Pregnancy Reduces Il33+ Hybrid Progenitor Accumulation in the Aged Mammary Gland.

Aging increases breast cancer risk while an early first pregnancy reduces a woman's life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary epithelial cells (MECs), but the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a differentiated cell state. Importantly, we uncover a minority population of Il33-expressing hybrid MECs with high cellular potency that accumulate in aged nulliparous mice but is significantly reduced in aged parous mice. Functionally, IL33 treatment of basal, but not luminal, epithelial cells from young mice phenocopies aged nulliparous MECs and promotes formation of organoids with Trp53 knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated loss of lineage integrity in the basal layer through a decrease in Il33+ hybrid MECs, potentially contributing to pregnancy-induced breast cancer protection.

Ovarian leukocytes: Association with follicular persistence and cyst formation in dairy cows.

One of the initial causes of cystic ovarian disease (COD) is a failure in the normal ovulation mechanism. This study aimed to characterize the populations of immune cells (T-lymphocytes, B-lymphocytes, monocytes-macrophages and granulocytes) present in the ovary of cows with COD and induced follicular persistence, and evaluate their relation with follicular persistence and cyst formation. The follicular persistence model was developed using a progesterone (P4) slow-release intravaginal device, to obtain subluteal concentrations of P4. Results evidenced that T-lymphocytes, B-lymphocytes and monocytes-macrophages in the cortex, medulla, and theca externa and interna of dominant follicles were higher in the control group than in the COD and all persistence groups. Granulocytes in the medulla and theca externa of dominant follicles were lower in the control group than in the COD group, and those in the cortex and medulla were lower in the control group than in the persistence groups. The presence of T-lymphocytes, B-lymphocytes and granulocytes in the follicular fluid was abundant, especially that of granulocytes, without differences between control and COD cows. These results suggest that the immune system potentially plays a role in the local mechanisms of COD pathogenesis in dairy cows. In spontaneous COD and in our follicular persistence model, the distribution of the cells studied was different from that in the control group. However, to our knowledge, this is the first report describing the presence of immune cells in bovine follicular fluid samples and the expression of steroid hormone receptors in infiltrating immune cells in the bovine ovary.

Influência da exposição ambiental na percepção do estado de saúde de indivíduos de cinco países latino-americanos / Effect of environmental exposure on the perceived health status of individuals from five Latin American countries

OBJETIVO: A relação entre exposição ambiental e risco à saúde é amplamente reconhecida e a avaliamos em cinco países da América Latina com condições culturais distintas, mas com Índices de Desenvolvimento Humano semelhantes. MÉTODOS: Estudo transversal envolvendo 3.016 indivíduos (18 a 75 anos) oriundos de: Argentina (n = 878), Brasil (n = 1.030), México (n = 272), Paraguai (n = 508) e Peru (n = 328). A seleção foi aleatória e todos responderam questionário padronizado (fatores sociodemográficos, fatores ambientais e hábitos de vida) derivado do Clinical Screening Tool for Air Pollution Risk. Segundo o estado atual de saúde, foram categorizados em: saúde regular/má/péssima ou excelente/boa. Tendo-a como desfecho, realizou-se análise multivariada.Os dados foram apresentados como razão de verossimilhança (RV) e intervalos de confiança de 95% (IC 95%), tendo-se 5% o nível de significância. RESULTADOS: Foram significantemente associados a pior percepção de situação de saúde: morar em qualquer um dos países, ter umidade na residência (OR = 1,68; IC 95%: 1,33-2,12), dirigir automóvel com janelas abertas (OR = 1,31; IC 95%: 1,03-1,65), ter baixa renda familiar (OR = 1,59; IC 95%: 1,26-2,01), nível educacional incompleto (OR = 1,54; IC 95%: 1,22-1,94), histórico pessoal/familiar de hipertensão arterial (OR = 2,25; IC 95%: 01,64-3,09), doença pulmonar obstrutiva crônica/asma (OR = 1,74; IC 95%: 1,28-2,36), diabete melito (OR = 3,74; IC 95%: 2,23-6,29), obesidade (OR = 1,84; IC 95%: 1,84-3,19) ou comorbidades oftalmológicas (OR = 1,89; IC 95%: 1,55-2,30); realizar exercícios ao ar livre (OR = 1,60; IC 95%: 1,31-1,96). CONCLUSÕES: Apesar das diferentes exposições a que foram submetidos, alguns fatores permanecem muito significativos, e ter baixa renda familiar, expor-se à poluição e ter antecedentes de doenças crônicas foram associados à percepção de condição ruim de saúde.

OBJECTIVE: The relationship between environmental exposure and health outcomes is well known.We investigated this relationship in five Latin American countries with different cultural backgrounds but similar Human Development Indexes. METHODS: This was a cross-sectional study involving 3,016 individuals (18 to 75 years old) from Argentina (n=878), Brazil (n=1030), Mexico (n=272), Paraguay (n=508), and Peru (n=328). Participants were randomly selected and responded to a standardized questionnaire (including sociodemographic and environmental factors and lifestyle habits) derived from a clinical screening tool for air pollution risk. Based on their current health status, participants were categorized as having regular/bad/very bad or excellent/good health. Multivariate analysis was conducted, and data were presented as likelihood ratios and 95% confidence intervals (95%CI).The significance level was set at 5%. RESULTS: Living in any of the study countries; indoor humidity (OR=1.68; 95%CI: 1.33-2.12); driving with the windows open (OR=1.31; 95%CI: 1.03-1.65); low family income (OR=1.59; 95%CI: 1.26-2.01); incomplete education (OR=1.54; 95%CI: 1.22-1.94); personal/family history of hypertension (OR=2.25; 95%CI: 01.643.09), chronic obstructive pulmonary disease/asthma (OR=1.74; 95%:CI: 1.28-2.36), diabetes (OR=3.74; 95%CI:2.23-6.29), obesity (OR=1.84; 95%CI: 1.84-3.19), or ocular comorbidities (OR=1.89; 95%CI: 1.55-2.30); and exercising outdoors (OR=1.60; 95%CI: 1.31-1.96) were significantly associated with a worse perceived health status. CONCLUSIONS: Despite the different exposures to which participants were subjected, some factors remain very significant. Low family income, exposure to pollution, and a history of chronic diseases were associated with the perception of a poor health condition.

Características y evolución clínica de pacientes con infarto agudo de miocardio y elevación del segmento ST con y sin bloqueo interauricular

Fundamento resulta novedoso establecer la relación entre bloqueo interauricular e infarto agudo de miocardio con elevación del segmento ST debido a los pocos estudios que abordan el tema. Objetivo evaluar las características y evolución clínica de pacientes con infarto agudo de miocardio con elevación del segmento ST con y sin bloqueo interauricular. Métodos: se realizó un estudio descriptivo y correlacional en unidades de cuidados progresivos del Hospital General Universitario Dr. Gustavo Aldereguía Lima de Cienfuegos. Se seleccionaron 169 sujetos con diagnóstico de infarto agudo de miocardio con elevación del segmento ST divididos en dos grupos con y sin bloqueo interauricular. Se analizaron como variables demográficas: edad, sexo, color de la piel y entre las clínicas hábitos tóxicos (fumador, exfumador); antecedentes patológicos (infarto de miocardio, angina, enfermedad arterial periférica, hipertensión arterial, diabetes mellitus tipo 2, enfermedad renal crónica; localización del infarto (anterior, inferior, bloqueo de rama izquierda); complicaciones: insuficiencia cardíaca, fibrilación auricular, taquicardia ventricular/fibrilación ventricular, trastornos de conducción aurículo ventricular, complicación mecánica, angina postinfarto, embolismo arterial) y estado al egreso (vivo o fallecido). Resultados el 52,17 % de los pacientes con infarto agudo de miocardio con elevación del segmento ST con bloqueo interauricular desarrollaron insuficiencia cardíaca, vs el 29,45 % de los pacientes sin bloqueo con significación estadística (p = 0.03). La relación entre la ocurrencia o no de complicaciones (así como el estado al egreso) y la presencia o no de bloqueo resultó muy significativa (p=0.01). Conclusiones el análisis minucioso en este contexto, de otros aspectos no habituales como la onda p, debe ser también rutinario, pues la documentación de bloqueo interauricular pudiera relacionarse con el curso clínico de los pacientes.

Foundation: it is novel to establish the relationship between interatrial block and acute myocardial infarction with ST-segment elevation due to the few studies that address the subject. Objective: to evaluate the characteristics and clinical evolution of patients with ST-segment elevation acute myocardial infarction with and without interatrial block. Methods: a descriptive and correlational study was carried out in progressive care units of the Dr. Gustavo Aldereguía Lima University General Hospital in Cienfuegos. 169 subjects with a diagnosis of ST-segment elevation myocardial infarction divided into two groups with and without interatrial block were selected. Demographic variables were analyzed: age, sex, skin color and between clinics: toxic habits (smoker, ex-smoker); medical history (myocardial infarction, angina, peripheral arterial disease, arterial hypertension, type 2 diabetes mellitus, chronic kidney disease; infarct location (anterior, inferior, left bundle branch block); complications: heart failure, atrial fibrillation, ventricular tachycardia/ventricular fibrillation, atrioventricular conduction disorders, mechanical complication, post infarction angina, arterial embolism) and discharge status (alive or deceased). Results: 52.17 % of patients with ST-segment elevation myocardial infarction with interatrial block developed heart failure, vs 29.45 % among patients without block with statistical significance (p = 0.03). The relationship between the occurrence or not of complications (as well as the state at discharge) and the presence or not of blockade was highly significant (p=0.01). Conclusions: the detailed analysis, in this context, of the p wave of the electrocardiogram should be routine, since the documentation of interatrial block could be related to the clinical course of the patients.

Identification of a minority population of LMO2+ breast cancer cells that integrate into the vasculature and initiate metastasis.

Metastasis is responsible for most breast cancer-related deaths; however, identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1+/VEGFA+ tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher abundance of LMO2+ basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrated that Lmo2 lineage-traced cells integrate into the vasculature and have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by tumor necrosis factor-α and interleukin-6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis.

Usp16 modulates Wnt signaling in primary tissues through Cdkn2a regulation.

Regulation of the Wnt pathway in stem cells and primary tissues is still poorly understood. Here we report that Usp16, a negative regulator of Bmi1/PRC1 function, modulates the Wnt pathway in mammary epithelia, primary human fibroblasts and MEFs, affecting their expansion and self-renewal potential. In mammary glands, reduced levels of Usp16 increase tissue responsiveness to Wnt, resulting in upregulation of the downstream Wnt target Axin2, expansion of the basal compartment and increased in vitro and in vivo epithelial regeneration. Usp16 regulation of the Wnt pathway in mouse and human tissues is at least in part mediated by activation of Cdkn2a, a regulator of senescence. At the molecular level, Usp16 affects Rspo-mediated phosphorylation of LRP6. In Down's Syndrome (DS), triplication of Usp16 dampens the activation of the Wnt pathway. Usp16 copy number normalization restores normal Wnt activation in Ts65Dn mice models. Genetic upregulation of the Wnt pathway in Ts65Dn mice rescues the proliferation defect observed in mammary epithelial cells. All together, these findings link important stem cell regulators like Bmi1/Usp16 and Cdkn2a to Wnt signaling, and have implications for designing therapies for conditions, like DS, aging or degenerative diseases, where the Wnt pathway is hampered.

Usp16 contributes to somatic stem-cell defects in Down's syndrome.

Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.

Manejo del cólico infantil / Manejo of infantile cólico

Expone que el cólico o llanto persistente en los infantes, es una consulta frecuente en la práctica médica. A pesar de no ser perjudicial para la salud del niño, crean gran tensión familiar. Se ha investigado una amplia variedad de terapias, incluyendo cambios de fórmulas infantiles, fármacos y maniobras posicionales de los infantes, pero los resultados han sido conflictivos controversiales e inconclusivos. Al momento, el manejo de conducta del niño y asesoramiento personal de ayuda y medidas para tranquilizar a los padres son la base principal del tratamiento. Fornulando un plan de manejo efectivo e individualizado, el médico puede ayudar a los padres en el difícl período del cólico infantil.