Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

The effect of improved metabolic syndrome parameters on live birth.

OBJECTIVE: To determine whether improvements in metabolic syndrome before ovarian stimulation with intrauterine insemination affects live birth among women with obesity and unexplained infertility after fertility treatment. DESIGN: Secondary analysis of the randomized controlled clinical trial Improving Reproductive Fitness Through Pretreatment With Lifestyle Modification in Obese Women With Unexplained Infertility (FIT-PLESE). SUBJECTS: Three hundred seventy-nine women with obesity and unexplained infertility who underwent standard infertility treatment after a lifestyle intervention. INTERVENTION: The FIT-PLESE trial evaluated whether prepregnancy lifestyle interventions (diet with weight loss medication and exercise vs. exercise alone) before ovarian stimulation with intrauterine insemination improved the live birth rate among women with obesity and unexplained infertility. Utilizing FIT-PLESE data, we compared the association between improved Metabolic Syndrome (by diagnostic criteria parameters and Metabolic Syndrome Z-scores) and live birth in a subset of women who have Metabolic Syndrome. MAIN OUTCOME MEASURES: Live birth by groups were compared using chi-square and Fisher's exact tests, and continuous variables were compared using Student's t-tests. Logistic regression was used to assess Metabolic Syndrome Z-score difference and live birth. RESULTS: 191 study participants were diagnosed with Metabolic Syndrome at baseline. Thirty of these women exhibited a decline in the number of metabolic syndrome parameters and 33 had decline in their Metabolic Syndrome Z-scores during the preconception lifestyle intervention phase. There were no statistically significant differences in live birth among those who exhibited decline in the number of metabolic parameters compared to those who had no decline (33.3% versus 19.9%; p=0.102). Those who improved their Metabolic Syndrome Z-score had a live birth rate of 17.2% compared to 20.8% of those whose Metabolic Syndrome Z-scores were worsened or unchanged (p=0.055). CONCLUSION: Analysis of the FIT-PLESE data was unable to demonstrate that women with improvement in Metabolic Syndrome prior to fertility treatment, as shown by decreased number of metabolic parameters and/or improved Metabolic Syndrome Z-scores, benefit with improved fertility and live birth outcomes.

Plasma oxysterols are associated with serum lipids and dementia risk in older women.

INTRODUCTION: Apolipoprotein E4 (APOE4) carriers' tendency toward hypercholesterolemia may contribute to Alzheimer's disease (AD) risk through oxysterols, which traverse the blood-brain barrier. METHODS: Relationships between baseline plasma oxysterols, APOE status, serum lipids, and cognitive impairment risk were examined in 328 postmenopausal women from the Women's Health Initiative Memory Study. Women were followed for 25 years or until incident dementia or cognitive impairment. RESULTS: Levels of 24(S)-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), and 24-OHC/27-OHC ratio did not differ by APOE status (p's > 0.05). Higher 24-OHC and 27-OHC were associated with higher total, low density lipoprotein (LDL), non-high density lipoprotein (HDL), remnant, LDL/HDL, and total/HDL cholesterol and triglycerides (p's < 0.05). Higher 24-OHC/27-OHC was associated with greater dementia risk (hazard ratio = 1.51, 95% confidence interval:1.02-2.22), which interaction analyses revealed as significant for APOE3 and APOE4+, but not APOE2+ carriers. DISCUSSION: Less favorable lipid profiles were associated with higher oxysterol levels. A higher ratio of 24-OHC/27-OHC may contribute to dementia risk in APOE3 and APOE4+ carriers.

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial. DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611). SETTING: A multicenter (n = 40) trial across the United States. PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer. INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo. MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

The Role of Force Fields and Water Models in Protein Folding and Unfolding Dynamics.

Protein folding is a fascinating, not fully understood phenomenon in biology. Molecular dynamics (MD) simulations are an invaluable tool to study conformational changes in atomistic detail, including folding and unfolding processes of proteins. However, the accuracy of the conformational ensembles derived from MD simulations inevitably relies on the quality of the underlying force field in combination with the respective water model. Here, we investigate protein folding, unfolding, and misfolding of fast-folding proteins by examining different force fields with their recommended water models, i.e., ff14SB with the TIP3P model and ff19SB with the OPC model. To this end, we generated long conventional MD simulations highlighting the perks and pitfalls of these setups. Using Markov state models, we defined kinetically independent conformational substates and emphasized their distinct characteristics, as well as their corresponding state probabilities. Surprisingly, we found substantial differences in thermodynamics and kinetics of protein folding, depending on the combination of the protein force field and water model, originating primarily from the different water models. These results emphasize the importance of carefully choosing the force field and the respective water model as they determine the accuracy of the observed dynamics of folding events. Thus, the findings support the hypothesis that the water model is at least equally important as the force field and hence needs to be considered in future studies investigating protein dynamics and folding in all areas of biophysics.

Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.

BACKGROUND: Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear. METHODS: Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCI-H660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660. RESULTS: DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity. CONCLUSIONS: The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.

Adverse pregnancy outcomes and risk of type 2 diabetes in postmenopausal women.

BACKGROUND: Although gestational diabetes mellitus and delivering high-birthweight infants are known to predict a higher risk of future type 2 diabetes mellitus, the association of hypertensive disorders of pregnancy and other adverse pregnancy outcomes with type 2 diabetes mellitus is not well established. OBJECTIVE: This study aimed to examine the associations between different types of adverse pregnancy outcomes and incident type 2 diabetes mellitus among postmenopausal women. STUDY DESIGN: The Women's Health Initiative, a nationwide cohort of postmenopausal women, collected self-reported history of adverse pregnancy outcomes, including gestational diabetes mellitus, hypertensive disorders of pregnancy, preterm birth, and delivering low- birthweight (<2500 g) or high-birthweight (>4500 g) infants. Participants were followed up annually for self-reported incident type 2 diabetes mellitus treated with medication from baseline (1993-1998) to March 2021. This study used logistic regression to examine the associations of any and individual adverse pregnancy outcomes with diabetes mellitus. Stratified analyses were performed to assess effect modification by body mass index, race and ethnicity, education, parity, breastfeeding, and age at first birth. RESULTS: This analysis included 49,717 women without a history of diabetes mellitus at enrollment who had a least 1 pregnancy and responded to the questionnaire about adverse pregnancy outcomes. After adjusting for body mass index, demographic, lifestyle, and reproductive factors, gestational diabetes mellitus (odds ratio, 2.26; 95% confidence interval, 1.94-2.63), high birthweight (odds ratio, 1.30; 95% confidence interval, 1.18-1.44), and hypertensive disorders of pregnancy (odds ratio, 1.18; 95% confidence interval, 1.08-1.30) were independently associated with higher odds of type 2 diabetes mellitus, whereas preterm birth and low birthweight were not associated with diabetes mellitus risk. A history of ≥2 adverse pregnancy outcomes was associated with higher odds of type 2 diabetes mellitus (odds ratio, 1.55; 95% confidence interval, 1.28-1.88). This study further observed higher odds of type 2 diabetes mellitus (odds ratio, 3.69; 95% confidence interval, 2.38-5.70) among women with a history of both gestational diabetes mellitus and hypertensive disorders of pregnancy than those without any adverse pregnancy outcomes. CONCLUSION: Postmenopausal women with a history of gestational diabetes mellitus, those delivering high-birthweight infants, or those with hypertensive disorders of pregnancy are at risk of future type 2 diabetes mellitus. In addition, women with ≥2 conditions had an augmented risk and might be prioritized for screening and prevention efforts for type 2 diabetes mellitus.

Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.

Vibrational Quenching of Optically Pumped Carbon Dimer Anions.

Careful control of quantum states is a gateway to research in many areas of science such as quantum information, quantum-controlled chemistry, and astrophysical processes. Precise optical control of molecular ions remains a challenge due to the scarcity of suitable level schemes, and direct laser cooling has not yet been achieved for either positive or negative molecular ions. Using a cryogenic wire trap, we show how the internal quantum states of C_{2}^{-} anions can be manipulated using optical pumping and inelastic quenching collisions with H_{2} gas. We obtained optical pumping efficiencies of about 96% into the first vibrational level of C_{2}^{-} and determined the absolute inelastic rate coefficient from v=1 to 0 to be k_{q}=(3.2±0.2_{stat}±1.3_{sys})×10^{-13} cm^{3}/s at 20(3) K, over 3 orders of magnitude smaller than the capture limit. Reduced-dimensional quantum scattering calculations yield a small rate coefficient as well, but significantly larger than the experimental value. Using optical pumping and inelastic collisions, we also realized fluorescence imaging of negative molecular ions. Our work demonstrates high control of a cold ensemble of C_{2}^{-}, providing a solid foundation for future work on laser cooling of molecular ions.

Supplemental findings of the 2021 National Blood Collection and Utilization Survey.

BACKGROUND: The Department of Health and Human Services' National Blood Collection and Utilization Survey (NBCUS) has been conducted biennially since 1997. Data are used to estimate national blood collection and use. Supplemental data from the 2021 NBCUS not presented elsewhere are presented here. METHODS: Data on survey participation, donor characteristics, blood component cost, transfusion-associated adverse reactions, and implementation of blood safety measures, including pathogen-reduction of platelets, during 2021, were analyzed. Comparisons are made to 2019 survey data where available (2013-2019 for survey participation). RESULTS: During 2021, there were 11,507,000 successful blood donations in the United States, a 4.8% increase from 2019. Persons aged 45-64 years accounted for 42% of all successful blood donations. Donations by persons aged 65 years and older increased by 40.7%, while donations among minorities and donors aged <25 years decreased. From 2019 to 2021, the median price hospitals paid per unit of leukoreduced red blood cells, leukoreduced and pathogen-reduced apheresis platelets, and fresh frozen plasma increased. The largest increase in price per unit of blood component in 2021 was for leukoreduced apheresis platelets, which increased by ~$51. Between 2019 and 2021, the proportion of transfusing facilities reporting use of pathogen-reduced platelets increased, from 13% to 60%. Transfusion-related adverse reactions declined slightly between 2019 and 2021, although the rate of transfusion-transmitted bacterial infections remained unchanged. CONCLUSION: During 2021, blood donations increased nationally, although donations from those aged <25 years and minorities declined. The prices hospitals paid for most blood products increased, as did the use of pathogen-reduced platelets.

Association of maternal birth weight and maternal preterm birth with subsequent risk for adverse reproductive outcomes: The Women's Health Initiative.

BACKGROUND: Advancements in medical technology and pharmacologic interventions have drastically improved survival of infants born preterm and low birth weight, but knowledge regarding the long-term health impacts of these individuals is limited and inconsistent. AIM: To investigate whether an individual's birthweight or history of being born preterm increases the risk of an adverse reproductive outcome. STUDY DESIGN: Nested case-control study within the Women's Health Initiative. SUBJECTS: 79,934 individuals who self-reported their personal birthweight category and/or preterm birth status. OUTCOMES MEASURES: Self-reported pregnancy outcomes: subfertility, miscarriage, stillbirth, preeclampsia, gestational diabetes, gestational hypertension, preterm birth, low birthweight infant, high birthweight infant. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR). RESULTS: After adjustments, individuals reporting their birthweight <6lbs. were 20 % more likely to have a stillbirth or 70 % more likely to have a low birthweight infant and were less likely to have a full-term birth or high birthweight infant during their pregnancy. Individuals reporting a birthweight ≥10 lbs. were more likely to have a high birthweight infant (OR 3.49, 95 % CI 2.73-4.39) and less likely to have a low birthweight infant (OR 0.64, 95 % CI 0.47-0.82). Individuals born preterm were at increased risk for infertility, miscarriage, preeclampsia, gestational diabetes, and delivering a preterm or low birthweight infant. CONCLUSIONS: As more individuals born preterm and/or low birthweight survive to adulthood, the incidence and prevalence of poor reproductive outcomes may increase. Women born at extremes of birthweight and prematurity may need to be monitored more closely during their own pregnancies.

Association of Later-Life Weight Changes With Survival to Ages 90, 95, and 100: The Women's Health Initiative.

BACKGROUND: Associations of weight changes and intentionality of weight loss with longevity are not well described. METHODS: Using longitudinal data from the Women's Health Initiative (N = 54 437; 61-81 years), we examined associations of weight changes and intentionality of weight loss with survival to ages 90, 95, and 100. Weight was measured at baseline, year 3, and year 10, and participants were classified as having weight loss (≥5% decrease from baseline), weight gain (≥5% increase from baseline), or stable weight (<5% change from baseline). Participants reported intentionality of weight loss at year 3. RESULTS: A total of 30 647 (56.3%) women survived to ≥90 years. After adjustment for relevant covariates, 3-year weight loss of ≥5% vs stable weight was associated with lower odds of survival to ages 90 (OR, 0.67; 95% CI, 0.64-0.71), 95 (OR, 0.65; 95% CI, 0.60-0.71), and 100 (OR, 0.62; 95% CI, 0.49-0.78). Compared to intentional weight loss, unintentional weight loss was more strongly associated with lower odds of survival to age 90 (OR, 0.83; 95% CI, 0.74-0.94 and OR, 0.49; 95% CI, 0.44-0.55, respectively). Three-year weight gain of ≥5% vs stable weight was not associated with survival to age 90, 95, or 100. The pattern of results was similar among normal weight, overweight, and obese women in body mass index (BMI)-stratified analyses. CONCLUSIONS: Weight loss of ≥5% vs stable weight was associated with lower odds of longevity, more strongly for unintentional weight loss than for intentional weight loss. Potential inaccuracy of self-reported intentionality of weight loss and residual confounding were limitations.

KEAP1/NFE2L2 Pathway Signature Outperforms KEAP1/NFE2L2 Mutation Status and Reveals Alternative Pathway-Activating Mutations in NSCLC.

INTRODUCTION: Activation of the antioxidant KEAP1/NFE2L2 (NRF2) pathway leads to increased glutamine dependence and an aggressive phenotype in NSCLC. Because this pathway has been explored as a clinical target, we developed a transcriptomic signature for identifying KEAP1/NFE2L2-activated tumors. METHODS: A total of 971 NSCLC samples were used to train an expression signature (K1N2-score) to predict KEAP1/NFE2L2 mutations. There were 348 in-house NSCLCs that were analyzed using a NanoString expression panel for validation. RESULTS: The 46-gene K1N2 score robustly predicted KEAP1/NFE2L2 mutations in the validation set irrespective of histology and mutation (area under the curve: 89.5, sensitivity: 90.2%), suggesting that approximately 90% of KEAP1/NFE2L2 mutations are pathway-activating. The K1N2-score outperformed KEAP1/NFE2L2 mutational status when predicting patient survival (score p = 0.047; mutation p = 0.215). In K1N2 score-positive but KEAP1/NFE2L2 wild-type samples, enrichment testing identified SMARCA4/BRG1 and CUL3 mutations as mimics of KEAP1/NFE2L2 mutations. CONCLUSIONS: The K1N2-score identified KEAP1/NFE2L2-activated NSCLC by robustly detecting KEAP1/NFE2L2mut cases and discovering alternative genomic activators. It is a potential means for selecting patients with a constitutively active KEAP1/NFE2L2 pathway.

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We have previously shown that KEAP1 mutant tumors have increased glutamine consumption to support the metabolic rewiring associated with NRF2 activation. Here, using patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the novel glutamine antagonist DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumor growth by inhibiting glutamine-dependent nucleotide synthesis and promoting anti-tumor CD4 and CD8 T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we discover that DRP-104 reverses T cell exhaustion and enhances the function of CD4 and CD8 T cells culminating in an improved response to anti-PD1 therapy. Our pre-clinical findings provide compelling evidence that DRP-104, currently in phase 1 clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer. Furthermore, we demonstrate that by combining DRP-104 with checkpoint inhibition, we can achieve suppression of tumor intrinsic metabolism and augmentation of anti-tumor T cell responses.

Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype.

INTRODUCTION: Whether apolipoprotein E's (APOE's) involvement in lipid metabolism contributes to Alzheimer's disease (AD) risk remains unknown. METHODS: Incident probable dementia and cognitive impairment (probable dementia+mild cognitive impairment) were analyzed in relation to baseline serum lipids (total, low-density lipoprotein [LDL], high-density lipoprotein [HDL], non-HDL cholesterol, total-to-HDL, LDL-to-HDL, remnant cholesterol, and triglycerides) using Mendelian randomization in 5358 postmenopausal women from the Women's Health Initiative Memory Study. We also examined associations of baseline dietary cholesterol and fat with lipids based on APOE status. RESULTS: After an average of 11.13 years, less favorable lipid levels related to greater dementia and cognitive impairment risk. Dementia (odds ratio [OR] = 3.13; 95% confidence interval [CI]: 2.31 to 4.24) and cognitive impairment (OR = 2.38; 95% CI: 1.85 to 3.06) risk were greatest in relation to higher remnant cholesterol levels. Greater cholesterol consumption related to poorer lipids in APOE4+ compared to APOE3 carriers. DISCUSSION: APOE4+ carriers consuming more cholesterol had less favorable lipids, which were associated with greater dementia and cognitive impairment risk. HIGHLIGHTS: Less favorable serum lipids were associated with higher dementia incidence. Mendelian randomization findings suggest causality between lipids and dementia. Lipid levels in older women may be clinical indicators of dementia risk. APOE4 carriers had poorest lipid profiles in relation to cholesterol consumption. APOE risk for dementia may be modifiable through lipid management.

Three-Body Collisions Driving the Ion-Molecule Reaction C2- + H2 at Low Temperatures.

We report on the three-body reaction rate of C2- with H2 producing C2H- studied in a cryogenic 16-pole radio frequency ion trap. The reaction was measured in the temperature range from 10 to 28 K, where it was found to only take place via three-body collisions. The experimentally determined termolecular rate coefficient follows the form of a·(T/T0)b with T0 = 20 K, where a = 8.2(3) × 10-30 cm6/s and b = -0.82(12) denotes the temperature dependence. We additionally performed accurate ab initio calculations of the forces between the interacting partners and carried out variational transition state theory calculations, including tunneling through the barrier along the minimum energy path. We show that, while a simple classical model can generally predict the temperature dependence, the variational transition state theoretical calculations, including accurate quantum interactions, can explain the dominance of three-body effects in the molecular reaction mechanism and can reproduce the experimentally determined reaction coefficients, linking them to a temperature-dependent coupling parameter for energy dissipation within the transition complex.

Healthy Lifestyle Index and Risk of Cardiovascular Disease Among Postmenopausal Women With Normal Body Mass Index.

Background A lifestyle comprising a healthy diet, light alcohol consumption, no smoking, and moderate or intense physical activity has been associated with reduced risk of cardiovascular disease (CVD). We examined the association of a healthy lifestyle index (HLI), derived from scores for each of these components plus waist circumference, with the risk of incident CVD and CVD subtypes in postmenopausal women with normal body mass index (18.5-<25.0 kg/m2). Methods and Results We studied 40 118 participants in the Women's Health Initiative, aged 50 to 79 years at enrollment, with a normal body mass index and no history of CVD. The HLI score was categorized into quintiles. We estimated multivariable adjusted hazard ratios (HR) and 95% CIs for the association of HLI with risk of CVD and CVD subtypes using Cox regression models. A total of 3821 cases of incident CVD were ascertained during a median follow-up of 20.1 years. Compared with the lowest quintile (unhealthiest lifestyle), higher HLI quintiles showed inverse associations with the risk of CVD (HRquintile-2=0.74 [95% CI, 0.67-0.81]; HRquintile-3=0.66 [95% CI, 0.60-0.72]; HRquintile-4=0.57 [95% CI, 0.51-0.63]; and HRquintile-5=0.48 [95% CI, 0.43-0.54], P-trend=<0.001). HLI was also inversely associated with risks of stroke, coronary heart disease, myocardial infarction, angina, and coronary revascularization. Subgroup analyses, stratified by age (≤63 years vs >63 years), body mass index (

Pre-diagnosis lipid levels and mortality after obesity-related cancer diagnosis in the Women's Health Initiative cardiovascular disease biomarker cohort.

BACKGROUND: Published studies have demonstrated inconclusive relationships between serum lipid levels and mortality after cancer. METHODS: The primary objective was to evaluate the relationship between fasting lipid levels and mortality after cancer. Data were obtained on baseline lipids and outcomes after cancer from 1263 postmenopausal women diagnosed with 13 obesity-related cancers who were part of the Women's Health Initiative (WHI) lipid biomarkers cohort. Obesity-related cancers included incident invasive cancers of the breast, colorectum, endometrium, esophagus (adenocarcinoma), kidney, liver, gallbladder, pancreas, ovaries, small intestine, thyroid, stomach, as well as multiple myeloma. Baseline lipid measurements included high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and non-HDL-cholesterol. Outcomes were all cause, cancer-specific, and CVD mortality. Multivariable Cox proportional hazards models were used to measure associations between lipid levels and mortality (all cause, cancer, and CVD) after a cancer diagnosis, with lipids analyzed as continuous variables. RESULTS: Among women with obesity-related cancer, there were 707 deaths, of which 379 (54%) were due to cancer and 113 (16%) were due to CVD. Mean time from blood draw to cancer diagnosis was 5.1 years (range: 0.05-10 years). LDL-C values above the 95th percentile were associated with higher risk of all-cause mortality (p < 0.001), and cancer-specific mortality (p < 0.001), but not mortality due to CVD. Non-HDL-C values above the 65th percentile were associated with higher risk of all-cause mortality (p = 0.01) and mortality due to CVD (p = 0.003), but not cancer-specific mortality (p = 0.37). HDL-C values above the 95th percentile were associated with lower all-cause mortality (p = 0.002), and above the 65th percentile with lower cancer-specific mortality (p = 0.003), but no significant relationship with mortality due to CVD was observed. CONCLUSIONS: The relationship between pre-diagnosis fasting lipid levels and mortality after cancer diagnosis is complex. These results suggest that improved lipid control through lifestyle and anti-lipid medications could have a meaningful impact on outcomes after cancer.

Associations of maternal preterm birth with subsequent risk for type 2 diabetes in women from the women's health initiative.

Preterm birth has been associated with insulin resistance and beta-cell dysfunction, a hallmark characteristic of type 2 diabetes. However, studies investigating the relationship between a personal history of being born preterm and type 2 diabetes are sparse. We sought to investigate the potential association between a personal history of being born preterm and risk for type 2 diabetes in a racially and ethnically diverse population. Baseline and incident data (>16 years of follow-up) from the Women's Health Initiative (n = 85,356) were used to examine the association between personal history of being born preterm (born 1910-1940s) and prevalent (baseline enrollment; cross-sectional) or incident (prospective cohort) cases of type 2 diabetes. Logistic and Cox proportional hazards regression models were used to estimate odds and hazards ratios. Being born preterm was significantly, positively associated with odds for prevalent type 2 diabetes at enrollment (adjOR = 1.79, 95% CI 1.43-2.24; P < 0.0001). Stratified regression models suggested the positive associations at baseline were consistent across race and ethnicity groups. However, being born preterm was not significantly associated with risk for incident type 2 diabetes. Regression models stratified by age at enrollment suggest the relationship between being born preterm and type 2 diabetes persists only among younger age groups. Preterm birth was associated with higher risk of type 2 diabetes but only in those diagnosed with type 2 diabetes prior to study enrollment, suggesting the association between preterm birth and type 2 diabetes may exist at earlier age of diagnosis but wane over time.