Dietary methionine influences therapy in mouse cancer models and alters human metabolism.

Nutrition exerts considerable effects on health, and dietary interventions are commonly used to treat diseases of metabolic aetiology. Although cancer has a substantial metabolic component1, the principles that define whether nutrition may be used to influence outcomes of cancer are unclear2. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. By contrast, whether specific dietary interventions can influence the metabolic pathways that are targeted in standard cancer therapies is not known. Here we show that dietary restriction of the essential amino acid methionine-the reduction of which has anti-ageing and anti-obesogenic properties-influences cancer outcome, through controlled and reproducible changes to one-carbon metabolism. This pathway metabolizes methionine and is the target of a variety of cancer interventions that involve chemotherapy and radiation. Methionine restriction produced therapeutic responses in two patient-derived xenograft models of chemotherapy-resistant RAS-driven colorectal cancer, and in a mouse model of autochthonous soft-tissue sarcoma driven by a G12D mutation in KRAS and knockout of p53 (KrasG12D/+;Trp53-/-) that is resistant to radiation. Metabolomics revealed that the therapeutic mechanisms operate via tumour-cell-autonomous effects on flux through one-carbon metabolism that affects redox and nucleotide metabolism-and thus interact with the antimetabolite or radiation intervention. In a controlled and tolerated feeding study in humans, methionine restriction resulted in effects on systemic metabolism that were similar to those obtained in mice. These findings provide evidence that a targeted dietary manipulation can specifically affect tumour-cell metabolism to mediate broad aspects of cancer outcome.

Consumption of Berries and Flavonoids in Relation to Mortality in NHANES, 1999-2014.

BACKGROUND: Berries are foods that are abundant in nutrients, especially flavonoids, that promote good health; however, the effects of total berries on mortality are not well characterized. OBJECTIVES: We evaluated whether intakes of total berries and specific berry types including blueberries, strawberries, cranberries, flavonoids, and subclasses of flavonoids (anthocyanidins, flavonols, flavones, flavanones, flavan-3-ols, and isoflavones) in relation to mortality risk in United States adults. METHODS: A nationally representative sample of the United States adult population was obtained using data from the 1994-2014 NHANES (n = 37,232). Intake of berries was estimated using 24-h food recalls (1999-2014), and flavonoids intake was calculated using the matched USDA's expanded flavonoid database. Mortality outcomes based on 8 y of follow-up were obtained using linked death certificates. RESULTS: Compared with nonconsumers, the multivariable-adjusted hazard ratio for all-cause mortality was 0.79 [95% confidence intervals (CI): 0.7, 0.89] for any berry consumption, 0.86 (0.75, 0.99) for strawberry consumption 0.79 (0.66, 0.95) for blueberries, and 0.69 (0.51, 0.93) for cranberries. Compared with the lower median of intake, risk of all-cause mortality for greater intake was 0.85 (0.74, 0.97) for total flavonoids, 0.85 (0.76, 0.95) for anthocyanidins, 0.9 (0.82, 0.99) for flavan-3-ols, 0.89 (0.79, 0.9) for flavanols, and 0.89 (0.8, 0.99) for flavones. There was a dose-response relationship between intakes of total flavonoids, anthocyanidins, and flavones and lower all-cause mortality risks (Ptrend < 0.05). Risk for cardiometabolic mortality was 0.75 (0.58, 0.98) for berry consumers and 0.49 (0.25, 0.98) for cranberry consumers. For respiratory disease mortality, risk was 0.41 (0.2, 0.86), compared with blueberry nonconsumers. CONCLUSION: Higher intakes of berries and flavonoids were associated with a lower overall mortality risk in adult Americans. Few adults regularly consume berries, indicating that increased intake of berries and flavonoid-rich foods may be beneficial to health.

The Epidemiology of Berry Consumption and Association of Berry Consumption with Diet Quality and Cardiometabolic Risk Factors in United States Adults: The National Health and Nutrition Examination Survey, 2003-2018.

BACKGROUND: Berries are rich in important nutrients and bioactive compounds, which could potentially contribute to maintenance of normal lipid and glucose profiles. OBJECTIVE: We reported the epidemiology of berry consumption and examined associations of berry consumption with diet quality [measured by Healthy Eating Index (HEI-2015)] and levels of cardiometabolic risk factors, including body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), glycated hemoglobin, and fasting biomarkers: triglycerides, low-density lipoprotein cholesterol (LDL cholesterol), glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). METHODS: We evaluated 33,082 adults (aged ≥20 y) using two 24-h diet recalls from National Health and Nutrition Examination Survey (2003-2018). Multivariable linear regression models were applied to examine the associations of total and individual berry intake with diet quality and cardiometabolic risk factors using appropriate sample weights. RESULTS: Approximately 25 % of the United States adults consumed berries (0.08 ± 0.003 cup-equivalents/d), representing ∼10 % of the daily mean total fruit intake. Among berry consumers, the mean intake of strawberries (0.31 ± 0.01 cup-equivalents) was higher than for other berries. Berry consumers had a significantly higher HEI-2015 score than nonconsumers (mean HEI-2015 score = 58.8 compared with 52.3, P < 0.0001). Berry consumers had significantly lower concentrations of cardiometabolic indices than nonconsumers, including BMI, WC, SBP, total cholesterol, LDL cholesterol, triglycerides, fasting insulin, HOMA-IR, and higher mean HDL cholesterol, after adjusting for sociodemographic, lifestyle, and dietary confounders (all P < 0.05). CONCLUSIONS: United States adult berry consumers had a higher diet quality and lower concentrations of cardiometabolic risk factors, suggesting a favorable role for berries in diets and cardiometabolic disease prevention in United States adult population.

Free Radicals in Little Cigar Mainstream Smoke and the Potential Influence of Flavoring Chemicals on Free Radical Production.

Implementation of the Tobacco Control Act in 2009 banned characterizing flavors in cigarettes (except menthol and tobacco), but substitution has occurred by the continued availability of alternative flavored products (i.e., flavored little cigars). Little is known about how flavorants in noncigarette tobacco products impact human health. Thus, we investigated the impact of flavorants on free radical production in the mainstream smoke of little cigars. Gas- and particulate-phase free radical yields in mainstream smoke generated from 12 commercial little cigar brands and research little cigars and cigarettes were measured via electron paramagnetic resonance spectroscopy using the International Organization of Standardization (ISO) smoking protocol. Flavorants were extracted from unsmoked little cigars and analyzed by gas chromatography-mass spectroscopy. Gas- and particulate-phase radical yields from little cigars ranged from 13.5 to 97.6 and 0.453-1.175 nmol/unit, respectively. Comparatively, research cigarettes yielded an average of 4.9 nmol gas-phase radicals/unit and 0.292 nmol particulate-phase radicals/unit. From the products, 66 flavorants were identified, with each brand containing 4-24 individual flavorants. The free radical content was strongly correlated with the number of flavorants present in each cigar (r = 0.74, p = 0.01), indicating that highly flavored little cigars may produce higher levels of toxic free radicals. The presence of the flavorant ethyl methylphenylglycidate (strawberry) was associated with >2-fold higher levels of GP radicals (p = 0.001). Our results show that free radical delivery from little cigars is greater than that from research cigarettes and provide empirical evidence for the harmfulness of flavored tobacco products. Additionally, it demonstrates that flavorants present in combustible tobacco products can influence the levels of free radicals produced. Therefore, future tobacco product standards should consider little cigars.

Nicotine Delivery of a Menthol-Flavored Heat-not-Burn Tobacco Product During Directed Use.

INTRODUCTION: IQOS was authorized by the U.S. Food and Drug Administration (FDA) as a modified-risk tobacco product. We conducted a pharmacokinetic study evaluating the nicotine delivery and subjective effects of IQOS use among current menthol cigarette smokers to better understand if IQOS is an acceptable cigarette alternative in light of the proposed menthol cigarette ban. AIMS AND METHODS: Participants were adult smokers of >4 menthol cigarettes per day. After 14-hour nicotine abstinence, participants were provided an IQOS device and menthol heatstick to puff every 20 seconds for a total of 14 puffs. Blood samples were collected at baseline and during active use to calculate nicotine boost from baseline to peak concentration. Nicotine withdrawal symptoms were collected before and after IQOS use. In addition, a modified Product Evaluation Scale for IQOS was collected after use. RESULTS: Participants (n = 8) were a mean age of 43.9 years, 63% were female, 88% identified as White, and they smoked a mean of 17.1 menthol cigarettes per day. After IQOS use, the mean nicotine boost obtained was 15.96 ng/mL (SD = 6.91) (range 9.31 to 30.55 ng/mL). Most (75%) participants reported enjoying use of the product "a lot" or greater and more than half (62.5%) reported reduced cigarette cravings. Most participants reported no side effects after use; however, two experienced dry mouth, three experienced dizziness, one experienced throat irritation, and one experienced headache. CONCLUSION: We found that directed use (14 puffs) of menthol IQOS delivered a mean nicotine boost of 15.96 ng/mL which reduced craving for a cigarette. The majority of participants enjoyed use of IQOS and reported mild side effects. IMPLICATIONS: Menthol IQOS delivered a sufficient dose of nicotine perceived as satisfying by menthol cigarette smokers and it reduced craving with mild side effects. Menthol IQOS has potential to serve as a less harmful alternative for menthol cigarette smokers. The availability of modified risk products like IQOS should be considered by FDA's Comprehensive Plan for Tobacco and Nicotine Regulation.

Tobacco Nitrate and Free Radical Levels in the Mainstream Smoke of US Cigarette Brands.

Tobacco nitrate levels have been known to impact the levels of toxicants such as polyaromatic hydrocarbons and tobacco-specific nitrosamines (TSNAs) produced during smoking. Recent work in our group showed that the intrinsic nitrate levels in individual tobacco varieties also have a large influence on the formation of gas-phase (GP) free radicals in the mainstream smoke of cigarettes produced with a single tobacco variety. As tobacco nitrate content is a potential target for future regulatory policies, we investigated whether the levels of GP free radicals in the smoke from commercially available cigarettes is also dependent on the nitrate content in the corresponding tobacco blends. GP and particulate-phase (PP) free radical yields in mainstream smoke produced from 25 popular US cigarette brands were measured by electron paramagnetic resonance (EPR) spectroscopy. For each brand, we also measured levels of the TSNAs NNN (N'-nitrosonornicotine) and NNK (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) via HPLC-MS and the nicotine content via GC-FID. Our results show that the intrinsic nitrate levels varied >15-fold and GP radicals varied 4-fold among the 25 brands tested. The GP radicals were correlated with intrinsic nitrate levels (r = 0.87, p < 0.001). NNK and NNN levels varied >8-fold and 12-fold, respectively. We found that NNK was moderately correlated to nitrate content (r = 0.42, p = 0.03) while the NNN was strongly correlated to the nitrate content (r = 0.65, p < 0.001). Nicotine levels varied the least (<3-fold) but showed a moderate negative correlation to nitrate content (r = -0.47, p = 0.02). No statistically significant correlation was observed between nicotine and TSNA levels in mainstream smoke. Overall, this demonstrates that the nitrate content of tobacco blends used in US cigarette brands impacts toxicant output in the mainstream smoke, although other proprietary variables (total ventilation, additives, filter type, etc.) may also modulate these results.

Influence of Tobacco Variety and Curing on Free Radical Production in Cigarette Smoke.

INTRODUCTION: Cigarette smoke contains highly reactive free radicals thought to play an important role in tobacco smoke-induced harm. Previously, large variations in free radical and toxicant output have been observed in commercial cigarettes. These variations are likely because of cigarette design features (paper, filter, and additives), tobacco variety (burley, bright, oriental, etc.), and tobacco curing methods (air, sun, flue, and fire). Previous reports show that tobacco varieties and curing methods influence the production of tobacco smoke constituents like the tobacco-specific carcinogen nicotine-derived nitrosamine ketone (NNK). AIMS AND METHODS: We evaluated free radical, nicotine, and NNK production in cigarette smoke from cigarettes produced with 15 different types of tobacco. Gas-phase free radicals were captured by spin trapping with N-tert-butyl-α-phenylnitrone and particulate-phase radicals were captured on a Cambridge Filter pad (CFP). Both types of radicals were analyzed using electron paramagnetic resonance spectroscopy. Nicotine and NNK were extracted from the CFP and analyzed by gas chromatography flame ionization detection and liquid chromatography-mass spectrometry, respectively. RESULTS: Gas-phase radicals varied nearly 8-fold among tobacco types with Saint James Perique tobacco producing the highest levels (42 ±â€…7 nmol/g) and Canadian Virginia tobacco-producing the lowest levels (5 ±â€…2 nmol/g). Nicotine and NNK levels in smoke varied 14-fold and 192-fold, respectively, by type. Gas-phase free radicals were highly correlated with NNK levels (r = 0.92, p < .0001) and appeared to be most impacted by tobacco curing method. CONCLUSIONS: Altogether, these data suggest that tobacco types used in cigarette production may serve as a target for regulation to reduce harm from cigarette smoking. IMPLICATIONS: Variations in cigarette free radical and NNK levels vary based on the tobacco variety and curing method. Reducing the ratio of high-producing free radical and NNK tobacco types offer a potential tool for regulators and producers looking to reduce toxicant output from cigarettes.

Detection of DNA adducts derived from the tobacco carcinogens, benzo[a]pyrene and dibenzo[def,p]chrysene in human oral buccal cells.

Polycyclic aromatic hydrocarbons (PAHs) are recognized as potential etiological agents in the development of oral cancer in smokers. In particular, benzo[a]pyrene (B[a]P) and dibenzo[def,p]chrysene (DB[a,l]P) are detected in cigarette smoke and the environment and can induce DNA damage, mutagenesis and carcinogenesis in the oral cavity of rodents. Consequently, DNA adducts are regarded as the most direct markers of genotoxicity and can be used as biomarkers of cancer risk. Thus, this study used LC-MS/MS analysis with isotope labeled internal standard to detect and quantify DNA adducts derived from B[a]P and DB[a,l]P in buccal cells of cigarette smokers and non-smokers. Participants in this study include 21 smokers and 16 non-smokers. Our data are the first to report that levels (mean ± SD) of BPDE-N2-dG were significantly (P < 0.001) higher in smokers (20.18 ± 8.40 adducts/108 dG) than in non-smokers (0.84 ± 1.02 adducts/108 dG). Likewise, levels of DBPDE-N6-dA in smokers (5.49 ± 3.41 adducts/108 dA) were significantly higher (P = 0.019) than non-smokers (2.76 ± 2.29 adducts/108 dA). Collectively, the results of this clinical study support that PAHs in tobacco smoke can contribute to the development of oral cancer in humans.

Cumulative Consumption of Sulfur Amino Acids and Risk of Diabetes: A Prospective Cohort Study.

BACKGROUND: Cross-sectional studies have suggested that consumption of sulfur amino acids (SAAs), including methionine and cysteine, is associated with a higher risk of type 2 diabetes (T2D) in humans and with T2D-related biomarkers in animals. But whether higher long-term SAA intake increases the risk of T2D in humans remains unknown. OBJECTIVES: We aimed to investigate the association between long-term dietary SAA intake and risk of T2D. METHODS: We analyzed data collected from 2 different cohorts of the Framingham Heart Study, a long-term, prospective, and ongoing study. The Offspring cohort (1991-2014) included participants from fifth through ninth examinations, and the Third-Generation cohort (2002-2011) included participants from first and second examinations. After excluding participants with a clinical history of diabetes, missing dietary data, or implausible total energy intake, 3222 participants in the Offspring cohort and 3205 participants in the Third-Generation cohort were included. Dietary intake was assessed using a validated FFQ. The relations between energy-adjusted total SAA (methionine and cysteine) intake or individual SAA intake (in quintiles) and risk of incident T2D were estimated via Cox proportional hazards models after adjusting for dietary and nondietary risk factors. Associations across the 2 cohorts were determined by direct combination and meta-analysis. RESULTS: During the 23 y of follow-up, 472 participants reported a new diagnosis of T2D in the 2 cohorts. In the meta-analysis, the HRs of T2D comparing the highest with the lowest intake of total SAAs, methionine, and cysteine were 1.8 (95% CI: 1.3, 2.5), 1.7 (95% CI: 1.2, 2.3), and 1.4 (95% CI: 1.0, 2.1), respectively. The association of SAA intake with T2D was attenuated after adjusting animal protein intake in sensitivity analyses. CONCLUSIONS: Our findings show that excess intake of SAAs is associated with higher risk of T2D. Dietary patterns that are low in SAAs could help in preventing T2D.

Effect of Electronic Nicotine Delivery Systems on Cigarette Abstinence in Smokers With No Plans to Quit: Exploratory Analysis of a Randomized Placebo-Controlled Trial.

INTRODUCTION: The extent to which use of electronic nicotine delivery systems (ENDS) for smoking reduction leads to cigarette abstinence in smokers with no plans to quit smoking is unclear. This exploratory analysis examined the effects of ENDS delivering different amounts of nicotine on cigarette abstinence up to 24-week follow-up, in comparison to placebo or a behavioral substitute. METHODS: This four-arm parallel-group, randomized, placebo-controlled trial took place at two academic medical centers in the United States (Penn State Hershey and Virginia Commonwealth University). Participants were current adult smokers (N = 520) interested in reducing but not planning to quit. They received brief advice and were randomized to one of four 24-week conditions, receiving either an eGo-style ENDS paired with 0, 8, or 36 mg/ml nicotine liquid (double-blind) or a cigarette-shaped tube, as a cigarette substitute (CS). Self-reported daily cigarette consumption and exhaled carbon monoxide (CO) were measured at all study visits. Outcomes included intent-to-treat, self-reported 7-day cigarette abstinence, biochemically confirmed by exhaled CO at 24 weeks after randomization. RESULTS: At 24 weeks, significantly more participants in the 36 mg/ml condition (14/130, 10.8%) than in the 0 mg/ml condition (1/130, 0.8%) and the CS condition (4/130, 3.1%) were abstinent (relative risk = 14 [95% CI = 1.9-104.9] and 3.5 [95% CI = 1.2-10.4], respectively). The abstinence rate in the 8 mg/ml condition was 4.6% (6/130). CONCLUSIONS: When smokers seeking to reduce smoking tried ENDS, few quit smoking in the short term. However, if smokers continued to use an ENDS with cigarette-like nicotine delivery, a greater proportion completely switched to ENDS, as compared with placebo or a cigarette substitute. IMPLICATIONS: The extent to which use of electronic nicotine delivery systems (ENDS) for smoking reduction leads to cigarette abstinence in smokers with no plans to quit smoking was unclear. This randomized trial found that ENDS with nicotine delivery approaching that of a cigarette are more effective in helping ambivalent smokers to quit cigarette smoking.

Association of dietary sulfur amino acid intake with mortality from diabetes and other causes.

PURPOSE: Sulfur amino acid (SAA) consumption in Western countries is far greater than recommended levels. In preclinical studies, reduced SAA intake enhanced longevity and reduced risk for numerous chronic diseases. The current objective was to examine for associations between the intake of total SAA, including methionine (Met) and cysteine (Cys), and all-cause and disease-specific mortality US adults. METHODS: This prospective analysis included 15,083 US adult participants (mean age = 46.7 years) from the Third National Examination and Nutritional Health Survey (NHANES III, 1988-1994) with available mortality status (National Death Registry, 1988-2011). Dietary SAA intake was obtained from 24-h recall data. Associations between quintile (Q) of SAA intake (expressed as absolute intake or protein density) and mortality were assessed using Cox proportional hazard models and expressed as hazard ratio (HR). RESULTS: During follow-up (mean = 16.9 years), 4636 deaths occurred. After multivariable adjustment (including demographics and traditional risk factors, such as fat and other micronutrients intake), diabetes-caused mortality rates were nearly threefold higher in the highest compared to lowest SAA intake quintiles [HRQ5-Q1 total SAA, 2.68 (1.46-4.90); HRQ5-Q1 methionine, 2.45 (1.37-4.38); HRQ5-Q1 cysteine, 2.91 (1.57-5.37)] (P < 0.01)]. Higher total SAA protein density was also associated with diabetes-caused mortality [HRQ5-Q1 1.75 (1.31-2.35)]. Associations between SAA intake and all-cause mortality, and mortality caused by other major diseases were not detected. CONCLUSION: Results suggest that high-SAA diets are associated with increased risk for diabetes mortality and that lowering intake towards to Recommended Dietary Allowance levels could lead to reductions in lifetime risk.

Switching to Progressively Reduced Nicotine Content Cigarettes in Smokers With Low Socioeconomic Status: A Double-Blind Randomized Clinical Trial.

INTRODUCTION: The Food and Drug Administration issued an advanced notice of proposed rulemaking for setting a product standard for nicotine levels in cigarettes, with an emphasis on minimally or non-addicting very low nicotine content (VLNC). METHODS: A 33 week, two-arm, double-blind randomized trial conducted in Hershey, Pennsylvania, USA and Washington, DC, USA included adult daily cigarette smokers (≥5 cigarettes per day) with less than a college degree, and who had no plans to quit within the next six months. Participants were randomized to either reduced nicotine content (RNC) study cigarettes tapered every three weeks to a final VLNC (0.2 mg/cigarette) for six weeks or to usual nicotine content (UNC) study cigarettes (11.6 mg/cigarette). Outcomes included acceptability of study cigarettes measured by attrition (primary outcome), compliance, reduction in cigarette dependence and tobacco biomarkers, and post-intervention cessation. RESULTS: The RNC (n = 122) versus UNC (n = 123) group had higher attrition (adjusted Hazard Ratio 3.4; 95% confidence interval [CI] 1.99 to 5.81). At the end of the intervention, cotinine levels were 50% lower in the RNC group (mean group difference -137 ng/mL; 95% CI -172, -102). The RNC group smoked fewer CPD (-4.1; 95% CI -6.44, -1.75) and had lower carbon monoxide levels (-4.0 ppm; 95% CI -7.7, -0.4). Forty seven percent (29/62) of the RNC group were biochemically-confirmed compliant with smoking VLNC cigarettes (mean cotinine = 8.9 ng/ml). At three month follow-up, only compliant VLNC smokers quit with an assisted quit attempt (N = 6/22, 27%). CONCLUSIONS: This study supports a VLNC standard in cigarettes. IMPLICATIONS: Differential dropout and noncompliance indicate some smokers had difficulty transitioning to cigarettes with reduced nicotine. These smokers will benefit from supplemental nicotine in medicinal or noncombustible tobacco products if a nicotine reduction standard is established. Other smokers successfully transitioned to very low nicotine content cigarettes exclusively and substantially reduced their exposure to nicotine.

Association of mushroom consumption with all-cause and cause-specific mortality among American adults: prospective cohort study findings from NHANES III.

BACKGROUND: Whether mushroom consumption, which is rich in several bioactive compounds, including the crucial antioxidants ergothioneine and glutathione, is inversely associated with low all-cause and cause-specific mortality remains uncertain. This study aimed to prospectively investigate the association between mushroom consumption and all-cause and cause-specific mortality risk. METHODS: Longitudinal analyses of participants from the Third National Health and Nutrition Examination Survey (NHANES III) extant data (1988-1994). Mushroom intake was assessed by a single 24-h dietary recall using the US Department of Agriculture food codes for recipe foods. All-cause and cause-specific mortality were assessed in all participants linked to the National Death Index mortality data (1988-2015). We used Cox proportional hazards regression models to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for all-cause and cause-specific mortality. RESULTS: Among 15,546 participants included in the current analysis, the mean (SE) age was  44.3 (0.5) years. During a mean (SD) follow-up duration of 19.5 (7.4) years , a total of 5826 deaths were documented. Participants who reported consuming mushrooms had lower risk of all-cause mortality compared with those without mushroom intake (adjusted hazard ratio (HR) = 0.84; 95% CI: 0.73-0.98) after adjusting for demographic, major lifestyle factors, overall diet quality, and other dietary factors including total energy. When cause-specific mortality was examined, we did not observe any statistically significant associations with mushroom consumption. Consuming 1-serving of mushrooms per day instead of 1-serving of processed or red meats was associated with lower risk of all-cause mortality (adjusted HR = 0.65; 95% CI: 0.50-0.84). We also observed a dose-response relationship between higher mushroom consumption and lower risk of all-cause mortality (P-trend = 0.03). CONCLUSION: Mushroom consumption was associated with a lower risk of total mortality in this nationally representative sample of US adults.

Prospective study of dietary mushroom intake and risk of mortality: results from continuous National Health and Nutrition Examination Survey (NHANES) 2003-2014 and a meta-analysis.

BACKGROUND: Whether mushroom consumption, which is a rich source of potent antioxidants ergothioneine and glutathione, vitamins, and minerals (e.g., selenium & copper), is associated with a lower mortality risk is not well understood. This study aimed to examine the association between mushroom consumption and risk of mortality in a prospective cohort study and a meta-analysis of prospective cohort studies. METHODS: We followed 30,378 participants from the continuous National Health and Nutrition Examination Survey (NHANES) extant data (2003-2014). Dietary mushroom intake was assessed using up to two 24-h recalls. Mortality was evaluated in all participants linked to the National Death Index mortality data through December 31, 2015. We used Cox proportional hazards regression models to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs). We also conducted a meta-analysis, including results from our present study and 4 other cohort studies. RESULTS: During a mean (SD) of 6.7 (3.4) years of follow-up, a total of 2855 death cases were documented among NHANES participants. In our analysis of continuous NHANES, we found a non-significant association between mushroom consumption and all-cause mortality (adjusted hazard ratio (HR) = 0.84; 95% CI: 0.67-1.06) after adjusting for demographic, major lifestyle factors, overall diet quality, and other dietary factors, including total energy. The meta-analysis of prospective cohort studies, including 601,893 individuals, showed that mushroom consumption was associated with a lower risk of all-cause mortality (pooled risk ratio: 0.94; 95% CI: 0.91, 0.98). CONCLUSION: In a meta-analysis of prospective cohort studies, mushroom consumption was associated with a lower risk of all-cause mortality.

Free Radical Production and Characterization of Heat-Not-Burn Cigarettes in Comparison to Conventional and Electronic Cigarettes.

With conventional cigarettes, the burning cone reaches temperatures of >900 °C, resulting in the production of numerous toxicants and significant levels of highly reactive free radicals. In attempts to eliminate combustion while still delivering nicotine and flavorings, a newer alternative tobacco product has emerged known as "heat-not-burn" (HnB). These products heat tobacco to temperatures of 250-350 °C depending on the device allowing for the volatilization of nicotine and flavorants while potentially limiting the production of combustion-related toxicants. To better understand how the designs of these new products compare to conventional cigarettes and different styles of electronic cigarettes (e-cigs), we measured and partially characterized their production of free radicals. Smoke or aerosols were trapped by a spin trap phenyl-N-tert-butylnitrone (PBN) and analyzed for free radicals using electron paramagnetic resonance (EPR). Free radical polarity was assessed by passing the aerosol or smoke through either a polar or nonpolar trap prior to being spin trapped with PBN. Particulate-phase radicals were detected only for conventional cigarettes. Gas-phase free radicals were detected in smoke/aerosol from all products with levels for HnB (IQOS, Glo) (12 pmol/puff) being similar to e-cigs (Juul, SREC, box mod e-cig) and hybrid devices (Ploom) (5-40 pmol/puff) but 50-fold lower than conventional cigarettes (1R6F). Gas phase radicals differed in polarity with HnB products and conventional cigarettes producing more polar radicals compared to those produced from e-cigs. Free radical production should be considered in evaluating the toxicological profile of nicotine delivery products and identification of the radicals is of paramount importance.

Free Radical and Nicotine Yields in Mainstream Smoke of Chinese Marketed Cigarettes: Variation with Smoking Regimens and Cigarette Brands.

Free radicals and nicotine are components of cigarette smoke that are thought to contribute to the development of smoking-induced diseases. China has the largest number of smokers in the world, yet little is known about the yields of tobacco smoke constituents in different Chinese brands of cigarettes. In this study, gas-phase and particulate-phase free radicals as well as nicotine yields were quantified in mainstream cigarette smoke from five popular Chinese brands and two research cigarettes (3R4F and 1R6F). Mainstream smoke was generated under International Organization of Standardization (ISO) and Canadian Intense (CI) smoking regimens using a linear smoking machine. Levels of free radicals and nicotine were measured by electron paramagnetic resonance spectroscopy (EPR) and gas chromatography with flame-ionization detection, respectively. Under the ISO puffing regimen, Chinese brand cigarettes produced an average of 3.0 ± 1.2 nmol/cig gas-phase radicals, 118 ± 44.7 pmol/cig particulate-phase radicals, and 0.6 ± 0.2 mg/cig nicotine. Under the CI puffing regimen, Chinese brand cigarettes produced an average of 5.6 ± 1.2 nmol/cig gas-phase radicals, 282 ± 92.1 pmol/cig particulate-phase radicals, and 2.1 ± 0.4 mg/cig nicotine. Overall, both gas- and particulate-phase free radicals were substantially lower compared to the research cigarettes under both regimens, whereas no significant differences were observed for nicotine levels. When Chinese brands were compared, the highest free radical and nicotine yields were found in "LL" and "BS" brands, while lowest levels were found in "YY". These results suggested that the lower radical delivery by Chinese cigarettes compared to United States reference cigarettes may be associated with reductions in oxidant-related harm.

Are Ergothioneine Levels in Blood Associated with Chronic Peripheral Neuropathy in Colorectal Cancer Patients Who Underwent Chemotherapy?

Objective: Chronic Chemotherapy-Induced Peripheral Neuropathy (CIPN) is highly prevalent among colorectal cancer (CRC) patients. Ergothioneine (ET) - a dietary antioxidant -protected against CIPN in experimental models, but human studies are lacking. We explored whether whole blood ET levels were associated with chronic peripheral neuropathy among CRC patients who had completed chemotherapy.Methods: At diagnosis, median ET-concentration in whole blood of 159 CRC patients was 10.2 µg/ml (7.2-15.8). Patients completed questionnaires on peripheral neuropathy 6 months after completion of chemotherapy. We calculated prevalence ratios (PR) to assess associations of ET-concentrations and prevalence of peripheral neuropathy and used linear regression to assess associations with severity of peripheral neuropathy.Results: Prevalence of total and sensory peripheral neuropathy were both 81%. Higher ET-concentrations tended to be associated with lower prevalence of total and sensory peripheral neuropathy, but not statistically significant (highest versus lowest tertile of ET: PR = 0.93(0.78, 1.11) for total neuropathy, and PR = 0.84(0.70, 1.02) for sensory neuropathy). ET-concentrations were not associated with severity of neuropathy.Conclusion: Statistically significant associations were not observed, possibly because of limited sample size. Although data may putatively suggest higher levels of ET to be associated with a lower prevalence of neuropathy, analyses should be repeated in larger populations with larger variability in ET-concentrations.

Pharmacokinetic Profile of Spectrum Reduced Nicotine Cigarettes.

INTRODUCTION: Spectrum research cigarettes have been developed with varying nicotine content for use in studies evaluating the effects of a regulatory policy reducing the permissible nicotine content in cigarettes. This study aimed to characterize the nicotine pharmacokinetic profile of Spectrum cigarettes. METHODS: Twelve daily smokers attended four sessions and had blood nicotine, exhaled carbon monoxide, and subjective effects measured before and after smoking either a single cigarette of their preferred brand or high (10.9 mg/cigarette), medium (3.2 mg/cigarette), or low (0.2 mg/cigarette) nicotine content Spectrum research cigarettes, in a double-blind design with order counterbalanced. RESULTS: The boost in blood nicotine concentration was dose-dependent, with a boost of 0.3, 3.9, and 17.3 ng/mL for low-, medium-, and high-nicotine content Spectrum cigarettes. The high dose Spectrum had a similar nicotine boost to the "preferred brand" cigarettes (19 ng/mL). Subjects took longer puffs on the low nicotine cigarettes, but smoked these cigarettes faster than other cigarette types. High nicotine Spectrum cigarettes reduced the urge to smoke more than other cigarette types. CONCLUSIONS: This study shows that Spectrum research cigarettes produce blood nicotine absorption in a dose-dependent manner, and therefore, are appropriate for use in studies of nicotine reduction in cigarettes. IMPLICATIONS: This is the first study to determine the pharmacokinetic profile of Spectrum reduced nicotine content research cigarettes following an overnight abstinence. These data could provide evidence to regulatory agencies about the effects of reduced nicotine cigarettes when considering regulations on tobacco reduction.

Emissions of Free Radicals, Carbonyls, and Nicotine from the NIDA Standardized Research Electronic Cigarette and Comparison to Similar Commercial Devices.

E-cigarettes (e-cigs) are a diverse and continuously evolving group of products with four generations currently in the market. The National Institute on Drug Abuse (NIDA) standardized research e-cigarette (SREC) is intended to provide researchers with a consistent e-cig device with known characteristics. Thus, we conducted laboratory-based characterizations of oxidants and nicotine in aerosols produced from SREC and other closed-system, breath-activated, commercially available e-cigs (Blu and Vuse). We hypothesized that oxidant and nicotine production will be significantly affected in all devices by changes in puffing parameters. All e-cigs were machine vaped and the aerosols generated were examined for nicotine, carbonyls, and free-radicals while varying the puff-volumes and puff-durations to reflect typical human usage. The data were normalized on a per puff, per gram aerosol, and per milligram nicotine basis. We found that aerosol production generally increased with increasing puff-duration and puff-volume in all e-cigs tested. Increased puff-duration and puff-volume increased nicotine delivery for Blu and Vuse but not the SREC. We report, for the first time, reactive free-radicals in aerosols from all closed-system e-cigs tested, albeit at levels lower than cigarette smoke. Formaldehyde, acetaldehyde, acetone, and propionaldehyde were detected in the aerosols of all tested e-cigs. Carbonyl and free radical production is affected by puff-duration and puff volume. Overall, SREC was more efficient at aerosol and nicotine production than both Blu and Vuse. In terms of carbonyl and free radical levels, SREC delivered lower or similar levels to both other devices.

Free Radical, Carbonyl, and Nicotine Levels Produced by Juul Electronic Cigarettes.

INTRODUCTION: Free radicals and carbonyls produced by electronic cigarettes (e-cigs) have the potential to inflict oxidative stress. Recently, Juul e-cigs have risen drastically in popularity; however, there is no data on nicotine and oxidant yields from this new e-cig design. METHODS: Aerosol generated from four different Juul flavors was analyzed for carbonyls, nicotine, and free radicals. The e-liquids were analyzed for propylene glycol (PG) and glycerol (GLY) concentrations. To determine the effects of e-liquid on oxidant production, Juul pods were refilled with nicotine-free 30:70 or 60:40 PG:GLY with or without citral. RESULTS: No significant differences were found in nicotine (164 ± 41 µg/puff), free radical (5.85 ± 1.20 pmol/puff), formaldehyde (0.20 ± 0.10 µg/puff), and acetone (0.20 ± 0.05 µg/puff) levels between flavors. The PG:GLY ratio in e-liquids was ~30:70 across all flavors with GLY being slightly higher in tobacco and mint flavors. In general, when Juul e-liquids were replaced with nicotine-free 60:40 PG:GLY, oxidant production increased up to 190% and, with addition of citral, increased even further. CONCLUSIONS: Juul devices produce free radicals and carbonyls, albeit, at levels substantially lower than those observed in other e-cig products, an effect only partially because of a low PG:GLY ratio. Nicotine delivery by these devices was as high as or higher than the levels previously reported from cigarettes. IMPLICATIONS: These findings suggest that oxidative stress and/or damage resulting from Juul use may be lower than that from cigarettes or other e-cig devices; however, the high nicotine levels are suggestive of a greater addiction potential.