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Biomedical subjects

R M Ray

Publications and source records attributed to R M Ray.

At least 19 recordsLinked to original sources
PubMed2006

Occupational risk factors for pancreatic cancer among female textile workers in Shanghai, China.

OBJECTIVES: To investigate whether occupational exposures to dusts and chemicals in the Shanghai textile industry are associated with risk of pancreatic cancer. METHODS: A case cohort study nested in a cohort of 267,400 female textile workers in Shanghai, China was conducted among 180 incident pancreatic cancer cases and an age stratified randomly selected comparison subcohort (n = 3188). A complete occupational history of work in the textile industry was obtained for each woman, and was linked to a job exposure matrix developed for the textile industry to estimate exposures to specific dusts and chemicals. Cumulative exposures to cotton dust and endotoxin were reconstructed from historical and contemporaneous measurements. RESULTS: After adjusting for smoking status, a trend of decreasing risk of pancreatic cancer was observed for increasing cumulative exposures to cotton dust and endotoxin with a lag of 20 years. The hazard ratios for women cumulatively exposed to >143.4 mg/m3 x years of cotton dust and >3530.6 EU/m3 x years of endotoxin were 0.6 (95% CI 0.3 to 0.9) and 0.5 (95% CI 0.3 to 0.9), respectively, compared to unexposed women. There was little evidence that exposures to other textile dusts and chemicals were associated with risk of pancreatic cancer. CONCLUSIONS: Occupational exposure to cotton dust and endotoxin in the textile industry may have reduced risks of pancreatic cancer in this cohort. These associations should be replicated by others before making a firm conclusion of their possible effects on pancreatic cancer.

Adult↗
PubMed2006

Akt-mediated GSK-3beta inhibition prevents migration of polyamine-depleted intestinal epithelial cells via Rac1.

The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3beta have been implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase (PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3beta (Ser9) phosphorylation. Pretreatment with 20 microM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells grown in control medium. Treatment of cells with a GSK-3beta inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response to polyamine depletion inhibits migration through GSK-3beta and Rac1.

Actins↗
PubMed2006

Occupational risk factors for nasopharyngeal cancer among female textile workers in Shanghai, China.

AIMS: To investigate whether occupational exposure to dusts and chemicals in the Chinese textile industry are associated with risk of nasopharyngeal cancer. METHODS: Sixty seven nasopharyngeal carcinoma (NPC) cases identified during 1989-98 and a random sample (n = 3188) of women were included in a case cohort study nested in a cohort of 267,400 women textile workers in Shanghai, China. A complete occupational history of work in the textile industry was obtained for each woman. A job exposure matrix developed by experienced industrial hygienists was used to assess exposures to specific dusts and chemicals. RESULTS: Risk of NPC is associated with cumulative exposure to cotton dust. The hazard ratio for women cumulatively exposed to >143.4 mg/m3 x years of cotton dust was 3.6 (95% CI 1.8 to 7.2) compared with unexposed women. Trends of increasing risk were also found with increasing duration of exposure to acids and caustics (p = 0.05), and with years worked in dyeing processes (p = 0.06). Women who worked at least 10 years in dyeing processes had a 3.6-fold excess risk of NPC (95% CI 1.0 to 12.1). CONCLUSIONS: Occupational exposure to cotton dust, acids, and caustics, and work in dyeing and printing jobs in the textile industry may have increased risk of NPC in this cohort.

Adult↗
PubMed2005

Decreased apoptosis in polyamine depleted IEC-6 cells depends on Akt-mediated NF-kappaB activation but not GSK3beta activity.

The PI3-kinase/Akt pathway promotes cell survival in many different cell types including intestinal epithelial cells. Increased AKT activation in polyamine depleted intestinal epithelial cells correlated well with the decrease in TNF-alpha-induced apoptosis. Increased Akt activation and GSK3beta (Ser 9) phosphorylation without significant effect on Bad (Ser136) phosphorylation indicate that Akt-mediated protection is independent of Bad phosphorylation but may depend on GSK3beta. Pretreatment of polyamine-depleted cells with LY294002 increased caspase-9 and caspase-3 activation and decreased basal levels of GSK-3beta phosphorylation. Inhibition of GSK3beta activity using AR-A014418 or lithium chloride or siRNA-mediated downregulation of its expression had no effect on apoptosis. Inhibition of PI3-kinase and over-expression of dominant negative Akt (DN-AKT), significantly increased apoptosis in polyamine depleted cells. DN-Akt expression reversed the protective effect of polyamine depletion on apoptosis. DN-Akt, as well as the PI3-kinase inhibitors, prevented Akt activation and subsequent translocation of NF-kappaB to the nucleus. Constitutively active Akt (CA-AKT) expression increased resistance to TNF-alpha-induced apoptosis. Constitutively active-Akt expression increased nuclear staining of NF-kappaB. Moreover, polyamine depletion of DN-Akt cells prevented basal and TNF-alpha-induced IkappaBalpha phosphorylation. Prevention of NF-kappaB activation in DN-IkappaBalpha-transfected cells increased apoptosis in control cells and restored it in polyamine-depleted cells to control levels. These data indicate that Akt regulates the mitochondrial pathway, preventing activation of caspase-9 and thereby caspase-3 via NF-kappaB and these effects are independent of GSK-3beta activity.

Androstadienes↗
PubMed2005

Colorectal cancer incidence among female textile workers in Shanghai, China: a case-cohort analysis of occupational exposures.

Previous studies have suggested increased risks of colorectal cancers among textile industry workers, potentially related to synthetic fibers. To investigate risks of colon and rectum cancers in relation to these and other textile industry exposures, we conducted a case-cohort study nested within a cohort study of female employees from the Shanghai Textile Industry Bureau (STIB). Cox proportional hazard regression modeling was used to estimate hazard ratios (HR) for colon and rectum cancers associated with duration of employment (e.g., 0, >0 to <10, 10 to <20 years, > or =20 years) in various jobs classified according to process type and exposures to specific agents. Our findings indicate that certain long term exposures may pose increased risk of colorectal cancers, especially dyes and dye intermediates with colon cancer (> or =20 years exposure versus never, HR=3.9; 95% CI: 1.4-10.6), and maintenance occupation (HR = 2.3; 95% CI: 1.0-5.7) and metals exposure (HR = 2.0; 95% CI: 1.1-3.6) with rectum cancer. A decreased risk of rectum cancer was associated with exposure to natural fibers such as cotton (HR = 0.7; 95% CI: 0.5-0.9), and a trend of decreasing rectum cancer incidence was observed by category of cumulative quantitative cotton dust or endotoxin exposures, when exposures were lagged by 20 years.

Adult↗
PubMed2004

Contraceptive methods and induced abortions and their association with the risk of colon cancer in Shanghai, China.

267400 female textile workers in Shanghai, who were administered a questionnaire at enrollment into a randomised trial of breast self-examination between October 1989 and October 1991, were followed up until the middle of 2000. Based on the 655 women who developed colon cancer, rate ratios (RRs) were estimated and trends in risk assessed using Cox Proportional Hazards Models. Risk was increased in women who used oral contraceptives for over 3 years (RR=1.56, 95% Confidence Interval (CI) 1.01-2.40). A possible increase in risk was also observed in women who received progestational injections during pregnancy (RR=1.24, 95% CI 0.95-1.62), but not in relation to the use of injectable contraceptives. A possible reduction in risk was associated with tubal ligation (RR=0.86, 95% CI 0.71-1.03) and ever having had an induced abortion (RR=0.84, 95% CI 0.71-1.00). No trends in risk were observed in relation to the duration of hormonal contraceptive use or the number of induced abortions. Additional studies of the possible roles contraceptives may play in the aetiology of colon cancer in women at low risk of this disease are warranted.

Abortion, Induced↗
PubMed2002

Breast cancer in relation to induced abortions in a cohort of Chinese women.

The possible influence of induced abortion on breast cancer risk was assessed in a cohort of 267 040 women enrolled in a randomised trial of breast self-examination in Shanghai, China. Based on answers to a baseline questionnaire, subsequent breast cancer risk was not significantly associated with ever having an induced abortion. After adjustment for potential confounders, the relative risk estimate was 1.06 (95% C.I.: 0.91, 1.25), and there was no trend in risk with number of abortions. Analysis of data from more detailed interviews of 652 cases and 694 controls from the cohort yielded similar results. There was also no overall increase in risk in women with induced abortion after first birth. Few women had undergone an abortion after 13 weeks gestation or before their first child. Although increases in risk were observed in such women, they were not statistically significant and could have been due to recall bias. Abortions as they have been performed in China are not an important cause of breast cancer.

Abortion, Induced↗
PubMed2001

Polyamine depletion induces rapid NF-kappa B activation in IEC-6 cells.

The proliferation of the rat intestinal mucosal IEC-6 cell line requires polyamines, whose synthesis is catalyzed by the enzyme ornithine decarboxylase (ODC). ODC inhibition leads to polyamine depletion, as well as inhibition of both cell proliferation and apoptosis by regulating gene expression. The NF-kappa B transcription factor regulates genes involved in apoptotic, immune, and inflammatory responses. In the present study we tested the hypothesis that NF-kappa B is activated following ODC inhibition. We found that the inhibition of ODC by alpha-difluoromethylornithine (DFMO) resulted in a approximately 50% decrease in intracellular putrescine levels within 1 h. NF-kappa B is activated by DFMO through the degradation of the inhibitory protein I kappa B alpha that sequesters NF-kappa B in the cytoplasm. The DFMO-induced NF-kappa B complexes contain the p65 and p50 members of the Rel protein family. DFMO-induced NF-kappa B activation was accompanied by the translocation of p65 from the cytoplasm into the nucleus. DFMO selectively inhibited a gene reporter construct dependent on the kappa B site present in the HLA-B7 gene. In contrast, DFMO had no effect on a gene reporter construct dependent on the kappa B site present in the interleukin-8 gene. Thus, we report that ODC inhibition activates the NF-kappa B transcription factor, which may mediate the altered physiological state of intestinal cells that occurs following polyamine depletion.

Animals↗
PubMed2001

Human papillomaviruses and cervical cancer in Bangkok. I. Risk factors for invasive cervical carcinomas with human papillomavirus types 16 and 18 DNA.

Personal interviews, tests for antibodies to herpes simplex virus type 2, Treponema pallidum, and hepatitis B, tests for hepatitis B surface antigen (HBsAg), and polymerase chain reaction-based assays for human papillomavirus (HPV) DNA in cervical scrapings were obtained from 190 women with squamous cell and 42 women with adenomatous cervical carcinoma and from 291 hospitalized controls diagnosed in Bangkok, Thailand, between September 1991 and September 1993. Risk was strongly associated with oncogenic HPV types, with types 16 and 18 predominating in squamous and adenomatous lesions, respectively. The 126 cases with HPV-16 and the 42 cases with HPV-18 were compared with 250 controls with no evidence of any HPV. The risk of both viral tumor types increased with decreasing age at first intercourse in this predominantly monogamous population, which may be explained by more visits to prostitutes by the husbands of cases with early than late age at first intercourse. HPV-16 tumors were weakly associated with HBsAg carrier state and smoking. The risk of tumors of both viral types increased with parity and use of oral contraceptives but not with injectable progestogens. Factors that may predispose to persistent, oncogenic HPV-16 or -18 infection may include estrogens or progestins in the presence of estrogens, immunosuppression, and smoking, but other factors related to low socioeconomic status are also involved.

Adult↗
PubMed2001

Human papillomaviruses and cervical cancer in Bangkok. II. Risk factors for in situ and invasive squamous cell cervical carcinomas.

To identify risk factors for progression of intraepithelial cervical lesions, 190 women with invasive cervical cancer were compared with 75 women with in situ disease diagnosed in Bangkok, Thailand, between September 1991 and September 1993. Polymerase chain reaction-based assays for type-specific human papillomavirus (HPV) DNA in cervical scrapings revealed oncogenic types in 79% of invasive and 57% of intraepithelial tumors. Types 16 and 18, but not types 31/33/35/39, were more common in invasive than intraepithelial tumors, and untyped HPV DNA was found more commonly in the in situ lesions, suggesting that in situ disease is four times more likely to become invasive if due to type 16 or 18 than to other causes, and that tumors with only untyped HPV are not at increased risk of progression. After controlling for HPV type, the risk of developing invasive diseases, compared with the risk of developing intraepithelial lesions, was not related to any of a large number of sexual and hormonal factors considered or to smoking, suggesting that any cofactors these variables represent act before the development of in situ carcinoma. Two indices of socioeconomic status were associated with a reduced risk of only invasive disease, suggesting the existence of unknown protective factors that operate after intraepithelial lesions develop.

Adult↗
PubMed2001

Human papillomaviruses and cervical cancer in Bangkok. III. The role of husbands and commercial sex workers.

Between September 1991 and September 1993, husbands of women with and without cervical neoplasia and commercial sex workers in one brothel and one massage parlor in Bangkok, Thailand, were interviewed; serologic tests for sexually transmitted infections were performed; and cervical and penile scrapings were tested for human papillomavirus (HPV) DNA. The risks of cervical carcinoma in monogamous women and of oncogenic HPV in their husbands were associated with the men's having unprotected intercourse with prostitutes. The prevalence of oncogenic HPV was higher in commercial sex workers than in women attending gynecologic and family planning clinics. Oncogenic HPV prevalence declined with age in human immunodeficiency virus (HIV)-negative, but not in healthy HIV-positive, commercial sex workers and was weakly associated with hepatitis B antigenemia, suggesting that persistence of HPV infection is due to subtle changes in immunity. Associations of HPV with recent pregnancy and oral contraceptive use suggest that hormonal factors may increase the risk of cervical neoplasia by enhancing persistence of HPV infection. The prevalence of high-grade squamous intraepithelial lesions was strongly related to oncogenic HPV types and weakly to HIV infection only in their presence. Commercial sex workers in Bangkok are reservoirs of oncogenic HPV, and cervical cancer in monogamous Thai women develops in part as a result of transmission of these viruses to them by their husbands from prostitutes.

Adolescent↗
PubMed2001

Airway management in the obese child.

Airway management in severely obese children requires familiarity with the equipment and techniques used for establishing a patent airway. Normal anatomic landmarks are obscured in these patients, making assessment a challenge. Therapy should be individualized, and because the airway is marginal in many of these patients, small insults, such as respiratory tract infection or loss of muscle tone during sleep, can result in a perilous airway. Pediatric airway charts should be maintained and reviewed frequently in emergency departments and clinics caring for these patients. Currently, the body of literature devoted to airway management in obese children is small. Inconsistencies in parameters make comparison of studies difficult. Continued, consistent reporting of airway-management issues in these patients is needed.

Acute Disease↗
PubMed2001

Focal adhesion kinase signaling is decreased in polyamine-depleted IEC-6 cells.

Polyamines are essential to the migration of epithelial cells in the intestinal mucosa. Cells depleted of polyamines do not attach as rapidly to the extracellular matrix and do not form the actin stress fibers essential for migration. Because both attachment and stress fiber formation depend on integrin signaling and the formation of focal adhesions, we examined these and related processes in polyamine-depleted IEC-6 cells. There was general decreased tyrosine phosphorylation of focal adhesion kinase (FAK), and, specifically, decreased phosphorylation of Tyr-925, the paxillin binding site. In control cells, FAK phosphorylation was rapid after attachment to the extracellular matrix, while attached cells depleted of polyamines had significantly delayed phosphorylation. FAK activity was also significantly inhibited in polyamine-depleted cells as was the phosphorylation of paxillin. Polyamine-depleted cells failed to spread normally after attachment, and immunocytochemistry showed little colocalization of FAK and actin compared with controls. Focal adhesion complex formation was greatly reduced in the absence of polyamines. These data suggest that defective integrin signaling may, at least in part, account for the decreased rates of attachment, actin stress fiber formation, spreading, and migration observed in polyamine-depleted cells.

Actins↗
PubMed2001

Polyamine regulation of ornithine decarboxylase and its antizyme in intestinal epithelial cells.

Ornithine decarboxylase (ODC) is feedback regulated by polyamines. ODC antizyme mediates this process by forming a complex with ODC and enhancing its degradation. It has been reported that polyamines induce ODC antizyme and inhibit ODC activity. Since exogenous polyamines can be converted to each other after they are taken up into cells, we used an inhibitor of S-adenosylmethionine decarboxylase, diethylglyoxal bis(guanylhydrazone) (DEGBG), to block the synthesis of spermidine and spermine from putrescine and investigated the specific roles of individual polyamines in the regulation of ODC in intestinal epithelial crypt (IEC-6) cells. We found that putrescine, spermidine, and spermine inhibited ODC activity stimulated by serum to 85, 46, and 0% of control, respectively, in the presence of DEGBG. ODC activity increased in DEGBG-treated cells, despite high intracellular putrescine levels. Although exogenous spermidine and spermine reduced ODC activity of DEGBG-treated cells close to control levels, spermine was more effective than spermidine. Exogenous putrescine was much less effective in inducing antizyme than spermidine or spermine. High putrescine levels in DEGBG-treated cells did not induce ODC antizyme when intracellular spermidine and spermine levels were low. The decay of ODC activity and reduction of ODC protein levels were not accompanied by induction of antizyme in the presence of DEGBG. Our results indicate that spermine is the most, and putrescine the least, effective polyamine in regulating ODC activity, and upregulation of antizyme is not required for the degradation of ODC protein.

Animals↗
PubMed2001

Polyamine depletion arrests growth of IEC-6 and Caco-2 cells by different mechanisms.

The polyamines spermidine and spermine and their precursor, putrescine, are required for the growth and proliferation of eukaryotic cells. This study compares and contrasts growth arrest caused by polyamine depletion in the untransformed IEC-6 cell line with that in the p53-mutated colon cancer Caco-2 cell line. Cells were grown in the presence or absence of alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, the first rate-limiting enzyme in the synthesis of polyamines. Depletion of polyamines inhibited the growth of both cell lines equally and over the same time frame. However, whereas IEC-6 cells were arrested in the G(1) phase of the cell cycle, there was no accumulation of Caco-2 cells in any particular phase. In IEC-6 cells, growth arrest was accompanied by elevated levels of p53 and p21(Waf1/Cip1) (p21). There were no changes in p53 levels in Caco-2 cells. Levels of p21 increased in Caco-2 cells on day 2 without any effect on cell cycle progression. The amount of cyclin-dependent kinase (Cdk)2 protein was unchanged by polyamine depletion in both cell lines. However, the activity of Cdk2 was significantly inhibited by DFMO in IEC-6 cells. These data suggest that in the untransformed IEC-6 cells the regulation of Cdk2 activity and progression through the cell cycle are p53- and p21 dependent. Growth arrest in the p53-mutated Caco-2 line after polyamine depletion occurs by a different, yet unknown, mechanism.

CDC2-CDC28 Kinases↗
PubMed2000

Polyamine depletion delays apoptosis of rat intestinal epithelial cells.

The polyamines spermidine, spermine, and their precursor putrescine are essential for cell growth and the regulation of the cell cycle. Recent studies suggest that excessive accumulation of polyamines favors either malignant transformation or apoptosis, depending on the cell type and the stimulus. This study examines the involvement of polyamines in the induction of apoptosis by the DNA topoisomerase I inhibitor, camptothecin. In IEC-6 cells, camptothecin induced apoptosis within 6 h, accompanied by detachment of cells. Detached cells showed DNA laddering and caspase 3 induction, characteristic features of apoptosis. Depletion of putrescine, spermidine, and spermine by DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC) that is the first rate-limiting enzyme for polyamine biosynthesis, decreased the apoptotic index. Delayed apoptosis was accompanied by a decrease in caspase 3 activity in polyamine-depleted cells. Addition of putrescine restored the induction of apoptosis as indicated by an increase in the number of detached cells and caspase 3 activity. Polyamine depletion did not change the level of caspase 3 protein. Inhibition of S-adenosylmethionine decarboxylase by a specific inhibitor [diethylglyoxal bis-(guanylhydrazone); DEGBG] led to depletion of spermidine and spermine with a significant accumulation of putrescine and induction of ODC. The DEGBG-treated cells showed an increase in apoptosis, suggesting the importance of putrescine in the apoptotic process. Addition of putrescine to DFMO-treated cell extracts did not increase caspase 3 activity. The above results indicate that polyamine depletion delays the onset of apoptosis in IEC-6 cells and confers protection against DNA damaging agents, suggesting that polyamines might be involved in the caspase activating signal cascade.

Animals↗