95% confidence interval [CI], 0.96 to 1.20; I(2) = 3.5%). Also, in sensitivity meta-analysis by cumulative duration of PPI use, there was no association between PPI use of 1 year or longer and the risk of colorectal cancer in a fixed-effects meta-analysis (OR, 1.09; 95% CI, 0.98 to 1.22; I(2) = 0%). CONCLUSION: Although hypergastrinemia could be an important factor in the pathogenesis of some colorectal cancers, our study suggests that this does not lead to significant clinical risk for most PPI users. Further prospective studies or randomized controlled trials related to PPI use and colorectal cancer risk are needed to investigate this association.

Meta-analysis: selective serotonin reuptake inhibitors and colon cancer.

OBJECTIVE: To perform meta-analyses using observational studies to assess the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of colorectal cancer. METHODS: A systematic search of relevant studies published through February 2012 was carried out using the Medline (PubMed), Embase, and Cochrane Library databases. We reviewed the observational studies that were associated with our subject and carried out a meta-analysis. RESULTS: Out of 324 screened articles, six observational studies were included in the final analyses. According to this meta-analysis, the use of SSRIs was not associated with an increased risk of colorectal cancer in pooled analyses (adjusted odds ratio 0.89, 95% confidence interval 0.79-1.01). This finding was consistently observed in subgroup analyses of study area, location of colorectal cancer, duration of SSRI use, study quality, adjustment for NSAID use, and the prevalence of overweight. CONCLUSION: Our research shows that the use of SSRIs does not increase the risk of colorectal cancer. Further studies are needed to confirm the association between SSRIs and colorectal cancer.

Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies.

PURPOSE: Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H(2)RAs) and fracture risk. We investigated this association using meta-analysis. METHODS: We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity. RESULTS: Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H(2)RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H(2)RA use was not significantly associated with fracture risk. CONCLUSIONS: We found possible evidence linking PPI use to an increased risk of fracture, but no association between H(2)RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.

Aging-associated increase of gelsolin for apoptosis resistance.

Gelsolin, a Ca(2+)-dependent actin regulatory protein, was recently suggested to participate in apoptosis regulation. In this study, we found that the level of gelsolin is elevated in senescent human diploid fibroblasts (HDFs) and also in the tissues of old rats, i.e., in the liver, kidney, heart, spleen, stomach, and brain, etc. The ubiquitous increase of gelsolin in the aged organs and cells led us to assume that it might be related with one of the cardinal senescent phenotypes, aging-associated apoptosis resistency. Thus, we tested the sensitivity of senescent cells to apoptosis by menadione, an apoptosis-inducing agent, before and after the down-regulation of gelsolin. The down-regulation of gelsolin in senescent HDFs, independently of Bcl-2 family expression, resulted in an increased sensitivity to menadione-induced apoptotic cell death. The observed ubiquitous increase of gelsolin in the senescent states of cells and tissues, and the increased sensitivity to apoptosis-induction by gelsolin down-regulation, suggests that gelsolin would be partly responsible for age-related apoptosis resistance.

Senescent phenotype can be reversed by reduction of caveolin status.

Hyporesponsiveness to growth factors is one of the fundamental characteristics of senescent cells. We previously reported that the up-regulation of caveolin attenuates the growth factor response and the subsequent downstream signal cascades in senescent human diploid fibroblasts. Therefore, in the present experiment, we investigated the modulation of caveolin status in senescent cells to determine the effect of caveolin on mitogenic signaling efficiency and cell cycling. We reduced the level of caveolin-1 in senescent human diploid fibroblasts using its antisense oligonucleotides and small interfering RNA, and this resulted in the restoration of normal growth factor responses such as the increased phosphorylation of Erk, the nuclear translocation of p-Erk, and the subsequent activation of p-Elk upon epidermal growth factor stimulation. Moreover, DNA synthesis and the re-entry of senescent cells into cell cycle were resumed upon epidermal growth factor stimulation concomitantly with decreases in p53 and p21. Taken together, we conclude that the loss of mitogenic signaling in senescent cells is strongly related to their elevated levels of caveolin-1 and that the functional recovery of senescent cells at least in the terms of growth factor responsiveness and cell cycle entry might be achieved simply by lowering the caveolin level.

Altered cAMP signaling induced by lysophosphatidic acid in senescent human diploid fibroblasts.

Lysophosphatidic acid (LPA) is a lipid mitogen that acts through G-protein-coupled receptors. LPA responsiveness has been reported to be dependent on the senescent state of the cells. To solve the mechanism underlying, we observed LPA-dependent cAMP status and found its age-dependent contrasting profile such as high level of cAMP in the senescent cells vs its low level in the young cells. In order to clarify the molecular mechanism of the ageing effect, we examined various molecular species involved in the cAMP signaling pathway by semi-quantitative RT-PCR. EDG-1 and EDG-4 were unchanged, but EDG-2 and EDG-7 were reduced with age. Senescent cells showed a partial reduction of Gi1, Gi2, and Gi3, but no change in the level of Gq. Decreased Gis and Gi-coupled LPA receptors may reduce the inhibitory effect of Gi alpha on adenylyl cyclases (ACs), resulting in cAMP accumulation via activation of adenylyl cyclase in senescent fibroblasts. We also observed an age-dependent increase in some of AC isoforms: II, IV, and VI. In conclusion, multiple changes in the cAMP signaling pathway of the senescent cells might explain the altered responsiveness to the mitogenic stimuli.

Gelsolin for senescence-associated resistance to apoptosis.

One of the characteristics of the senescent cell is apoptotic resistance. Gelsolin, a Ca(2+)-dependent actin regulatory protein, is believed to regulate the intracellular movements which are necessary for cell growth, proliferation, and differentiation. Recently, gelsolin was suggested to play a role in apoptotic resistance, which led us to examine its involvement in the apoptotic resistance of senescent cells. We found that the protein and mRNA levels of gelsolin were increased in senescent human diploid fibroblasts (HDFs). Gelsolin was intracellularly co-localized to the actin stress fiber and distributed to the nucleus and mitochondria in old HDFs. To examine the anti-apoptotic function of gelsolin in senescent HDFs, we tried to downregulate the expression of gelsolin by using antisense oligonucleotide in old HDFs. We then treated the senescent HDFs with the apoptosis-inducing agent menadione. Downregulation of gelsolin in senescent HDFs resulted in increased sensitivity to menadione-induced apoptotic cell death. This suggests that gelsolin plays a role in the apoptotic resistance observed in senescent HDFs.

Down-regulation of receptor-mediated endocytosis is responsible for senescence-associated hyporesponsiveness.

Human diploid fibroblasts (HDF) do not divide indefinitely and eventually lead to an arrest of cell division by a process termed cellular or replicative senescence. Irreversible growth arrest of senescent cells is strongly related to the attenuated response to growth factors. Recently, we reported that up-regulation of caveolin in the senescent cells is responsible for the attenuated response to growth factors. Senescent cells did not phosphorylate Erk-1/2 after EGF stimulation, whereas young cells did. In those senescent cells, we found an increased level of caveolin proteins and strong interactions between caveolin-1 and EGFR. When we overexpressed caveolin-1 in young HDF, the activation of Erk-1/2 on EGF stimulation was significantly suppressed. These results suggest that the hyporesponsiveness of senescent fibroblasts to EGF stimulation might be due to the overexpression of caveolin. In addition, the clathrin-dependent endocytosis system plays the more active and dominant role over the caveolae system. Therefore, we monitored the efficiency of clathrin-dependent receptor-mediated endocytosis in the senescent cells in order to elucidate the exact mode of the attenuated response to growth factors in the senescent cells. Using a transferrin-uptake assay and Western blot analysis of endocytosis-related proteins, we found a significant decrease of amphiphysin-1 in human diploid fibroblasts of multipassages. By adjusting the level of amphiphysin, we could modulate the efficiency of receptor-mediated endocytosis either in young or old cells toward growth factors: that is, a dominant negative mutant of amphiphysin-1 blocked the endocytosis in the young cells, while microinjection of the gene resumed its activity in the old cells. Taken together, we conclude that the loss of endocytotic activity of senescent cells is directly related to the down-regulation of amphiphysin-1 and/or up-regulation of caveolins. This opens a new field of functional recovery of the senescent cells simply through adjusting the receptor-mediated endocytosis capacity.