Red Blood Cell Polyunsaturated Fatty Acids and Mortality Following Breast Cancer.

BACKGROUND: Intake of polyunsaturated fatty acids (PUFAs) may impact mortality following breast cancer (BC); however, epidemiological studies have relied on self-reported assessment of PUFA intake. Herein, we examined the associations between red blood cell (RBC) PUFAs and mortality. METHODS: This nested case-control study included 1,104 women from, the Women's Healthy Eating and Living Study, a multi-site randomized controlled trial. Cases (n=290) were women who died from 1995-2006. Matched controls (n=814) were women who were alive at the end of follow-up. PUFAs were measured in baseline RBC samples and included four ω-3 and seven ω-6 PUFAs. We examined each PUFA individually and Principal Components Factor Analysis (PCFA)-derived scores in association with all-cause mortality (ACM) and BC-specific mortality (BCM) using conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In fully-adjusted models, ACM ORs were elevated among women with PUFAs >median (versus ≤median) for α-linolenic acid (ALA, OR=1.63, 95%CI=1.18-2.24) and for linolenic acid (LA, OR=1.56, 95%CI=1.16-2.09), and BCM ORs were elevated for ALA (OR=1.83, 95%CI=1.27-2.63), LA (OR=1.70, 95%CI=1.23-2.37), and γ-linolenic acid (GLA, OR=1.50; 95%CI=1.04-2.16). PCFA-Factor 1 [arachidonic acid/adrenic acid/docosapentaenoic acid] scores >median (versus ≤median) were associated with lower odds of ACM (OR=0.71; 95%CI=0.52-0.97) and BCM (OR=0.69; 95%CI=0.49-0.97), and PCFA-Factor 4 [ALA/GLA] scores >median (versus ≤median) were associated with increased odds of BCM (OR=1.47; 95%CI=1.04-2.09). CONCLUSIONS: RBC ALA, LA, and GLA may be prognostic indicators among BC survivors. IMPACT: These results are important for understanding the associations between a biomarker of PUFA intake and mortality among BC survivors.

Effects of genetically predicted posttraumatic stress disorder on autoimmune phenotypes.

Observational studies suggest that posttraumatic stress disorder (PTSD) increases risk for various autoimmune diseases. Insights into shared biology and causal relationships between these diseases may inform intervention approaches to PTSD and co-morbid autoimmune conditions. We investigated the shared genetic contributions and causal relationships between PTSD, 18 autoimmune diseases, and 3 immune/inflammatory biomarkers. Univariate MiXeR was used to contrast the genetic architectures of phenotypes. Genetic correlations were estimated using linkage disequilibrium score regression. Bi-directional, two-sample Mendelian randomization (MR) was performed using independent, genome-wide significant single nucleotide polymorphisms; inverse variance weighted and weighted median MR estimates were evaluated. Sensitivity analyses for uncorrelated (MR PRESSO) and correlated horizontal pleiotropy (CAUSE) were also performed. PTSD was considerably more polygenic (10,863 influential variants) than autoimmune diseases (median 255 influential variants). However, PTSD evidenced significant genetic correlation with nine autoimmune diseases and three inflammatory biomarkers. PTSD had putative causal effects on autoimmune thyroid disease (p = 0.00009) and C-reactive protein (CRP) (p = 4.3 × 10-7). Inferences were not substantially altered by sensitivity analyses. Additionally, the PTSD-autoimmune thyroid disease association remained significant in multivariable MR analysis adjusted for genetically predicted inflammatory biomarkers as potential mechanistic pathway variables. No autoimmune disease had a significant causal effect on PTSD (all p values > 0.05). Although causal effect models were supported for associations of PTSD with CRP, shared pleiotropy was adequate to explain a putative causal effect of CRP on PTSD (p = 0.18). In summary, our results suggest a significant genetic overlap between PTSD, autoimmune diseases, and biomarkers of inflammation. PTSD has a putative causal effect on autoimmune thyroid disease, consistent with existing epidemiologic evidence. A previously reported causal effect of CRP on PTSD is potentially confounded by shared genetics. Together, results highlight the nuanced links between PTSD, autoimmune disorders, and associated inflammatory signatures, and suggest the importance of targeting related pathways to protect against disease and disability.

Living Alone, Physical Health, and Mortality in Breast Cancer Survivors: A Prospective Observational Cohort Study.

Living alone, particularly for individuals with poor physical health, can increase the likelihood of mortality. This study aimed to explore the individual and joint associations of living alone and physical health with overall mortality among breast cancer survivors in the Women's Healthy Eating and Living (WHEL). We collected baseline, 12-month and 48-month data among 2869 women enrolled in the WHEL cohort. Living alone was assessed as a binary variable (Yes, No), while scores of physical health were measured using the RAND Short Form-36 survey (SF-36), which include four domains (physical function, role limitation, bodily pain, and general health perceptions) and an overall summary score of physical health. Cox proportional hazard models were used to evaluate associations. No significant association between living alone and mortality was observed. However, several physical health measures showed significant associations with mortality (p-values < 0.05). For physical function, the multivariable model showed a hazard ratio (HR) of 2.1 (95% CI = 1.02-4.23). Furthermore, the study examined the joint impact of living alone and physical health measures on overall mortality. Among women with better physical function, those living alone had a 3.6-fold higher risk of death (95% CI = 1.01-12.89) compared to those not living alone. Similar trends were observed for pain. However, regarding role limitation, the pattern differed. Breast cancer survivors living alone with worse role limitations had the highest mortality compared to those not living alone but with better role limitations (HR = 2.6, 95% CI = 1.11-5.95). Similar trends were observed for general health perceptions. Our findings highlight that living alone amplifies the risk of mortality among breast cancer survivors within specific health groups.

Serum Phosphorus, Serum Bicarbonate, and Renal Function in Relation to Liver CYP1A2 Activity.

The liver plays an important role in normal metabolism and physiological functions such as acid-base balance; however, limited epidemiologic studies have investigated how the liver contributes toward acid-base balance using non-invasive biomarkers. We determined associations between serum biomarkers related to acid-base balance and renal function with liver CYP1A2 activity. We used data from 1381 participants of the 2009-2010 National Health and Nutrition Examination Survey (NHANES) with measurements of serum phosphorus, serum bicarbonate, caffeine intake, caffeine metabolites, and estimated glomerular filtration rate (eGFR). Liver CYP1A2 activity was estimated using urine caffeine metabolite indices, which were calculated as the ratio of one of the urine caffeine metabolites (i.e., paraxanthine and 1-methyluric acid) to caffeine intake. We analyzed associations in the whole data set and in different strata of hepatic steatosis index (HSI) based on different cut-points. We found that serum bicarbonate was positively associated with CYP1A2 activity in the whole data set when comparing persons with bicarbonate at Q4 to Q1 (ß = 0.18, p = 0.10 for paraxanthine; ß = 0.20, p = 0.02 for 1-methyluric acid). Furthermore, serum phosphorus was positively associated with CYP1A2 activity only in the stratum of 30 ≤ HSI < 36. Lastly, low eGFR was significantly associated with lower CYP1A2 activity measured with paraxanthine in the whole dataset and in all the strata with HSI < 42; when comparing eGFR < 60 to eGFR > 90, ß estimates ranged from -0.41 to -1.38, p-values ranged from 0.0018 to 0.004. We observed an opposite trend in the highest stratum (HSI ≥ 42). Non-invasive measurements of serum bicarbonate, serum phosphorus, and eGFR have dynamic associations with CYP1A2 activity. These associations depend on the extent of liver damage and the caffeine metabolite used to assess CYP1A2 activity.

Development and Characterization of Benzoselenazole Derivatives as Potent and Selective c-MYC Transcription Inhibitors.

Developing c-MYC transcription inhibitors that target the G-quadruplex has generated significant interest; however, few compounds have demonstrated specificity for c-MYC G-quadruplex and cancer cells. In this study, we designed and synthesized a series of benzoazole derivatives as potential G-quadruplex ligand-based c-MYC transcription inhibitors. Surprisingly, benzoselenazole derivatives, which are rarely reported as G-quadruplex ligands, demonstrated greater c-MYC G-quadruplex selectivity and cancer cell specificity compared to their benzothiazole and benzoxazole analogues. The most promising compound, benzoselenazole m-Se3, selectively inhibited c-MYC transcription by specifically stabilizing the c-MYC G-quadruplex. This led to selective inhibition of hepatoma cell growth and proliferation by affecting the MYC target gene network, as well as effective tumor growth inhibition in hepatoma xenografts. Collectively, our study demonstrates that m-Se3 holds significant promise as a potent and selective inhibitor of c-MYC transcription for cancer treatment. Furthermore, our findings inspire the development of novel selenium-containing heterocyclic compounds as c-MYC G-quadruplex-specific ligands and transcription inhibitors.

Discovery of Clinically Used Octenidine as NRAS Repressor That Effectively Inhibits NRAS-Mutant Melanoma.

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.

Cold Exposures in Relation to Dysmenorrhea among Asian and White Women.

Dysmenorrhea is highly prevalent, ranging from 16% to 91% among women, and it can lead to multiple reproductive disorders. However, risk factors associated with dysmenorrhea remain unexamined. Cold exposures can significantly disturb blood circulation and prostaglandin production in the uterus, leading to dysmenorrhea. This study investigated the relationship between cold exposures and dysmenorrhea, as well as potential disparities between Asians and Whites and the potential cultural influences on these associations. This was a cross-sectional survey among 197 Asian and 222 non-Asian women recruited from the U.S., with more than 40% from California. We assessed cold exposures, such as the frequency of consumption of cold water/drinks and ice cream, as well as room temperatures at home and public places, for both summer and winter over the past 12 months. The type of cold exposure associated with dysmenorrhea differs between Asian and White women. We found that among Asian women, a higher frequency of ice cream consumption in winter (beta = 1.19, p = 0.0002 when comparing high to low categories) was associated with dysmenorrhea; however, among White women, increased consumption of cold water/drinks in winter (beta = 0.49, p = 0.04 when comparing high to low categories) was also associated with dysmenorrhea. Higher home room temperatures in winter were associated with reduced severity of dysmenorrhea among White women but not among Asian women. All these associations supported our hypothesis and were stronger among women who lived in states with colder winters. However, there are a few exceptions. For instance, women who drank cold water/drinks less frequently during their menstrual period were more likely to experience more severe dysmenorrhea. In conclusion, this study provides crucial evidence to support the link between cold exposures and dysmenorrhea among Asians and Whites. The associations contradictory to our hypothesis are likely due to reserved causation influenced by Asian cultural practice. This paper sheds light on an understudied area that profoundly affects women's quality of life.

The Independent and Joint Associations of Whole Grain and Refined Grain with Total Mortality among Breast Cancer Survivors: A Prospective Cohort Study.

Breast cancer survivors often have a reduced digestive capacity to digest whole grains due to cancer treatment. The purpose of this study was to investigate the independent and joint associations of whole grain and refined grain consumption with total mortality among breast cancer survivors. We studied a cohort of 3081 female breast cancer survivors who provided demographic, dietary, and lifestyle data at baseline, year 1 and year 4. Mortality was assessed via semi-annual telephone interviews and confirmed by the National Death Index (NDI) and death certificates. We assessed the associations of whole grain and refined grain with incident of mortalities using Cox proportional hazards models. Increased whole grain consumption was marginally associated with an increased risk of total mortality (p = 0.07) but was not significantly associated with breast cancer-specific mortality (p = 0.55). An increased intake of refined grains was associated with an increased risk of both total (HR = 1.74; 95% CI,1.17 to 2.59) and breast cancer-specific mortality (HR = 1.16; 95% CI, 1.08 to 1.26). Furthermore, we examined the joint associations of whole grain and refined grain with total mortality. Among those with a high consumption of refined grain, those with high consumption of whole grain had a higher risk of total mortality (HR = 1.52, 95% CI, 1.07 to 2.14) than those with a low consumption of whole grain. Increased consumption of whole grains may exacerbate the adverse associations of refined grain with mortality among breast cancer survivors. Our findings indicate the need to revisit current dietary guidelines for breast cancer survivors regarding whole grain intake.

eEF2 in the prefrontal cortex promotes excitatory synaptic transmission and social novelty behavior.

Regulation of mRNA translation is essential for brain development and function. Translation elongation factor eEF2 acts as a molecular hub orchestrating various synaptic signals to protein synthesis control and participates in hippocampus-dependent cognitive functions. However, whether eEF2 regulates other behaviors in different brain regions has been unknown. Here, we construct a line of Eef2 heterozygous (HET) mice, which show a reduction in eEF2 and protein synthesis mainly in excitatory neurons of the prefrontal cortex. The mice also show lower spine density, reduced excitability, and AMPAR-mediated synaptic transmission in pyramidal neurons of the medial prefrontal cortex (mPFC). While HET mice exhibit normal learning and memory, they show defective social behavior and elevated anxiety. Knockdown of Eef2 in excitatory neurons of the mPFC specifically is sufficient to impair social novelty preference. Either chemogenetic activation of excitatory neurons in the mPFC or mPFC local infusion of the AMPAR potentiator PF-4778574 corrects the social novelty deficit of HET mice. Collectively, we identify a novel role for eEF2 in promoting prefrontal AMPAR-mediated synaptic transmission underlying social novelty behavior.

Independent and Joint Associations of Pessimism, Total Calorie Intake and Acid-Producing Diets with Insomnia Symptoms among Breast Cancer Survivors.

Insomnia is prevalent in up to 40% of breast cancer survivors. Few studies have examined pessimism and dietary factors as risk factors for insomnia among breast cancer survivors. We leveraged a cohort of 2944 breast cancer survivors who enrolled in the Women's Healthy Eating and Living study; these survivors provided dietary, insomnia, mental health, demographic, and lifestyle information at baseline and at 1- and 4-year follow-up assessments. Insomnia symptoms were assessed using the Women's Health Initiative (WHI)-Insomnia Rating Scale, and pessimism was assessed using the Life Orientation Test Revised (LOT-R). Total calorie intake and acid-producing diets were assessed using 24 h dietary recalls. Multivariable-adjusted generalized estimating equation (GEE) models were used to test the independent and joint effects of psychological and dietary factors on insomnia. In the multivariable model, women in the third tertile of pessimism had greater odds (OR = 1.57 95% CI [1.37−1.79]) of insomnia when compared to women in the lowest tertile. Total calorie intake and acid-producing diets were each independently and significantly associated with insomnia symptoms. Further, pessimism and calorie intake/acid-producing diets were jointly associated with insomnia. For instance, women with pessimism scores in tertile 3 and total calorie intakes < median reported 2 times the odds (OR = 2.09; 95% CI [1.51−3.47]) of insomnia compared to women with pessimism score in tertile 1 and calorie intakes < median. Our results highlight the need for patient care regarding mental health, and recommendations of healthy dietary intakes for breast cancer survivors.

Benzoselenazolium-based hemicyanine dye for G-Quadruplex detection.

Benzothiazolium and benzoxazolium are common groups for the construction of hemicyanine dyes; however, their isosteric analogue benzoselenazolium have rarely been studied. Here, we report the development of the first benzoselenazolium-based hemicyanine dye for the selective detection of G-quadruplexes. This molecule, SEMA-1, was validated as a red-emitting and activatable fluorescent probe whose fluorescence would only be activated in the presence of G-quadruplexes in buffer solution. Consistent with this, SEMA-1 was found to accumulate in nucleoli and could be used to detect the high abundance of nucleolar rDNA and rRNA G-quadruplexes in fixed HeLa cells. On the other hand, due to the retained mitochondrial membrane potential in live HeLa cells, SEMA-1 was captured by mitochondria and had the potential to detect the mitochondrial G-quadruplexes. Collectively, this work demonstrates the value of developing G-quadruplex-specific fluorescent probes from novel benzoselenazolium-based hemicyanine scaffold.

Independent and Joint Impacts of Acid-Producing Diets and Depression on Physical Health among Breast Cancer Survivors.

The purpose of this study was to examine the independent and joint associations of acid-producing diets and depressive symptoms with physical health among breast cancer survivors. We studied a cohort of 2944 early stage breast cancer survivors who provided dietary, physical health, demographic, and lifestyle information at baseline, year 1, and year 4. We assessed the intakes of acid-producing diets via two commonly used dietary acid load scores: potential renal acid load (PRAL) and net endogenous acid production (NEAP). Physical health was measured using the Rand 36-Item Short Form Health Survey (SF-36), consisting of physical functioning, role limitation due to physical function, bodily pain, general health, and overall physical health subscales. Increased dietary acid load and depression were each independently and significantly associated with reduced physical health subscales and overall physical health. Further, dietary acid load and depression were jointly associated with worse physical health. For instance, depressed women with dietary acid load higher than median reported 2.75 times the risk (odds ratio = 2.75; 95% confidence interval: 2.18-3.47) of reduced physical function and 3.10 times the risk of poor physical health (odds ratio = 3.10; 95% confidence interval: 2.53-3.80) compared to non-depressed women with dietary acid load lower than median. Our results highlight the need of controlling acid-producing diets and the access of mental care for breast cancer survivors.

Tobacco Smoke and CYP1A2 Activity in a US Population with Normal Liver Enzyme Levels.

Non-alcoholic fatty liver disease (NAFLD) is common among 30% of American adults. Former and current smokers are at higher risk for NAFLD compared to never smokers. The ratio of urine caffeine metabolites to caffeine intake-namely, urine caffeine metabolite indices-has previously been used as a proxy for CYP1A2 activity, which is one of the main liver metabolizing enzymes. CYP1A2 activity is associated with NAFLD progression. No studies to our knowledge have examined the associations of liver enzymes, smoking intensity, and secondhand smoke (SES) with CYP1A2 activity (using caffeine metabolite indices) across smoking status. We analyzed national representative samples from the 2009-2010 National Health and Nutrition Examination Survey (NHANES). Interestingly, even within a normal range, several liver enzymes were associated with caffeine metabolite indices, and patterns of many of these associations varied by smoking status. For instance, within a normal range, aspartate aminotransferase (AST) in never smokers and bilirubin in current smokers were inversely associated with 1-methyluric acid and 5-acetylamino-6-amino-3-methyluracil (URXAMU). Furthermore, we observed a common pattern: across all smoking statuses, higher AST/alanine aminotransferase (AST/ALT) was associated with 1-methyluric acid and URXAMU. Moreover, in current smokers, increased lifelong smoking intensity was associated with reduced caffeine metabolite indices, but acute cigarette exposure as measured by SES levels was associated with increased caffeine metabolite indices among never smokers. In summary, commonly used liver enzyme tests can reflect the CYP1A2 activity even within a normal range, but the selection of these enzymes depends on the smoking status; the associations between smoking and the CYP1A2 activity not only depend on the intensity but also the duration of tobacco exposure.

Interrelationship of Seasons with Inflammation, Red Meat, Fruit, and Vegetable Intakes, Cardio-Metabolic Health, and Smoking Status among Breast Cancer Survivors.

Seasons can affect human inflammatory status and the occurrence of diseases, and foods may also have differential impacts on inflammation across seasons; however, few studies have investigated whether there are independent and joint impacts of seasons and red meat, fruit and vegetable intakes on inflammation in breast cancer survivors. We conducted a cross-sectional study by leveraging a large cohort, the Women's Healthy Eating and Living (WHEL) study. The WHEL study comprised primarily early stage breast cancer survivors and collected blood samples, dietary intake, demographic, and health status information at baseline. We selected 2919 participants who provided baseline dietary information and had measurement of C-reactive protein (CRP), a general marker of inflammation. In our multivariable-adjusted analyses, we found that red meat intakes were positively associated, while fruit and vegetable intakes were inversely associated with CRP; blood collected in the winter season was associated with lower CRP when compared to summer; and increased smoking intensity and body mass index (BMI) as well as having cardio-metabolic conditions (such as heart disease or diabetes) were positively associated with CRP. Furthermore, we examined the joint associations of food intakes and the season of blood draw with CRP in different subgroups. We found that moderate intakes of red meat were associated with a reduction of CRP in winter but not in other seasons; increased intakes of fruit and vegetables were associated with reduced inflammation in most seasons except winter. These associations were observed in most subgroups except past smokers with pack-years ≥ 15, in whom we observed no benefit of red meat intakes in winter. Our study provides valuable evidence for considering seasonal impacts on inflammation and seasonal food impacts in different subgroups among breast cancer survivors. The results of our study are in line with one of the emphases of the current NIH 2020-2030 nutrition strategy plan-namely, pay attention to what, when, and who should eat.

Dietary Acid Load, Serum Polychlorinated Biphenyl Levels, and Mortality Following Breast Cancer in the Long Island Breast Cancer Study Project.

Dietary acid load (DAL) may be associated with all-cause mortality (ACM) and breast cancer-specific mortality (BCM), and these associations may be modified by serum polychlorinated biphenyl (PCB) levels. Participants included 519 women diagnosed with first primary in situ or invasive breast cancer in 1996/1997 with available lipid-corrected PCB data. After a median of 17 years, there were 217 deaths (73 BCM). Potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores calculated from a baseline food frequency questionnaire estimated DAL. Cox regression estimated covariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between PRAL and NEAP with mortality. We evaluated effect measure modification by total serum PCB levels (>median vs. ≤median). PRAL quartile 4 versus quartile 1 was associated with an ACM HR of 1.31 (95%CI = 0.90-1.92). In the upper median of PCBs, ACM HRs were 1.43 (95%CI = 0.96-2.11) and 1.40 (95%CI = 0.94-2.07) for PRAL and NEAP upper medians, respectively. In the lower median of PCBs, the upper median of NEAP was inversely associated with BCM (HR = 0.40, 95%CI = 0.19-0.85). DAL may be associated with increased risk of all-cause mortality following breast cancer among women with high total serum PCB levels, but inversely associated with breast cancer mortality among women with low PCB levels.

Acid-Producing Diet and Depressive Symptoms among Breast Cancer Survivors: A Longitudinal Study.

The incidence of depression is two-to-three times higher in cancer survivors than the general population. Acid-producing diets may play important roles in the development of depression. Cancer survivors are more susceptible to acid-producing diets, yet few prospective studies have investigated the association of acid-producing diets with depression among breast cancer survivors. We leveraged a large cohort of 2975 early stage breast cancer survivors, which collected detailed dietary data via 24-h recalls. Potential renal acid load (PRAL) and net endogenous acid production (NEAP), two commonly used dietary acid load scores, were used to estimate acid-producing diets. Intakes of PRAL and NEAP were assessed at baseline and years one and four. Increased PRAL and NEAP were each independently associated with increased depression in the longitudinal analyses, after adjusting for covariates. The magnitude of the associations was stronger for PRAL than NEAP. Women with the highest quartile intakes of PRAL had 1.34 (95% CI 1.11-1.62) times the risk of depression compared to women with the lowest quartile. Furthermore, we also observed a joint impact of PRAL and younger age on depression, as well as a joint impact of PRAL and physical activity on depression. Decreasing the consumption of acid-producing diets may be a novel and practical strategy for reducing depressive symptoms among breast cancer survivors, especially those who are younger and have a sedentary lifestyle.

Understanding the Relationship between Environmental Arsenic and Prostate Cancer Aggressiveness among African-American and European-American Men in North Carolina.

High-level exposure to arsenic, a known carcinogen and endocrine disruptor, is associated with prostate cancer (PCa) mortality. Whether low-level exposure is associated with PCa aggressiveness remains unknown. We examined the association between urinary arsenic and PCa aggressiveness among men in North Carolina. This cross-sectional study included 463 African-American and 491 European-American men with newly diagnosed, histologically confirmed prostate adenocarcinoma. PCa aggressiveness was defined as low aggressive (Gleason score < 7, stage = cT1-cT2, and PSA < 10 ng/mL) versus intermediate/high aggressive (all other cases). Total arsenic and arsenical species (inorganic arsenic (iAsIII + iAsV), arsenobetaine, monomethyl arsenic, and dimethyl arsenic)) and specific gravity were measured in spot urine samples obtained an average of 23.7 weeks after diagnosis. Multivariable logistic regression was used to estimate the covariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for PCa aggressiveness in association with arsenic tertiles/quantiles overall and by race. The highest (vs. lowest) tertile of total arsenic was associated with PCa aggressiveness ORs of 1.77 (95% CI = 1.05-2.98) among European-American men, and 0.94 (95% CI = 0.57-1.56) among African-American men (PInteraction = 0.04). In contrast, total arsenic and arsenical species were not associated with PCa aggressiveness in unstratified models. Low-level arsenic exposure may be associated with PCa aggressiveness among European-Americans, but not among African-Americans.

Increased Acid-Producing Diet and Past Smoking Intensity Are Associated with Worse Prognoses Among Breast Cancer Survivors: A Prospective Cohort Study.

Current dietary guidelines do not consider cancer survivors' and past smokers' low capacity to regulate their acid-base balance. People with a low capacity to regulate their acid-base balance are more susceptible to acid-producing diets. We studied a cohort of 2950 early stage breast cancer survivors who provided dietary information at baseline and during follow-up. We assessed the intakes of acid-producing diets via two commonly used dietary acid load scores: potential renal acid load (PRAL) and net endogenous acid production (NEAP). We assessed past smoking intensity by pack-years of smoking. After an average of 7.3 years of follow-up, there were 295 total deaths, 249 breast cancer-specific deaths, and 490 cases of recurrent breast cancer. Increased intakes of dietary acid load and pack-years of smoking were each independently and jointly associated with increased total mortality and breast cancer-specific mortality; tests for trends and overall associations were statistically significant for NEAP and marginally significant for PRAL. Compared to women in the lowest tertile of NEAP and pack-year of smoking = 0, women in the highest tertile of NEAP and pack-years of smoking >15 had the greatest increased risk of total mortality (HR = 3.23, 95%CI 1.99-5.26). Further, dietary acid scores were associated with increased breast cancer recurrence among women with pack-years of smoking >0 but not in those with pack-years of smoking = 0 (p values for interactions <0.05). Our study provides valuable evidence for adding dietary acid load scores to dietary guidelines for breast cancer survivors and developing specific guidelines for past smokers among these survivors.

A drug-like imidazole-benzothiazole conjugate inhibits malignant melanoma by stabilizing the c-MYC G-quadruplex.

Aberrant expression of c-MYC oncogene is significantly associated with the occurrence and development of malignant melanoma. Suppression of the c-MYC transcriptional activity accordingly provides a new idea for treating melanoma. Notably, stabilizing the G-quadruplex (G4) structure in the promoter is proved to be effective in downregulating c-MYC transcription. In this work, we developed a drug-like imidazole-benzothiazole conjugate called IZTZ-1, which was confirmed to preferentially stabilize the promoter G4 and thus lower c-MYC expression. Intracellular assays revealed that IZTZ-1 induced cell cycle arrest, apoptosis, thereby inhibiting cell proliferation. Furthermore, IZTZ-1 was demonstrated to effectively inhibit tumor growth in a melanoma mouse model. Consequently, IZTZ-1 showed good potential in the treatment of melanoma. This study provides an alternative strategy to treat melanoma by targeting the c-MYC G4.

Hemoglobin A1c Levels Modify Associations between Dietary Acid Load and Breast Cancer Recurrence.

BACKGROUND: Metabolic acidosis promotes cancer metastasis. No prospective studies have examined the association between dietary acid load and breast cancer recurrence among breast cancer survivors, who are susceptible to metabolic acidosis. Hyperglycemia promotes cancer progression and acid formation; however, researchers have not examined whether hyperglycemia can modify the association between dietary acid load and breast cancer recurrence. METHODS: We studied 3081 early-stage breast cancer survivors enrolled in the Women's Healthy Eating and Living study who provided dietary information through 24-h recalls at baseline and during follow-up and had measurements of hemoglobin A1c (HbA1c) at baseline. We assessed dietary acid load using two common dietary acid load scores, potential renal acid load (PRAL) score and net endogenous acid production (NEAP) score. RESULTS: After an average of 7.3 years of follow-up, dietary acid load was positively associated with recurrence when baseline HbA1c levels were ≥ 5.6% (median level) and ≥5.7% (pre-diabetic cut-point). In the stratum with HbA1c ≥ 5.6%, comparing the highest to the lowest quartile of dietary acid load, the multivariable-adjusted hazard ratio was 2.15 (95% confidence interval [CI] 1.34-3.48) for PRAL and was 2.31 (95% CI 1.42-3.74) for NEAP. No associations were observed in the stratum with HbA1c levels were <5.6%. P-values for interactions were 0.01 for PRAL and 0.05 for NEAP. CONCLUSIONS: Our study demonstrated for the first time that even at or above normal to high HbA1c levels, dietary acid load was associated with increased risk of breast cancer recurrence among breast cancer survivors. IMPACTS: Our study provides strong evidence for developing specific dietary acid load guidelines based on HbA1c levels.