An artificial intelligence approach for investigating multifactorial pain-related features of endometriosis.

Endometriosis is a debilitating, chronic disease that is estimated to affect 11% of reproductive-age women. Diagnosis of endometriosis is difficult with diagnostic delays of up to 12 years reported. These delays can negatively impact health and quality of life. Vague, nonspecific symptoms, like pain, with multiple differential diagnoses contribute to the difficulty of diagnosis. By investigating previously imprecise symptoms of pain, we sought to clarify distinct pain symptoms indicative of endometriosis, using an artificial intelligence-based approach. We used data from 473 women undergoing laparoscopy or laparotomy for a variety of surgical indications. Multiple anatomical pain locations were clustered based on the associations across samples to increase the power in the probability calculations. A Bayesian network was developed using pain-related features, subfertility, and diagnoses. Univariable and multivariable analyses were performed by querying the network for the relative risk of a postoperative diagnosis, given the presence of different symptoms. Performance and sensitivity analyses demonstrated the advantages of Bayesian network analysis over traditional statistical techniques. Clustering grouped the 155 anatomical sites of pain into 15 pain locations. After pruning, the final Bayesian network included 18 nodes. The presence of any pain-related feature increased the relative risk of endometriosis (p-value < 0.001). The constellation of chronic pelvic pain, subfertility, and dyspareunia resulted in the greatest increase in the relative risk of endometriosis. The performance and sensitivity analyses demonstrated that the Bayesian network could identify and analyze more significant associations with endometriosis than traditional statistical techniques. Pelvic pain, frequently associated with endometriosis, is a common and vague symptom. Our Bayesian network for the study of pain-related features of endometriosis revealed specific pain locations and pain types that potentially forecast the diagnosis of endometriosis.

Endometriosis diagnosis, staging and typology and adverse pregnancy outcome history.

BACKGROUND: Women with endometriosis may have an increased risk of adverse pregnancy outcomes. Research has focused on infertility clinic populations limiting generalisability. Few studies report differences by endometriosis severity. OBJECTIVES: We investigated the relationships between endometriosis diagnosis, staging and typology and pregnancy outcomes among an operative and population-based sample of women. METHODS: Menstruating women ages 18-44 years enrolled in the ENDO Study (2007-2009), including the operative cohort: 316 gravid women undergoing laparoscopy/laparotomy at surgical centres in Utah and California; and the population cohort: 76 gravid women from the surgical centres' geographic catchment areas. Pregnancy outcomes were ascertained by questionnaire and included all pregnancies prior to study enrolment. Endometriosis was diagnosed via surgical visualisation in the operative cohort and pelvic magnetic resonance imaging in the population cohort. Adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) were estimated using generalised linear mixed models for pregnancy outcomes, adjusting for women's age at study enrolment and at pregnancy, surgical site, body mass index and lifestyle factors. RESULTS: Women in the operative cohort with visualised endometriosis (n = 109, 34%) had a lower prevalence of live births, aPR 0.94 (95% CI 0.85, 1.03) and a higher prevalence of miscarriages, aPR 1.48 (95% CI 1.23, 1.77) compared with women without endometriosis. The direction and magnitude of estimates were similar in the population cohort. Women with deep endometriosis were 2.98-fold more likely (95% CI 1.12, 7.95) to report a miscarriage compared with women without endometriosis after adjusting for women's age at study enrolment and at pregnancy, surgical site and body mass index. No differences were seen between endometriosis staging and pregnancy outcomes. CONCLUSIONS: While there was no difference in number of pregnancies among women with and without endometriosis in a population-based sample, pregnancy loss was more common among women with endometriosis, notably among those with deep endometriosis.

Insulin facilitates corneal wound healing in the diabetic environment through the RTK-PI3K/Akt/mTOR axis in vitro.

Diabetic patients can develop degenerative corneal changes, termed diabetic keratopathy, during the course of their disease. Topical insulin has been shown to reduce corneal wound area and restore sensitivity in diabetic rats, and both the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) stimulate cell signaling of the PI3K-Akt pathway. The purpose of this study was to assess a mechanism by which improved wound healing occurs by characterizing expression within the PI3K-Akt pathway in corneal epithelial and stromal cells. In vitro scratch tests were used to evaluate wound healing outcomes under variable glucose conditions in the presence or absence of insulin. Protein expression of intracellular kinases in the PI3K pathway, stromal cell markers, and GLUT-1 was evaluated by immunoblotting.TGF-ß1 expression was evaluated by ELISA. Insulin promoted in vitro wound healing in all cell types. In human corneal epithelial cells, insulin did not induce PI3K-Akt signaling; however, in all other cell types evaluated, insulin increased expression of PI3K-Akt signaling proteins compared to vehicle control. Fibroblasts variably expressed α-SMA under all treatment conditions, with significant increases in α-SMA and TGF-ß1 occurring in a dose-dependent manner with glucose concentration. These results indicate that insulin can promote corneal cellular migration and proliferation by inducing Akt signaling. Exogenous insulin therapy may serve as a novel target of therapeutic intervention for diabetic keratopathy.

Adiposity and Endometriosis Severity and Typology.

STUDY OBJECTIVE: Prior research has collectively shown that endometriosis is inversely related to women's adiposity. The aim of this study was to assess whether this inverse relationship holds true by disease severity and typology. DESIGN: Cross-sectional study among women with no prior diagnosis of endometriosis. SETTING: Fourteen clinical centers in Salt Lake City, UT, and San Francisco, CA. PATIENTS: A total of 495 women (of which 473 were analyzed), aged 18-44 years, were enrolled in the operative cohort of the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) Study. INTERVENTIONS: Gynecologic laparoscopy/laparotomy regardless of clinical indication. MEASUREMENTS AND MAIN RESULTS: Participants underwent anthropometric assessments, body composition measurements, and evaluations of body fat distribution ratios before surgery. Surgeons completed a standardized operative report immediately after surgery to capture revised American Society for Reproductive Medicine staging (I-IV) and typology of disease (superficial endometriosis [SE], ovarian endometrioma [OE], and deep infiltrating endometriosis [DIE]). Linear mixed models, taking into account within-clinical-center correlation, were used to generate least square means (95% confidence intervals) to assess differences in adiposity measures by endometriosis stage (no endometriosis, I-IV) and typology (no endometriosis, SE, DIE, OE, OE + DIE) adjusting for age, race/ethnicity, and parity. Although most confidence intervals were wide and overlapping, 3 general impressions emerged: (1) women with incident endometriosis had the lowest anthropometric/body composition indicators compared with those without incident endometriosis, (2) women with stage I or IV endometriosis had lower indicators compared with women with stage II or III, and (3) women with OE and/or DIE tended to have the lowest indicators, whereas women with SE had the highest indicators. CONCLUSION: Our research highlights that the relationship between women's adiposity and endometriosis severity and typology may be more complicated than prior research indicates.

Cervical cancer screening decentralized policy adaptation: an African rural-context-specific systematic literature review.

BACKGROUND: Worldwide, nearly 570,000 women are diagnosed with cervical cancer each year, with 85% of new cases in low- and middle-income countries. The African continent is home to 35 of 40 countries with the highest cervical cancer mortality rates. In 2014, a partnership involving a rural region of Senegal, West Africa, was facing cervical cancer screening service sustainability barriers and began adapting regional-level policy to address implementation challenges. OBJECTIVE: This manuscript reports the findings of a systematic literature review describing the implementation of decentralized cervical cancer prevention services in Africa, relevant in context to the Senegal partnership. We report barriers and policy-relevant recommendations through Levesque's Patient-Centered Access to Healthcare Framework and discuss the impact of this information on the partnership's approach to shaping Senegal's regional cervical cancer screening policy. METHODS: The systematic review search strategy comprised two complementary sub-searches. We conducted an initial search identifying 4272 articles, then applied inclusion criteria, and ultimately 19 studies were included. Data abstraction focused on implementation barriers categorized with the Levesque framework and by policy relevance. RESULTS: Our findings identified specific demand-side (clients and community) and supply-side (health service-level) barriers to implementation of cervical cancer screening services. We identify the most commonly reported demand- and supply-side barriers and summarize salient policy recommendations discussed within the reviewed literature. CONCLUSIONS: Overall, there is a paucity of published literature regarding barriers to and best practices in implementation of cervical cancer screening services in rural Africa. Many articles in this literature review did describe findings with notable policy implications. The Senegal partnership has consulted this literature when faced with various similar barriers and has developed two principal initiatives to address contextual challenges. Other initiatives implementing cervical cancer visual screening services in decentralized areas may find this contextual reporting of a literature review helpful as a construct for identifying evidence for the purpose of guiding ongoing health service policy adaptation.

Alterations in quadriceps muscle cellular and molecular properties in adults with moderate knee osteoarthritis.

OBJECTIVE: Quadriceps muscle weakness is common in knee osteoarthritis (OA). While pain, disuse, and atrophy are commonly cited causes for muscle weakness in OA, emerging evidence suggests changes in muscle quality also occur. Alterations in muscle quality are not well understood, but likely include both cellular and morphologic adaptions. The purpose of this study was to conduct the first cellular-level analysis of the vastus lateralis in adults with moderate knee OA. METHODS: Vastus lateralis biopsies were obtained from 24 subjects with moderate knee OA and 15 healthy controls. Quadriceps strength, muscle fiber cross sectional area (CSA), fiber type distribution, extracellular matrix (ECM) content, satellite cell abundance, and profibrotic gene expression were assessed. RESULTS: Relative to controls, quadriceps strength was significantly lower in OA subjects (OA 62.23, 50.67-73.8 Nm vs 91.46, 75.91-107.0 Nm, P = 0.003) despite no difference in fiber CSA. OA subjects had significantly fewer Type I fibers (OA 41.51, 35.56-47.47% vs 53.07, 44.86-61.29%, P = 0.022) and more hybrid IIa/x fibers (OA 24.61, 20.61-28.61% vs 16.4, 11.60-21.20%, P = 0.009). Significantly greater ECM content, lower satellite cell density, and higher profibrotic gene expression was observed with OA, and muscle collagen content was inversely correlated to strength and satellite cell (SC) density. CONCLUSION: Lower quadriceps function with moderate OA may not result from fiber size impairments, but is associated with ECM expansion. Impaired satellite cell density, high profibrotic gene expression, and a slow-to-fast fiber type transition may contribute to reduced muscle quality in OA. These findings can help guide therapeutic interventions to enhance muscle function with OA.

Endometrial Cancers Harboring Mutated Fibroblast Growth Factor Receptor 2 Protein Are Successfully Treated With a New Small Tyrosine Kinase Inhibitor in an Orthotopic Mouse Model.

OBJECTIVES: AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors (VEGFR1, VEGFR2/KDR, and VEGFR3), stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFß), and fibroblast growth factor receptors (FGFR1, FGFR2, and FGFR3). This study evaluates the efficacy of AL3818 studying tumor regression in an orthotopic murine endometrial cancer model. METHODS: We tested the cytotoxicity of AL3818 on a panel of 7 human endometrial cancer cell lines expressing either wild-type or mutant FGFR2 and also assessed the in vivo antitumor efficacy in a murine, orthotopic AN3CA endometrial cancer model. AL3818 was administered daily per os either alone or in combination with carboplatin and paclitaxel, which represent the current standard of adjuvant care for endometrial cancer. RESULTS: AL3818 significantly reduces AN3CA cell number in vitro, characterized by high expression of a mutated FGFR2 protein. Daily oral administration of AL3818 (5 mg/kg) resulted in a complete response in 55% of animals treated and in a reduced tumor volume, as well as decreased tumor weights of AN3CA tumors by 94% and 96%, respectively, following a 29-day treatment cycle. Whereas carboplatin and paclitaxel failed to alter tumor growth, the combination with AL3818 did not seem to exhibit a superior effect when compared with AL3818 treatment alone. CONCLUSIONS: AL3818 shows superior efficacy for the treatment of endometrial cancer irresponsive to conventional carboplatin and paclitaxel combination and warrants further investigation.

Beyond Body Mass Index: Using Anthropometric Measures and Body Composition Indicators to Assess Odds of an Endometriosis Diagnosis.

BACKGROUND: Body mass index (BMI) and endometriosis have been inversely associated. To address gaps in this research, we examined associations among body composition, endometriosis, and physical activity. MATERIALS AND METHODS: Women from 14 clinical sites in the Salt Lake City, Utah and San Francisco, California areas and scheduled for laparoscopy/laparotomy were recruited during 2007-2009. Participants (N = 473) underwent standardized anthropometric assessments to estimate body composition before surgery. Using a cross-sectional design, odds of an endometriosis diagnosis (adjusted odds ratio [aOR]; 95% confidence interval [CI]) were calculated for anthropometric and body composition measures (weight in kg; height in cm; mid upper arm, waist, hip, and chest circumferences in cm; subscapular, suprailiac, and triceps skinfold thicknesses in mm; arm muscle and fat areas in cm2; centripetal fat, chest-to-waist, chest-to-hip, waist-to-hip, and waist-to-height ratios; arm fat index; and BMI in kg/m2). Physical activity (metabolic equivalent of task-minutes/week) and sedentariness (average minutes sitting on a weekday) were assessed using the International Physical Activity Questionnaire-Short Form. Measures were modeled continuously and in quartiles based on sample estimates. Adjusted models were controlled for age (years, continuous), site (Utah/California), smoking history (never, former, or current smoker), and income (below, within 180%, and above of the poverty line). Findings were standardized by dividing variables by their respective standard deviations. We used adjusted models to examine whether odds of an endometriosis diagnosis were moderated by physical activity or sedentariness. RESULTS: Inverse relationships were observed between endometriosis and standardized: weight (aOR = 0.71, 95% CI 0.57-0.88); subscapular skinfold thickness (aOR = 0.79, 95% CI 0.65-0.98); waist and hip circumferences (aOR = 0.79, 95% CI 0.64-0.98 and aOR = 0.76, 95% CI 0.61-0.94, respectively); total upper arm and upper arm muscle areas (aOR = 0.76, 95% CI 0.61-0.94 and aOR = 0.74, 95% CI 0.59-0.93, respectively); and BMI (aOR = 0.75, 95% CI 0.60-0.93), despite similar heights. Women in the highest versus lowest quartile had lower adjusted odds of an endometriosis diagnosis for: weight; mid-upper arm, hip, and waist circumferences; total upper arm and upper arm muscle areas; BMI; and centripetal fat ratio. There was no evidence of a main effect or moderation of physical activity or sedentariness. CONCLUSION: In a surgical cohort, endometriosis was inversely associated with anthropometric measures and body composition indicators.

Endometriosis diagnosis and staging by operating surgeon and expert review using multiple diagnostic tools: an inter-rater agreement study.

OBJECTIVE: To determine agreement on endometriosis diagnosis between real-time laparoscopy and subsequent expert review of digital images, operative reports, magnetic resonance imaging (MRI), and histopathology, viewed sequentially. DESIGN: Inter-rater agreement study. SETTING: Five urban surgical centres. POPULATION: Women, aged 18-44 years, who underwent a laparoscopy regardless of clinical indication. A random sample of 105 women with and 43 women without a postoperative endometriosis diagnosis was obtained from the ENDO study. METHODS: Laparoscopies were diagnosed, digitally recorded, and reassessed. MAIN OUTCOME MEASURES: Inter-observer agreement of endometriosis diagnosis and staging according to the revised American Society for Reproductive Medicine criteria. Prevalence and bias-adjusted kappa values (κ) were calculated for diagnosis, and weighted κ values were calculated for staging. RESULTS: Surgeons and expert reviewers had substantial agreement on diagnosis and staging after viewing digital images (n = 148; mean κ = 0.67, range 0.61-0.69; mean κ = 0.64, range 0.53-0.78, respectively) and after additionally viewing operative reports (n = 148; mean κ = 0.88, range 0.85-0.89; mean κ = 0.85, range 0.84-0.86, respectively). Although additionally viewing MRI findings (n = 36) did not greatly impact agreement, agreement substantially decreased after viewing histological findings (n = 67), with expert reviewers changing their assessment from a positive to a negative diagnosis in up to 20% of cases. CONCLUSION: Although these findings suggest that misclassification bias in the diagnosis or staging of endometriosis via visualised disease is minimal, they should alert gynaecologists who review operative images in order to make decisions on endometriosis treatment that operative reports/drawings and histopathology, but not necessarily MRI, will improve their ability to make sound judgments. TWEETABLE ABSTRACT: Endometriosis diagnosis and staging agreement between expert reviewers and operating surgeons was substantial.

Female infertility, infertility-associated diagnoses, and comorbidities: a review.

PURPOSE: The purpose of the study is to evaluate existing literature for possible associations between female infertility, infertility-associated diagnoses, and the following areas of disease: psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. METHODS: The design of the study is a literature review. The patients were women included in 26 selected studies due to a diagnosis of infertility or a reproductive disorder associated with infertility. This study has no interventions, and the main outcome measure is the association between female infertility or a related diagnosis and psychiatric disorders, breast cancer, ovarian cancer, endometrial cancer, cardiovascular disease, and metabolic dysfunction. RESULTS: Female infertility and related reproductive disorders may have ramifications for women beyond reproductive health. An analysis of publications shows that women with infertility had higher rates of psychiatric disorders and endometrial cancer than the general population [1-10]. Data is conflicting about whether infertile women are at increased risk for breast cancer and ovarian cancer [7, 8, 10-20]. A generalized diagnosis of infertility was not clearly associated with an increased risk of cardiovascular disease or metabolic dysfunction, but women with infertility related to polycystic ovarian syndrome (PCOS) do appear more likely to develop cardiovascular disease and metabolic disorders such as diabetes than the general population [16, 21-26]. CONCLUSIONS: Female infertility and associated diagnoses have overall health implications. Beyond treatment of patients' immediate reproductive needs, healthcare professionals must be aware of the broader health impact of specific causes of infertility in order to provide accurate counseling regarding long-term risk.

Nanoparticle Based Combination Treatments for Targeting Multiple Hallmarks of Cancer.

Treatment of cancer remains one of the most challenging tasks facing the healthcare system. Cancer affects the lives of millions of people and is often fatal. Current treatment methods include surgery, chemotherapy, radiation therapies or some combinations of these. However, recurrence is a major problem. These treatments can be invasive with severe side effects. Inefficacies in treatments are a result of the complex and variable biology of cancerous cells. Malignant tumor cells and normal functioning cells share many of the same biological characteristics but the main difference is that in cancer cells there is in an overuse and over expression of these biological characteristics. These pertinent characteristics can be grouped into eight hallmarks, as illustrated by Hanahan and Weinberg. These characteristics include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction. In order to provide a noninvasive, effective treatment, delivery methods must be explored in order to transport cytotoxic agents used for targeting the hallmarks of cancer in a safer and more effective fashion. The use of nanoparticles as drug delivery carriers provides an effective method in which multiple cytotoxic agents can be safely delivered to cancer tissue to simultaneously target multiple hallmarks. By targeting multiple hallmarks of cancer at once, the efficacy of cancer treatments could be improved drastically. This review explores the uses and efficacy of combination therapies using nanoparticles that can simultaneously target multiple hallmarks of cancer.

Women's Reproductive History Before the Diagnosis of Incident Endometriosis.

BACKGROUND: Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction. MATERIALS AND METHODS: The study sample comprised 473 women (aged 18-44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007-2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs <1.0 denote a longer TTP or diminished fecundity. RESULTS: Approximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46-1.10). While FORs were consistently <1.0, irrespective of endometriosis staging, CIs included 1. CONCLUSIONS: Women with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment.

Imiquimod Induces Apoptosis in Human Endometrial Cancer Cells In vitro and Prevents Tumor Progression In vivo.

PURPOSE: The increasing incidence of endometrial cancer (EC), in younger age at diagnosis, calls for new tissue-sparing treatment options. This work aims to evaluate the potential of imiquimod (IQ) in the treatment of low-grade EC. METHODS: Effects of IQ on the viabilities of Ishikawa and HEC-1A cells were evaluated using MTT assay. The ability of IQ to induce apoptosis was evaluated by testing changes in caspase 3/7 levels and expression of cleaved caspase-3, using luminescence assay and western blot. Apoptosis was confirmed by flow cytometry and the expression of cleaved PARP. Western blot was used to evaluate the effect of IQ on expression levels of Bcl-2, Bcl-xL, and BAX. Finally, the in vivo efficacy of IQ was tested in an EC mouse model. RESULTS: There was a decrease in EC cell viability following IQ treatment as well as increased caspase 3/7 activities, cleaved caspase-3 expression, and Annexin-V/ 7AAD positive cell population. Western blot results showed the ability of IQ in cleaving PARP, decreasing Bcl-2 and Bcl-xL expressions, but not affecting BAX expression. In vivo study demonstrated IQ's ability to inhibit EC tumor growth and progression without significant toxicity. CONCLUSIONS: IQ induces apoptosis in low-grade EC cells in vitro, probably through its direct effect on Bcl-2 family protein expression. In, vivo, IQ attenuates EC tumor growth and progression, without an obvious toxicity. Our study provides the first building block for the potential role of IQ in the non-surgical management of low-grades EC and encouraging further investigations.

Sexual and physical abuse and gynecologic disorders.

STUDY QUESTION: Is sexual and/or physical abuse history associated with incident endometriosis diagnosis or other gynecologic disorders among premenopausal women undergoing diagnostic and/or therapeutic laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: No association was observed between either a history of sexual or physical abuse and risk of endometriosis, ovarian cysts or fibroids; however, a history of physical abuse was associated with a higher likelihood of adhesions after taking into account important confounding and mediating factors. WHAT IS KNOWN ALREADY: Sexual and physical abuse may alter neuroendocrine-immune processes leading to a higher risk for endometriosis and other noninfectious gynecologic disorders, but few studies have assessed abuse history prior to diagnosis. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at 1 of the 14 surgical centers located in Salt Lake City, UT, USA or San Francisco, CA, USA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Prior to surgery, women completed standardized abuse questionnaires. Relative risk (RR) of incident endometriosis, uterine fibroids, adhesions or ovarian cysts by abuse history were estimated, adjusting for age, race/ethnicity, education, marital status, smoking, gravidity and recruitment site. We assessed whether a history of chronic pelvic pain, depression, or STIs explained any relationships via mediation analyses. MAIN RESULTS AND ROLE OF CHANCE: 43 and 39% of women reported experiencing sexual and physical abuse. No association was observed between either a history of sexual or physical abuse, versus no history, and risk of endometriosis (aRR: 1.00 [95% confidence interval (CI): 0.80-1.25]); aRR: 0.83 [95% CI: 0.65-1.06]), ovarian cysts (aRR: 0.67 [95% CI: 0.39-1.15]); aRR: 0.60 [95% CI: 0.34-1.09]) or fibroids (aRR: 1.25 [95% CI: 0.85-1.83]); aRR: 1.36 [95% CI: 0.92-2.01]). Conversely, a history of physical abuse, versus no history, was associated with higher risk of adhesions (aRR: 2.39 [95% CI: 1.18-4.85]). We found no indication that the effect of abuse on women's adhesion risk could be explained by a history of chronic pelvic pain, depression or STIs. LIMITATIONS, REASONS FOR CAUTION: Limitations to our study include inquiries on childhood physical but not sexual abuse. Additionally, we did not inquire about childhood or adulthood emotional support systems, found to buffer the negative impact of stress on gynecologic health. WIDER IMPLICATIONS OF THE FINDINGS: Abuse may be associated with some but not all gynecologic disorders with neuroendocrine-inflammatory origin. High prevalence of abuse reporting supports the need for care providers to screen for abuse and initiate appropriate follow-up. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Design and Characterization of Bioengineered Cancer-Like Stem Cells.

Cancer stem cells (CSCs) are a small subset of cancer cells responsible for maintenance and progression of several types of cancer. Isolation, propagation, and the differentiation of CSCs in the proper stem niches expose the intrinsic difficulties for further studies. Here we show that induced cancer like stem cells (iCLSCs) can be generated by in vitro oncogenic manipulation of mouse embryonic stem cells (mESCs) with well-defined oncogenic elements; SV40 LTg and HrasV12 by using a mouse stem virus long terminal repeat (MSCV-LTR)-based retroviral system. The reprogrammed mESCs using both oncogenes were characterized through their oncogenic gene expression, the enhancement of proliferation, and unhampered maintenance of stem properties in vitro and in vivo. In addition, these transformed cells resulted in the formation of malignant, immature ovarian teratomas in vivo. To successfully further expand these properties to other organs and species, more research needs to be done to fully understand the role of a tumor- favorable microenvironment. Our current study has provided a novel approach to generate induced cancer like stem cells through in vitro oncogenic reprogramming and successfully initiated organ-specific malignant tumor formation in an orthotopic small animal cancer model.

Pain typology and incident endometriosis.

STUDY QUESTION: What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication? SUMMARY ANSWER: Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis. WHAT IS KNOWN ALREADY: Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management. STUDY DESIGN, SIZE, DURATION: The study population for these analyses includes the ENDO Study (2007-2009) operative cohort: 473 women, ages 18-44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months. MAIN RESULTS AND THE ROLE OF CHANCE: There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location. LIMITATIONS, REASONS FOR CAUTION: Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons. WIDER IMPLICATIONS OF THE FINDINGS: Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed. STUDY FUNDING/COMPETING INTERESTS: Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.

Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration.

Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (>40%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of >1000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver pro-regenerative therapies.

An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations.

Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in ß-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH.

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

Thermosensitive progesterone hydrogel: a safe and effective new formulation for vaginal application.

PURPOSE: The safe and functional delivery of progesterone through the vaginal route remains an unmet clinical need. The purpose of this work is to prepare a new progesterone (P4) gel for vaginal application using a thermosensitive mucoadhesive polymer, glycol chitin (GC). METHOD: Thermogelling, mucoadhesive, mechanical, and viscoelastic properties of GC and the new formulation were evaluated using rheometry. In vitro release profile and the bioactivity of P4 were determined using vaginal fluid simulant (VFS) pH 4.2, and PR-reporter gene assay, respectively. In vitro safety of the formulations was tested using (VK2/E6E7) vaginal epithelial cell line and Lactobacillus Crispatus. Finally, in vivo safety and the efficacy of this formulation were evaluated using an endometrial hypoplasia mouse model. RESULTS: Results shows the aqueous solution of 5%; (w/v) GC loaded with 0.1%; (w/v) P4 prepared in pH 4.2, (GC-P4), forms a thermosensitive mucoadhesive hydrogel and can maintain stable physical properties at 37 °C. GC-P4 gel release 50% of P4 in 4 h after exposure to VFS, and no significant decrease in % viability of VK2/E6E7 or Lactobacillus was found after exposure to 5% GC or GC-P4. GC-P4 does not exhibit obvious toxicities to vaginal tissue in vivo even after repeated application. Efficacy studies indicated that GC-P4 was capable of preventing the progression of simple endometrial hyperplasia (SEH) to complex atypical endometrial hyperplasia (CAEH) in vivo. CONCLUSIONS: Results indicates that GC-P4 retains many characteristics for an effective vaginal delivery system for P4. Therefore we believe that GC-P4 formulation is a promising alternative to current vaginal P4 formulation.