Incorporating an intersectional gender approach to improve access to maternal and child health screening services.

BACKGROUND: In the Americas, the Pan American Health Organization (PAHO) has promoted initiatives that aim at the elimination of mother-to-child transmitted diseases for over two decades. Although Guatemala has assumed the commitment to improve access and coverage of reproductive and perinatal services, the goals have not yet been reached. Often, the implementation of these efforts is hampered by complexities rooted in social, cultural, and environmental intersections. The objective of this work is to share our experience applying gender intersectionality as a methodological and analytical tool in a participatory research project that aims to improve access to maternal and child health screening services. The study shows the novel strategy that incorporates intersectionality contributing to evidence on how it can be applied to strengthen public health efforts around the implementation of the EMTCT Plus (Elimination of mother-to-child transmission of HIV, Syphilis, Hepatitis B, and Chagas disease) framework, in the mostly rural municipality of Comapa, in Guatemala. METHODS: We applied a participatory methodology, integrating theoretical and methodological frameworks to have an intersectional understanding of health services delivered by both, midwives, and the public health institution, for the prevention, diagnosis, treatment, and follow-up of HIV, Syphilis, Hepatitis B, and Chagas. The data was collected by conducting interviews, focus groups, workshops, and reviewing laboratory databases, guided by five strategies from a cultural appropriateness framework. RESULTS: The intersectional analysis shed light on the synergies and gaps of the current efforts and protocols implemented by both the midwives and the Ministry of Health. The services offered for the four diseases were often delivered independently from each other, and a comprehensive educational and communication material strategy was absent. However, our findings will be used to inform consistent, locally relevant, and culturally appropriate educational content for the local population, also following the national policy guidelines. CONCLUSIONS: Using intersectionality as a method and as an analytical tool allowed us to understand the (1) interrelation of diverse social, cultural, and environmental determinants which influence the delivery of health services, as well as (2) the dynamics between the traditional and institutional health systems. (3) Community engagement and the participation of different stakeholders in a consultative process have been fundamental for the conceptual and methodological tenets of this research. (4) Finally, giving a more prominent role to midwives can strengthen sustainability and cultural appropriateness, which is complementary to the delivery of institutional health services.

RESUMEN: ANTECEDENTES: La Organización Panamericana de la Salud (OPS) ha impulsado iniciativas que buscan la eliminación de las enfermedades de transmisión materno infantil en las Américas desde hace más de dos décadas. Si bien Guatemala ha asumido el compromiso de mejorar el acceso y la cobertura de los servicios reproductivos y perinatales, las metas aún no se han alcanzado. Muchas veces, la implementación de estos esfuerzos se ve obstaculizada por complejidades arraigadas en intersecciones sociales, culturales y ambientales. Este estudio muestra una estrategia novedosa que incorpora la interseccionalidad como un componente metodológico y analítico. Esto contribuye a evidenciar la manera en que la interseccionalidad y la participación comunitaria pueden ser aplicadas para fortalecer los esfuerzos de salud pública en torno a la implementación de la estrategia ETMI Plus (Eliminación de la transmisión materno infantil del VIH, sífilis, hepatitis B y enfermedad de Chagas), en el municipio de Comapa, en Guatemala, el cual es mayoritariamente rural. MéTODOS: Implementamos una metodología participativa, integrando marcos teóricos y metodológicos para comprender la prestación de servicios de salud, tanto por parte de comadronas como de la institución de salud pública, desde una perspectiva interseccional para la prevención, diagnóstico, tratamiento y seguimiento de VIH, sífilis, hepatitis B y Chagas. Los datos fueron recolectados a través de entrevistas, grupos focales, talleres y tras la revisión de bases de datos de laboratorio, y nos guiamos por cinco estrategias propuestas en un marco para pertinencia cultural. RESULTADOS: El análisis interseccional permitió entender las sinergias y brechas de los esfuerzos y los protocolos que se implementan actualmente, tanto por parte de las comadronas como por el Ministerio de Salud. Encontramos que los servicios que actualmente se prestan para las cuatro enfermedades son en su mayoría independientes entre sí, y no se contaba con una estrategia integral de material educativo y de comunicación. Sin embargo, nuestros resultados se utilizarán como base para una estrategia de comunicación que sea coherente, localmente relevante y culturalmente apropiada para la población local, y también siga las regulaciones de las políticas nacionales. CONCLUSIONES: El uso de la interseccionalidad como método y como herramienta analítica nos permitió comprender (1) la interrelación de diversos determinantes sociales, culturales y ambientales que influyen en la prestación de servicios de salud, así como (2) la dinámica entre los sistemas de salud tradicional e institucional. (3) El compromiso de la comunidad y la participación de las diferentes partes interesadas en un proceso consultivo han sido fundamentales para los principios conceptuales y metodológicos de esta investigación. (4) Por último, otorgar un papel más destacado a las matronas puede reforzar la sostenibilidad y la adecuación cultural, que es complementaria a la prestación de servicios de salud institucionales.

The Effect of a Compression Bandage on Dual Energy X-ray Absorptiometry Body Composition Scores.

BACKGROUND: Dual-energy X-ray absorptiometry (DXA) measures are affected by the noise produced by external factors such as textile compression found in loose clothing. The study aimed to determine the effect of a compression bandage (CB) on body composition (BC) assessed by DXA. METHODS: Sixty volunteers (age=21.4±4.7yr.) underwent full-body DXA scans on a control (CTRL) condition and after wearing a 30-mmHg CB on the trunk, legs, and arms. ANOVA (2 genders by 2 experimental conditions) determined mean interactions in BC variables tissue body fat% (BF%), region body fat% (RBF%), body tissue (BT), fat mass (FM), lean mass (LM), bone mineral content (BMC), and total mass (TM). Absolute reliability in BC scores was studied by the typical error of the measurement (TEM), the coefficient of variability (CV), and Bland-Altman plots. RESULTS: ANOVA interactions were found on tissue total BF% (p=0.049), RBF% (p=0.048), android lean mass (p=0.004), and android total mass (p=0.019). The CV was small for tissue BF% (2.61±0.93%, CI95%=0.79, 4.43%), RBF% (2.66±1.78%, CI95%=-0.83, 6.15%), BT (4.82±2.19%, CI95%=0.54, 9.10kg), FM (4.17±2.25%, CI95%=-0.24, 8.58kg), LM (3.25±2.44%, CI95%=-1.53, 8.04kg), BMC (4.81±2.96%, CI95%=-0.99, 10.62kg), and TM (2.84±2.80%, CI95%=-2.65, 8.33kg). Bland-Altman plots showed random error for BF%, LM, and BMC. A bias of 0.5% was observed on BF% in males. CONCLUSION: A CB worn during a full-body DXA scan elicited similar BC scores than not wearing it. The variation in scores was <10% for most BC variables, and a trivial bias of 0.5% in BF% was detected in male scores.

Witnessing inter-parental violence in childhood and help-seeking behaviours in violence against women in Peru.

BACKGROUND: Violence against women (VAW) severely impacts their physical and mental health. In some cultures, women can normalize certain types of violence if they were linked to home models in childhood and, eventually, do not seek for help in adulthood. We aimed to determine, in Peruvian women, (1) the association between witnessing violence in their family of origin and VAW experienced in adulthood, (2) the extent to which women who have experienced VAW seek some help, and (3) identify VAW prevalence by Peruvian region. METHODS: Cross-sectional study of secondary data obtained from the 2019 National Demographic and Family Health Survey (ENDES). The outcome was VAW (psychological, physical and sexual violence), whereas the exposure was witnessing violence in the home of origin. Help-seeking behavior was a secondary outcome, for which VAW was the exposure. Prevalence ratios (PR) were estimated to assess both associations, unadjusted and adjusted for covariates (aPR). RESULTS: Data from 14,256 women aged 15 to 49 years were analysed. 51.5% reported having experienced VAW and 43.8% witnessed violence in the home of origin during childhood. Witnessing inter-parental violence in childhood was associated with psychological violence aPR = 1.25 (95% CI: 1.17-1.33), physical aPR = 1.52 (95% CI: 1.38-1.67), and sexual aPR = 1.99 (95% CI: 1.57-2.52). Women who have experienced both types of violence (physical and sexual) were more likely to help-seeking (aPR = 1.30, 95% CI: 1.14-1.50) than women suffering only one type of violence. CONCLUSION: Women who reported having witnessed home violence in their childhood are more likely to experience Violence Against Women (VAW) by their current partner. Physical and sexual violence with a current partner was more associated with witnessing inter-parental violence in childhood, and when physical and sexual violence jointly occurred women were more help-seeking. The southern region of Peru is identified as an area of high vulnerability for women. It is crucial to promote educative and community-based programs aimed at the prevention and early recognition of VAW.

Effect of exercise-induced body fluid redistribution on body composition in males using dual energy X-ray absorptiometry.

We studied the effect of exercise-induced body fluid redistribution on dual-energy x-ray absorptiometry (DXA) body composition scores. Thirty males completed 30-min of upper-body exercise (UBE), lower-body exercise, and seated non-exercise control (NEC). ANOVA determined interactions between experimental conditions and measurements on body composition variables. For UBE, mean pre to post differences were found on tissue fat (M = 0.35 ± 0.12%; CI95%diff = 0.10 to 0.59%; p = 0.007), region fat (M = 0.32 ± 0.11%; CI95%diff = 0.09 to 0.55%; p = 0.008), lean mass (M = 0.27 ± 0.01 kg; CI95%diff = 0.18 to 0.37 kg; p ≤ 0.0001), and total mass (M = 0.27 ± 0.05 kg; CI95%diff = 0.17 to 0.36 kg; p ≤ 0.0001). Mean tissue pre to post differences were found for the total body in the NEC (M = 0.10 ± 0.04 kg; CI95%diff = 0.03 to 0.18 kg; p = 0.008), UBE (M = 0.19 ± 0.03 kg; CI95%diff = 0.14 to 0.24 kg; p ≤ 0.0001), and LBE (M = 0.31 ± 0.04 kg; CI95%diff = 0.24 to 0.39 kg; p ≤ 0.0001) conditions. High absolute reliability was found within experimental conditions. These findings have practical implications for technicians, since acute exercise elicited small changes in body composition scores using DXA.

Adoption of community-based strategies for sustainable vector control and prevention.

Community engagement strategies provide tools for sustainable vector-borne disease control. A previous cluster randomized control trial engaged nine intervention communities in seven participatory activities to promote management of the domestic and peri-domestic environment to reduce risk factors for vector-borne Chagas disease. This study aims to assess the adoption of this innovative community-based strategy, which included chickens' management, indoor cleaning practices, and domestic rodent infestation control, using concepts from the Diffusion of Innovations Theory. We used questionnaires and semi-structured interviews to understand perceptions of knowledge gained, intervention adoption level, innovation attributes, and limiting or facilitating factors for adoption. The analysis process focused on five innovation attributes proposed by the Diffusion of Innovations Theory: relative advantage, compatibility, complexity, trialability, and observability. Rodent management was highly adopted by participants, as it had a relative advantage regarding the use of poison and was compatible with local practices. The higher complexity was reduced by offering several types of trapping systems and having practical workshops allowed trialability. Observability was limited because the traps were indoors, but information and traps were shared with neighbors. Chicken management was not as widely adopted due to the higher complexity of the method, and lower compatibility with local practices. Using the concepts proposed by the Diffusion of Innovations Theory helped us to identify the enablers and constraints in the implementation of the Chagas vector control strategy. Based on this experience, community engagement and intersectoral collaboration improve the acceptance and adoption of novel and integrated strategies to improve the prevention and control of neglected diseases.

Low-Intensity Resistance Training Improves Flow-Mediated Dilation in Young Hispanic Adults.

ABSTRACT: Briceño-Torres, JM, Carpio-Rivera, E, Solera-Herrera, A, Forsse, J, Grandjean, PW, and Moncada-Jiménez, J. Low-intensity resistance training improves flow-mediated dilation in young hispanic adults. J Strength Cond Res 37(2): 298-304, 2023-The purpose of this study was to compare the effects of 2 resistance exercise training (RET) intensities on brachial artery flow-mediated dilatation (FMD) in sedentary males. Thirty-four men (age = 20.6 ± 1.8 years, height = 171.3 ± 5.2 cm, body mass = 65.2 ± 10.6 kg, and DXA fat mass = 22.3 ± 7.4%) were randomly assigned to a control group (no exercise CTRL, n = 12), RET at 50% of 1 repetition maximum (1RM) (RET50%, n = 12), and RET at 80% 1RM (RET80%, n = 10). The RET program was performed twice per week for 8 weeks; subjects performed the same RET exercises at similar total workloads (1920 arbitrary units [AUs] for the RET80% and 1950 AUs for the RET50%). The FMD% was measured before and after 8 weeks by ultrasound. Mixed factorial analysis of variance (3 groups × 2 measurements), effect size (ES), and 95% confidence intervals (95% CIs) were computed for FMD%. The level of significance was set at p ≤ 0.05. A significant increase ( p = 0.001) was found on post-test FMD% in RET50% (mean = 9.9 ± 3.7%, ES = 1.9, and 95% CIs = 2.8-0.9) compared with CTRL (mean = 5.7 ± 1.7%, ES = 0.2, and 95% CIs = -0.4 to 0.8), and there were no significant differences found between RET50% and RET80% and between RET80% and CTRL. Results support the concept of training specificity and provide preliminary evidence that lower resistance and higher repetition RET elicit greater short-term reduced endothelium dysfunction than higher intensity RET at similar training volume.

Predictive validity of the body adiposity index in costa rican students.

OBJECTIVE: To verify the validity of the body adiposity index (BAI) in a sample of Costa Rican students. METHODS: Volunteers were 93 females (mean age = 18.6 ± 2.4 years) and 106 males (mean age = 19.2 ± 2.8 years). Dual-energy X-ray absorptiometry (DXA) was used as the "gold standard" to determine body fat percentage (BF%). Pearson's correlation coefficient and paired samples t-test studied the association and mean differences between BAI and DXA BF%. Concordance between BAI and DXA BF% was determined by the Lin's concordance correlation coefficient and the Bland-Altman agreement analysis. RESULTS: Significant correlations between BAI and DXA BF% were found for females (r = 0.74) and males (r = 0.53) (P < 0.001). Differences between methods were found for females (BAI = 29.3 ± 4.1% vs. DXA = 36.5 ± 7.9%) and males (BAI = 24.8 ± 3.7% vs. DXA = 21.9 ± 8.6%; P < 0.001). Concordance was poor in females and males. Bland-Altman plots showed BAI underestimating and overestimating BF% in relation to the "gold standard" in females and males, respectively. CONCLUSIONS: BAI presented low agreement with BF% measured by DXA; therefore, BAI is not recommended for BF% prediction in this Central American sample studied. Am. J. Hum. Biol. 28:394-397, 2016. © 2015 Wiley Periodicals, Inc.

Perceptions of the Role of Living Alone in Providing Services to Patients With Cognitive Impairment.

Importance: The potential role of living alone in either facilitating or hampering access to and use of services for older adults with cognitive impairment is largely unknown. Specifically, it is critical to understand directly from health care and social services professionals how living alone creates barriers to the access and use of supportive health care and social services for racially and ethnically diverse patients with cognitive impairment. Objective: To identify the potential role of living alone in the access and use of health care and social services for diverse patients with cognitive impairment by investigating professionals' perceptions of caring for such patients who live alone in comparison with counterparts living with others. Design, Setting, and Participants: This qualitative study of 76 clinicians, social workers, and other professionals used semistructured interviews conducted between February 8, 2021, and June 8, 2022, with purposively sampled professionals providing services to diverse patients with cognitive impairment in Michigan, California, and Texas. Main Outcomes and Measures: Clinicians, social workers, and other professionals compared serving patients with cognitive impairment and living alone vs counterparts living with others. An inductive content analysis was used to analyze the interview transcripts. Results: A total of 76 professionals were interviewed (mean [SD] age, 49.3 [12.7] years); 59 were female (77.6%), 8 were Black or African American (11%), and 35 were White (46%). Participants included physicians, nurses, social workers, and home-care aides, for a total of 20 professions. Participants elucidated specific factors that made serving older adults living alone with cognitive impairment more challenging than serving counterparts living with others (eg, lacking an advocate, incomplete medical history, requiring difficult interventions), as well as factors associated with increased concerns when caring for older adults living alone with cognitive impairment, such as isolation and a crisis-dominated health care system. Participants also identified reasons for systematic unmet needs of older adults living alone with cognitive impairment for essential health care and social services, including policies limiting access and use to public home-care aides. Conclusions and Relevance: In this qualitative study of professionals' perspectives, findings suggest that living alone is a social determinant of health among patients with cognitive impairment owing to substantial barriers in access to services. Results raised considerable concerns about safety because the US health care system is not well equipped to address the unique needs of older adults living alone with cognitive impairment.

The Effects of Acute and Chronic Exercise on Paraoxonase-1 (PON1): A Systematic Review With Meta-Analysis.

Purpose: To determine the acute and chronic effects of exercise on Paraoxonase-1 (PON1) concentration and activity. Methods: A literature search was performed using 16 electronic databases. Effect sizes (ES) were computed and two-tailed α values < .05 and non-overlapping 95% confidence intervals (95%CI) were considered statistically significant. Heterogeneity, inconsistency (I2), and small-study effects using the LFK index were examined. Results: Eighteen studies (n = 377 participants) met the criteria for inclusion. The acute effects of exercise on PON1 concentration were trivial and non-significant (ES = -.03, 95%CI = -.39 to .34, p > .05), heterogeneous (p = .05), moderately inconsistent (I2 = 48%), with minor asymmetry (LFK index = 1.34). The chronic effects of exercise on PON1 concentration were also trivial and non-significant (ES = -.04, 95%CI = -.53 to.45, p > .05), homogenous (p = .65), displayed low inconsistency (I2 = 0%), and minor asymmetry (LFK index = -1.14). The acute effects of exercise on PON1 activity were trivial and non-significant (ES = .11, 95%CI = -.02 to.24, p > .05), homogenous (p = .85), showed low inconsistency (I2 = 0%), and no asymmetry (LFK index = .82). The chronic effects of exercise on PON1 activity were trivial and non-significant (ES = .31, 95%CI = -.03 to.65, p > .05), homogenous (p = .17), moderately inconsistent (I2 = 36%), with no asymmetry (LFK index = .60). Conclusion: Acute and chronic exercise training, overall, exerted a trivial effect on PON1 concentration and activity.

The Effects of the COVID-19 Pandemic on the Lived Experience of Diverse Older Adults Living Alone With Cognitive Impairment.

BACKGROUND AND OBJECTIVES: Even before the COVID-19 pandemic, older adults with cognitive impairment living alone (an estimated 4.3 million individuals in the United States) were at high risk for negative health outcomes. There is an urgent need to learn how this population is managing during the pandemic. RESEARCH DESIGN AND METHODS: This is a qualitative study of 24 adults aged 55 and older living alone with cognitive impairment from diverse racial/ethnic backgrounds. Participants' lived experiences during the pandemic were elicited via 59 ethnographic interviews conducted over the phone either in English, Spanish, or Cantonese. Using a qualitative content analysis approach, interview transcripts were analyzed to identify codes and themes. RESULTS: Qualitative analysis of transcripts revealed 5 themes: (a) fear generated by the pandemic, (b) distress stemming from feeling extremely isolated, (c) belief in misinformation, (d) strategies for coping during the pandemic, and (e) the importance of access to essential services. DISCUSSION AND IMPLICATIONS: This pandemic put a spotlight on the precarity and unmet needs of older adults living alone with cognitive impairment. Findings underscore the need to expand access to home care aides and mental health services for this population.

Haploidentical transplantation outcomes are comparable with those obtained with identical human leukocyte antigen allogeneic transplantation in Chilean patients with benign and malignant hemopathies.

INTRODUCTION: Patients with benign or malignant blood disorders, who require allogeneic stem cell transplantation and lack an identical human leukocyte antigen HLA identicalHL sibling donor, could be transplanted with hematopoietic stem cells from unrelated adult or umbilical cord donors. However, in our country, both approaches are costly and time-consuming options. METHODS: Over the last few years, haploidentical modalities have been investigated as an alternative donor source, showing similar results to those obtained with identical HLA donors. We started using T-cell-replete haploidentical with post-transplant cyclophosphamide in 2012 and we presented our experience with patients undergoing haploidentical ransplantation compared to SIB. RESULTS: Since January 2012 to date, 91 allogeneic transplants have been performed, of which 49 were haploidentical and 42 were HLA identical. The mean age of the patients was 35 years (range: 17-62). The mean CD34/kg×106 infused per group was 5.93 and 5.89, respectively. Time to granulocyte and platelet engraftment was 11 and 15 days, respectively, for haploidentical, and 12 and 14 days, respectively, for HLA identical (p=0.10). The 100-day cumulative incidence of global acute GVHD was 34% for haploidentical and 29% for SIHLA identical (p=0.9). The 2-year overall global graft-versus-host disease was 43% for haploidentical and 41% for HLA identical (p=0.8). Overall survival, relapse, and transplant and relapse-related mortality were similar between both groups. CONCLUSION: Our experience showed that haploidentical has similar outcomes to those obtained with HLA idential and can be performed in our country safely.

Understanding Pharmacokinetic Disconnect in Preclinical Species for 4-Aminoquinolines: Consequences of Low Permeability and High P-glycoprotein Efflux Ratio on Rat and Dog Oral Pharmacokinetics.

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies. Structurally similar analogues incorporating polarity at C-7 position of 4-aminoquinoline resulted in identification of GSKC - GSKF. Interestingly, following oral administration to rat at similar low dose, GSKC - GSKF demonstrated significantly low systemic drug exposure compared to GSKA and GSKB (3-17-fold difference). However, in dog, dose normalized oral systemic exposure for GSKC - GSKF was comparable to GSKA and GSKB (within 2-fold). A series of studies were conducted to understand the disconnect which highlighted that an intrinsic reduction in permeability and high P-glycoprotein (P-gp) efflux ratio for C-7 substituted analogues were driving pharmacokinetic disconnect between rat and dog. Oral absorption was minimally impacted in dog by P-gp mediated efflux compared to rat because the leakier gastrointestinal tract in dog likely overcomes this effect.

Optimization and Characterization of Protein Nanoparticles for the Targeted and Smart Delivery of Cytochrome c to Non-Small Cell Lung Carcinoma.

The delivery of Cytochrome c (Cyt c) to the cytosol stimulates apoptosis in cells where its release from mitochondria and apoptotic induction is inhibited. We developed a drug delivery system consisting of Cyt c nanoparticles decorated with folate-poly(ethylene glycol)-poly(lactic-co-glycolic acid)-thiol (FA-PEG-PLGA-SH) to deliver Cyt c into cancer cells and tested their targeting in the Lewis Lung Carcinoma (LLC) mouse model. Cyt c-PLGA-PEG-FA nanoparticles (NPs) of 253 ± 55 and 354 ± 11 nm were obtained by Cyt c nanoprecipitation, followed by surface decoration with the co-polymer SH-PLGA-PEG-FA. The internalization of Cyt c-PLGA-PEG-FA nanoparticles (NPs) in LLC cells was confirmed by confocal microscopy. NP caspase activation was more efficient than the NP-free formulation. Caspase activity assays showed NPs retained 88-96% Cyt c activity. The NP formulations were more effective in decreasing LLC cell viability than NP-free formulation, with IC50 49.2 to 70.1 µg/mL versus 129.5 µg/mL, respectively. Our NP system proved to be thrice as selective towards cancerous than normal cells. In vivo studies using near infrared-tagged nanoparticles show accumulation in mouse LLC tumor 5 min post-injection. In conclusion, our NP delivery system for Cyt c shows superiority over the NP-free formulation and reaches a folic acid-overexpressing tumor in an immune-competent animal model.

Tumor-infiltrating regulatory T cells, CD8/Treg ratio, and cancer stem cells are correlated with lymph node metastasis in patients with early breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes are an important component of the tumor microenvironment (TME) in breast cancer. They have been linked with tumor pathogenesis in advanced stages. However, little is known about their contribution in early phases. In this study, we analyzed the infiltration of leukocytes and cancer stem cells (CSC) in tumors from patients with early breast cancer. METHODS: Samples of blood and tumor tissue from 30 patients with breast cancer were collected, and the number of dendritic cells (DC), T cells, and CSC were analyzed by flow cytometry. RESULTS: Tumor-infiltrating CD4 and CD8 T cells expressed higher levels of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) compared with peripheral T cells. Regulatory T cells (Treg) were enriched in tumors and overexpressed glucocorticoid-induced TNFR-related protein and CTLA-4. Tumor Treg had a positive correlation with the amount of myeloid DC (mDC) and disease progression. The CD8/Treg ratio was associated with lymph node metastasis and tumor stages. The main subset of DC in early breast tumors was mDC, while plasmacytoid DC were almost absent. CSC were present in most tumors with higher frequencies in patients with lymph node metastasis. CSC were also associated with the amount of tumor-infiltrating Treg. CONCLUSION: Early breast cancer has an inflammatory milieu characterized by mDC, Treg, and CSC infiltration. The frequencies of Treg, CSC and CD8/Treg ratio were associated with disease progression. The composition of leukocytes and the presence of CSC in early breast tumors should be considered for the development of new therapeutic approaches.

Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.].

[Nutritional assessment and phytoestrogen exposure in a diet of students of the University of Costa Rica]. / Valoracion nutricional y exposición a fitoestrógenos en la dieta de estudiantes de la Universidad de Costa Rica.

INTRODUCTION: Introduction: this study presents the results regarding diet and an analysis of natural estrogens (phytoestrogens) intake and how they affect other important aspects, which can modulate biological health functions among university students. Objectives: assessing nutritional habits and estimating the intake of phytoestrogens in the population under study. Materials and methods: Costa Rican female (n: 211, 18.83 ± 2.06 years) and male (n: 199, 19.64 ± 3.05 years) university population of the University of Costa Rica applied anthropometric tests using DEXA, the Food Frequency Questionnaire (FFQ) and the 24-hour Reminder (R-24). Results: the most serious nutritional bad habits were high ingestion of sodium, lipids and animal origin proteins in men and women and a deficit of fiber and folic acid in women. The total intake of phytoestrogens referred to: daidzein 0.23 ± 0.40 mg/day and 7.01 ± 11.94 mg/month in women and 0.17 ± 0.13 mg/day and 5.14 ± 3.96 mg/month in men; mainly consumed in the form of lignans 0.24 ± 0.12 mg/day (women) and 0.23 ± 0.14 mg/day (men). The intake of isoflavones was 0.09 ± 0.38 mg/day (women) and 0.04 ± 0.08 mg/day (men). Conclusions: The study population presented high fat percentage although the consumption of vegetables, cereals, whole grains and fruits tends slightly to be a Mediterranean diet; their food pattern was much closer to the Western diet.

INTRODUCCIÓN: Introducción: este estudio presenta resultados respecto a dieta y un análisis más en profundidad de la exposición a estrógenos naturales (fitoestrógenos) en la ingesta, y como este tipo de compuestos influye y se relaciona con otros aspectos importantes que pueden modular funciones biológicas relacionadas con la salud en estudiantes universitarios. Objetivos: valorar hábitos nutricionales y estimar la ingesta de fitoestrógenos de la población en estudio. Material y métodos: población costarricense universitaria femenina (n: 211, edades 18,83 ± 2,06 años) y masculina (n: 199, edades 19,64 ± 3,05 años) de la Universidad de Costa Rica y se han aplicado pruebas antropométricas mediante el DEXA y cuestionarios de Frecuencia de Consumo de Alimentos (FFQ) y Recuerdos de 24 Horas (R-24). Resultados: los errores nutricionales más graves fueron: la elevada ingesta de sodio, lípidos y proteínas de origen animal en hombres y mujeres, y el déficit importante de fibra y ácido fólico en las mujeres. La ingesta total de fitoestrógenos referidos a la daizdeína fue de 0.23 ± 0.40 mg/día y 7,01 ± 11,94 mg/mes en mujeres y de 0,17 ± 0,13 mg/día y de 5,14 ± 3,96 mg/mes en varones; principalmente consumida en forma de lignanos 0,24 ± 0,12 mg/día (mujeres) y 0,23 ± 0,14 mg/día (hombres), mientras la ingesta de isoflavonas fue de 0,09 ± 0,38 mg/día (mujeres) y de 0,04 ± 0,08 mg/día (hombres). Conclusiones: la población de estudio presentó porcentajes de grasa elevados nutricionalmente hablando, aunque el consumo de vegetales, cereales, granos enteros y frutas tiende un poco a la dieta mediterránea, su patrón alimentario se acerca mucho más a la dieta occidental.

Identification of a RIP1 Kinase Inhibitor Clinical Candidate (GSK3145095) for the Treatment of Pancreatic Cancer.

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

Discovery and Lead-Optimization of 4,5-Dihydropyrazoles as Mono-Kinase Selective, Orally Bioavailable and Efficacious Inhibitors of Receptor Interacting Protein 1 (RIP1) Kinase.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.