Cabergoline as a Novel Strategy for Post-Pregnancy Breast Cancer Prevention in Mice and Human.

Post-pregnancy breast cancer often carries a poor prognosis, posing a major clinical challenge. The increasing trend of later-life pregnancies exacerbates this risk, highlighting the need for effective chemoprevention strategies. Current options, limited to selective estrogen receptor modulators, aromatase inhibitors, or surgical procedures, offer limited efficacy and considerable side effects. Here, we report that cabergoline, a dopaminergic agonist, reduces the risk of breast cancer post-pregnancy in a Brca1/P53-deficient mouse model, with implications for human breast cancer prevention. We show that a single dose of cabergoline administered post-pregnancy significantly delayed the onset and reduced the incidence of breast cancer in Brca1/P53-deficient mice. Histological analysis revealed a notable acceleration in post-lactational involution over the short term, characterized by increased apoptosis and altered gene expression related to ion transport. Over the long term, histological changes in the mammary gland included a reduction in the ductal component, decreased epithelial proliferation, and a lower presence of recombinant Brca1/P53 target cells, which are precursors of tumors. These changes serve as indicators of reduced breast cancer susceptibility. Additionally, RNA sequencing identified gene expression alterations associated with decreased proliferation and mammary gland branching. Our findings highlight a mechanism wherein cabergoline enhances the protective effect of pregnancy against breast cancer by potentiating postlactational involution. Notably, a retrospective cohort study in women demonstrated a markedly lower incidence of post-pregnancy breast cancer in those treated with cabergoline compared to a control group. Our work underscores the importance of enhancing postlactational involution as a strategy for breast cancer prevention, and identifies cabergoline as a promising, low-risk option in breast cancer chemoprevention. This strategy has the potential to revolutionize breast cancer prevention approaches, particularly for women at increased risk due to genetic factors or delayed childbirth, and has wider implications beyond hereditary breast cancer cases.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Promoting Physical Activity in a Primary Care Practice in People Living with Dementia and Their Family Caregivers.

People living with dementia (PLWD) and their family caregivers report higher rates of having a sedentary lifestyle than their non-disabled peers do. This study analyzed the effectiveness of an intervention designed to increase physical activity among PLWD and their family caregivers in primary health care settings. A cluster-randomized multicenter clinical trial was conducted. Participants from four health centers were randomly assigned to the intervention group (IG) or the control group (CG) in a 1:1 ratio using Epidat software. After a seven-day period with a digital pedometer (Omron Hj-321 lay-UPS), participants were asked to complete the International Physical Activity Questionnaire Short Form (IPAQ-SF). PLWD and caregivers allocated to the IG were given brief advice, educational materials and an additional 15 min appointment to prescribe an individualized physical activity plan. Seventy PLWD and 80 caregivers were assigned to the CG and 70 PLWD and 96 caregivers were assigned to the IG. Results of the pedometer assessment show that in PLWD, the IG's activity increased by 52.89 aerobic steps at 6 months and the CG's activity decreased by 615.93 aerobic steps, showing a net increase in the IG of 668.82 (95% CI: -444.27 to 1781.91; p = 0.227). For caregivers in the IG, activity increased by 356.91 aerobic steps and in the CG it decreased by 12.95 aerobic steps, showing a net increase in favor of the IG of 369.86 (95%CI: -659.33 to 1399.05; p = 0.476). The effectiveness of interventions to increase physical activity in this group of people with dementia and their caregivers did not achieved positive results overall but may have provided suggestions for family physicians and physical therapists to improve physical activity among people with dementia and their families.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Relationship of Different Anthropometric Indices with Vascular Ageing in an Adult Population without Cardiovascular Disease-EVA Study.

The objectives of this study were to analyse the capacity of different anthropometric indices to predict vascular ageing and this association in Spanish adult population without cardiovascular disease. A total of 501 individuals without cardiovascular disease residing in the capital of Salamanca (Spain) were selected (mean age: 55.9 years, 50.3% women), through stratified random sampling by age and sex. Starting from anthropometric measurements such as weight, height, and waist circumference, hip circumference, or biochemical parameters, we could estimate different indices that reflected general obesity, abdominal obesity, and body fat distribution. Arterial stiffness was evaluated by measuring carotid-femoral pulse wave velocity (cf-PWV) using a SphygmoCor® device. Vascular ageing was defined in three steps: Step 1: the participants with vascular injury were classified as early vascular ageing (EVA); Step 2: classification of the participants using the 10 and 90 percentiles of cf-PWV in the study population by age and sex in EVA, healthy vascular ageing (HVA) and normal vascular ageing (NVA); Step 3: re-classification of participants with arterial hypertension or type 2 diabetes mellitus included in HVA as NVA. The total prevalence of HVA and EVA was 8.4% and 21.4%, respectively. All the analysed anthropometric indices, except waist/hip ratio (WHpR), were associated with vascular ageing. Thus, as the values of the different anthropometric indices increase, the probability of being classified with NVA and as EVA increases. The capacity of the anthropometric indices to identify people with HVA showed values of area under the curve (AUC) ≥ 0.60. The capacity to identify people with EVA, in total, showed values of AUC between 0.55 and 0.60. In conclusion, as the values of the anthropometric indices increased, the probability that the subjects presented EVA increased. However, the relationship of the new anthropometric indices with vascular ageing was not stronger than that of traditional parameters. Therefore, BMI and WC can be considered to be the most useful indices in clinical practice to identify people with vascular ageing in the general population.

Cultural Adaptation and Validation into Spanish of the Scale to Measure Attitudes Towards the Sex Trafficking of Women and Girls in Students of the University of Salamanca.

The aim of this study was to validate and analyze the psychometric properties of a Spanish version of the Sexual Trafficking Attitudes Scale towards women and girls (STAS). A sample of 204 students from the University of Salamanca (Spain) was used. The exploratory factor analysis and confirmatory factor analysis confirmed a multifactorial structure of six factors (70.1% of variance). The Cronbach's α internal consistency index obtained for the sample was 0.87 and composite reliability was 0.94. Convergent validity was determined between the full scale and the six dimensions, and divergent between subscales. The Spanish version of the instrument consisted of 25 items, proving to be a reliable and parsimonious measure.

Vascular target organ damage in patients with Philadelphia negative myeloproliferative syndrome: A propensity score analysis.

PURPOSE: To assess whether subjects with Philadelphia negative myeloproliferative neoplasms (Ph-MPNs) show differences in the presence of vascular, cardiac or renal target organ damage (TOD) and other vascular function parameters as compared to individuals without this condition. METHODS: An observational study was conducted. Fifty-seven subjects diagnosed with Ph-MPNs used as cases and 114 subjects without Ph-MPNs as controls. We matched the subjects with and without Ph-MPNs using the propensity scores in a 1:2 ratio using the variables gender, type 2 diabetes mellitus, high blood pressure, hyperlipidaemia and smoking. Vascular, cardiac and renal TOD were established according to the criteria of the European Society of Hypertension and Cardiology guidelines. Arterial stiffness was also assessed using the cardio-ankle vascular index (CAVI). RESULTS: Mean age was 63.50±11.70 and 62.90±8.32 years in subjects with and without Ph-MPNs, 32 females (56%) in the first group and 62 (54%) in the second. Subjects with Ph-MPNs have a higher percentage of carotid injury than subjects without Ph-MPNs (35.1% vs. 21.1%) and higher albumin/creatinine ratio. In the logistic regression analysis, subjects with Ph-MPNs had an OR=2.382 (IC95% 1.066-5.323) for carotid injury versus those without haematological disease. CONCLUSIONS: Subjects with Ph-MPNs have twice the risk of by carotid injury than those without haematological disease.

Retinal blood vessel calibre and vascular ageing in a general Spanish population: A EVA study.

INTRODUCTION: The aim of this work was to analyse the association of the retinal arteriolar calibre and the arteriole/venule index (AV index) with vascular ageing in a general population without previous cardiovascular disease. MATERIALS AND METHODS: Descriptive cross-sectional study. A total of 482 individuals without cardiovascular disease (mean age: 55.6 ± 14.2 years) were selected by random sampling, stratified by age and sex. The retinal arteriolar calibre was measured using digital fundus images of the back of the eye captured with a validated, semiautomatized and computer-assisted software (Index calculator). Vascular ageing was defined using three criteria based on the values of: (1) Carotid-femoral Pulse Wave Velocity (cfPWV), (2) Brachial-ankle Pulse Wave Velocity (baPWV) and (3) Carotid Intima-Media Thickness. RESULTS: The AV index and arteriolar calibre show a negative correlation with age, arterial pressure, cardiovascular risk and parameters of vascular structure and function (p < 0.001 in all cases). We found lower mean values of the AV index and arteriolar calibre in the individuals with early vascular ageing compared to those with healthy vascular ageing. AV index was negatively correlated with cfPWV ((ß=-2.9; 95% CI (-4.7; -1.1)), baPWV ((ß=-3.2; 95% CI (-5.4; -0.9)) and vascular ageing index ((ß=-1.7; 95% CI (-2.7; -0.7)). Arteriolar calibre showed a negative correlation with baPWV (ß=-0.1; 95% CI (-0.2; -0.1)). In the logistic regression analysis, lower values of AV index ((OR=0.01; 95% CI (0.01-0.10), OR=0.03; 95% CI (0.01-0.11) and OR=0.09; 95% CI (0.01-0.67)) were associated with EVA defined with cfPWV, baPWV and vascular ageing index respectively, and lower values of arteriolar calibre ((OR=0.71; 95% CI (0.55-0.91)) were associated with EVA defined with vascular ageing index. CONCLUSIONS: Lower values of AV index and retinal arteriolar calibre were associated with vascular ageing in a general Spanish population without previous cardiovascular disease.

Reference values of central blood pressure and central haemodynamic parameters and their relationship with cardiovascular risk factors in a Spanish population: early vascular ageing study.

OBJECTIVES: Central blood pressure (BP) predicts mortality independent of office brachial BP. The aim was to describe reference values for central blood pressure and pulsatile hemodynamic parameters, and their relationship with cardiovascular risk factors in an adult Spanish population without cardiovascular disease. METHODS: Cross-sectional study. We included 501 participants stratified by age and sex by random sampling, with a mean age of 56 years (50.3% women). The SphygmoCor System device's pulse wave analysis software was used to perform the measurements. RESULTS: The following values were obtained: central blood pressure median (109/76 mmHg), central pulse pressure (33 mmHg), pulse pressure amplification (8.5 mmHg), ejection duration (130 ms) and subendocardial viability ratio (163%). All parameters were greater in men, except heart rate and ejection duration. In the logistic regression analysis, controlled for age, sex and taking antihypertensive drugs, being hypertensive was associated with cSBP (OR = 1.265), cDBP (OR = 1.307), cPP (OR = 1.067), pulse wave amplification (OR = 1.034) and SEVR (OR = 0.982); being diabetic was associated with SEVR (OR = 0.982); being obese was associated with cSBP (OR = 1.028) and cDBP (OR = 1.058) and being a smoker was associated with ejection duration (OR = 0.980) and SEVR (OR = 0.984). CONCLUSION: This study provides reference values for central blood pressure and parameters derived from the pulse wave analysis in a random sample of the Spanish population. The only risk factor that is not associated with any of the parameters analysed is dyslipidaemia. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT02623894.

Nomophobia Questionnaire (NMP-Q): Factorial structure and cut-off points for the Spanish version. / Cuestionario de Nomofobia (NMP-Q): Estructura factorial y puntos de corte de la versión española.

Nomophobia is a situational phobia leading to a deep, irrational, and disproportionate fear of not being able to use the smartphone. An instrumental study on the Spanish version of the Nomophobia Questionnaire (NMP-Q) was carried out. The objectives were: 1) To analyse its factor structure and reliability; 2) to test for the invariance of sex and age groups, and 3) to obtain specific cut-off points by sex and age non-existent to date. Sampling was incidental and non-probabilistic with 5012 participants (57.9%, females) aged 12-24 years (M = 18.04, SD = 3.3). The confirmatory factor analysis revealed a hierarchical model with four correlated factors explained by a general second-order factor. The internal validity and reliability values of the NMP-Q dimensions are satisfactory, ranging between .78, .85, .86, and .92 (Omega w). A multigroup analysis confirmed the invariance across sex and age groups. Building on the NMP-Q scores, we calculated 3 cut-off points using percentiles 15th, 80th and 95th (unnomophobic, at risk of nomophobia, and nomophobic). Females aged 12-15 years had the highest nomophobic scores. We can conclude that the proposed sex and age cut-off points will allow us to better identify nomophobic problems from a clinical point of view.

La nomofobia es una fobia situacional en la que se experimenta un miedo intenso, irracional y desproporcionado a no poder usar el smartphone. Se realizó un estudio instrumental de la versión española del cuestionario de Nomofobia (NMP-Q) con los objetivos de: 1) analizar su estructura factorial y fiabilidad; 2) analizar su invarianza con relación al sexo y la edad, y 3) obtener puntos de cortes específicos para distintas edades y sexo. El muestreo fue incidental y no probabilístico. Hubo 5012 participantes (57.9%, mujeres) de 12-24 años (M = 18,04, SD = 3,3). El análisis factorial confirmatorio mostró un modelo jerárquico de 4 factores correlacionados y explicados por uno general de segundo orden. Los índices de fiabilidad de las dimensiones del NMP-Q fueron satisfactorios oscilando entre ,78, ,85, ,86 y ,92 (Omega w). Un análisis multigrupo confirmó la invarianza por sexo y edad. A partir de las puntuaciones del NMP-Q se calcularon 3 puntos de corte siguiendo los percentiles 15, 80 y 95 (sin nomofobia, riesgo de nomofobia, y nomofóbico). Las mujeres de 12-15 años tuvieron las puntuaciones más altas en nomofobia. Podemos concluir que el NMP-Q nos permite identificar problemas de nomofobia por sexo y edad desde un punto de vista clínico.

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach.

BACKGROUND: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. RESULTS: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. CONCLUSIONS: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.