Exploring the Micro-Mosaic Landscape of FGFR3 Mutations in the Ageing Male Germline and Their Potential Implications in Meiotic Differentiation.

Advanced paternal age increases the risk of transmitting de novo germline mutations, particularly missense mutations activating the receptor tyrosine kinase (RTK) signalling pathway, as exemplified by the FGFR3 mutation, which is linked to achondroplasia (ACH). This risk is attributed to the expansion of spermatogonial stem cells carrying the mutation, forming sub-clonal clusters in the ageing testis, thereby increasing the frequency of mutant sperm and the number of affected offspring from older fathers. While prior studies proposed a correlation between sub-clonal cluster expansion in the testis and elevated mutant sperm production in older donors, limited data exist on the universality of this phenomenon. Our study addresses this gap by examining the testis-expansion patterns, as well as the increases in mutations in sperm for two FGFR3 variants-c.1138G>A (p.G380R) and c.1948A>G (p.K650E)-which are associated with ACH or thanatophoric dysplasia (TDII), respectively. Unlike the ACH mutation, which showed sub-clonal expansion events in an aged testis and a significant increase in mutant sperm with the donor's age, as also reported in other studies, the TDII mutation showed focal mutation pockets in the testis but exhibited reduced transmission into sperm and no significant age-related increase. The mechanism behind this divergence remains unclear, suggesting potential pleiotropic effects of aberrant RTK signalling in the male germline, possibly hindering differentiation requiring meiosis. This study provides further insights into the transmission risks of micro-mosaics associated with advanced paternal age in the male germline.

High prevalence of somatic PIK3CA and TP53 pathogenic variants in the normal mammary gland tissue of sporadic breast cancer patients revealed by duplex sequencing.

The mammary gland undergoes hormonally stimulated cycles of proliferation, lactation, and involution. We hypothesized that these factors increase the mutational burden in glandular tissue and may explain high cancer incidence rate in the general population, and recurrent disease. Hence, we investigated the DNA sequence variants in the normal mammary gland, tumor, and peripheral blood from 52 reportedly sporadic breast cancer patients. Targeted resequencing of 542 cancer-associated genes revealed subclonal somatic pathogenic variants of: PIK3CA, TP53, AKT1, MAP3K1, CDH1, RB1, NCOR1, MED12, CBFB, TBX3, and TSHR in the normal mammary gland at considerable allelic frequencies (9 × 10-2- 5.2 × 10-1), indicating clonal expansion. Further evaluation of the frequently damaged PIK3CA and TP53 genes by ultra-sensitive duplex sequencing demonstrated a diversified picture of multiple low-level subclonal (in 10-2-10-4 alleles) hotspot pathogenic variants. Our results raise a question about the oncogenic potential in non-tumorous mammary gland tissue of breast-conserving surgery patients.

Abordaje de problemas crónicos en atención primaria mediante el modelo tareas orientadas a los procesos de cuidado (TOPIC) / Approaching chronic problems in primary-care using the task-oriented processes in care (TOPIC)

Resumen El cuidado integral de las personas demanda un entrenamiento para atender problemas crónicos frecuentes en la consulta ambulatoria. Los casos de hipertensión, diabetes mellitus y asma pueden ser abordados mediante modelos de atención en la práctica ambulatoria del primer nivel de atención; uno de ellos es el modelo TOPIC (del inglés: Task-Oriented Processes in Care), el cual permite ordenar la consulta en una secuencia estructurada de cuatro tareas mayores: procesamiento de la información, desarrollo de una adecuada relación médico-paciente-familia, integración de la información y aprendizaje de por vida. El procesamiento de la información contempla cuatro sub-actividades en las que se evalúa las expectativas y preocupaciones del paciente, la gravedad y el control de las condiciones, la adherencia y los efectos adversos del tratamiento, se analiza los daños de órgano blanco propios de la enfermedad y se revisan las comorbilidades. La aplicación de este modelo puede ayudar a los médicos y sus pacientes a ser más eficientes en el manejo de problemas crónicos, teniendo en cuenta el poco tiempo del que se dispone en una consulta ambulatoria.

The integrative approach to care for patients demands training to evaluate frequent chronic problems in the outpatient clinic. Patients with hypertension, diabetes mellitus and asthma can be approach using models of evaluations such as the TOPIC that allows to order the evaluations in a structured sequence of four mayor tasks: processing of the information, development of an adequate physician-patient-family relationship and integrating information and learning for life. Processing information implies four sub-activities in which we evaluate patient´s expectations and concerns, severity and control of conditions, adherence and side effects of treatments focusing on damage to target organs and comorbidities. Applying this model can help physicians and their patients to be more efficient in managing chronic problems considering the short time available for ambulatory care.