Frequency of diminished ovarian reserve in women with multiple sclerosis in Chile: An exploratory study.

INTRODUCTION: Multiple Sclerosis (MS) is a chronic disease affecting around 2.8 million people worldwide. Two-thirds are women, and the mean age at diagnosis is about 30 years old. Social trends are moving towards older age at first pregnancy, both in women with and without MS. OBJECTIVES: To determine the frequency of diminished ovarian reserve (DOR) through anti-Mullerian Hormone (AMH) measurement in women with MS at fertile age and Healthy Females (HF) in Chile. METHODS: Case-control, multicentric, cross-sectional study including relapsing-remitting people with MS (pwMS) between 18 and 40 years and sex and age-matched HF. We obtained a blood sample to determine AMH levels. We defined DOR as AMH <1.5 ng/mL and very-low AMH levels as <0.5 ng/mL. Also, we performed questions regarding reproductive decision-making. RESULTS: We included 79 sex and age-matched HF and 92 pwMS, median age 32(19-40) years, median disease duration 6 (1-17)years, median EDSS 1.0 (0-6), 95% were receiving disease-modifying therapy (DMT), 70% high-efficacy DMT and 37% with a treatment that contraindicates pregnancy. DOR was observed in 24% (n = 22) of the pwMS, compared to 14% (n = 11) of the HF (p = 0.09), while very-low AMH levels were observed in 7.6% (n = 7) of pwMS and none of the HF (p = 0.0166). We observed an inverse correlation between age and AMH levels. Age was the only significant risk factor for low AMH levels in pwMS (OR 1.14 95%CI(1.00-1-31), p = 0.04), including smoking, body mass index (BMI), hormonal contraception, autoimmune comorbidity, high/low-moderate efficacy DMT, and active disease as covariables. We did not find statistically significant differences in age at diagnosis, BMI, disease duration, EDSS, autoimmune comorbidity, use of hormonal contraception, or percentage of active disease between MS women with normal vs DOR. Over 70% of pwMS desired to become pregnant in the future, while 60% considered that the diagnosis of MS was a limitation for pregnancy planning. CONCLUSIONS: No differences in DOR, measured by levels of AMH, were observed between pwMS MS and HF in Chile. As expected, AMH levels were correlated only with ageing. This information may be evaluated early during the disease course to help patients and neurologists with fertility counselling and family planning considerations regarding DMT use.

A randomized clinical trial of precision prevention materials incorporating MC1R genetic risk to improve skin cancer prevention activities among Hispanics.

Purpose: Skin cancer incidence is increasing among Hispanics, who experience worse outcomes than non-Hispanic Whites. Precision prevention incorporating genetic testing for MC1R, a skin cancer susceptibility marker, may improve prevention behavior. Patients and Methods: Hispanic participants (n=920) from Tampa, FL and Ponce, PR, were block-randomized within MC1R higher- and average-risk groups to precision prevention or generic prevention arms. We collected baseline information on demographics, family history of cancer, phenotypic characteristics, health literacy, health numeracy, and psychosocial measures. Participants reported weekday and weekend sun exposure (in hours), number of sunburns, frequency of five sun protection behaviors, intentional outdoor and indoor tanning, and skin examinations at baseline, three months, and nine months. Participants also reported these outcomes for their eldest child ≤10 years old. Results: Among MC1R higher-risk participants, precision prevention increased sunscreen use (OR=1.74, p=0.03) and receipt of a clinical skin exam (OR=6.51, p=0.0006); and it decreased weekday sun exposure hours (ß=-0.94, p=0.005) and improved sun protection behaviors (ß=0.93, p=0.02) in their children. There were no significant intervention effects among MC1R average risk participants. The intervention did not elevate participant cancer worry. We also identified moderators of the intervention effect among both average- and higher-risk participants. Conclusions: Receipt of MC1R precision prevention materials improved some skin cancer prevention behaviors among higher-risk participants and their children and did not result in reduced prevention activities among average-risk participants. Despite these encouraging findings, levels of sun protection behaviors remained suboptimal among participants, warranting more awareness and prevention campaigns targeted to Hispanics.

Longitudinal Collection of Patient-Reported Outcomes and Activity Data during CAR-T Therapy: Feasibility, Acceptability, and Data Visualization.

Background: Clinicians must closely monitor patients for toxicities after chimeric antigen receptor T-cell therapy (CAR-T). Patient-reported outcomes (PROs) (e.g., toxicities, quality of life) and activity data (e.g., steps, sleep) may complement clinicians' observations. This study tested the feasibility and acceptability of collecting PROs and activity data from patients with hematologic malignancies during CAR-T and explored preliminary data patterns. Methods: Participants wore a Fitbit tracker and completed PROs at several timepoints through 90-days post-infusion. Feasibility was assessed with a priori benchmarks for recruitment (≥50%), retention (≥70%), PRO completion (≥70%), and days wearing the Fitbit (≥50%). Acceptability was assessed with participant satisfaction (a priori benchmark > 2 on a 0−4 scale). Results: Participants (N = 12) were M = 66 years old (SD = 7). Rates of recruitment (68%), retention (83%), PRO completion (85%), and days wearing the Fitbit (85%) indicated feasibility. Satisfaction with completing the PROs (M = 3.2, SD = 0.5) and wearing the Fitbit (M = 2.9, SD = 0.5) indicated acceptability. Preliminary data patterns suggested that participants with better treatment response (vs. progressive disease) had a higher toxicity burden. Conclusions: Longitudinal PRO and activity data collection was feasible and acceptable. Data collected on a larger scale may be used to specify risk prediction models to identify predictors of severe CAR-T-related toxicities and inform early interventions.

Assessment of melanoma precision prevention materials incorporating MC1R genetic risk information.

Few studies have examined cognitive responses to mailed precision prevention materials. MC1R is a robust, well-described melanoma susceptibility marker. The purpose was to assess cognitive responses to generic or precision prevention materials incorporating MC1R genetic risk. Non-Hispanic White participants (n = 1134) enrolled in a randomized controlled trial received either precision prevention materials incorporating MC1R genetic risk (higher/average) or generic prevention (standard) materials. Six months after baseline, 808 (71.3%) participants reported on the amount of prevention materials read (5-point scale); believability and clarity of materials; intention to change preventive behaviors (7-point Likert scale); and recall of their MC1R genetic risk. Comparisons were conducted using Kruskal-Wallis and chi-squared tests. Overall, participants read most to all (Mdn = 4, IQR = 2) of the prevention materials, reported high believability (Mdn = 7, IQR = 1) and clarity (Mdn = 7, IQR = 1), and moderate intention to change preventive behaviors (Mdn = 5, IQR = 2). Higher-risk participants reported slightly less clarity (Mdn = 6, IQR = 2) than either average-risk (Mdn = 6, IQR = 1, p = 2.50 × 10-3) or standard participants (Mdn = 7, IQR = 1, p = 2.30 × 10-5); and slightly less believability (Mdn = 6, IQR = 1) than standard participants (Mdn = 7, IQR = 1, p = .005). Higher-risk participants were 2.21 times as likely (95% CI = 1.43-3.43) to misremember or forget their risk compared to average-risk participants; misremembering was observed only among higher-risk participants (14%). Mailed precision prevention information were mostly read, highly believable and clear, and resulted in moderate levels of intention to change sun protection behaviors, bolstering the feasibility of population-level precision prevention. Defensive reactions may explain lower clarity, believability, and higher incorrect risk recall among higher-risk participants.

Precision prevention uses an individual's genetics, environment, and/or lifestyle to promote prevention behaviors. However, if materials incorporating precision prevention information are not easily accessible, individuals may misinterpret or distrust findings. Few studies have examined participant-reported believability and clarity of mailed precision prevention materials, how much they read, and whether they intend to change preventive behaviors. We assessed genetic risk for melanoma by determining DNA variation at the MC1R gene, a known melanoma risk marker. Participants were mailed either precision prevention materials conveying their MC1R genetic risk or generic (without genetic risk information) prevention materials. Overall, participants read most of the materials, gave high believability and clarity scores, and reported moderate levels of intention to change preventive behavior. However, participants at higher genetic risk had slightly lower believability and clarity scores than the generic group and were more likely to forget or misremember their genetic risk than participants at average genetic risk. Among participants who correctly recalled their genetic risk, differences in believability diminished, while differences in clarity remained. We conclude that precision prevention materials are highly believable and clear, but additional strategies may be necessary to maximize believability, clarity, and risk recall for individuals at a higher genetic risk.

Metformin Treatment Regulates the Expression of Molecules Involved in Adiponectin and Insulin Signaling Pathways in Endometria from Women with Obesity-Associated Insulin Resistance and PCOS.

Polycystic ovary syndrome (PCOS) is an endocrine/metabolic disorder associated with insulin resistance (IR) and obesity. Endometria from women with PCOS present failures in insulin action, glucose uptake and signaling of insulin-sensitizing molecules, such as adiponectin, with consequences for reproduction. Metformin (MTF) treatment improves insulin signaling in endometrial tissues, but its mechanism is not fully understood. This study addresses the MTF effect, as well as adiponectin agonist action, on levels of molecules associated with insulin and adiponectin signaling pathways in endometrial tissue and cells, as assessed by immunohistochemistry and immunocytochemistry, respectively. Endometrial tissues were obtained from women and divided into five groups: Normal Weight (control); Obesity + IR; Obesity + IR + PCOS; Obesity + IR + MTF; Obesity + IR + PCOS + MTF. Endometrial cells stimulated with TNFα (as obesity-marker) were also used to partially emulate an obesity environment. The results showed low levels of insulin/adiponectin signaling in the endometria from women with obesity, IR and PCOS compared with the control group. MTF re-established these levels, independently of PCOS. TNFα-associated molecules were elevated in pathologic endometria, whereas MTF diminished these levels. The low levels of insulin/adiponectin molecules in endometrial cells treated with TNFα were reverted by MTF, similar to what was observed in the case of the adiponectin agonist. Therefore, independently of PCOS, MTF can re-establish levels of molecules involved in insulin/adiponectin signaling in endometrial cells, suggesting an improvement in insulin action and reproductive failures observed in endometria from women with obesity/PCOS.

A multilevel, low literacy dual language intervention to promote colorectal cancer screening in community clinics in Florida: A randomized controlled trial.

One of the largest disparities in cancer mortality in the United States occurs with colorectal cancer (CRC). The objectives of this multilevel two-arm intervention trial were to compare the efficacy of two interventions to promote CRC screening (CRCS) with fecal immunochemical test (FIT) and examine sociodemographic and psychosocial predictors of FIT screening. Individuals ages 50-75 (n = 326) who were not up-to-date with CRCS, could understand English or Spanish, and were at average CRC risk were recruited from two federally qualified health centers (FQHCs) in Florida. Prior to intervention, CRCS rates in the FQHCs were 27.1% and 32.9%, respectively. Study enrollment occurred April 2018-November 2019. System-level intervention components included leveraging electronic medical record (EMR) systems and delivering patient reminders. Participants were randomized to C-CARES (education+FIT) or C-CARES Plus (C-CARES+personalized coaching [for those not completing FIT within 90 days]). Primary outcome was completed FIT returned <1 year. Primary outcome analyses were performed using logistic regression. 225 participants completed FIT (69.0% [95% CI: 64.0-74.0%]), with no significant difference in FIT uptake by intervention arm (67.3% C-CARES Plus vs. 70.8% C-CARES; p = .49). FIT uptake was significantly higher among patients who received intervention materials in Spanish (77.2%) compared to those who received materials in English (63.2%, p < .01). The personalized coaching in the C-CARES Plus arm did not appear to provide added benefit beyond the C-CARES intervention. Multilevel approaches that include EMR prompts, reminders, FIT access, and provision of low-literacy, language-concordant education can support efforts to improved community clinics' CRCS rates. Future efforts should focus on repeat FIT screening. Trial registration: The trial was registered at ClinicalTrials.gov (NCT03906110).

A Randomized Trial of Precision Prevention Materials to Improve Primary and Secondary Melanoma Prevention Activities among Individuals with Limited Melanoma Risk Phenotypes.

Inherited variation at MC1R is associated with elevated melanoma risk among non-Hispanic whites (NHWs). MC1R genetic testing may unmask previously unrecognized disease risk, especially among individuals with few melanoma phenotypic risk factors. We recruited NHW individuals with limited phenotypic risk factors from two primary care clinics in west-central Florida. Participants (n = 1134) were randomized within MC1R genotype risk group (average/higher) to receive mailed precision prevention (i.e., intervention) or generic prevention materials. Participants reported hours of weekday and weekend sun exposure, frequency of intentional outdoor tanning and sun protection behaviors, number of sunburns, indoor tanning episodes, and skin examinations at baseline, and after 6 and 12 months. Among MC1R higher-risk participants, the intervention increased the likelihood of often or always wearing a shirt with sleeves (OR = 1.49, p = 0.03) and seeking shade or using an umbrella (OR = 1.42, p = 0.046), and it decreased the number of sunburns among their young children (ß = -0.13, p = 0.03). Intervention effects were not noted among MC1R average-risk participants. Moderation analyses identified intervention effects within subgroups in average-risk and higher-risk participants. Precision prevention information conveying MC1R testing results can increase the practice of some sun protection behaviors among at-risk individuals with limited melanoma risk phenotypes and may provide a cross-generational tool to counteract increasing incidence of melanoma.

Enabling Precision Medicine in Cancer Care Through a Molecular Data Warehouse: The Moffitt Experience.

PURPOSE: The use of genomics within cancer research and clinical oncology practice has become commonplace. Efforts such as The Cancer Genome Atlas have characterized the cancer genome and suggested a wealth of targets for implementing precision medicine strategies for patients with cancer. The data produced from research studies and clinical care have many potential secondary uses beyond their originally intended purpose. Effective storage, query, retrieval, and visualization of these data are essential to create an infrastructure to enable new discoveries in cancer research. METHODS: Moffitt Cancer Center implemented a molecular data warehouse to complement the extensive enterprise clinical data warehouse (Health and Research Informatics). Seven different sequencing experiment types were included in the warehouse, with data from institutional research studies and clinical sequencing. RESULTS: The implementation of the molecular warehouse involved the close collaboration of many teams with different expertise and a use case-focused approach. Cornerstones of project success included project planning, open communication, institutional buy-in, piloting the implementation, implementing custom solutions to address specific problems, data quality improvement, and data governance, unique aspects of which are featured here. We describe our experience in selecting, configuring, and loading molecular data into the molecular data warehouse. Specifically, we developed solutions for heterogeneous genomic sequencing cohorts (many different platforms) and integration with our existing clinical data warehouse. CONCLUSION: The implementation was ultimately successful despite challenges encountered, many of which can be generalized to other research cancer centers.

TIMEx: tumor-immune microenvironment deconvolution web-portal for bulk transcriptomics using pan-cancer scRNA-seq signatures.

SUMMARY: The heterogeneous cell types of the tumor-immune microenvironment (TIME) play key roles in determining cancer progression, metastasis and response to treatment. We report the development of TIMEx, a novel TIME deconvolution method emphasizing on estimating infiltrating immune cells for bulk transcriptomics using pan-cancer single-cell RNA-seq signatures. We also implemented a comprehensive, user-friendly web-portal for users to evaluate TIMEx and other deconvolution methods with bulk transcriptomic profiles. AVAILABILITY AND IMPLEMENTATION: TIMEx web-portal is freely accessible at http://timex.moffitt.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cohort Identification for Translational Bioinformatics Studies.

Translational studies for therapeutic development require cohort identification to identify appropriate biological materials from patients that can be utilized to test a specific hypothesis. Robust health information systems exist, but there are numerous challenges in accessing the information to select appropriate biological specimens needed for translational experiments. This chapter on methods describes the current standard process for cohort identification utilized by the Cutaneous Oncology Program and the Collaborative Data Services Core (CDSC) at Moffitt Cancer Center. The methods include utilization of graphical user interfaces coupled with database querying. As such, this chapter outlines the regulatory and procedural processes needed to utilize a health information management system to filter patients for cohort identification.

PDXGEM: patient-derived tumor xenograft-based gene expression model for predicting clinical response to anticancer therapy in cancer patients.

BACKGROUND: Cancer is a highly heterogeneous disease with varying responses to anti-cancer drugs. Although several attempts have been made to predict the anti-cancer therapeutic responses, there remains a great need to develop highly accurate prediction models of response to the anti-cancer drugs for clinical applications toward a personalized medicine. Patient derived xenografts (PDXs) are preclinical cancer models in which the tissue or cells from a patient's tumor are implanted into an immunodeficient or humanized mouse. In the present study, we develop a bioinformatics analysis pipeline to build a predictive gene expression model (GEM) for cancer patients' drug responses based on gene expression and drug activity data from PDX models. RESULTS: Drug sensitivity biomarkers were identified by performing an association analysis between gene expression levels and post-treatment tumor volume changes in PDX models. We built a drug response prediction model (called PDXGEM) in a random-forest algorithm by using a subset of the drug sensitvity biomarkers with concordant co-expression patterns between the PDXs and pretreatment cancer patient tumors. We applied the PDXGEM to several cytotoxic chemotherapies as well as targeted therapy agents that are used to treat breast cancer, pancreatic cancer, colorectal cancer, or non-small cell lung cancer. Significantly accurate predictions of PDXGEM for pathological response or survival outcomes were observed in extensive independent validations on multiple cancer patient datasets obtained from retrospective observational studies and prospective clinical trials. CONCLUSION: Our results demonstrated the strong potential of using molecular profiles and drug activity data of PDX tumors in developing a clinically translatable predictive cancer biomarkers for cancer patients. The PDXGEM web application is publicly available at http://pdxgem.moffitt.org .

Exploring patient and provider perspectives on the intersection between fertility, genetics, and family building.

OBJECTIVE: Adolescent and young adult (AYA) cancer patients have distinct medical and psychosocial needs and fertility is a key concern. Early age of onset is a risk factor for hereditary cancer and AYAs are more likely to experience reduced fertility. This has implications for future family building decisions and fertility preservation (FP) and genetic testing/counseling (GT/GC) education. METHODS: Patients diagnosed with cancer between the ages of 18 and 39 and health care providers (HCPs) who treat AYA cancer patients were recruited from a single institution. Qualitative interviews explored AYA patients' and HCPs' concerns regarding their experiences discussing genetics and FP. RESULTS: The majority of patients (n = 17) were female (59%), and the majority of HCPs (n = 18) were male (67%). Overall, participants had differing perceptions of FP and GT/GC-related information provided during the clinical visit. Patients indicated initiating the conversation about FP and did not recall HCPs discussing GT/GC with them. HCPs indicated patients were often overwhelmed with too much information and comprehension of this discussion is limited. HCPs also felt patients' emotions/beliefs determined their information-seeking behavior specific to FP and GT/GC. Participants felt educational materials should be developed and delivered in a video format depicting a patient-provider interaction or patient testimonial. CONCLUSION: AYA patients are often overwhelmed by a cancer diagnosis; the complexity/volume of information regarding FP and GT/GC may hinder understanding and decision-making about family building. Educational materials that help patients understand what questions to ask HCPs about FP and GT/GC should be developed to improve knowledge, psychosocial well-being, and future family building decisions.

Vitrificación de ovocitos en pacientes oncológicas: experiencia en clínica ivi chile y revisión de la literatura / Vitrification of oocytes in oncological patients: experience in clinica ivi chile and review of literature

La sobrevida de pacientes con cáncer ha mejorado con el tiempo, especialmente en pacientes en edad fértil. La criopreservación de los ovocitos a través de la estimulación ovárica controlada (EOC) es la técnica más frecuente de preservación de la fertilidad. El objetivo del presente estudio es realizar un análisis descriptivo de los ciclos de pacientes que, previo al tratamiento de cáncer, realizaron un tratamiento de preservación de fertilidad. Se analizaron datos demográficos como edad, diagnóstico de ingreso y resultados clínicos, tales como tipo de protocolo de estimulación utilizado, número de ovocitos obtenidos, duración de la estimulación y momento de inicio en el ciclo. Resultados: La edad promedio fue 28.9 años. La duración media de la estimulación fue de 12 días, con un promedio de ovocitos obtenidos en total de 12. Se utilizaron 2 protocolos de estimulación ovárica, obteniendo mejores resultados con el esquema de antagonistas de GnRH asociado a letrozole y doble gatillante. Respecto al momento del ciclo en que se inició la estimulación ovárica, no hubo diferencias. Conclusiones: Es posible realizar preservación de la fertilidad previo a un tratamiento oncológico con buenos resultados en pacientes jóvenes, por lo que sugerimos realizarlo en todos los pacientes con diagnóstico oncológico antes el tratamiento del cáncer. Es recomendable comenzar la estimulación ovárica en cualquier fase del ciclo ya que se obtienen los mismos resultados y permite un pronto inicio de la terapia oncológica.

Survival of patients with cancer has been improving over time, especially in young patient with fertility intention. Cryopreservation of oocytes through controlled ovarian stimulation (EOC) is the most frequent technique of fertility preservation. We analyzed the data obtained from oncological patients who attended IVI Chile between January 2008 and May 2017 in search of fertility preservation. Demographic data were obtained: age, diagnosis of admission, type of stimulation protocol used, number of oocytes obtained, duration of stimulation and pregnancy rate. Results: The average age: 28,9 years; average duration of stimulation:12 days. Number of oocytes obtained in total: 12. Two ovarian stimulation protocols were used. The one with the best results was the protocol with GnRH antagonists associated with letrozole and double triggering. Regarding the moment of the cycle where to start ovarian stimulation, there were no differences. Conclusions: It is possible to carry out a fertility preservation treatment prior to an oncological treatment with good results in young patients, so we suggest the preservation of fertility in all patients with an oncological diagnosis before oncological treatment. It is recommended to start ovarian stimulation at any phase of the cycle since the same results are obtained.

Musicoterapia y cáncer: La expresión como herramienta de acompañamiento terapéutico en etapa terminal / Music therapy and cancer: Expression as a therapeutic accompaniment tool in the terminal stage

La presente monografía de análisis de experiencia tiene por finalidad presentar un proceso musicoterapéutico, en el contexto de una práctica profesional, con una paciente oncológica terminal realizado en un contexto no institucional durante el primer semestre del 2017. En relación a los fundamentos teóricos que sostienen este trabajo, se busca explicar de forma acotada, en términos médicos, qué se entiende por cáncer, metástasis pulmonar y cómo eso se articula con la visión musicoterapéutica en razón a los contenidos de las sesiones, la pertinencia metodológica y los cuidados paliativos en el caso de una paciente terminal. A esto se suma la colaboración con la visión y enfoque psicológico. Finalmente se incorporan algunos fundamentos de las terapias holísticas que integra la paciente a las sesiones y que, en cierta medida, fueron parte de su propio proceso paralelo con otras disciplinas de líneas diferentes como la Acupuntura y el Reiki. Los fundamentos teóricos musicoterapéuticos que brindan fundamento en este trabajo, corresponden al Modelo Benenzon, el enfoque de Gauna y algunos aspectos del Abordaje Plurimodal, todos en conjugación con la visión y fundamentos psico oncológicos de Lawrence LeShan. El proceso contempló métodos musicoterapéuticos receptivos, como: escucha de música seleccionada para las inducciones y aprestos corporales, baño sonoro, selección y audición de canciones. También se hizo uso de métodos activos, tales como: la improvisación referencial y el uso de canciones en la creación y la adaptación de texto. Cabe señalar que la musicoterapia se sigue enmarcando como una terapia del arte, que puede abrir espacio a lo expresivo, desde la conexión con la emoción y el aspecto espiritual del individuo que está dispuesto a vivir tal proceso utilizando los sonidos, el cuerpo, la voz, la música y sus instrumentos. Posteriormente, se aborda el proceso musicoterapéutico de forma descriptiva de las tres fases o etapas y, por otro lado, se presenta la evidencia e impacto de la terapia en la paciente expresada por los familiares más directos como actores del proceso. Las conclusiones, al finalizar el proceso, ponen énfasis aquellos aspectos que englobaron el proceso, haciendo uso y recorrido por aquellas dimensiones cimentadas por el marco referencial y musicoterapéutico, que facilitan el despliegue del trabajo con C, que si bien está fuera de un contexto institucional, acoge y aterriza en lo que la paciente provee como material, brindando espacio a un proceso de acompañamiento emocional, social y espiritual. Finalmente se hace una reflexión de lo que se rescata en términos de fortalezas y debilidades del proceso, haciendo una propia mirada al quehacer del practicante en el escenario musicoterapéutico y el despliegue que ésta disciplina le permiten en el contexto particular donde la disposición de la paciente y la confianza de la familia fueron un vital elemento. (AU)

Hyperandrogenism Decreases GRP78 Protein Level and Glucose Uptake in Human Endometrial Stromal Cells.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) exhibit a low fertility by chronic hyperandrogenemia. Different evidence have shown that androgens could regulate the endoplasmic reticulum (ER) homeostasis and glucose metabolism. However, it is unclear whether androgens can exert these effects on human endometrial stromal cells. Our goal was to study the protein content of GRP78 (an ER homeostasis marker) in endometria from women with PCOS and healthy women and to assess the GRP78 protein levels and its relationship with glucose uptake on a human endometrial stromal cell line stimulated with testosterone. METHODS: Immunohistochemistry assays for GRP78 were performed on endometrial samples obtained from women with PCOS (n = 8) and control women subjected to hysterectomy (n = 8). Western blot analysis for GRP78 and glucose uptake was assessed in a telomerase-immortalized human endometrial stromal cell line (T-HESC) exposed to testosterone for 24 or 48 hours and challenged to an insulin short-term stimulation. Tukey test was performed for human samples comparison. Student t test or ANOVA-Bonferroni test was carried out according to the in vitro experiment. P < .05 was considered as significant. RESULTS: GRP78 stromal immunostaining was reduced in PCOS endometria compared to controls (P < .05). The T-HESC shows a testosterone-dependent downregulation of GRP78 protein content (P < .05), concomitant with half-reduction in glucose uptake compared to controls (P < .05). Moreover, enhanced small interfering RNA against GRP78 messenger RNA leads to a decrease in glucose uptake (P < .05). Such effects were reverted by hydroxyflutamide, an inhibitor of androgen receptor. CONCLUSION: These results suggest that hyperandrogenemic PCOS environment could compromise the endometrial homeostasis confirmed by the decrease in glucose uptake induced by testosterone and exhibited by stromal cells.

Expression of steroid sulfated transporters and 3ß-HSD activity in endometrium of women having polycystic ovary syndrome.

Intracrinology mechanism involves the metabolism of steroids in peripheral tissues, such as DHEA, to molecules with estrogenic or androgenic activity. Proliferation rate of endometria from Polycystic Ovary Syndrome women (PCOS) is increased, favoring hyperplasia development. Besides, in endometria from PCOS-women the synthesis of androst-5-ene-3ß,17ß-diol (androstenediol), an estrogenic molecule, is enhanced concomitantly to increased cellular proliferation. DHEA, the major intracrinological precursor, circulates mainly in its sulfated form and requires transporters for cell intake, that belong to the families of organic anion transporting polypeptides (OATP) and organic anion transporters (OAT). The aim of this study was to determine protein levels and activity of sulfated steroid transporters OATP2B1, OATP3A1, OATP4A1 and OAT4 in endometria from control and PCOS-women and to evaluate the activity of the enzyme 3ß-HSD. Levels of transporters were done by RT-PCR (OAT4 only) and Western-blot (WB). Additionally, in primary culture cells stimulated with steroids, protein levels by WB and uptake of tritiated DHEAS, were evaluated; 3ß-HSD activity was assessed using radiolabel substrate. PCOS-endometrium had higher levels of OATP2B1 and OATP4A1 than CE (p<0.05); decreased OATP4A1 levels were found in androstenediol or testosterone-stimulated cells. Accordingly, the entry of DHEAS to cells was lower in cells stimulated with testosterone (p<0.05); 3ß-HSD-activity was similar in control and PCOS-endometria. Therefore, this study describes that steroids can modulate the expression and activity of transporters of OATPs-family in human endometria and that some transporter levels are increased in PCOS-endometria, suggesting a potential role in the pathogenesis of endometrial hyperplasia of these patients.

Clinical parameters and biomarkers for anti-TNF treatment prognosis in rheumatoid arthritis patients.

Tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). This finding has led to the development of TNF blockers for RA treatment. However, response to these therapies is heterogeneous with success in only two thirds of patient. Some clinical aspects useful in the attempt to predict the response to TNF inhibitors is the promptness and the magnitude of the response at the first weeks and a low basal disease activity, while comorbidities, tobacco, glucocorticoids treatment, and high basal radiological score correlate with a poorer response. The role of TNF promoter polymorphisms in clinical response to anti-TNF therapies is controversial. A correlation between the presence of high baseline titers of rheumatoid factor (RF) and decreased response to anti-TNF treatment has been reported. Most studies show decreased RF titers during anti-TNF treatment mainly in patients who responded to treatment. There is no consensus about the usefulness of basal anti-citrullinated protein antibodies (ACPA) levels, and a decrease in ACPA titers as predictor of clinical response to anti-TNF therapy. Despite some promising markers identified to fulfill this role, currently the predictive value of single markers seems not strong enough to predict treatment response in an individual RA patient.

Affecting African American men's prostate cancer screening decision-making through a mobile tablet-mediated intervention.

African American men experience a 60% higher incidence of prostate cancer and are more than twice as likely to die from it than White men. Evidence is insufficient to conclude that definitively screening for prostate cancer reduces the likelihood of morbidity or death. Patients are encouraged to discuss screening alternatives with health care providers for informed decision-making (IDM). The extent of IDM in clinical or community setting is not known. This study uses data from a community-based, computer-mediated, IDM intervention that targeted 152 African American aged 40 to 70. Pretest-posttest differences in means for prostate cancer knowledge, screening decisional conflict, and screening decisional self-efficacy were examined by two-tailed t-tests. Overall, the intervention significantly improved respondents' prostate cancer knowledge (p<.0001), significantly improved decisional self-efficacy (p<.0001) and significantly reduced decisional conflict (p<.0001). Specifically, the intervention significantly promoted IDM among men who reported more education, being married, having financial resources, and younger age.

The role of androst-5-ene-3ß,17ß-diol (androstenediol) in cell proliferation in endometrium of women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) show high prevalence of endometrial hyperplasia and adenocarcinoma. Endometrial proliferation is increased, evaluated by high levels of Ki67 (cell cycle marker) and low levels of p27 (negative regulator of cell cycle). Nevertheless, endometrial changes in cyclin D1 (positive regulator of cell cycle) in PCOS-women are not described. Androst-5-ene-3ß,17ß-diol (androstenediol), steroid with estrogenic activity present in endometria, could be related to increased endometrial cell proliferation. The objective of this study was to determine protein content of cyclin D1 and androstenediol levels in endometria from PCOS and control-women and to evaluate the possible mechanism favoring cell proliferation associated with hormonal characteristics of patients. Therefore, cyclin D1 protein content in PCOS-women and control-endometrial tissue were assessed by western blot and immunohistochemistry. The androstenediol levels were evaluated by ELISA. To further analyze the effect of steroids (androstenediol, 17ß-estradiol, testosterone) in cell proliferation, levels of proteins cyclin D1, p27 and Ki67 were evaluated in an in vitro model of stromal endometrial cells T-HESC and St-T1b. An increase in cyclin D1 and androstenediol was observed in tissues from PCOS-women relative to control group (p<0.05). In the in vitro model, androstenediol exerted increase in cyclin D1 (p<0.05) and a decrease in p27 protein level (p<0.05), while Ki67 in St-T1b cells increased under this stimulus (p<0.05). Testosterone produces opposite effects in the levels of the above markers (p<0.05). Therefore, the hormonal imbalance associated with this syndrome could alter endometrial tissue homeostasis, promoting cell proliferation. Androstenediol is a molecule that could be involved by stimulating proliferation, whereas testosterone elicits a role of cell cycle repressor.

Meningitis bacteriana aguda por Streptococcus suis en criadores de cerdos: comunicación de los primeros dos casos en Chile / Streptococcus suis meningitis in pig farmers: report of first two cases in Chile

Human infection by Streptococcus suis is a zoonosis with a known occupational risk. Meningitis is its most frequent clinical manifestation. We present the first two cases in Chile. First case: 54-year-old female patient, pig-farmer. She presented headache, vomiting, confusion and meningismus. She presented septic shock. Second case: 48-year-old male patient, also pig farmer, presented headache, vomiting and meningismus. A Gram's staining of cerebrospinal fluid (CSF) showed gram-positive cocci in both cases. Ceftriaxone and dexamethasone treatment was administered. The CSF cultures were positive for Streptococcus suis serotype 2. The patients experienced a good outcome, without neurological sequelae at the time of discharge. It is considerable to evaluate epidemiologic factors in order to suspect this etiological agent in cases of meningitis. These cases enhance the need of heighten awareness of potential for occupational exposure and infection by this emerging human pathogen. Educating population at risk about simple preventive measures must be considered.

La infección humana por Streptococcus suis es una zoonosis con riesgo ocupacional conocido, siendo la meningitis aguda su manifestación clínica más frecuente. Se presentan los dos primeros casos en Chile. Primer caso: Mujer de 54 años con un cuadro de cefalea y vómitos, confusión y signos meníngeos. Evolucionó con un shock séptico. Segundo caso: Varón de 48 años, refirió cefalea y vómitos. Presentó signos meníngeos al examen físico. En ambos casos en la tinción de Gram de líquido cefalorraquídeo (LCR) se observaron cocáceas grampositivas. Fueron tratados con ceftriaxona y dexametasona. El cultivo de LCR fue positivo en ambos casos para S. suis serotipo 2. En los dos pacientes la evolución clínica fue favorable, sin alteraciones neurológicas al alta. En ambos casos se obtuvo en forma retrospectiva el antecedente de realizar labores de crianza de ganado porcino. Se destaca la importancia de investigar los antecedentes epidemiológicos para sospechar este agente etiológico en meningitis aguda. Se debe considerar el riesgo ocupacional en una posible infección por este patógeno humano emergente y educar a la población en riesgo sobre medidas preventivas simples.