Identifying and Targeting Molecular Deregulations in Uterine Leiomyosarcoma: A Role for mTOR Inhibition-Based Combination Therapies

Uterine leiomyosarcoma (ULMS) is an aggressive malignancy characterized by marked chemoresistance, frequent relapses, and poor outcome. Despite efforts to improve survival over the past several decades, only minimal advances have been made. Hence, there is an urgent and unmet need for better understanding of the molecular deregulations that underlay ULMS and development of more effective therapeutic strategies. This work identified several common deregulations in a large (n=208) tissue microarray of ULMS compared to GI smooth muscle, myometrium, and leiomyoma controls. Our results suggest that significant loss of smooth muscle and gynecological differentiation markers is common in ULMS, a finding that could help render improved ULMS diagnosis, especially for advanced disease. Similarly to reports in other malignancies, we found that several cancer-related proteins were differentially expressed; these could be useful together as biomarkers for ULMS. Notably, we identified significant upregulation and overexpression of the mTOR pathway in ULMS, examined the possible contribution of tyrosine kinase receptor deregulation promoting mTOR activation, and unraveled a role for pS6RP and p4EBP1 as molecular disease prognosticators. The significance of mTOR activation in ULMS and its potential as a therapeutic target were further investigated. Rapamycin abrogated ULMS cell growth and cell cycle progression in vitro but induced only sight growth delay in vivo. Given that effective mTOR therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora A kinase (Aurk A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. Combined therapy with rapamycin (an mTORC1 inhibitor) and MLN8237 (an investigational Aurk A inhibitor) profoundly and synergistically abrogated ULMS growth in vitro. Interestingly, the superior effects were noted only when MLN8237 was pre-administered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. Together, these data support further exploration of dual mTOR and Aurk A blockade for the treatment of human ULMS.

A Genomic Approach to Identify The Notch Pathway as a Putative Tumor Suppressor in Endometrial Cancer

Endometrial cancer is the most common gynecological malignancy and the fourth most frequently diagnosed cancer among women. The molecular changes that distinguish normal endometrium from endometrial carcinoma are not thoroughly understood. Identification of these changes could potentially aid in identifying at-risk women who are especially prone to develop endometrial cancer, such as obese women and women with Lynch Syndrome. A microarray analysis was performed using normal endometrium from thin and obese women and cancerous endometrium from obese women. We validated the differential expression of ten genes whose expression was significantly up-regulated or down-regulated using qRT-PCR. All of the genes had distinct expression levels depending on the endometrial carcinoma histotype. As a result, they could serve as molecular markers to distinguish between normal endometrium and endometrial cancer, as well as between low grade endometrial carcinomas and high grade endometrial carcinomas. Two of the ten genes validated, HEYL and HES1, are down-stream targets of the Notch signaling pathway. HEYL and HES1 were identified by microarray and qRT-PCR to have a significant decrease in expression in endometrial carcinomas compared to normal endometrium. We further analyzed the differential expression of other components of the Notch signaling pathway, Notch4 and Jagged1. They were also identified by qRT-PCR to be significantly down-regulated in endometrial carcinomas compared to normal endometrium. Therefore, we believe the Notch signaling pathway to act as a tumor suppressor in endometrial carcinomas.

Salud e interculturalidad : un estudio en una población migrante en Mendoza

Los objetivos propuestos en la investigación han posibilitado identificar y documentar las barreras de acceso y los factores de riesgo en los cuidados de salud en ginecología y obstetricia y evaluar la situación sociofamiliar en la población migrante instrumentando acciones de inclusión en el sistema de salud de la provincia en aquellas pacientes que requirieron una atención de mayor complejidad. La experiencia de trabajo interdisciplinario en una comunidad ha posibilitado estudiar a 99 mujeres en edad fértil, en un 45% de origen boliviano, con alta vulnerabilidad social que habitan en el Distrito Belgrano de Guaymallén. Se realizó un estudio protocolizado, descriptivo y observacional con entrevistas semiestructuradas y control ginecológico, con toma de muestras para Papanicolaou y colposcopía en un consultorio que se instaló en el jardín maternal. Se aplicó un consentimiento informado a todas las mujeres antes de la realización de los estudios. La lectura de las muestras y los estudios específicos incluyeron mamografías y ecografías que se realizaron en los servicios de anatomía patológica y rayos del Hospital Universitario. El equipo del Hospital Universitario que concurrió a terreno estuvo formado por ginecólogos, trabajadores sociales, enfermeros y alumnos de las carreras de grado.

Roles of nitric oxide in tumor growth.

A subclone of the human colon adenocarcinoma cell line DLD-1, which grew reproducibly as subcutaneous tumors in nude mice, was isolated. Such cells, when engineered to generate nitric oxide (NO) continuously, grew more slowly in vitro than the wild-type parental cells. This growth retardation was reversed by the addition of N-iminoethyl-L-ornithine. In nude mice, however, the tumors from these cells grew faster than those derived from wild-type cells and were markedly more vascularized, suggesting that NO may act as part of a signaling cascade for neovascularization. Recent observations that the generation of NO in human breast and gynecological cancers correlates positively with tumor grade are consistent with this hypothesis. We suggest that NO may have a dual pro- and antitumor action, depending on the local concentration of the molecule.

Constructing the Vulvar Pain Assessment Questionnaire Inventory

The goals of this program of research were to examine the link between self-reported vulvar pain and clinical diagnoses, and to create a user-friendly assessment tool to aid in that process. These goals were undertaken through a series of four empirical studies (Chapters 2-6): one archival study, two online studies, and one study conducted in a Women’s Health clinic. In Chapter 2, the link between self-report and clinical diagnosis was confirmed by extracting data from multiple studies conducted in the Sexual Health Research Laboratory over the course of several years. We demonstrated the accuracy of diagnosis based on multiple factors, and explored the varied gynecological presentation of different diagnostic groups. Chapter 3 was based on an online study designed to create the Vulvar Pain Assessment Questionnaire (VPAQ) inventory. Following the construct validation approach, a large pool of potential items was created to capture a broad selection of vulvar pain symptoms. Nearly 300 participants completed the entire item pool, and a series of factor analyses were utilized to narrow down the items and create scales/subscales. Relationships were computed among subscales and validated scales to establish convergent and discriminant validity. Chapters 4 and 5 were conducted in the Department of Obstetrics & Gynecology at Oregon Health & Science University. The brief screening version of the VPAQ was employed with patients of the Program in Vulvar Health at the Center for Women’s Health. The accuracy and usefulness of the VPAQscreen was determined from the perspective of patients as well as their health care providers, and the treatment-seeking experiences of patients was explored. Finally, a second online study was conducted to confirm the factor structure, internal consistency, and test-retest reliability of the VPAQ inventory. The results presented in these chapters confirm the link between targeted questions and accurate diagnoses, and provide a guideline that is useful and accessible for providers and patients.

Guide to deliveries in Illinois hospitals /

Gynecological hospitalizations report will be published later.

Transactions of the Southern Surgical Association.

Imprint varies: Philadelphia : Lippincott <1985->

Transactions of the Western Surgical Association.

Mode of access: Internet.

Symptoms and diagnosis of borderline, early and advanced epithelial ovarian cancer

Objective. To document symptoms associated with borderline, early and advanced ovarian cancer and identify personal characteristics associated with early versus late diagnosis. Methods. Information concerning symptoms and diagnosis history was available from 811 women with ovarian cancer who took part in an Australian case–control study in the early 1990s. Women were classified into three groups for comparison based on their diagnosis: borderline, early (stage I–II) and advanced (stage III–IV) invasive cancer. Results. Sixteen percent of women with borderline tumors, 7% with early cancer and 4% with advanced cancer experienced no symptoms before diagnosis (P < 0.0001). Among women with symptoms, abdominal pain (44%) or swelling (39%) were most frequently reported; an abdominal mass (12%) and gynecological symptoms (12%) were less common. Compared to advanced stage cancer, women with early stage cancer were more likely to report an abdominal mass or urinary symptoms but less likely to report gastrointestinal problems or general malaise. General malaise and ‘other’ symptoms were least common in borderline disease. Older women, and those with higher parity or a family history of breast or ovarian cancer, were more likely to be diagnosed at an advanced stage of disease. Conclusions. Women who experience persistent or recurrent abdominal symptoms, particularly swelling and/or pain should be encouraged to seek medical attention and physicians should be alert to the possibility of ovarian cancer even in the absence of an abdominal mass. Further information about the prevalence of these symptoms in the general population is essential to assist physicians in patient management.

Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26

Endometriosis is a common gynecological disease that affects up to 10% of women in their reproductive years. It causes pelvic pain, severe dysmenorrhea, and subfertility. The disease is defined as the presence of tissue resembling endometrium in sites outside the uterus. Its cause remains uncertain despite 150 years of hypothesis-driven research, and thus the therapeutic options are limited. Disease predisposition is inherited as a complex genetic trait, which provides an alternative route to understanding the disease. We seek to identify susceptibility loci, using a positional-cloning approach that starts with linkage analysis to identify genomic regions likely to harbor these genes. We conducted a linkage study of 1,176 families ( 931 from an Australian group and 245 from a U. K. group), each with at least two members-mainly affected sister pairs-with surgically diagnosed disease. We have identified a region of significant linkage on chromosome 10q26 ( maximum LOD score [MLS] of 3.09; genomewide P = .047) and another region of suggestive linkage on chromosome 20p13 MLS p 2.09). Minor peaks with MLS > 1.0) were found on chromosomes 2, 6, 7, 8, 12, 14, 15, and 17. This is the first report of linkage to a major locus for endometriosis. The findings will facilitate discovery of novel positional genetic variants that influence the risk of developing this debilitating disease. Greater understanding of the aberrant cellular and molecular mechanisms involved in the etiology and pathophysiology of endometriosis should lead to better diagnostic methods and targeted treatments.

Psychological therapies for chronic pelvic pain:systematic review of randomized controlled trials

Chronic pelvic pain (CPP), a common cause of disability in women, is a condition best viewed in the biopsychosocial framework. Psychological interventions are frequently considered alongside medical and surgical treatments. Our objective was to evaluate the effectiveness of psychological therapies for the treatment of CPP. Electronic literature searches were conducted in Medline, Embase, PsycInfo and DARE databases from database inception to April 2010. Reference lists of selected articles were searched for further articles. The studies selected were randomized controlled trials of psychological therapies in patients with CPP compared with no treatment, standard gynecological treatment or another form of psychological therapy. Two reviewers independently selected articles without language restrictions and extracted data covering study characteristics, study quality and results. Reduction in pain, measured using visual analog scales or other measurements, was the main outcome measure. Of the 107 citations identified, four studies satisfied the inclusion criteria. Compared with no psychological intervention, therapy produced a standardized mean pain score of -3.27 [95% confidence interval (CI) -4.52 to -2.02] and 1.11 (95% CI -0.05 to 2.27) at 3 months and -3.95 (95% CI -5.35 to -2.55) and 0.54 (95% CI -0.78 to 1.86) at 6 months and greater, based on a visual analog scale score of 0-10. The current evidence does not allow us to conclude whether psychological interventions have an effect on self-reported pain scores in women with CPP.

Levonorgestrel intrauterine system versus medical therapy for menorrhagia

ABSTRACT: Menorrhagia is a common problem that interferes with a woman’s physical, emotional, and social life. Evidence to guide physicians for decision about therapy for heavy menstrual bleeding is lacking. One treatment option, the levonorgestrel-releasing intrauterine system (levonorgestrel-IUS), has been available in the United States since 2009. Updated meta-analyses comparing the levonorgestrel-IUS with nonhormonal and hormonal treatments showed that the levonorgestrel-IUS produced a greater reduction in menstrual blood loss at 3 to 12 months of follow-up. It is not clear whether these short-term benefits persist. Moreover, the rates of discontinuation of the levonorgestrel-IUS at 2 years are as high as 28%, and effects on bleeding-related quality of life are not known. This pragmatic, multicenter, randomized trial compared the effectiveness of the levonorgestrel-IUS with that of usual medical treatment among women with menorrhagia in a primary care setting. A total of 571 women with menorrhagia were randomized to treatment with levonorgestrel-IUS (n = 285) or usual medical treatment (n = 286). Usual treatment was tranexamic acid, mefenamic acid, combined estrogen-progestogen, or progesterone alone. The primary study outcome measure was the patient-reported score on the condition-specific Menorrhagia Multi-Attribute Scale (MMAS) assessed over a 2-year period. The MMAS scores range from 0 to 100, with lower scores indicating greater severity. Summary MMAS scores were assessed at 6, 12, and 24 months. Secondary outcome measures included general health-related quality of life, sexual-activity scores, and surgical intervention. There was a significant improvement in total MMAS scores from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group; the mean increase was 32.7 and 21.4 points, respectively; P < 0.001 for both comparisons. Over the 2-year follow-up, improvements were maintained in both groups but were significantly greater in the levonorgestrel-IUS group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9–16.9; P < 0.001). Significantly greater improvements in all MMAS domains (practical difficulties, social life, psychological health, physical health, work and daily routine, and family life and relationships) occurred with the levonorgestrel-IUS than with the usual treatment (P < 0.001 with the use of a test for trend). This was also found for 7 of the 8 quality-of-life domains. At the 2-year end point, almost twice as many women were still using the levonorgestrel-IUS than were those receiving the usual medical treatment (64% vs 38%, P < 0.001). No significant between-group differences were noted in the rates of surgical intervention or sexual-activity scores as well as in the frequency of serious adverse events. These data show that levonorgestrel-IUS is more effective than usual medical treatment in improving the quality of life of women with menorrhagia in a primary care setting.

Down-regulation of angiopoietin-1 expression in menorrhagia

Angiogenesis is an essential component of endometrial repair and regeneration following menses. Perturbation of this process is associated with menorrhagia, a common gynecological disorder that results in excessive menstrual bleeding. Angiopoietin-1 (Ang-1) promotes vascular maturation via the Tie-2 receptor, while angiopoietin-2 (Ang-2) is its natural antagonist that destabilizes vessels and initiates neovascularization in the presence of vascular endothelial growth factor. To test the hypothesis that menorrhagia arises as a result of poor signal for vascular maturation, we have examined the expression of Ang-1, Ang-2, and Tie-2 in endometrium throughout the menstrual cycle from 30 normal women and 28 patients with menorrhagia. Ribonuclease protection assay and Western blot analysis showed Ang-2 expression was consistently higher than Ang-1 in normal endometrium throughout the cycle. However, with menorrhagia Ang-1 mRNA and protein were not detected or down-regulated, while Ang-2 was observed at similar levels in both normal and menorrhagic endometrium resulting in a greater than a 50% decrease in the ratio of Ang-1 to Ang-2 protein. In situ hybridization and immunohistochemical studies supported these findings and revealed cyclical changes in the expression of Ang-1 and Ang-2. These results suggest that the angiopoietin/Tie-2 system promotes vascular remodeling in endometrium and loss of normal Ang-1 expression may contribute to the excessive blood loss observed in menorrhagia.

Dimensions of gender relations and reproductive health inequity perceived by female undergraduate students in the Mekong Delta of Vietnam: a qualitative exploration

Introduction Increasing evidence indicates that gender equity has a significant influence on women’s health; yet few culturally specific indicators of gender relations exist which are applicable to health. This study explores dimensions of gender relations perceived by female undergraduate students in southern Vietnamese culture, and qualitatively examines how this perceived gender inequity may influence females’ sexual or reproductive health. Methods Sixty-two female undergraduate students from two universities participated in eight focus group discussions to talk about their perspectives regarding national and local gender equity issues. Results Although overall gender gaps in the Mekong Delta were perceived to have decreased in comparison to previous times, several specific dimensions of gender relations were emergent in students’ discussions. Perceived dimensions of gender relations were comparable to theoretical structures of the Theory of Gender and Power, and to findings from several reports describing the actual inferiority of women. Allocation of housework and social paid work represented salient dimensions of labor. The most salient dimension of power related to women in positions of authority. Salient dimensions of cathexis related to son preference, women’s vulnerability to blame or criticism, and double standards or expectations. Findings also suggested that gender inequity potentially influenced women’s sexual and reproductive health as regards to health information seeking, gynecological care access, contraceptive use responsibility, and child bearing. Conclusion Further investigations of the associations between gender relations and different women’s sexual and reproductive health outcomes in this region are needed. It may be important to address gender relations as a distal determinant in health interventions in order to promote gender-based equity in sexual and reproductive health.

Avaliação do pré-natal na atenção primária à saúde no Rio grande do Norte: visão das usuárias

ABSTRACT This study aimed to evaluate the quality of prenatal Primary Care in Rio G rande do Norte, Brazil in 2012 under the program Improving Access and Quality of Primary Care. The study was cross - sectional, quantitative. Included 156 mothers of children under 2 years who received prenatal care at the health evaluated. We applied a ques tionnaire on profile, minimum queries, regularity of attendance, laboratory tests, vaccination, participation in educational activities, guidance received, clinical and obstetric procedures and prescription Ferrous sulphate and folic acid. The descriptive analysis of the criteria used Humanization Program Prenatal and Birth. The results showed that 92% of mothers had six or more visits; 85% with the same care was professional; 94% subsequent appointments scheduled. As for tests and procedures the percentage s were: Urine 98%; HIV - 96%; VDRL and 88%; 91% glucose; tetanus vaccination 93%; educational groups 56% with 36% participation, knowledge of the delivery location and 59% achievement breast exam 65%, 33% and preventive gynecological 43%; 98% supplemented wi th 96% Ferrous Sulfate and Folic Acid. It was concluded that there were advances in Rio Grande do Norte concerning assistance and there are weaknesses in the educational practices and conducting some minimal clinical examinations.