Well-being in healthy Icelandic women varies with extreme seasonality in ambient light.

Seasonal variation in photoperiod may affect psychosocial and physical well-being in healthy persons. We tested this hypothesis in healthy pre-menopausal women, without a history of mood disorders, living year-round in Reykjavik, Iceland (64.1°N). Participants reported daily self-assessments of well-being throughout a complete ovulatory menstrual cycle in summer and/or winter (70% participated in both seasons). Scores for mood, cognitive acuity, social support, physical health and a composite of these four indicators were each significantly higher in summer than in winter (linear mixed effects models: p < .001 for each model); tiredness did not differ by season. The effect of season was not significantly changed by inclusion of body mass index and/or age as covariates. Some prior studies have been hampered by sparse time sampling, inattention to covariates and/or relying on recalled data. This is to our knowledge the first investigation to test the study hypothesis with daily real-time data spanning complete ovulatory menstrual cycles in each of two seasons. This dense sampling has revealed modest seasonal variation in well-being in healthy women. Daylength (sunlight exposure) is likely a major, but not necessarily sole, factor in these seasonal differences in well-being; temperature is likely less important given Iceland's relatively moderate (for its high latitude) seasonal temperature swings.

More than blood: app-tracking reveals variability in heavy menstrual bleeding construct.

BACKGROUND: Heavy menstrual bleeding (HMB) is associated with impaired quality of life and may signal serious health problems. Unresolved challenges in measuring menstrual bleeding and identifying HMB have hampered research and clinical care. Self-reported bleeding histories are commonly used but these may be influenced by recall bias, personal beliefs regarding "normal" flow volume, and the experience of other physical symptoms or disruptions to daily life. The potential usefulness of menstrual-tracking mobile applications, which allow real-time user-entered data recording, for assessing HMB has not been studied. We evaluated recall bias in reported period duration, the relationship of tracked period duration and daily flow volume to subsequently reported period heaviness, variation in quality of life associated with increasing period heaviness, and the advantages and limitations of using app-tracked data for clinical and research purposes. METHODS: An online questionnaire was distributed to current users of Clue, a commercially available menstrual health tracking app, asking them to characterize their last period. We compared responses to the user's corresponding Clue app-tracked data. The study sample comprised 6546 U.S.-based users (aged 18-45 years). RESULTS: Increasing reported heaviness was associated with increasing app-tracked period length and days of heavy flow, impaired quality-of-life (especially body pain severity), and disrupted activities. Of those reporting having had a heavy/very heavy period, ~ 18% had not tracked any heavy flow, but their period length and quality-of-life indicators were similar to those who had tracked heavy flow. Sexual/romantic activities were the most affected across all flow volumes. Compared to app-tracked data, 44% recalled their exact period length; 83% recalled within ± 1 day. Overestimation was more common than underestimation. However, those with longer app-tracked periods were more likely to underestimate period length by ≥ 2 days, a pattern which could contribute to under-diagnosis of HMB. CONCLUSION: Period heaviness is a complex construct that encapsulates flow volume and, for many, several other bleeding-associated experiences (period length, bodily impairments, disruptions of daily activities). Even very precise flow volume assessments cannot capture the multi-faceted nature of HMB as experienced by the individual. Real-time app-tracking facilitates quick daily recording of several aspects of bleeding-associated experiences. This more reliable and detailed characterization of bleeding patterns and experiences can potentially increase understanding of menstrual bleeding variability and, if needed, help to guide treatment.

Adaptation of metabolism to multicellular aggregation, hypoxia and obese stromal cell incorporation as potential measure of survival of ovarian metastases.

Ovarian metastases exfoliate from the primary tumor and it is thought that aggregation supports their survival in the peritoneal cavity during dissemination but the underlying mechanisms are not clearly identified. We have previously shown that ovarian cancer cells acquire an increasingly glycolytic and metabolic flexible phenotype during progression. In the present study, we investigated how hypoxia, aggregation, and the incorporation of the obese stromal vascular fraction (SVF) affect cellular metabolism and the response to common anti-cancer and anti-diabetic drugs. Our results show a reduction of glucose uptake, lactate secretion, cellular respiration and ATP synthesis in response to hypoxia and aggregation, suggesting that the observed reduced proliferation of cells aggregated into spheroids is the result of a down-regulation of respiration. Recruitment of SVF to spheroids increased the spheroids invasive capacity but reduced respiration only in the most aggressive cells. Further, aggregation and hypoxia reduced the response to the metabolic drugs AICAR and metformin, and the chemotherapeutic agents cisplatin and paclitaxel. Our results suggest that the adaptation of cellular metabolism may contribute to enhanced survival under non-permissive conditions, and that these metabolic alterations may provide targets for future interventions that aim to enhance the survival of women with metastatic ovarian cancer.

Assessment of App-Based Versus Conventional Survey Modalities for Reproductive Health Research in India, South Africa, and the United States: Comparative Cross-Sectional Study.

BACKGROUND: There is a widely acknowledged global need for more research on reproductive health (including contraception, menstrual health, sexuality, and maternal morbidities) and its impact on overall well-being. However, several factors-notably, high costs, considerable effort, and the sensitivity of these topics-impede the collection of the necessary data, especially in less accessible and lower-income populations. The burgeoning ownership of smartphones and growing use of menstrual tracking apps (MTAs) may present an opportunity to conduct reproductive health research with fewer impediments than those associated with conventional survey methods. OBJECTIVE: The main objective was to ascertain the feasibility, potential usefulness, and limitations of conducting reproductive health research using a mainstream MTA. METHODS: In each of the 3 countries, we evaluated questionnaire responses from (1) current users of an MTA (Clue) and (2) participants surveyed using conventional survey modalities (in-person interviews, SMS text messaging, and web-based questionnaires). We compared these responses with published data collected from large nationally representative benchmark samples (the United States Census and the Demographic and Health Surveys for South Africa and India). RESULTS: Given a sufficiently large user base, app-distributed surveys were able to quickly capture large samples on par with other methods and at low cost, with the additional advantage of being able to deploy remotely and simultaneously across countries. In each country, neither the app nor the conventional modality sample emerged as a consistently closer match to the distributions of the demographic attributes and the patterns of contraceptive use reported for the respective benchmark sample. Despite efforts to obtain representative samples, the conventional modality samples sometimes over- and other times underrepresented some subgroups (eg, underrepresentation of married persons in the United States and overrepresentation of rural residents in India). In all 3 countries, app users were younger, more educated, more likely to be urban residents, and more likely to use nonhormonal rather than hormonal contraceptive methods compared with the respective national benchmark. App users, compared with the conventional modality samples, consistently reported being more comfortable discussing their menstrual periods with other persons (eg, family, friends, and health care providers), suggesting that MTA users may be more likely to respond truthfully to questions on sensitive or taboo health topics. The app samples' consistency across countries regarding users' demographic profiles, contraceptive choices, and personal attitudes toward menstruation supports the validity of making cross-country comparisons of survey findings for a given app's users. CONCLUSIONS: MTAs such as Clue can provide a quick, scalable, and cost-effective method for collecting health data, including on sensitive topics, across a wide variety of settings and countries. With expanding global access to technology and the increasing use of these tools, consumer MTAs can be a viable survey modality to strengthen reproductive health research.

Obesity modulates the cellular and molecular microenvironment in the peritoneal cavity: implication for ovarian cancer risk.

Introduction: Abdominal obesity increases the risk of developing ovarian cancer but the molecular mechanisms of how obesity supports ovarian cancer development remain unknown. Here we investigated the impact of obesity on the immune cell and gene expression profiles of distinct abdominal tissues, focusing on the peritoneal serous fluid (PSF) and the omental fat band (OFB) as critical determinants for the dissemination of ovarian metastases and early metastatic events within the peritoneal cavity. Methods: Female C57BL/6 mice were fed a low-fat (LFD) or a high-fat diet (HFD) for 12 weeks until the body weights in the HFD group were significantly higher and the mice displayed an impaired glucose tolerance. Then the mice were injected with the murine ovarian cancer cells (MOSE-LTICv) while remaining on their diets. After 21 days, the mice were sacrificed, tumor burden was evaluated and tissues were harvested. The immune cell composition of abdominal tissues and changes in gene expression in the PSF and OFB were evaluated by flow cytometry and qPCR RT2-profiler PCR arrays and confirmed by qRT-PCR, respectively. Other peritoneal adipose tissues including parametrial and retroperitoneal white adipose tissues as well as blood were also investigated. Results: While limited effects were observed in the other peritoneal adipose tissues, feeding mice the HFD led to distinct changes in the immune cell composition in the PSF and the OFB: a depletion of B cells but an increase in myeloid-derived suppressor cells (MDSC) and mono/granulocytes, generating pro-inflammatory environments with increased expression of cyto- and chemokines, and genes supporting adhesion, survival, and growth, as well as suppression of apoptosis. This was associated with a higher peritoneal tumor burden compared to mice fed a LFD. Changes in cellular and genetic profiles were often exacerbated by the HFD. There was a large overlap in genes that were modulated by both the HFD and the cancer cells, suggesting that this 'genetic fingerprint' is important for ovarian metastases to the OFB. Discussion: In accordance with the 'seed and soil' theory, our studies show that obesity contributes to the generation of a pro-inflammatory peritoneal environment that supports the survival of disseminating ovarian cancer cells in the PSF and the OFB and enhances the early metastatic adhesion events in the OFB through an increase in extracellular matrix proteins and modulators such as fibronectin 1 and collagen I expression as well as in genes supporting growth and invasion such as Tenacin C. The identified genes could potentially be used as targets for prevention strategies to lower the ovarian cancer risk in women with obesity.

Interleukin-12 Immunomodulation Delays the Onset of Lethal Peritoneal Disease of Ovarian Cancer.

The omental fat band (OFB) is the predominant site for metastatic seeding of ovarian cancer. Previously, we highlighted the influx and accumulation of neutrophils and macrophages in the OFB following syngeneic ovarian cancer cell seeding as an important factor in the development of a protumorigenic cascade. Here we investigated localized immunomodulation as a means of promoting a successful protective response. As an important TH1-type immunomodulator, interleukin (IL)-12 has previously been investigated clinically as an anticancer therapeutic. However, systemic IL-12 administration was associated with serious side effects, galvanizing the development of immune or accessory cells engineered to express secreted or membrane-bound IL-12 (mbIL-12). Using an mbIL-12-expressing cell variant, we demonstrate that localized IL-12 in the tumor microenvironment significantly delays disease development. The mbIL-12-mediated decrease in tumor burden was associated with a significant reduction in neutrophil and macrophage infiltration in the OFB, and correlated with a reduced expression of neutrophil and macrophage chemoattractants (CXCL1, -2, -3 and CCL2, -7). Vaccination with mitotically impaired tumor cells did not confer protection against subsequent tumor challenge, indicating that IL-12 did not impact the immunogenicity of the cancer cells. Our findings are in agreement with previous reports suggesting that IL-12 may hold promise when delivered in a targeted and sustained manner to the omental microenvironment. Furthermore, resident cells within the omental microenvironment may provide a reservoir that can be activated and mobilized to prevent metastatic seeding within the peritoneum and, therefore, may be targets for chemotherapeutics.

The parity-associated microenvironmental niche in the omental fat band is refractory to ovarian cancer metastasis.

Ovarian cancer is an insidious and aggressive disease of older women, typically undiscovered before peritoneal metastasis due to its asymptomatic nature and lack of early detection tools. Epidemiologic studies suggest that child-bearing (parity) is associated with decreased ovarian cancer risk, although the molecular mechanisms responsible for this phenomenon have not been delineated. Ovarian cancer preferentially metastasizes to the omental fat band (OFB), a secondary lymphoid organ that aids in filtration of the peritoneal serous fluid (PSF) and helps combat peritoneal infections. In the present study, we assessed how parity and age impact the immune compositional profile in the OFB of mice, both in the homeostatic state and as a consequence of peritoneal implantation of ovarian cancer. Using fluorescence-activated cell sorting analysis and quantitative real-time PCR, we found that parity was associated with a significant reduction in omental monocytic subsets and B1-B lymphocytes, correlating with reduced homeostatic expression levels of key chemoattractants and polarization factors (Ccl1, Ccl2, Arg1, and Cxcl13). Of note, parous animals exhibited significantly reduced tumor burden following intraperitoneal implantation compared with nulliparous animals. This was associated with a reduction in tumor-associated neutrophils and macrophages, as well as in the expression levels of their chemoattractants (Cxcl1 and Cxcl5) in the OFB and PSF. These findings define a preexisting "parity-associated microenvironmental niche" in the OFB that is refractory to metastatic tumor seeding and outgrowth. Future studies designed to manipulate this niche may provide a novel means to mitigate peritoneal dissemination of ovarian cancer.

Intra-abdominal fat depots represent distinct immunomodulatory microenvironments: a murine model.

White adipose tissue (WAT) is a multi-faceted endocrine organ involved in energy storage, metabolism, immune function and disease pathogenesis. In contrast to subcutaneous fat, visceral fat (V-WAT) has been associated with numerous diseases and metabolic disorders, indicating specific functions related to anatomical location. Although visceral depots are often used interchangeably in V-WAT-associated disease studies, there has been a recent subdivision of V-WAT into "true visceral" and non-visceral intra-abdominal compartments. These were associated with distinct physiological roles, illustrating a need for depot-specific information. Here, we use FACS analysis to comparatively characterize the leukocyte and progenitor populations in the stromal vascular fraction (SVF) of peritoneal serous fluid (PSF), parametrial (pmWAT), retroperitoneal (rpWAT), and omental (omWAT) adipose tissue from seven-month old C57BL/6 female mice. We found significant differences in SVF composition between all four microenvironments. PSF SVF was comprised almost entirely of CD45(+) leukocytes (>99%), while omWAT contained less, but still almost two-fold more leukocytes than pmWAT and rpWAT (75%, 38% and 38% respectively; p<0.01). PmWAT was composed primarily of macrophages, whereas rpWAT more closely resembled omWAT, denoted by high levels of B1 B-cell and monocyte populations. Further, omWAT harbored significantly higher proportions of T-cells than the other tissues, consistent with its role as a secondary lymphoid organ. These SVF changes were also reflected in the gene expression profiles of the respective tissues. Thus, intra-abdominal fat pads represent independent immunomodulatory microenvironments and should be evaluated as distinct entities with unique contributions to physiological and pathological processes.

Actin filaments play a primary role for structural integrity and viscoelastic response in cells.

This atomic force microscopy (AFM) study is devoted to the analysis of the mouse ovarian cancer cell's cytoskeleton components and the impact of both actin and microtubulin filaments on a cell's deformation behavior. Early stage, non-tumorigenic cancer cells show abundant well-organized cytoskeletal structures consisting of both actin and microtubule filaments. In sharp contrast, cells representing late and more aggressive stages of cancer display highly disorganized actin and microtubule structures. With the use of actin microfilament targeting drugs, together with the suberoylanilide hydroxamic acid (SAHA) and tubastatin A anti-cancer drugs, we modified the cell architectural framework and performed nano-indentation tests to evaluate cell elasticity and viscosity as a function of each biopolymer's weighted presence. Results demonstrate that both mechanical properties are heavily influenced by the levels and organization state of actin microfilaments; decreasing the actin organization of cells results in 85% and 79% decrease in cell elasticity and viscosity, respectively. In contrast, microtubule organization was shown to exert only marginal effects on either property. Furthermore, the anti-cancer drug, SAHA, was shown to exert little impact on the viscoelastic response of cancer cells. Finally, we report for the first time that tubastatin A, a specific HDAC6 inhibitor, increased cell elasticity as revealed by AFM tests without exerting drastic changes to the actin microfilament or microtubule networks. Our findings raise interest in a potential HDAC6 target that affects cellular mechanics just as effectively as the conventionally known cytoskeleton components.