Calorie Restriction Impairs Anti-Tumor Immune Responses in an Immunogenic Preclinical Cancer Model.

(1) Background: Although the important role of dietary energy intake in regulating both cancer progression and host immunity has been widely recognized, it remains unclear whether dietary calorie restriction (CR) has any impact on anti-tumor immune responses. (2) Methods: Using an immunogenic B16 melanoma cell expressing ovalbumin (B16-OVA), we examined the effect of the CR diet on B16-OVA tumor growth and host immune responses. To further test whether the CR diet affects the efficacy of cancer immunotherapy, we examined the effect of CR against anti-PD-1 monoclonal antibody (anti-PD-1 Ab) treatment. (3) Results: The CR diet significantly slowed down the tumor growth of B16-OVA without affecting both CD4+ and CD8+ T cell infiltration into the tumor. Although in vivo depletion of CD8+ T cells facilitated B16-OVA tumor growth in the control diet group, there was no significant change in the tumor growth in the CR diet group with or without CD8+ T cell-depletion. Anti-PD-1 Ab treatment lost its efficacy to suppress tumor growth along with the activation and metabolic shift of CD8+ T cells under CR condition. (4) Conclusions: Our present results suggest that a physical condition restricted in energy intake in cancer patients may impair CD8+ T cell immune surveillance and the efficacy of immunotherapy.

CAMSAP3 negatively regulates lung cancer cell invasion and angiogenesis through nucleolin/HIF-1α mRNA complex stabilization.

AIMS: Cancer metastasis is a major cause of lung cancer-related mortality, so identification of related molecular mechanisms is of interest. Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) has been implicated in lung cancer malignancies; however, its role in metastatic processes, including invasion and angiogenesis, is largely unknown. MAIN METHOD: The clinical relevance of CAMSAP3 expression in lung cancer was evaluated. The relevance of CAMSAP3 expression to in vitro cell invasion and angiogenesis was assessed in human lung cancer cells and endothelial cells, respectively. The molecular mechanism was identified by qRT-PCR, immunoprecipitation, mass spectrometry, and RNA immunoprecipitation. The in vivo metastatic and angiogenic activities of lung cancer cells were assessed. KEY FINDINGS: Low CAMSAP3 expression was found in malignant lung tissues and strongly correlated with a poor prognosis in lung adenocarcinoma (LUAD). CAMSAP3-knockout NSCLC exhibited high invasive ability, and CAMSAP3 knockout induced HUVEC proliferation and tube formation; these effects were significantly attenuated by reintroduction of exogenous wild-type CAMSAP3. Mechanistically, in the absence of CAMSAP3, the expression of hypoxia-inducible factor-1α (HIF-1α) was upregulated, which increased the levels of downstream HIF-1α targets such as vascular endothelial growth factor A (VEGFA) and matrix metalloproteinases (MMPs) 2 and 9. Proteomic analysis revealed that nucleolin (NCL) bound to CAMSAP3 to regulate HIF-1α mRNA stabilization. In addition, CAMSAP3-knockout lung cancer cells displayed highly aggressive behavior in metastasis and angiogenesis in vivo. SIGNIFICANCE: This study reveals that CAMSAP3 plays a negative regulatory role in lung cancer cell metastatic behavior both in vitro and in vivo through NCL/HIF-1α mRNA complex stabilization.

Association between selenium intake and breast cancer risk: results from the Women's Health Initiative.

PURPOSE: It has been hypothesized that selenium (Se) can prevent cancer, and that Se deficiency may be associated with an increased risk of breast cancer. However, findings from epidemiological studies have been inconsistent. The objective of this study was to assess the association between Se intake and risk of breast cancer in the Women's Health Initiative (WHI). METHODS: This study included 145,033 postmenopausal women 50-79 years who completed baseline questionnaires between October 1993 and December 1998, which addressed dietary and supplemental Se intake and breast cancer risk factors. The association between baseline Se intake and incident breast cancer was examined in Cox proportional hazards analysis. RESULTS: During a mean follow-up of 15.5 years, 9487 cases of invasive breast cancer were identified. Total Se (highest versus lowest quartile: HR 1.00, 95% CI 0.92-1.09, Ptrend = 0.66), dietary Se (highest versus lowest quartile: HR 0.99, 95% CI 0.89-1.08, Ptrend = 0.61), and supplemental Se (yes versus no: HR 0.99, 95% CI 0.95-1.03) were not associated with breast cancer incidence. CONCLUSIONS: This study indicates that Se intake is not associated with incident breast cancer among postmenopausal women in the United States. Further studies are needed to confirm our findings by using biomarkers such as toenail Se to reduce the potential for misclassification of Se status.

Physical activity and risk of bladder cancer among postmenopausal women.

Physical activity is associated with decreased risk for many cancers. Studies on the association between physical activity and risk of bladder cancer are limited, and findings are inconsistent. Postmenopausal women (mean age = 63.3) were recruited into the Women's Health Initiative from 1993 to 1998. Self-reported baseline information on physical activity and other covariates were available in 141 288 participants. Incident bladder cancer cases were collected through 2018 and centrally adjudicated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined by Cox proportional hazard regression models. Effect modification due to smoking was assessed. During an average of 18.5 years of follow-up, 817 bladder cancer cases were identified. Compared to physically inactive women, those who engaged in ≥15 MET-hours/week of total physical activity, ≥8.75 MET-hours/week of walking or ≥11.25 MET-hours/week of moderate to vigorous physical activity had lower risk of bladder cancer (HR = 0.74, 95% CI: 0.59-0.94, P for linear trend = .02; HR = 0.79, 95% CI: 0.63-0.98, P for linear trend = .03; and HR = 0.76, 95% CI: 0.61-0.94, P for linear trend = .02, respectively). No effect modification was found by smoking status (P for interaction = .06, 0.91 and 0.27, respectively). We found that total physical activity, walking and moderate to vigorous physical activity were inversely associated with bladder cancer incidence among postmenopausal women in a dose-response manner. Physical activity may play a potential role in the primary prevention of bladder cancer. Further studies with objective measurements of physical activity are needed to confirm these findings.

The association between type 2 diabetes mellitus and bladder cancer risk among postmenopausal women.

INTRODUCTION: Evidence on the association between diabetes and risk of bladder cancer has been controversial. In addition, findings on the associations between duration of diabetes, diabetes treatment, and risk of bladder cancer have been inconsistent. METHODS: A total of 148,208 participants in Women's Health Initiative study were included. Information on diabetes status, diabetes duration, and treatment was collected both at baseline and during follow-up. Information on potential confounders including age, race/ethnicity, education, occupation, family history of cancer, smoking status, alcohol consumption, total physical activity, body mass index, and daily dietary intake were collected at baseline. Bladder cancer cases were collected and confirmed by a centralized review of pathology reports. Cox proportional hazard models with time-varying covariates were used to examine associations of diabetes status, duration of diabetes, and diabetes treatment with bladder cancer risk. RESULTS: During a median follow-up of 18.5 years, 865 bladder cancer cases were identified. There were no significant associations of diabetes, duration of diabetes, or diabetes treatment with risk of bladder cancer. Participants with prevalent diabetes did not have significantly higher risk of bladder cancer compared with those without diabetes. CONCLUSION: Diabetes was not significantly associated with risk of bladder cancer among postmenopausal women.

Smoking Cessation and the Risk of Bladder Cancer among Postmenopausal Women.

Smoking is the strongest established risk factor for bladder cancer. Former smokers have a lower risk of bladder cancer compared with current smokers, but findings on the dose-response relationship between years after quitting and the risk of bladder cancer are inconsistent. A total of 143,279 postmenopausal women from the Women's Health Initiative Study were included. Cox proportional hazards regression models were applied for estimating age- and multivariable-adjusted HRs and their 95% confidence intervals (CI). There were 870 bladder cancer cases identified over an average of 14.8 years of follow-up. After adjusting for pack-years of smoking, bladder cancer risk among former smokers declined by 25% within the first 10 years of cessation and continued to decrease as cessation time increased but remained higher than never smokers after 30 years of quitting (HR, 1.92; 95% CI, 1.43-2.58). Smokers who quit smoking had a lower risk of bladder cancer compared with current smokers (HR, 0.61; 95% CI, 0.40-0.94). We conclude that among postmenopausal women, there is a significant reduction in the risk of bladder cancer after quitting smoking. In addition to primary prevention, smoking cessation is critical to prevent the incidence of bladder cancer in older women.

Urinary cadmium concentration and the risk of ischemic stroke.

OBJECTIVES: To examine the association between urinary cadmium levels and the incidence of ischemic stroke and to explore possible effect modifications. METHODS: A case-cohort study was designed nested in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, including 680 adjudicated incident cases of ischemic stroke and 2,540 participants in a randomly selected subcohort. Urinary creatinine-corrected cadmium concentration was measured at baseline. Multivariable-adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were estimated with the Barlow weighting method for the Cox proportional hazards regression model. RESULTS: The median urinary cadmium concentration was 0.42 (interquartile range 0.27-0.68) µg/g creatinine. After adjustment for potential confounders, urinary cadmium was associated with increased incidence of ischemic stroke (quintile 5 vs quintile 1: HR 1.50, 95% CI 1.01-2.22, p for trend = 0.02). The observed association was more pronounced among participants in the lowest serum zinc tertile (tertile 3 vs tertile 1: HR 1.82, 95% CI 1.06-3.11, p for trend = 0.004, p for interaction = 0.05) but was attenuated and became nonsignificant among never smokers (tertile 3 vs tertile 1: never smokers: HR 1.27, 95% CI 0.80-2.03, p for trend = 0.29; ever smokers: HR 1.60, 95% CI 1.06-2.43, p for trend = 0.07, p for interaction = 0.51). CONCLUSIONS: Findings from this study suggest that cadmium exposure may be an independent risk factor for ischemic stroke in the US general population. Never smoking and maintaining a high serum zinc level may ameliorate the potential adverse effects of cadmium exposure.

Association of herbal/botanic supplement use with quality of life, recurrence, and survival in newly diagnosed stage II colon cancer patients: A 2-y follow-up study.

OBJECTIVES: Our objective was to investigate the association between herbal/botanic supplement use and perceived quality of life (QoL), cancer recurrence, and all-cause mortality in colon cancer patients. METHODS: Patients (n = 453) newly diagnosed with stage II adenocarcinoma of the colon between 2009 and 2011 were recruited from the North Carolina Central Cancer Registry. Data including demographic variables, herbal medicine use and frequency, lifestyle, diet, cancer treatment, and QoL were collected by interviews at diagnosis (baseline) and 1 and 2 y after diagnosis. Mortality information was obtained via the National Death Index. The Functional Assessment of Cancer Therapy-Colorectal (FACT-C) and Medical Outcomes Short Form 12 (SF-12) were used to evaluate QoL. RESULTS: At baseline, herbal/botanic supplement users were more likely to have a healthier lifestyle than non-users, including more physical activity (P <0.01), more fruit and vegetable consumption (P = 0.01), less smoking (P <0.01), and less energy intake from fat (P = 0.02). After adjustment for potential confounders, no significant association was found between herbal/botanic supplement use and QoL assessed by FACT-C and SF-12. Similarly, herbal/botanic supplement use was not associated with the risk of recurrence, all-cause mortality or the combined. CONCLUSION: In this study, patients with stage II colon cancer using herbal/botanic supplements had no significant improvement in their QoL and no difference in odds of colon cancer recurrence and all-cause mortality over 2 y after diagnosis compared with those who did not use herbs/botanicals. Further studies are warranted to confirm the findings and to focus on types of herbal/botanic supplements.

Association of physical activity and sitting time with incident colorectal cancer in postmenopausal women.

Findings from epidemiological studies have found that physical activity (PA) is associated with a lower risk of colorectal cancer (CRC). Recent studies have found an increased CRC risk with higher sitting time (ST); however, many studies did not include PA as a potential confounder. The objective of this project was to investigate the independent and combined associations of ST and PA with the risk of incident CRC, specifically colon and rectal cancer. Participants in the Women's Health Initiative Observational Study (n=74 870), 50-79 years of age self-reported ST and PA at baseline, years 3 and 6. Incident CRC was the primary outcome; colon and rectal cancers were the secondary outcomes, which were centrally adjudicated. Over a 13-year follow-up period, 1145 incident cases of CRC were documented. A positive age-adjusted association was found between higher ST (≥10 vs. <5 h/day) and CRC (P for trend=0.04) and colon cancer (P for trend=0.05); however, these associations were attenuated and no longer significant in multivariable-adjusted models. Compared with inactive women (≤1.7 MET-h/week), the multivariable risk of CRC in the high PA (>20 MET-h/week) group was 0.81 (95% confidence interval: 0.66-1.00; P for trend 0.04). Compared with inactive women with high ST (≥10 h/day), there was a trend toward reduced multivariable CRC risks with higher PA irrespective of ST level (interaction=0.64). We observed an inverse association between leisure time PA and the risk of CRC, particularly for rectal cancer. There was no association between ST and CRC in multivariable models.

Association of Iodine and Iron with Thyroid Function.

Iodine and iron are essential elements for healthy thyroid function. However, little is known about the association of iron and iodine with thyroid function in the general US population. We investigated iron and iodine status in relation to concentrations of thyroid hormones. We included 7672 participants aged 20 and older from three surveys (2007-2008, 2009-2010, and 2011-2012) of the National Health and Nutrition Examination Survey. Serum thyroid measures (including free and total T3 and T4, and TSH), serum iron concentration, and urinary iodine concentrations were measured. Multivariate linear regression models were conducted with serum thyroid measures as dependent variables and combinations of serum iron concentration and urinary iodine concentration as predictors with covariate adjustment. Logistic regression models were performed with TSH levels (low, normal, and high) and combinations of serum iron concentration and urinary iodine concentration. Overall, 10.9% of the study population had low iron; 32.2 and 18.8% had low or high iodine levels, respectively. Compared with normal levels of iron and iodine, normal iron and high iodine were associated with reduced free T3 and increased risk of abnormal high TSH. Combined low iron and low iodine was associated with reduced free T3 and increased TSH. In addition, high iodine was associated with increased risk of abnormal high TSH in females but not in males. Thyroid function may be disrupted by low levels of iron or abnormal iodine, and relationships are complex and sex-specific. Large prospective studies are needed to understand the mechanisms by which iron interacts with iodine on thyroid function.

Antioxidant Supplementation Is Not Associated with Long-term Quality of Life in Stage-II Colorectal Cancer Survivors: A Follow-up of the Study of Colorectal Cancer Survivors Cohort.

Cancer survivors are motivated to change lifestyle following diagnosis, but studies investigating the outcomes are scarce. The purpose of this study was to examine the associations between antioxidant supplementation and quality of life (QoL) in stage-II colorectal cancer survivors. Four-hundred-fifty-three survivors were enrolled from the North Carolina Cancer Registry from 2009 to 2011. Interview data on demography, treatment, health behaviors, and QoL were collected at diagnosis, and at 12 and 24 mo post-diagnosis. Antioxidant supplementation was self-reported as use of selenium, zinc, beta-carotene, vitamin A, vitamin E, or vitamin C at baseline. Two-hundred-sixty-one subjects completed the 24-mo interview. After adjusting for multiple confounders, there was no association between antioxidant use and the Functional Assessment of Cancer Treatment-Colorectal [ß = 1.41; 95% confidence interval (CI): -2.48, 5.30] or the medical outcomes 12-item short form (physical composite score: ß = 0.84; 95% CI: -1.39, 3.07; mental composite score: ß = -0.61; 95% CI: -2.65, 1.43). This study revealed no benefit of antioxidant use among survivors, possibly explained by a limited sample size of antioxidant users. More prospective studies are necessary to assess the benefits of antioxidants.

Association between Blood Mercury Level and Visceral Adiposity in Adults.

BACKGROUND: Few studies have examined the association between mercury exposure and obesity. The aim of this study is to investigate the association between blood mercury concentrations and indices of obesity in adults. METHODS: A total of 200 healthy subjects, aged 30 to 64 years, who had no history of cardiovascular or malignant disease, were examined. Anthropometric and various biochemical profiles were measured. Visceral adipose tissue (VAT) was measured using dual-energy X-ray absorptiometry (DXA). RESULTS: All subjects were divided into three groups according to blood mercury concentrations. Compared with the subjects in the lowest tertile of mercury, those in the highest tertile were more likely to be male; were current alcohol drinkers and smokers; had a higher body mass index (BMI), waist circumference (WC), and VAT; had higher levels of blood pressure, fasting glucose, and insulin resistance; and consumed more fish. The blood mercury concentration was significantly associated with anthropometric parameters, showing relationships with BMI, WC, and VAT. After adjusting for multiple risk factors, the odds ratios (ORs) for high mercury concentration was significantly higher in the highest VAT tertile than in the lowest VAT tertile (OR, 2.66; 95% confidence interval, 1.05 to 6.62; P<0.05). CONCLUSION: The blood mercury concentration was significantly associated with VAT in healthy adults. Further studies are warranted to confirm our findings.

Cadmium exposure and risk of prostate cancer: a meta-analysis of cohort and case-control studies among the general and occupational populations.

We aimed to evaluate the association of cadmium exposure with the risk of prostate cancer in both the general and occupational populations. Online database searches were performed for studies of prostate cancer risk and cadmium exposure. Twelve cohort studies (5 in the general, 7 in occupational populations) and 9 case-control studies (3 in the general, 6 in occupational populations) were identified. Five/seven cohort studies in the general and occupational populations consist of 78,263/13, 434 participants with a mean follow-up of 12.1/43.0 years, respectively. Case-control studies include 334 cases/670 controls in the general population, and 1,315 cases/4,477 controls in occupational populations. Comparing the highest to the lowest category of cadmium exposure in the general population, the weighted relative risk of prostate cancer incidence and mortality among cohort studies, and the weighted odds ratio in case-control studies were 1.05 (95%CI [0.91, 1.22]), 0.83 (95%CI [0.35, 1.98]), and 1.27 (95%CI [0.58,2.78]), respectively. For occupational populations, the weighted OR in case-control studies was 1.17 (95%CI [0.85, 1.62]), and the weighted standardized mortality ratio in cohort studies was 98 (95%CI [75, 126]). Accumulated epidemiological evidence does not support the hypothesis that cadmium exposure may increase the risk of prostate cancer in either the general or occupational populations.

Racial differences in dietary changes and quality of life after a colorectal cancer diagnosis: a follow-up of the Study of Outcomes in Colorectal Cancer Survivors cohort.

BACKGROUND: Substantial racial disparities exist in colorectal cancer (CRC) survival. OBJECTIVE: This was an exploratory study to assess the racial differences in dietary changes in relation to quality of life (QoL), recurrence, and survival after a CRC diagnosis. DESIGN: Four hundred fifty-three stage II CRC patients were enrolled in the cohort study through the North Carolina Central Cancer Registry. Self-reported diet, physical activity, treatment, comorbidities, demographic characteristics, and QoL were collected at diagnosis and 12 and 24 mo after diagnosis. QoL was assessed with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) and the Medical Outcomes 12-Item Short Form Health Survey (SF-12) inventories. An overall dietary index score was calculated. Generalized estimating equations and logistic regression models were used to explore potential associations. Statistical power for this study was ∼50%. RESULTS: African Americans (n = 81) were more likely to increase intakes of reduced-fat milk, vegetables, and fruit and decrease intakes of regular cheese, red meat, fried food, fast food, and fat (P < 0.05) than were Caucasians (n = 184) 24 mo after diagnosis. The least-squares means ± SEs for changes in dietary index were 6.05 ± 0.40 and 4.07 ± 0.27 for African Americans and Caucasians, respectively (P < 0.001). African Americans exhibited higher scores on portions of the FACT-C (colorectal cancer subscale: ß = 1.04; 95% CI: 0.26, 1.82) and the SF-12 (Physical Component Summary: ß = 2.49; 95% CI: 0.51, 4.48). Those who improved their dietary quality over 24 mo had lower risk of recurrence and mortality combined (OR: 0.42; 95% CI: 0.25, 0.72). CONCLUSIONS: African Americans made more healthful changes in diet and had a higher QoL than did Caucasians in this underpowered study that used self-reported dietary data. No racial differences in recurrence or survival were evident, although improvements in dietary quality did reveal survival benefits overall. More prospective research on racial disparities in health behavior changes after diagnosis is desperately needed.

Cadmium exposure and risk of lung cancer: a meta-analysis of cohort and case-control studies among general and occupational populations.

The association between cadmium exposure and risk of lung cancer is still unclear. We quantitatively reviewed the observational studies that investigated the association between cadmium exposure and lung cancer risk in both general and occupational populations published through April 2015. The final data set is comprised of three cohort studies in the general population totaling 22,551 participants (354 events) with a mean follow-up of 15 years, five occupational cohort studies including 4205 individuals (180 events) with an average follow-up of 31 years, and three occupational case-control studies including 4740 cases and 6268 controls. Comparing the highest to the lowest category of cadmium exposure, the weighted relative risk and 95% confidence interval of lung cancer in the general population was 1.42 (95% CI (0.91, 2.23)); the weighted risk estimates (95% CIs) of lung cancer in three occupational cohort studies and three case-control studies were 0.68 (95% CI (0.33, 1.41)) and 1.61 (95% CI (0.94, 2.75)), respectively. No linear association was found. When comparing participants exposed to cadmium with non-exposed based on available data, the association became statistically significant. According to findings from this meta-analysis, the possibility that cadmium exposure may increase risk of lung cancer cannot be completely ruled out in either general or occupational population.

Longitudinal association between toenail zinc levels and the incidence of diabetes among American young adults: The CARDIA Trace Element Study.

Data on primary prevention of zinc status and diabetes risk are sparse and inconsistent. Of note, the previous studies measured either dietary zinc intake with questionnaire or zinc status in serum or hair. Toenail zinc levels are reliable biomarkers of a relatively long-term exposure. A total of 3,960 American young adults, aged 20-32 years, free of diabetes at baseline in 1987 when toenail clippings were collected, were examined for incident diabetes through 2010. Toenail zinc levels were measured with an inductively-coupled-plasma mass spectroscopy method. Incident diabetes cases were identified by fasting or non-fasting plasma glucose levels, oral glucose tolerance tests, hemoglobin A1C levels, and/or antidiabetic medications. During the 23-year follow-up, 418 incident diabetes occurred. After adjusted for age, sex, ethnicity, study center, body mass index, education, smoking status, alcohol consumption, physical activity, family history of diabetes, homeostasis model assessment of insulin resistance, and other dietary and non-dietary potential confounders, the hazard ratio of incident diabetes comparing the highest to the lowest quartile of toenail zinc levels was 1.21 (95% CI: 0.90-1.63; Ptrend = 0.20). Findings from this study do not support the hypothesis that zinc status is inversely and longitudinally associated with the incidence of diabetes in American young adults.