Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Associations between common contraceptive use and circulating inflammatory biomarkers.

Ovarian cancer incidence has declined in recent decades, due in part to oral contraceptive (OC) use and tubal ligation. However, intrauterine device (IUD) use has increasingly replaced OC use. As ovarian cancer is an inflammation-related disease, we examined the association of OC use, IUD use, and tubal ligation with plasma levels of C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor α receptor 2 (sTNFR2), in the Nurses' Health Study (NHS) and NHSII. After adjusting for reproductive, hormonal, and lifestyle factors, and mutual adjustment for other methods of contraception, there were no differences in inflammatory markers between ever and never use of each method. However, CRP levels decreased from an average 30.4% (-53.6, 4.4) with every 5 years since initial IUD use (P-trend=0.03), while CRP increased an average 9.9% (95% CI: 5.7, 14.3) with every 5 years of use of OC (P-trend<0.0001) as well as differences by BMI and menopausal status. Our results suggest IUD use and tubal ligation are not associated with higher circulating inflammatory markers long term, although long duration of OC use may increase generalized inflammation, which may in part explain why its protective effect wanes over time.

Artificial intelligence assisted diagnosis of early tc markers and its application.

Thyroid cancer (TC) is a common endocrine malignancy with an increasing incidence worldwide. Early diagnosis is particularly important for TC patients, because it allows patients to receive treatment as early as possible. Artificial intelligence (AI) provides great advantages for complex healthcare systems by analyzing big data based on machine learning. Nowadays, AI is widely used in the early diagnosis of cancer such as TC. Ultrasound detection and fine needle aspiration biopsy are the main methods for early diagnosis of TC. AI has been widely used in the detection of malignancy in thyroid nodules by ultrasound images, cytopathology images and molecular markers. It shows great potential in auxiliary medical diagnosis. The latest clinical trial has shown that the performance of AI models matches with the diagnostic efficiency of experienced clinicians, and more efficient AI tools will be developed in the future. Therefore, in this review, we summarized the recent advances in the application of AI algorithms in assessing the risk of malignancy in thyroid nodules. The objective of this review was to provide a data base for the clinical use of AI-assisted diagnosis in TC, as well as to provide new ideas for the next generation of AI-assisted diagnosis in TC.

Use of melatonin supplements and risk of type 2 diabetes and cardiovascular diseases in the USA: insights from three prospective cohort studies.

BACKGROUND: Use of melatonin supplements has been increasing substantially in both children and adults in the USA; however, their long-term cardiometabolic effects remain unclear. We aimed to assess the associations between regular use of melatonin supplements and the risk of developing type 2 diabetes or cardiovascular disease in adults. METHODS: In this study, we included individuals from three US cohorts: the Nurses' Health Study (women only), the Health Professionals Follow-up Study (men only), and the Nurses' Health Study II (women only). Women aged 25-55 years and men aged 45-75 years at baseline, who had no diagnosis of cancer at baseline, and who responded to the question about melatonin supplement use (yes or no) were included. We excluded baseline prevalent cardiovascular disease and baseline prevalent type 2 diabetes for the main analyses. The main outcomes were cardiovascular disease and type 2 diabetes incidence. In secondary analyses, we stratified by duration of rotating night shift work in the Nurses' Health Study and Nurses' Health Study II to examine whether the associations with melatonin supplement use differed by rotating night shift work. FINDINGS: For the cardiovascular disease analysis, we included 67 202 women from the Nurses' Health Study (follow-up 1998-2019, mean age at baseline: 63·6 years [SD 7·1]), 26 629 men from the Health Professionals Follow-up Study (1998-2020, 62·9 years [8·8], and 65 241 women from the Nurses' Health Study II (2003-19, 48·2 years [4·7]). Follow-up for incident type 2 diabetes was from 1998 to June 30, 2021, for the Nurses' Health Study; 2003 to Jan 31, 2023, for the Nurses' Health Study II; and from 1998 to Jan 31, 2020, for the Health Professionals' Follow-up Study. Melatonin supplement use in the study cohorts doubled over recent decades from less than 2% in 1998-2007 to 4% or higher in 2014-15 (4·0% in men and 5·3% in women). We documented 16 917 incident cardiovascular disease events during 2 609 068 person-years of follow-up and 12 730 incident cases of type 2 diabetes during 2 701 830 person-years of follow-up. In a pooled analysis of the three cohorts, comparing users with non-users of melatonin supplements, the pooled multivariable-adjusted hazard ratios were 0·94 (95% CI 0·83-1·06, p=0·32) for cardiovascular disease and 0·98 (0·86-1·12, p=0·80) for type 2 diabetes. In secondary analyses, melatonin supplement use appeared to attenuate the positive association between long-term shift work (>5 years) and risk of cardiovascular disease (pinteraction=0·013) among the female nurses. INTERPRETATION: With up to 23 years of follow-up of three large prospective cohorts of middle-aged and older men and women, self-reported melatonin supplement use was not associated with risk of type 2 diabetes or cardiovascular disease. Further research is warranted to assess if melatonin supplement use could mitigate the potential risks of type 2 diabetes and cardiovascular disease associated with rotating night shift work. FUNDING: US National Institutes of Health.

Aircraft noise exposure and body mass index among female participants in two Nurses' Health Study prospective cohorts living around 90 airports in the United States.

OBJECTIVE: Aircraft noise exposure is linked to cardiovascular disease risk. One understudied candidate pathway is obesity. This study investigates the association between aircraft noise and obesity among female participants in two prospective Nurses' Health Study (NHS and NHSII) cohorts. METHODS: Aircraft day-night average sound levels (DNL) were estimated at participant residential addresses from modeled 1 dB (dB) noise contours above 44 dB for 90 United States (U.S.) airports in 5-year intervals 1995-2010. Biennial surveys (1994-2017) provided information on body mass index (BMI; dichotomized, categorical) and other individual characteristics. Change in BMI from age 18 (BMI18; tertiles) was also calculated. Aircraft noise exposures were dichotomized (45, 55 dB), categorized (<45, 45-54, ≥55 dB) or continuous for exposure ≥45 dB. Multivariable multinomial logistic regression using generalized estimating equations were adjusted for individual characteristics and neighborhood socioeconomic status, greenness, population density, and environmental noise. Effect modification was assessed by U.S. Census region, climate boundary, airline hub type, hearing loss, and smoking status. RESULTS: At baseline, the 74,848 female participants averaged 50.1 years old, with 83.0%, 14.8%, and 2.2% exposed to <45, 45-54, and ≥55 dB of aircraft noise, respectively. In fully adjusted models, exposure ≥55 dB was associated with 11% higher odds (95% confidence interval [95%CI]: -1%, 24%) of BMIs ≥30.0, and 15% higher odds (95%CI: 3%, 29%) of membership in the highest tertile of BMI18 (ΔBMI 6.7 to 71.6). Less-pronounced associations were observed for the 2nd tertile of BMI18 (ΔBMI 2.9 to 6.6) and BMI 25.0-29.9 as well as exposures ≥45 versus <45 dB. There was evidence of DNL-BMI trends (ptrends ≤ 0.02). Stronger associations were observed among participants living in the West, arid climate areas, and among former smokers. DISCUSSION: In two nationwide cohorts of female nurses, higher aircraft noise exposure was associated with higher BMI, adding evidence to an aircraft noise-obesity-disease pathway.

Another benefit of regular sleep.

A large observational study has found that irregular sleep-wake patterns are associated with a higher risk of overall mortality, and also mortality from cancers and cardiovascular disease.

Biological function and clinical application prospect of tsRNAs in digestive system biology and pathology.

tsRNAs are small non-coding RNAs originating from tRNA that play important roles in a variety of physiological activities such as RNA silencing, ribosome biogenesis, retrotransposition, and epigenetic inheritance, as well as involvement in cellular differentiation, proliferation, and apoptosis. tsRNA-related abnormalities have a significant influence on the onset, development, and progression of numerous human diseases, including malignant tumors through affecting the cell cycle and specific signaling molecules. This review introduced origins together with tsRNAs classification, providing a summary for regulatory mechanism and physiological function while dysfunctional effect of tsRNAs in digestive system diseases, focusing on the clinical prospects of tsRNAs for diagnostic and prognostic biomarkers. Video Abstract.

A tRF-5a fragment that regulates radiation resistance of colorectal cancer cells by targeting MKNK1.

Radiotherapy serves as a crucial strategy in the treatment of colorectal cancer (CRC). However, its efficacy is often hindered by the challenge of radiation resistance. Although the literature suggests that some tRNA-derived small RNAs (tsRNAs) are associated with various cancers, studies reporting the relationship of tsRNAs with cancer cell radiosensitivity have not been published yet. In our study, we utilized tsRNAs sequencing to predict differentially expressed tsRNAs in two CRC cells and their radioresistant cells, and 10 tsRNAs with significant differences in expression were validated by qPCR. The target genes of tRF-16-7X9PN5D were predicted and verified by the bioinformatics, dual-luciferase reporter gene assay and western blotting analyses. Wound healing, colony formation, transwell invasion and CCK-8 assays were performed to detect the effects of tRF-16-7X9PN5D on cell function and radiosensitivity. Western blotting evaluated the relationship between tRF-16-7X9PN5D and the MKNK-eIF4E axis. Our findings demonstrated that tRF-16-7X9PN5D expression was substantially downregulated in radioresistant CRC cells. Furthermore, tRF-16-7X9PN5D could promote CRC cells' ability to proliferate, migrate, invade and obtain radiation resistance by targeting MKNK1. Finally, tRF-16-7X9PN5D could regulate eIF4E phosphorylation via MKNK1. This investigation indicated that tRF-16-7X9PN5D has an essential regulatory role in the radiation resistance of CRC by directly targeting MKNK1, and may be a new pathway for regulating the CRC radiosensitivity.

Chronotype, Unhealthy Lifestyle, and Diabetes Risk in Middle-Aged U.S. Women : A Prospective Cohort Study.

BACKGROUND: Evening chronotype may promote adherence to an unhealthy lifestyle and increase type 2 diabetes risk. OBJECTIVE: To evaluate the role of modifiable lifestyle behaviors in the association between chronotype and diabetes risk. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study II. PARTICIPANTS: 63 676 nurses aged 45 to 62 years with no history of cancer, cardiovascular disease, or diabetes in 2009 were prospectively followed until 2017. MEASUREMENTS: Self-reported chronotype using a validated question from the Morningness-Eveningness Questionnaire. The lifestyle behaviors that were measured were diet quality, physical activity, alcohol intake, body mass index (BMI), smoking, and sleep duration. Incident diabetes cases were self-reported and confirmed using a supplementary questionnaire. RESULTS: Participants reporting a "definite evening" chronotype were 54% (95% CI, 49% to 59%) more likely to have an unhealthy lifestyle than participants reporting a "definite morning" chronotype. A total of 1925 diabetes cases were documented over 469 120 person-years of follow-up. Compared with the "definite morning" chronotype, the adjusted hazard ratio (HR) for diabetes was 1.21 (CI, 1.09 to 1.35) for the "intermediate" chronotype and 1.72 (CI, 1.50 to 1.98) for the "definite evening" chronotype after adjustment for sociodemographic factors, shift work, and family history of diabetes. Further adjustment for BMI, physical activity, and diet quality attenuated the association comparing the "definite evening" and "definite morning" chronotypes to 1.31 (CI, 1.13 to 1.50), 1.54 (CI, 1.34 to 1.77), and 1.59 (CI, 1.38 to 1.83), respectively. Accounting for all measured lifestyle and sociodemographic factors resulted in a reduced but still positive association (HR comparing "definite evening" vs. "definite morning" chronotype, 1.19 [CI, 1.03 to 1.37]). LIMITATIONS: Chronotype assessment using a single question, self-reported data, and homogeneity of the study population. CONCLUSION: Middle-aged nurses with an evening chronotype were more likely to report unhealthy lifestyle behaviors and had increased diabetes risk compared with those with a morning chronotype. Accounting for BMI, physical activity, diet, and other modifiable lifestyle factors attenuated much but not all of the increased diabetes risk. PRIMARY FUNDING SOURCE: National Institutes of Health.

Daytime napping, nighttime sleeping duration, and risk of hepatocellular carcinoma and liver disease-related mortality.

Background & Aims: Sleep duration has been linked to metabolic dysfunction and chronic inflammation, which may contribute to the development of liver cancer and chronic liver disease (CLD). However, little is known about the relationship between sleep or napping duration and hepatocellular carcinoma (HCC) risk and CLD mortality. Methods: We followed 295,837 individuals in the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health Study. We examined the associations of nighttime sleep duration and daytime napping duration with risk of HCC incidence and CLD mortality. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results: A total of 357 incident HCC cases and 578 CLD deaths were identified after a median follow-up time of 15.5 years. After adjusting for confounder factors, we found U-shaped associations of nighttime sleep duration with the incidence of HCC (HR<5 vs. 7-8 h = 2.00, 95% CI: 1.22-3.26 and HR≥9 vs. 7-8 h = 1.63, 95% CI: 1.04-2.65) and CLD mortality (HR<5 vs. 7-8 h = 1.78, 95% CI: 1.18-2.69 and HR≥9 vs. 7-8 h = 1.91, 95% CI: 1.35-2.70). Daytime napping was associated with higher risk of HCC (HR≥1 vs. non-nappers = 1.46, 95% CI: 1.04-2.06) and higher CLD mortality (HR≥1 h vs. non-nappers = 1.54, 95% CI: 1.18-2.01) compared with no napping. Conclusions: We observed U-shaped associations for nighttime sleeping and risk of HCC and CLD mortality. Additionally, longer daytime napping duration was associated with higher risk of HCC and CLD death. Our study suggests that clinical follow up of individuals at risk for liver cancer or living with a liver disease should include information on nighttime and daytime sleep. Impact and implications: Sleep or napping duration may play a role in the development of liver cancer and chronic liver disease, but little is known about the relationship between them. In addition, abnormal sleep patterns in patients with chronic liver disease may further promote the development of liver disease, creating a vicious cycle. Our study suggests that clinical follow up of individuals at risk for liver cancer or living with a liver disease should include information on nighttime and daytime sleep, as they can be potentially important factors in the development and progression of liver disease.

Estimation of life's essential 8 score with incomplete data of individual metrics.

Background: The American Heart Association's Life's Essential 8 (LE8) is an updated construct of cardiovascular health (CVH), including blood pressure, lipids, glucose, body mass index, nicotine exposure, diet, physical activity, and sleep health. It is challenging to simultaneously measure all eight metrics at multiple time points in most research and clinical settings, hindering the use of LE8 to assess individuals' overall CVH trajectories over time. Materials and methods: We obtained data from 5,588 participants in the Nurses' Health Studies (NHS, NHSII) and Health Professionals Follow-up Study (HPFS), and 27,194 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) with all eight metrics available. Individuals' overall cardiovascular health (CVH) was determined by LE8 score (0-100). CVH-related factors that are routinely collected in many settings (i.e., demographics, BMI, smoking, hypertension, hypercholesterolemia, and diabetes) were included as predictors in the base models of LE8 score, and subsequent models further included less frequently measured factors (i.e., physical activity, diet, blood pressure, and sleep health). Gradient boosting decision trees were trained with hyper-parameters tuned by cross-validations. Results: The base models trained using NHS, NHSII, and HPFS had validated root mean squared errors (RMSEs) of 8.06 (internal) and 16.72 (external). Models with additional predictors further improved performance. Consistent results were observed in models trained using NHANES. The predicted CVH scores can generate consistent effect estimates in associational studies as the observed CVH scores. Conclusions: CVH-related factors routinely measured in many settings can be used to accurately estimate individuals' overall CVH when LE8 metrics are incomplete.

Neural tissue-engineered prevascularization in vivo enhances peripheral neuroregeneration via rapid vascular inosculation.

Neural tissue engineering techniques typically face a significant challenge, simulating complex natural vascular systems that hinder the clinical application of tissue-engineered nerve grafts (TENGs). Here, we report a subcutaneously pre-vascularized TENG consisting of a vascular endothelial growth factor-induced host vascular network, chitosan nerve conduit, and inserted silk fibroin fibers. Contrast agent perfusion, tissue clearing, microCT scan, and blood vessel 3D reconstruction were carried out continuously to prove whether the regenerated blood vessels were functional. Moreover, histological and electrophysiological evaluations were also applied to investigate the efficacy of repairing peripheral nerve defects with pre-vascularized TENG. Rapid vascular inosculation of TENG pre-vascularized blood vessels with the host vascular system was observed at 4 â€‹d bridging the 10 â€‹mm sciatic nerve defect in rats. Transplantation of pre-vascularized TENG in vivo suppressed proliferation of vascular endothelial cells (VECs) while promoting their migration within 14 â€‹d post bridging surgery. More importantly, the early vascularization of TENG drives axonal regrowth by facilitating bidirectional migration of Schwann cells (SCs) and the bands of Büngner formation. This pre-vascularized TENG increased remyelination, promoted recovery of electrophysiological function, and prevented atrophy of the target muscles when observed 12 weeks post neural transplantation. The neural tissue-engineered pre-vascularization technique provides a potential approach to discover an individualized TENG and explore the innovative neural regenerative process.

Dysregulation of Transfer RNA-derived Small RNAs that Regulate Cell Activity and its Related Signaling Pathways in Human Cancers.

tsRNAs are small noncoding RNAs that originate from tRNA cleavage and play important regulatory roles in gene expression, translation, transcription, and epigenetic modification. The dysregulation of tsRNAs in cancer disrupts gene expression and perturbs various cellular activities, including cell proliferation, apoptosis, migration, and invasion. Moreover, tsRNAs may influence cancer development by regulating related cell signaling pathways. In this review, we first examine the origins and classification of tsRNAs and their effects on tumor cell activity. To highlight the latest research progress of tsRNAs and signaling pathways, we summarize the possible mechanisms of tsRNAs in specific tumor-related signaling pathways, including the Wnt, TGFb1, MAPK, PI3K-AKT, Notch, and MDM2/p53 signaling pathways, that have been identified in recent research.

Estimated Ovulatory Years Prior to Menopause and Postmenopausal Endogenous Hormone Levels.

BACKGROUND: Lifetime ovulatory years (LOY) is estimated by the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influences sex hormone levels in postmenopausal women with at least one intact ovary not using hormones. METHODS: Estradiol, estrone, estrone sulfate, total testosterone, dehydroepiandrostendione sulfate, prolactin, and sex hormone binding globulin were measured in 1,976 postmenopausal women from the Nurses' Health Study. Associations of age, body mass index (BMI), smoking, alcohol use, and other factors on hormones were assessed by t tests and ANOVA. Linear regression was used to assess multivariable adjusted associations between LOY and hormones and trends in hormone levels per 5-year increases in LOY were estimated. RESULTS: Women averaged 61.4 years old, 11.0 years since menopause, with BMI of 25.8 kg/m2. A total of 13.6% had irregular cycles, 17.5% hysterectomy, 6.4% unilateral oophorectomy, and 13.8% were current smokers. Variables associated with one or more hormone levels were included as covariates. Each 5-year increase in LOY was significantly associated with a 5.2% increase in testosterone in women with BMI < 25 kg/m2 and a 7.4% increase in testosterone and 7.3% increase in estradiol in women with above-average BMI. CONCLUSIONS: This is the first study to show that greater LOY is associated with higher testosterone in postmenopausal women and higher estradiol in those with elevated BMI, suggesting accumulation of functioning stromal and thecal cells from repeated ovulations and peripheral conversion of testosterone. IMPACT: A possible explanation for why greater LOY increases risk for breast, endometrial, and ovarian cancer is offered.

Estimation of Life's Essential 8 Score with Incomplete Data of Individual Metrics.

Background: The American Heart Association's Life's Essential 8 (LE8) is an updated construct of cardiovascular health (CVH), including blood pressure, lipids, glucose, body mass index, nicotine exposure, diet, physical activity, and sleep health. It is challenging to simultaneously measure all eight metrics at multiple time points in most research and clinical settings, hindering the use of LE8 to assess individuals' overall CVH trajectories over time. Methods and Results: We obtained data from 5,588 participants in the Nurses' Health Studies (NHS, NHSII) and Health Professional's Follow-up Study (HPFS), and 27,194 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) with all eight metrics available. Individuals' overall cardiovascular health (CVH) was determined by LE8 score (0-100). CVH-related factors that are routinely collected in many settings (i.e., demographics, BMI, smoking, hypertension, hypercholesterolemia, and diabetes) were included as predictors in the base models of LE8 score, and subsequent models further included less frequently measured factors (i.e., physical activity, diet, blood pressure, and sleep health). Gradient boosting decision trees were trained with hyper-parameters tuned by cross-validations. The base models trained using NHS, NHSII, and HPFS had validated root mean squared errors (RMSEs) of 8.06 (internal) and 16.72 (external). Models with additional predictors further improved performance. Consistent results were observed in models trained using NHANES. The predicted CVH scores can generate consistent effect estimates in associational studies as the observed CVH scores. Conclusions: CVH-related factors routinely measured in many settings can be used to accurately estimate individuals' overall CVH when LE8 metrics are incomplete. Clinical Perspective: What Is New?: Life's Essential 8 (LE8) has great potential to assess and promote cardiovascular health (CVH) across life course, however, it is challenging to simultaneously collect all eight metrics at multiple time points in most research and clinical settings.We demonstrated that CVH-related factors routinely collected in many research and clinical settings can be used to accurately estimate individuals' overall CVH across time even when LE8 metrics are incomplete.What Are the Clinical Implications?: The approach introduced in this study provides a cost-effective and feasible way to estimate individuals' overall CVH.It can be used to track individuals' CVH trajectories in clinical settings.

Gut feelings: associations of emotions and emotion regulation with the gut microbiome in women.

BACKGROUND: Accumulating evidence suggests that positive and negative emotions, as well as emotion regulation, play key roles in human health and disease. Recent work has shown the gut microbiome is important in modulating mental and physical health through the gut-brain axis. Yet, its association with emotions and emotion regulation are understudied. Here we examined whether positive and negative emotions, as well as two emotion regulation strategies (i.e. cognitive reappraisal and suppression), were associated with the gut microbiome composition and functional pathways in healthy women. METHODS: Participants were from the Mind-Body Study (N = 206, mean age = 61), a sub-study of the Nurses' Health Study II cohort. In 2013, participants completed measures of emotion-related factors. Two pairs of stool samples were collected, 6 months apart, 3 months after emotion-related factors measures were completed. Analyses examined associations of emotion-related factors with gut microbial diversity, overall microbiome structure, and specific species/pathways and adjusted for relevant covariates. RESULTS: Alpha diversity was negatively associated with suppression. In multivariate analysis, positive emotions were inversely associated with the relative abundance of Firmicutes bacterium CAG 94 and Ruminococcaceae bacterium D16, while negative emotions were directly correlated with the relative abundance of these same species. At the metabolic pathway level, negative emotions were inversely related to the biosynthesis of pantothenate, coenzyme A, and adenosine. CONCLUSIONS: These findings offer human evidence supporting linkages of emotions and related regulatory processes with the gut microbiome and highlight the importance of incorporating the gut microbiome in our understanding of emotion-related factors and their associations with physical health.

Predictors of residual disease after debulking surgery in advanced stage ovarian cancer.

Objective: Optimal debulking with no macroscopic residual disease strongly predicts ovarian cancer survival. The ability to predict likelihood of optimal debulking, which may be partially dependent on tumor biology, could inform clinical decision-making regarding use of neoadjuvant chemotherapy. Thus, we developed a prediction model including epidemiological factors and tumor markers of residual disease after primary debulking surgery. Methods: Univariate analyses examined associations of 11 pre-diagnosis epidemiologic factors (n=593) and 24 tumor markers (n=204) with debulking status among incident, high-stage, epithelial ovarian cancer cases from the Nurses' Health Studies and New England Case Control study. We used Bayesian model averaging (BMA) to develop prediction models of optimal debulking with 5x5-fold cross-validation and calculated the area under the curve (AUC). Results: Current aspirin use was associated with lower odds of optimal debulking compared to never use (OR=0.52, 95%CI=0.31-0.86) and two tissue markers, ADRB2 (OR=2.21, 95%CI=1.23-4.41) and FAP (OR=1.91, 95%CI=1.24-3.05) were associated with increased odds of optimal debulking. The BMA selected aspirin, parity, and menopausal status as the epidemiologic/clinical predictors with the posterior effect probability ≥20%. While the prediction model with epidemiologic/clinical predictors had low performance (average AUC=0.49), the model adding tissue biomarkers showed improved, but weak, performance (average AUC=0.62). Conclusions: Addition of ovarian tumor tissue markers to our multivariable prediction models based on epidemiologic/clinical data slightly improved the model performance, suggesting debulking status may be in part driven by tumor characteristics. Larger studies are warranted to identify those at high risk of poor surgical outcomes informing personalized treatment.

Establishment and validation of a redox-related long non-coding RNAs prognostic signature in head and neck squamous cell carcinoma.

Reduction and oxidation (redox) reactions occur in living organisms as part of normal cellular metabolism. Here, we established a novel redox-related long non-coding RNAs (rrlncRNAs) signature to predict the prognosis and therapeutic response in Head and neck squamous cell carcinoma (HNSCC). The expression profile and clinical information were obtained from the TCGA project. In total, 10 differently expressed rrlncRNAs associated with prognosis were identified and involved in a prognostic risk score signature by the least absolute shrinkage and selection operator penalized Cox analysis. The area under the receiver operating characteristic curves of the survival rates predicted by the rrlncRNAs signature over one, two, and three years were found to be 0.651, 0.670, and 0.679. Following the completion of the Kaplan-Meier survival study, we discovered that the lower-risk cohort exhibited a much longer overall survival period in contrast with the higher-risk cohort. Univariate and multivariable Cox regression analyses demonstrated that the risk score independently served as a significant predictive factor. GO annotation and KEGG pathway analyses illustrated that the rrlncRNAs signature was strongly associated with immune-related functions as well as signaling pathways. The tumor-infiltrating immune cells, tumor microenvironment, immune-related functions, HLA gene family expression, immune checkpoint genes expression, and somatic variants differed substantially between the low- and high-risk cohorts. Moreover, patients in low-risk group were predicted to present a favorable immunotherapy responsiveness, while in contrast, the high-risk group patients might have a stronger sensitivity to "docetaxel". According to our findings, the rrlncRNAs signature showed an excellent prognosis predictive value and might indicate therapeutic response to immunotherapy in HNSCC.

Significance of Spliceosome-Related Genes in the Prediction of Prognosis and Treatment Strategies for Lung Adenocarcinoma.

Background: The leading cause of cancer-related fatalities globally is lung cancer; lung adenocarcinoma (LUAD) is the most common histological type in it. The spliceosome plays an important role in a majority of malignancies. However, it is yet unclear how spliceosome-related genes affect patients with LUAD in terms of treatment course and prognosis. Methods: Spliceosome-related genes were assessed from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database to obtain clinical information and gene expression in patients with LUAD. A spliceosome-related gene signature and prognostic model were constructed by using the least absolute shrinkage and selection operator (LASSO), time-dependent receiver operating characteristic (ROC), and nomogram. Immune infiltrate levels, mutation analysis, and pathway enrichment were predicted potential mechanisms of the signature by using single-sample gene set enrichment analysis (ssGSEA), Gene Set Cancer Analysis (GSCA) database, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) database. Then, a protein-protein interaction (PPI) network and transcription factor- (TF-) hub gene and drug mining network were also established by Cytoscape software. Results: Firstly, we constructed a prognostic model for 11 spliceosome signature genes. Based on the prognostic risk score, we stratified patients with LUAD into high- and low-risk groups. The high- and low-risk groups were closely related to the OS, tumor immune infiltration level, immune checkpoint molecules, and tumor mutation burden (TMB) of LUAD patients. Based on PPI networks, we also predict relevant TF genes that may regulate signature prognostic genes. Finally, drugs including oxaliplatin, arsenic trioxide, cisplatin, and sunitinib were excavated for the treatment of the 11 spliceosome signature genes in LUAD patients. Conclusion: In conclusion, this study is the first to explore the importance of spliceosome-related genes in the prognosis and treatment of LUAD. Through our study, we have innovatively provided potential prognosis genes and new therapeutic drug targets for the treatment of LUAD patients.

Pathway-Specific Polygenic Risk Scores Identify Obstructive Sleep Apnea-Related Pathways Differentially Moderating Genetic Susceptibility to Coronary Artery Disease.

BACKGROUND: Obstructive sleep apnea (OSA) and its features, such as chronic intermittent hypoxia, may differentially affect specific molecular pathways and processes in the pathogenesis of coronary artery disease (CAD) and influence the subsequent risk and severity of CAD events. In particular, competing adverse (eg, inflammatory) and protective (eg, increased coronary collateral blood flow) mechanisms may operate, but remain poorly understood. We hypothesize that common genetic variation in selected molecular pathways influences the likelihood of CAD events differently in individuals with and without OSA, in a pathway-dependent manner. METHODS: We selected a cross-sectional sample of 471 877 participants from the UK Biobank, with 4974 ascertained to have OSA, 25 988 to have CAD, and 711 to have both. We calculated pathway-specific polygenic risk scores for CAD, based on 6.6 million common variants evaluated in the CARDIoGRAMplusC4D genome-wide association study (Coronary ARtery DIsease Genome wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics), annotated to specific genes and pathways using functional genomics databases. Based on prior evidence of involvement with intermittent hypoxia and CAD, we tested pathway-specific polygenic risk scores for the HIF1 (hypoxia-inducible factor 1), VEGF (vascular endothelial growth factor), NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) and TNF (tumor necrosis factor) signaling pathways. RESULTS: In a multivariable-adjusted logistic generalized additive model, elevated pathway-specific polygenic risk scores for the Kyoto Encyclopedia of Genes and Genomes VEGF pathway (39 genes) associated with protection for CAD in OSA (interaction odds ratio 0.86, P=6×10-4). By contrast, the genome-wide CAD PRS did not show evidence of statistical interaction with OSA. CONCLUSIONS: We find evidence that pathway-specific genetic risk of CAD differs between individuals with and without OSA in a qualitatively pathway-dependent manner. These results provide evidence that gene-by-environment interaction influences CAD risk in certain pathways among people with OSA, an effect that is not well-captured by the genome-wide PRS. This invites further study of how OSA interacts with genetic risk at the molecular level and suggests eventual personalization of OSA treatment to reduce CAD risk according to individual pathway-specific genetic risk profiles.