PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study.

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.

Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis.

BACKGROUND: To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. METHODS: Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). RESULTS: Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0-1.8) for peptic ulcer to 78.0 (95% CI, 74.8-81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05-2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. CONCLUSION: Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone-related complications among adult asthma patients.

Clinicopathologic analysis of coxsackievirus a6 new variant induced widespread mucocutaneous bullous reactions mimicking severe cutaneous adverse reactions.

BACKGROUND: The cutaneous manifestations of human enterovirus (HEV) infection are usually limited, such as hand-foot-mouth disease. By comparison, Stevens-Johnson syndrome (SJS) is a life-threatening severe cutaneous adverse reaction (SCAR), mainly caused by drugs. During the HEV outbreaks in 2010-2012 in Taiwan, we identified 21 patients who developed widespread blistering mucocutaneous reactions without any suspected drug causality. METHODS: We screened possible pathogen(s) for detecting human herpes virus (HHV1-HHV7), HEV, or Mycoplasma pneumoniae infections using throat swab virus cultures, real-time PCR, DNA sequencing, immunochemistry and electron microscopy analyses. RESULTS: Coxsackievirus A6 (CVA6) DNA was identified in the blistering skin lesions in 6 of 21 patients. Cytotoxic T lymphocytes and natural killer cells expressing granulysin predominantly infiltrated into the skin lesions, sharing the histopathological features with SJS. Intact CVA6 viral particles were identified in the blister fluids and skin lesions by electron microscopy. The phylogenetic analysis of the viral genome showed the CVA6 DNA sequence sharing higher similarity (97.6%-98.1%) to CVA6 strains reported from Finland at 2008. CONCLUSIONS: This study identifies a new variant of CVA6 as the causative agent for severe mucocutaneous blistering reactions mimicking SCAR. An awareness of this unusual presentation of HEV infection is needed in the epidemic area.

Anti-tumor effects of deubiquitinating enzyme inhibitor PR-619 in human chondrosarcoma through reduced cell proliferation and endoplasmic reticulum stress-related apoptosis.

Chondrosarcoma, a treatment-resistant cancer with limited therapeutic options, lacks significant advancements in treatment methods. However, PR-619, a novel inhibitor of deubiquitinating enzymes, has demonstrated anti-tumor effects in various malignancies. This study aimed to investigate the impact of PR-619 on chondrosarcoma both in vitro and in vivo. Two human chondrosarcoma cell lines, SW11353 and JJ012, were utilized. Cell viability was assessed using an MTT assay, while flow cytometry enabled the detection of apoptosis and cell cycle progression. Western blotting analyses were conducted to evaluate apoptosis, cell stress, and endoplasmic reticulum (ER) stress. Furthermore, the in vivo anti-tumor effects of PR-619 were examined using a xenograft mouse model. The results revealed that PR-619 induced cytotoxicity, apoptosis, and cell cycle arrest at the G0/G1 stage by activating caspases, PARP cleavage, and p21. Moreover, PR-619 increased the accumulation of polyubiquitinated proteins and ER stress by activating IRE1, GRP78, caspase-4, CHOP, and other cellular stress responses, including JNK activation. In vivo analysis demonstrated that PR-619 effectively inhibited tumor growth with minimal toxicity in the xenograft mouse model. These findings provide evidence of the anti-tumor effects and induction of cellular and ER stress by PR-619 in human chondrosarcoma, suggesting its potential as a novel therapeutic strategy for in human chondrosarcoma.

Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009.

OBJECTIVES: Studies from the 1990s through mid-2000s report variable decreases in upper gastrointestinal (UGI) complications and differ regarding changes in lower gastrointestinal (LGI) complications. We determined incidence and case fatality of hospitalizations for GI complications in the United States over the past decade. METHODS: We used a national inpatient database to calculate yearly projections from 2001-2009 for incidence and case fatality of hospitalizations with primary discharge diagnoses of UGI and LGI complications (bleeding, perforation, and obstruction) and of undefined GI bleeding. RESULTS: Age/sex-adjusted incidence of GI complications decreased non-significantly from 236.1 to 223.7/100,000 population from 2001-2009. Components were UGI complications (85.0 to 66.0/100,000), LGI complications (100.3 to 104.4/100,000), and undefined bleeding (50.8 to 53.3/100,000). Decreases were seen in UGI bleeding (78.4 to 60.6/100,000), peptic ulcer bleeding (48.7 to 32.1/100,000), LGI bleeding (41.8 to 35.7/100,000), and colonic diverticular bleeding (30.4 to 23.9/100,000), whereas LGI obstruction increased (55.0 to 66.0/100,000). Age/sex-adjusted case fatality decreased from 3.78 to 2.70%. 2009 case fatality rates were 2.45% for UGI bleeding, 3.00% for undefined bleeding, 1.47% for LGI bleeding, 2.30% for LGI obstruction, 10.7% for UGI perforation, and 16.0% for LGI perforation. Case fatality increased with age, but was 3.54% in patients >75 years with bleeding or obstruction. CONCLUSIONS: Hospitalizations for UGI complications are decreasing in the United States owing to a decrease in UGI bleeding. LGI complications are relatively stable, with a decrease in LGI bleeding and a larger increase in LGI obstruction. Case fatality owing to bleeding or obstruction is low, increasing with age but remaining <5% even in the elderly.

Rectal Dose Is the Other Dosimetric Factor in Addition to Small Bowel for Prediction of Acute Diarrhea during Postoperative Whole-Pelvic Intensity-Modulated Radiotherapy in Gynecologic Patients.

We studied the association of rectal dose with acute diarrhea in patients with gynecologic malignancies undergoing whole-pelvic (WP) intensity-modulated radiotherapy (IMRT). From June 2006 to April 2019, 108 patients with previous hysterectomy who underwent WP IMRT were enrolled in this cohort study. WP irradiation of 39.6-45 Gy/22-25 fractions was initially delivered to the patients. Common Terminology Criteria for Adverse Events (CTCAE) version 3 was used to evaluate acute diarrhea during radiotherapy. Small bowel volume at different levels of isodose curves (Vn%) and mean rectal dose (MRD) were measured for statistical analysis. The multivariate analysis showed that the MRD ≥ 32.75 Gy (p = 0.005) and small bowel volume of 100% prescribed (V100%) ≥ 60 mL (p = 0.008) were independent factors of Grade 2 or higher diarrhea. The cumulative incidence of Grade 2 or higher diarrhea at 39.6 Gy were 70.5%, 42.2%, and 15.0% (p < 0.001) in patients with both high (V100% ≥ 60 mL and MRD ≥ 32.75 Gy), either high, and both low volume-dose factors, respectively. Strict constraints for the rectum/small bowel or image-guided radiotherapy to reduce these doses are suggested.

The association between serum activin A levels and albuminuria among community-dwelling middle-aged and older adults in Taiwan.

Activin A, a cytokine belonging to the transforming growth factor-ß family, has been shown to play pivotal roles in tissue remodeling after renal injury and is present in elevated levels in diabetic patients. However, the association between activin A and albuminuria remains unclear. We aimed to evaluate their association by using cross-sectional data from community-dwelling middle-aged and older adults in Taiwan. We assessed 466 participants (67% male; mean age 71 ± 13 years) from the I-Lan Longitudinal Aging study for whom data pertaining to serum activin A level and urine albumin-to-creatinine ratio (UACR) were available. Of these, 323 (69%) had normal albuminuria, 123 (26%) had microalbuminuria, and 20 (4%) had overt albuminuria. Patients with overt albuminuria and microalbuminuria had significantly higher activin A concentrations than those in the normal albuminuria group (p < 0.001). Circulating activin A was significantly correlated with multiple risk factors, including higher systolic blood pressure and higher UACR. Univariate and multivariate results indicated that activin A level was an independent variable for albuminuria. The cutoff value of 602 pg/mL of activin A demonstrated a sensitivity of 70.6% and specificity of 75.7% (AUC 0.774) in diagnosing overt albuminuria. In conclusion, middle-aged and older adults with elevated activin A levels were associated with a higher incidence of albuminuria.

Physical activity, sedentary behavior, and endometrial cancer risk in the NIH-AARP Diet and Health Study.

Consistent with a strong hormonal etiology, endometrial cancer is thought to be influenced by both obesity and physical activity. Although obesity has been consistently related to risk, associations with physical activity have been inconclusive. We examined relationships of activity patterns with endometrial cancer incidence in the NIH-AARP Diet and Health Study cohort, which included 109,621 women, ages 50-71, without cancer history, who in 1995-1996 completed a mailed baseline questionnaire capturing daily routine and vigorous (defined as any period of >or=20 min of activity at work or home causing increases in breathing, heart rate, or sweating) physical activity. A second questionnaire, completed by 70,351 women, in 1996-1997 collected additional physical activity information. State cancer registry linkage identified 1,052 primary incident endometrial cancers from baseline through December 31, 2003. In multivariate proportional hazards models, vigorous activity was inversely associated with endometrial cancer in a dose-response manner (p for trend = 0.02) (relative risk (RR) for >or=5 times/week vs. never/rarely = 0.77, 95% confidence interval (CI): 0.63-0.95); this association was more pronounced among overweight and obese women (body mass index >or=25; RR = 0.61, 95% CI: 0.47-0.79) than among lean women (body mass index <25; RR = 0.76, 95% CI: 0.52-1.10; p for interaction = 0.12). Although we observed no associations with light/moderate, daily routine or occupational physical activities, risk did increase with number of hours of daily sitting (p for trend = 0.02). Associations with vigorous activities, which may interact with body mass index, suggest directions for future research to clarify underlying biologic mechanisms, including those relating to hormonal alterations.

Polymorphisms in estrogen biosynthesis and metabolism-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists.

Ionizing radiation-associated breast cancer risk appears to be modified by timing of reproductive events such as age at radiation exposure, parity, age at first live birth, and age at menopause. However, potential breast cancer risk modification of low to moderate radiation dose by polymorphic estrogen metabolism-related gene variants has not been routinely investigated. We assessed breast cancer risk of 12 candidate variants in 12 genes involved in steroid metabolism, catabolism, binding, or receptor functions in a study of 859 cases and 1,083 controls within the US radiologic technologists (USRT) cohort. Using cumulative breast dose estimates from a detailed assessment of occupational and personal diagnostic ionizing radiation exposure, we investigated the joint effects of genotype on the risk of breast cancer. In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the CYP3A4 M445T minor allele (rs4986910, OR = 0.3; 95% CI 0.1-0.9). We found a borderline increased breast cancer risk with having both minor alleles of CYP1B1 V432L (rs1056836, CC vs. GG, OR = 1.2; 95% CI 0.9-1.6). Assuming a recessive model, the minor allele of CYP1B1 V432L significantly increased the dose-response relationship between personal diagnostic X-ray exposure and breast cancer risk, adjusted for cumulative occupational radiation dose (p (interaction) = 0.03) and had a similar joint effect for cumulative occupational radiation dose adjusted for personal diagnostic X-ray exposure (p (interaction) = 0.06). We found suggestive evidence that common variants in selected estrogen metabolizing genes may modify the association between ionizing radiation exposure and breast cancer risk.

Breast cancer epidemiology according to recognized breast cancer risk factors in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial Cohort.

BACKGROUND: Multidisciplinary attempts to understand the etiology of breast cancer are expanding to increasingly include new potential markers of disease risk. Those efforts may have maximal scientific and practical influence if new findings are placed in context of the well-understood lifestyle and reproductive risk factors or existing risk prediction models for breast cancer. We therefore evaluated known risk factors for breast cancer in a cancer screening trial that does not have breast cancer as a study endpoint but is large enough to provide numerous analytic opportunities for breast cancer. METHODS: We evaluated risk factors for breast cancer (N = 2085) among 70,575 women who were randomized in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Using Poisson regression, we calculated adjusted relative risks [RRs, with 95% confidence intervals (CIs)] for lifestyle and reproductive factors during an average of 5 years of follow-up from date of randomization. RESULTS: As expected, increasing age, nulliparity, positive family history of breast cancer, and use of menopausal hormone therapy were positively associated with breast cancer. Later age at menarche (16 years or older vs. < 12: RR = 0.81, 95% CI, 0.65-1.02) or menopause (55 years or older vs. < 45: RR = 1.29, 95% CI, 1.03-1.62) were less strongly associated with breast cancer than was expected. There were weak positive associations between taller height and heavier weight, and only severe obesity [body mass index (BMI; kg/m(2)) 35 or more vs. 18.5-24.9: RR = 1.21, 95% CI, 1.02-1.43] was statistically significantly associated with breast cancer. CONCLUSION: The ongoing PLCO trial offers continued opportunities for new breast cancer investigations, but these analyses suggest that the associations between breast cancer and age at menarche, age at menopause, and obesity might be changing as the underlying demographics of these factors change. CLINICAL TRIALS REGISTRATION: (http://www.clinicaltrials.gov), NCT00002540.

Genetic determinants of serum lipid levels in Chinese subjects: a population-based study in Shanghai, China.

We examined the associations between 21 single nucleotide polymorphisms (SNPs) of eight lipid metabolism genes and lipid levels in a Chinese population. This study was conducted as part of a population-based study in China with 799 randomly selected healthy residents who provided fasting blood and an in-person interview. Associations between variants and mean lipid levels were examined using a test of trend and least squares mean test in a general linear model. Four SNPs were associated with lipid levels: LDLR rs1003723 was associated with total cholesterol (P-trend = 0.002) and LDL (P-trend = 0.01), LDLR rs6413503 was associated with total cholesterol (P-trend = 0.05), APOB rs1367117 was associated with apoB (P-trend = 0.02), and ABCB11 rs49550 was associated with total cholesterol (P-trend = 0.01), triglycerides (P-trend = 0.01), and apoA (P-trend = 0.01). We found statistically significant effects on lipid levels for LDLR rs6413503 among those with high dairy intake, LPL rs263 among those with high allium vegetable intake, and APOE rs440446 among those with high red meat intake. We identified new associations between SNPs and lipid levels in Chinese previously found in Caucasians. These findings provide insight into the role of lipid metabolism genes, as well as the mechanisms by which these genes may be linked with disease.

Polymorphism of genes related to insulin sensitivity and the risk of biliary tract cancer and biliary stone: a population-based case-control study in Shanghai, China.

Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single-nucleotide polymorphisms in the PPAR-gamma, PPAR-delta, RXR-alpha, RXR-beta and INS genes with biliary cancer and stones in a population-based case-control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater cancer cases, 895 stone cases and 786 population controls. Relative to individuals with the RXR-beta C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 0.99-2.84], with a more pronounced association among men (OR = 2.30; 95% CI = 1.14-4.65; P interaction = 0.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (>or=23 kg/m(2)) (OR = 1.80; 95% CI = 1.09-2.94), although the interaction with BMI was not statistically significant (P interaction = 0.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones.

Serum lipid levels and the risk of biliary tract cancers and biliary stones: A population-based study in China.

Biliary tract cancers, encompassing the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a population-based case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (>/=160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI = 1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI = 1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI = 2.8-8.1), compared to the reference group (third quintile: 90-124 mg/dl). Participants in the lowest quintile of high-density lipoprotein (HDL) (<30 mg/dl) had a 4.2-fold risk of biliary stones (95% CI = 3.0-6.0), an 11.6-fold risk of gallbladder cancer (95% CI = 7.3-18.5), and a 16.8-fold risk of bile duct cancer (95% CI = 9.1-30.9), relative to the reference group (third quintile: 40-49 mg/dl). In addition, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A (apo A) were inversely associated with biliary stones; whereas low levels as well as high levels of total cholesterol, LDL, apo A and apolipoprotein B (apo B) were associated with excess risks of biliary tract cancers. Our findings support a role for serum lipids in gallstone development and biliary carcinogenesis.

Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.

Experimental and epidemiologic studies suggest that vitamin D metabolites (1,25-dihydroxyvitamin D [1,25(OH)(2)D] and its precursor 25-hydroxyvitamin D [25(OH)D]) may reduce breast cancer risk. We examined subsequent breast cancer risk related to serum levels of these metabolites. In a cohort of women ages 55 to 74 years, who donated blood at baseline (1993-2001) in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we identified 1,005 incident breast cancer cases during follow-up through 2005 (mean time between blood draw and diagnosis, 3.9 years). Noncases (n = 1,005) were frequency matched to the cases based on age and year of entry. Sample weights that accounted for unequal probabilities of selecting cases and noncases were applied to make inferences that reflected the entire Prostate, Lung, Colorectal, and Ovarian cohort. Using Cox proportional hazards modeling, we computed breast cancer relative risks (RR) and 95% confidence intervals (95% CI) by quintile for each metabolite. The RR of breast cancer for the highest quintile of 25(OH)D concentration versus the lowest was 1.04 (95% CI, 0.75-1.45; P(trend) = 0.81). Similarly, the breast cancer RR for the highest quintile of 1,25(OH)(2)D compared with the lowest was 1.23 (95% CI, 0.91-1.68; P(trend) = 0.14). Excluding the first 2 years of follow-up did not materially alter these estimates. There was also no evidence of inverse risk in older women (> or =60 years) versus younger women (<60 years). In this prospective study of postmenopausal women, we did not observe an inverse association between circulating 25(OH)D or 1,25(OH)(2)D and breast cancer risk, although we cannot exclude an association in younger women or with long-term or earlier exposure.

Diabetes mellitus and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

OBJECTIVE: A history of diabetes has been fairly consistently related to a reduced prostate cancer risk, but previous investigations have not always addressed whether the relation with diabetes varies by prostate cancer aggressiveness or the association between diabetes and prostate cancer is modified by physical activity level and body mass, variables closely related to glucose metabolism. METHODS: We prospectively examined the diabetes-prostate cancer risk relationship among 33,088 men in the screening arm of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. RESULTS: During 8.9 years follow-up, we ascertained 2,058 incident prostate cancer cases. Diabetes history was related to decreased risk of total prostate cancer (RR = 0.80, 95% CI = 0.68-0.95). The apparent protection afforded by diabetes was primarily due to the inverse relation with non-aggressive disease (i.e., the combination of low grade (Gleason sum <8) and low stage (clinical stages I or II); RR = 0.75; 95% CI = 0.62-0.91). In contrast, no association was noted between diabetes and aggressive disease (i.e., high grade or high stage (Gleason sum >or=8 or clinical stages III or IV); RR = 1.04, 95% CI = 0.74-1.45). In further analyses, the association between diabetes and aggressive prostate cancer was suggestively positive for men who were lean (RR = 1.64, 95% CI = 0.87-3.07; BMI < 25 kg/m(2)) and it was positive for men who were the most physically active (RR = 1.63; 95% CI = 1.07-2.62; 3+ hours vigorous activity/week). By comparison, no relations of diabetes to aggressive prostate cancer were noted for their heavier or physically less active counterparts (p-value for tests of interaction = 0.10 and 0.03 BMI and physical activity, respectively). CONCLUSION: In this study, diabetes showed divergent relations with prostate cancer by tumor aggressiveness. Specifically, diabetes was inversely associated with early stage prostate cancer but it showed no relation with aggressive prostate cancer. Exploratory analyses suggested a positive association between diabetes and aggressive prostate cancer in the subgroup of men with a low BMI.

Lifetime weight history and endometrial cancer risk by type of menopausal hormone use in the NIH-AARP diet and health study.

Obesity and menopausal estrogen therapy are established risk factors for endometrial cancer. However, the joint effects of obesity and menopausal hormone therapy on endometrial cancer risk are incompletely understood. We addressed this issue in a cohort of 103,882 women ages 50 to 71 years at baseline in 1995 to 1996. During a median of 4.6 years, which contributed to a total of 455,304 person-years of follow-up through 2000, 677 cases of endometrial cancer were ascertained. Both baseline body mass index (BMI) and adult weight gain were associated with increased endometrial cancer risk. The multivariate relative risk (RR) comparing obese with normal weight women (BMI >30 versus <25 kg/m(2)) was 3.03 [95% confidence interval (95% CI), 2.50-3.68]. Compared with women with stable weight (gained or lost <5 kg) between age 18 and baseline, women who gained >or=20 kg had a RR of 2.75 (95% CI, 1.96-3.86). Menopausal hormone therapy significantly modified the relations of BMI (P(interaction) < 0.001) and adult weight gain (P(interaction) = 0.004) to endometrial cancer risk. Compared with normal weight, the RRs for obesity were 5.41 (95% CI, 4.01-7.29) among women who never used menopausal hormone therapy, 2.53 (95% CI, 1.21-5.30) among former menopausal hormone therapy users, and 1.44 (95% CI, 1.00-2.05) among current users. Compared with a stable weight between age 18 and baseline, the RRs for weight gain of >or=20 kg among never users and ever users of menopausal hormone therapy were 5.35 (95% CI, 3.01-9.52) and 1.43 (95% CI, 0.96-2.15), respectively. We conclude that both current adiposity and adult weight gain are associated with substantial increases in the risk of endometrial cancer, with relations particularly evident among never users of menopausal hormone therapy.

Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

BACKGROUND: Several epidemiologic studies suggest that higher folate intakes are associated with lower breast cancer risk, particularly in women with moderate alcohol consumption. OBJECTIVE: We investigated the association between dietary folate, alcohol consumption, and postmenopausal breast cancer in women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort. DESIGN: Dietary data were collected at study enrollment between 1993 and 2001. Folate content was assigned on the basis of prefortification (ie, pre-1998) databases. Of the 25 400 women participants with a baseline age of 55-74 y and with complete dietary and multivitamin information, 691 developed breast cancer between September 1993 and May 2003. We used Cox proportional hazard models with age as the underlying time metric to generate hazard ratios (HRs) and 95% CIs. RESULTS: The adjusted HRs were 1.19 (95% CI: 1.01, 1.41; P for trend = 0.04) for women reporting supplemental folic acid intake >/=400 mug/d compared with subjects reporting no supplemental intake. Comparison of the highest with the lowest quintile gave adjusted HRs of 1.04 (95% CI: 0.83, 1.31; P for trend = 0.56) and 1.32 (95% CI: 1.04, 1.68; P for trend = 0.03) for food and total folate intake, respectively. Alcohol consumption was positively associated with breast cancer risk (highest compared with lowest quintile: HR = 1.37; 95% CI: 1.08, 1.76; P for trend = 0.02); the risk was greatest in women with lower total folate intake. CONCLUSIONS: Our results do not support the hypothesis that high folate intake reduces breast cancer risk; instead, they suggest that a high intake, generally attributable to supplemental folic acid, may increase the risk in postmenopausal women. However, our results confirm previous studies showing positive associations between moderate alcohol consumption and breast cancer.

High gestational weight gain does not improve birth weight in a cohort of African American adolescents.

BACKGROUND: Because pregnant African American women and teens are at risk of low birth weight, they are frequently counseled to strive for gestational weight gains at the upper limits of the Institute of Medicine's recommended ranges. OBJECTIVE: The objective was to examine whether such weight gains improve birth outcomes in a cohort of disadvantaged African American adolescents of low (<19.8), average (> or =19.8 to < or =26.0), or high (>26) prepregnancy body mass index (BMI; in kg/m2). DESIGN: Data were extracted from the medical charts of 1120 African American adolescents who received prenatal care at an inner-city maternity clinic between 1990 and 2000 and analyzed by using analysis of covariance and multivariate regression methods. RESULTS: Data were available for 815 adolescents, 711 of whom delivered at term (> or =37 wk). Fifty-eight percent (n = 409) of all term deliveries and 74% of the high-BMI adolescents (n = 126) had gains in the upper half of or above the recommended ranges. For all BMI groups, the most significant differences in birth outcomes were found in comparisons of teens who gained below the recommended ranges with those who gained in the lower half of the recommendation range. Further gains were not clearly beneficial, particularly for infants of high-BMI mothers. CONCLUSIONS: African American adolescents entering pregnancy underweight or at average weight should be counseled to gain within the recommended ranges, whereas overweight adolescents need support to avoid excessive gestational weight gain. Such advice would be prudent in light of the known associations between obesity and the increased likelihood of chronic diseases.

Association of energy intake and energy balance with postmenopausal breast cancer in the prostate, lung, colorectal, and ovarian cancer screening trial.

Energy restriction remains one of the most effective ways known to prevent breast cancer in animal models. However, energy intake has not been consistently associated with risk of breast cancer in humans. In a prospective study, we assessed whether energy intake, body size, and physical activity each independently influence breast cancer risk in postmenopausal women and estimated the joint effect of combinations of these individual factors. As part of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 38,660 women, ages 55 to 74 years and recruited from 10 centers in the United States during 1993 to 2001, were randomized to the screening arm of the trial. At baseline, the women completed a self-administered questionnaire, including a food frequency questionnaire. During follow-up from 1993 to 2003, 764 incident breast cancer cases were ascertained. Women in the highest quartile of energy intake (> or = 2,084 kcal/d) compared with those in the lowest quartile (<1,316 kcal/d) had a significantly increased risk for breast cancer [multivariate relative risk (RR), 1.25; 95% confidence interval (95% CI), 1.02-1.53; P(trend continuous) = 0.03]. Current body mass index (BMI) was also positively and significantly associated with risk (multivariate RR comparing >30 kg/m2 with <22.5 kg/m2, 1.35; 95% CI, 1.06-1.70; P(trend) = 0.01). Women with > or = 4 hours/wk of vigorous recreational physical activity had a significantly reduced risk of breast cancer compared with those who reported no recreational physical activity (multivariate RR, 0.78; 95% CI, 0.60-0.99; P(trend) = 0.15). None of these associations with individual energy balance measures was substantially confounded by the other two measures. When we estimated the joint effect of all three variables, women with the most unfavorable energy balance (the highest energy intake, highest BMI, and least physical activity) had twice the risk (RR, 2.10; 95% CI, 1.27-3.45) of women with the most favorable energy balance (the lowest energy intake, lowest BMI, and most physical activity). Although our estimates of absolute energy intake, based on a food frequency questionnaire, are imperfect, these results suggest that energy intake, in addition to BMI and physical activity may be independently associated with breast cancer risk. In addition, these three aspects of energy balance may act jointly in determining breast cancer risk.

MLN4924, a novel protein neddylation inhibitor, suppresses proliferation and migration of human urothelial carcinoma: In vitro and in vivo studies.

MLN4924, a small molecule inhibitor of NEDD8 activating enzyme (NAE), has been reported to elicit an anti-tumor effect on various malignancies. In this study, we investigated the anti-tumor effect of MLN4924 in human urothelial carcinoma (UC) in vitro and in vivo by using three human UC cell lines of various grading (T24, NTUB1 and RT4). The impact of MLN4924 on UC cells was determined by measuring viability (MTT), proliferation (BrdU incorporation), cell cycle progression (flow cytometry with propidium iodide staining) and apoptosis (flow cytometry with annexin V-FITC labeling). The cell cycle regulatory molecules, apoptosis-related molecules, and cell stress-related proteins were examined by Western blotting. The influence of tumor cell migration and invasion was analyzed by Transwell and wound healing assays. We also evaluated the effects of MLN4924 on tumor growth by a SCID xenograft mouse model. The data show that MLN4924 induced dose-dependent cytotoxicity, anti-proliferation, anti-migration, anti-invasion and apoptosis in human UC cells, accompanied by activations of Bad, phospho-histone H2A.X, caspase-3, 7 and PARP, decreased level of phospho-Bcl2, and caused cell cycle retardation at the G2M phase. Moreover, MLN4924 activated endoplasmic reticulum stress-related molecules (caspase-4, phospho-eIF2α, ATF-4 and CHOP) and other stress responses (JNK and c-Jun activations). Finally, we confirmed MLN4924 inhibited tumor growth in a UC xenograft mouse model with minimal general toxicity. We concluded that MLN4924 induces apoptosis and cell cycle arrest, as well as activation of cell stress responses in human UC. These findings imply MLN4924 provides a novel strategy for the treatment of UC.