Trauma, immigration, and sexual health among Latina women: Implications for maternal-child well-being and reproductive justice.

Latina immigrant women are vulnerable to traumatic stress and sexual health disparities. Without autonomy over their reproductive health and related decision-making, reproductive justice is elusive. We analyzed behavioral health data from 175 Latina immigrant participants (M age = 35; range = 18-64) of the International Latino Research Partnership (ILRP) study. We used descriptive and inferential statistics to compare immigrant mothers of minor children to those without, regarding their psychological and reproductive health, and correlates of past exposure to sexual trauma. Over one third (38%) of ILRP participants had minor children, and 58% had citizenship in their host country. The rate for sexual assault was 30 and 61%, respectively, for physical assault; these rates were similarly high for women with and without minor children. Women who reported sexual assault scored significantly higher for depression, posttraumatic stress disorder, and substance-abuse screens. Odds of experiencing sexual assault was highest for women who experienced physical assault (odds ratio = 10.74), and for those from the Northern Triangle (odds ratio = 8.41). Subgroups of Latina migrant mothers are vulnerable to traumatic stress and related sexual and mental health risks. Given these findings, we frame the implications in a reproductive justice framework and consider consequences for caregiver-child well-being.

Trasfondo: Las mujeres latinas inmigrantes son vulnerables al estrés traumático y a las disparidades de salud sexual. Sin autonomía sobre su salud reproductiva y las decisiones que se deben tomar al respecto, la justicia reproductiva es difícil de alcanzar. Métodos: Analizamos información sobre las actitudes con respecto a la salud de parte de 175 inmigrantes latinas participantes (edad promedio 35; entre 18 y 64) del estudio de Investigación Conjunta Internacional de Asuntos Latinos (ILRP). Usamos estadísticas descriptivas y deductivas para comparar las madres inmigrantes de niños menores con aquellas sin ellos, sin tomar en cuenta su salud sicológica y reproductiva, y correlacionar el haber estado expuestas a trauma sexual en el pasado. Resultados: Más de un tercio (38%) de las participantes del grupo de ILRP tenían niños menores, y 58% tenían ciudadanía en el país donde residían. El promedio en cuanto a la agresión sexual fue de 30% y 61% en el caso de agresión física; estos promedios fueron similarmente altos tanto para mujeres con niños pequeños como mujeres sin niños pequeños. Las mujeres que reportaron agresión sexual tuvieron puntajes significativamente más altos en el caso de depresión, trastorno por estrés postraumático (PTSD) y exámenes de detección de abuso de sustancias. Las posibilidades de experimentar agresión sexual fue lo más alto para mujeres que experimentaron agresión física (OR = 10.74), y para aquellas del Triángulo del Norte (OR = 8.41). Conclusiones: Los subgrupos de madres latinas inmigrantes son vulnerables al estrés traumático y los relacionados riesgos de salud sexual y mental. Dados estos resultados, colocamos las implicaciones dentro de un marco de trabajo de justicia reproductiva y consideramos las consecuencias para el bienestar de quien le presta cuidados al niño.

Contexte Les femmes immigrées latinas sont vulnérables au stress traumatique et aux disparités de santé sexuelle. Sans autonomie quant à leur santé reproductive et les décisions qui y sont liées, leur justice reproductive est insaisissable. Méthodes Nous avons analysé des données de santé comportementale de 175 participantes immigrées (moyenne d'âge 35 ans; éventail de 18 à 64 ans) de l'étude du partenariat de recherche international International Latino Research Partnership (ILRP). Nous avons utilisé des statistiques descriptives et déductives pour comparer les mères immigrées d'enfants mineurs à celles sans enfants, pour ce qui concerne leur santé psychologique et reproductive, ainsi que les corrélats d'exposition à un trauma sexuel dans le passé. Résultats Plus d'un tiers (38%) des participantes ILRP avaient des enfants mineurs et 58% détenaient la citoyenneté dans leur pays d'accueil. Le taux de violences sexuelles était de 30% et de 61% pour les aggressions physiques. Ces taux étaient aussi élevés chez les femmes avec ou sans enfants mineurs. Les femmes ayant déclaré des violences sexuelles ont fait état de scores bien plus élevés pour la dépression, le TSPT et la toxicomanie. Les probabilités de faire face à des violences sexuelles étaient les plus élevées chez les femmes ayant vécu une aggression physique (OR = 10,74), et pour celles du Triangle du Nord de l'Amérique centrale (OR = 8,41). Conclusions Des sous-groupes de mères migrantes latinas sont vulnérables au stress traumatique et à des risques de santé mentale qui y sont liés. Au vu de ces résultats, nous encadrons les implications dans une structure de justice de reproduction et considérons les conséquences pour le bien-être mère-enfant.

Carcinoma cells induce lumen filling and EMT in epithelial cells through soluble E-cadherin-mediated activation of EGFR.

In epithelial cancers, carcinoma cells coexist with normal cells. Although it is known that the tumor microenvironment (TME) plays a pivotal role in cancer progression, it is not completely understood how the tumor influences adjacent normal epithelial cells. In this study, a three-dimensional co-culture system comprising non-transformed epithelial cells (MDCK) and transformed carcinoma cells (MSV-MDCK) was used to demonstrate that carcinoma cells sequentially induce preneoplastic lumen filling and epithelial-mesenchymal transition (EMT) in epithelial cysts. MMP-9 secreted by carcinoma cells cleaves cellular E-cadherin (encoded by CDH1) from epithelial cells to generate soluble E-cadherin (sE-cad), a pro-oncogenic protein. We show that sE-cad induces EGFR activation, resulting in lumen filling in MDCK cysts. Long-term sE-cad treatment induced EMT. sE-cad caused lumen filling by induction of the ERK signaling pathway and triggered EMT through the sustained activation of the AKT pathway. Although it is known that sE-cad induces MMP-9 release and consequent EGFR activation in tumor cells, our results, for the first time, demonstrate that carcinoma cells can induce sE-cad shedding in adjacent epithelial cells, which leads to EGFR activation and the eventual transdifferentiation of the normal epithelial cells.

Examining the pathways linking lower socioeconomic status and advanced melanoma.

BACKGROUND: Low socioeconomic status (SES) is associated with more advanced melanoma at diagnosis and decreased survival. Exploring the pathways linking lower SES and thicker melanoma will help guide public and professional strategies to reduce deaths. METHODS: The authors surveyed 566 newly diagnosed patients at Stanford University Medical Center, Veterans Affairs Palo Alto Health Care System, and University of Michigan. SES was assessed by education level (high school/general education degree or less [HS], associate/technical school degree, or ≥college graduate). All data was obtained by self-report among patients within three months of their diagnosis. RESULTS: HS-educated individuals were significantly more likely than college graduates to believe that melanoma was not very serious (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.79-4.71) and were less likely to know the asymmetry, borders (irregular), color (variegated), and diameter (>6 mm) (ABCD) melanoma rule or the difference between melanoma and ordinary skin growths (OR, 0.34 [95% CI, 0.23-0.52] and 0.26 [95% CI, 0.16-0.41] respectively). Physicians were less likely to have ever told HS-educated versus college-educated individuals they were at risk for skin cancer (OR, 0.46; 95% CI, 0.31-0.71) or instructed them on how to examine their skin for signs of melanoma (OR, 0.40; 95% CI, 0.25-0.63). HS-educated individuals were less likely to have received a physician skin examination within the year before diagnosis (OR, 0.54; 95% CI, 0.37-0.80). CONCLUSIONS: Decreased melanoma risk perception and knowledge among low-SES individuals and decreased physician communication regarding skin examinations of these individuals may be key components of the consistently observed socioeconomic gradient in mortality. The current findings suggest the need to raise melanoma awareness among lower-SES patients and to increase physician awareness of socioeconomic disparities in clinical communication and care.

Which girls, which boys? The intersectional risk for depression by race and ethnicity, and gender in the U.S.

We sought to conduct the first systematic review of studies applying an intersectional lens to assessing risk and protective factors for depression in minority adolescents in the United States. Twenty-five studies were identified which investigated the role of racial and ethnic identity and gender for minority groups and how marginalization may be associated with differential outcomes in depression symptomology. The results showed substantial variability in whether studies intentionally operationalized intersectionality through theoretical frameworks, study design, sampling, and analyses. Studies were rated on a scale of 1 through 5; those with scores of 3 or higher were included in the review. A rating of 5 indicated studies had explicitly used an intersectional theoretical framework, integrating the process of racial/ethnic identity development and gender socialization during adolescence. Three studies met the criteria for 5, one study was rated 4, and 21 studies were rated 3. Attention to experiences with discrimination was common throughout. Overall, the collective findings point to the importance of using an intersectional lens for understanding differential mechanisms for how and why specific adolescent minority youth are at greater risk for reporting depression symptoms, identifying cultural and developmental protective factors, and informing how interventions can effectively target specific mechanisms for prevention and treatment.

Discovery of liver-directed glucokinase activator having anti-hyperglycemic effect without hypoglycemia.

Glucokinase activators (GKAs) are among the emerging drug candidates for the treatment of type 2 diabetes (T2D). Despite effective blood glucose lowering in clinical trials, many pan-GKAs "acting both in pancreas and liver" have been discontinued from clinical development mainly because of their potential to cause hypoglycemia. Pan-GKAs over sensitize pancreatic GK, resulting in insulin secretion even at sub-normoglycemic level which might be a possible explanation for hypoglycemia. An alternative approach to minimize the risk of hypoglycemia is to use liver-directed GKAs, which are reported to be advancing well in clinical development. Here, we report the discovery and structure-activity relationship (SAR) studies on a novel 2-phenoxy-acetamide series with the aim of identifying a liver-directed GKA. Incorporation of a carboxylic acid moiety as an active hepatocyte uptake recognizing element at appropriate position of 2-phenoxy-acetamide core led to the identification of 26, a potent GKA with predominant liver-directed pharmacokinetics in mice. Compound 26 on oral administration significantly reduced blood glucose levels during an oral glucose tolerance test (oGTT) performed in diet-induced obese (DIO) mice, while showing no sign of hypoglycemia in normal C57 mice over a 10-fold dose range, even when dosed at fasted condition. Together, these data demonstrate a liver-directed GKA has beneficial effect on glucose homeostasis with reduced risk of hypoglycemia.

Integrating mechanisms of response and resistance against the tubulin binding agent Eribulin in preclinical models of osteosarcoma.

Osteosarcoma is the most frequently occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common. Eribulin is a synthetic microtubule inhibitor that has demonstrated activity in preclinical osteosarcoma models. The effects of eribulin were evaluated in two human osteosarcoma cell lines as well as in eribulin-sensitive and -resistant osteosarcoma xenograft tumors of the Pediatric Preclinical Testing Program (PPTP) by characterizing cell viability, microtubule destabilization, mitotic arrest and mechanism of cell death. Eribulin demonstrated cytotoxic activity in vitro, through promotion of microtubule dynamic instability, arrest of cells in the G2/M phase, mitotic catastrophe and cell death. The microtubule-destabilizing protein stathmin-1 (STMN1) was coimmunoprecipitated with the cyclin-dependent kinase inhibitor p27 indicating that these cytoplasmic complexes can protect cells from the microtubule destabilizing effect of eribulin. Increased tumoral expression of P-glycoprotein (P-gp) and TUBB3 were also associated with lower drug sensitivity. In summary, eribulin successfully blocked cells in G2/M phase but interfered with mitochondria activity to inhibit proteins involved in apoptosis. Understanding the complex and inter-related mechanisms involved in the overall drug response to eribulin may help in the design of therapeutic strategies that enhance drug activity and improve benefits of eribulin in pediatric patients with osteosarcoma.

Wilms' tumor protein induces an epithelial-mesenchymal hybrid differentiation state in clear cell renal cell carcinoma.

The Wilms' tumor transcription factor (WT1) was originally classified as a tumor suppressor, but it is now known to also be associated with cancer progression and poor prognosis in several malignancies. WT1 plays an essential role in orchestrating a developmental process known as mesenchymal-to-epithelial transition (MET) during kidney development, but also induces the reverse process, epithelial-to-mesenchymal transition (EMT) during heart development. WT1 is not expressed in the adult kidney, but shows elevated expression in clear cell renal cell carcinoma (ccRCC). However, the role of WT1 in this disease has not been characterized. In this study, we demonstrate that WT1 is upregulated in ccRCC cells that are deficient in the expression of the von Hippel-Lindau tumor suppressor protein (VHL). We found that WT1 transcriptionally activated Snail, a master transcriptional repressor that is known to induce EMT. Although Snail represses E-cadherin and induces mesenchymal characteristics, we found partial maintenance of E-cadherin and associated epithelial characteristics in kidney cells and ccRCC cells that express WT1, since WT1 upregulates E-cadherin expression and competes with Snail repression. These findings support a novel paradigm in which WT1 induces an epithelial-mesenchymal hybrid transition (EMHT), characterized by Snail up-regulation with E-cadherin maintenance, a tumor cell differentiation state in which cancer cells keep both EMT and MET characteristics which may promote tumor cell plasticity and tumor progression.

Community-based participatory research skills and training needs in a sample of academic researchers from a clinical and translational science center in the Northeast.

PURPOSE: To determine the community-based participatory research (CBPR) training interests and needs of researchers interested in CBPR to inform efforts to build infrastructure for conducting community-engaged research. METHOD: A 20-item survey was completed by 127 academic health researchers at Harvard Medical School, Harvard School of Public Health, and Harvard affiliated hospitals. RESULTS: Slightly more than half of the participants reported current or prior experience with CBPR (58 %). Across all levels of academic involvement, approximately half of the participants with CBPR experience reported lacking skills in research methods and dissemination, with even fewer reporting skills in training of community partners. Regardless of prior CBPR experience, about half of the respondents reported having training needs in funding, partnership development, evaluation, and dissemination of CBPR projects. Among those with CBPR experience, more than one-third of the participants wanted a mentor in CBPR; however only 19 % were willing to act as a mentor. CONCLUSIONS: Despite having experience with CBPR, many respondents did not have the comprehensive package of CBPR skills, reporting a need for training in a variety of CBPR skill sets. Further, the apparent mismatch between the need for mentors and availability in this sample suggests an important area for development.

A funding initiative for community-based participatory research: lessons from the Harvard Catalyst Seed Grants.

BACKGROUND: The National Institutes of Health-funded Clinical and Translational Science Awards (CTSA) have increasingly focused on community-engaged research and funded investigators for community-based participatory research (CBPR). However, because CBPR is a collaborative process focused on community-identified research topics, the Harvard CTSA and its Community Advisory Board (CERAB) funded community partners through a CBPR initiative. OBJECTIVES: We describe lessons learned from this seed grants initiative designed to stimulate community-academic CBPR partnerships. METHODS: The CBPR program of the Harvard CTSA and the CERAB developed this initiative and each round incorporated participant and advisory feedback toward program improvement. LESSONS LEARNED: Although this initiative facilitated relevant and innovative research, challenges included variable community research readiness, insufficient project time, and difficulties identifying investigators for new partnerships. CONCLUSION: Seed grants can foster innovative CBPR projects. Similar initiatives should consider preliminary assessments of community research readiness as well as strategies for meaningful academic researcher engagement.