Evolutionary trajectories of small cell lung cancer under therapy.

The evolutionary processes that underlie the marked sensitivity of small cell lung cancer (SCLC) to chemotherapy and rapid relapse are unknown1-3. Here we determined tumour phylogenies at diagnosis and throughout chemotherapy and immunotherapy by multiregion sequencing of 160 tumours from 65 patients. Treatment-naive SCLC exhibited clonal homogeneity at distinct tumour sites, whereas first-line platinum-based chemotherapy led to a burst in genomic intratumour heterogeneity and spatial clonal diversity. We observed branched evolution and a shift to ancestral clones underlying tumour relapse. Effective radio- or immunotherapy induced a re-expansion of founder clones with acquired genomic damage from first-line chemotherapy. Whereas TP53 and RB1 alterations were exclusively part of the common ancestor, MYC family amplifications were frequently not constituents of the founder clone. At relapse, emerging subclonal mutations affected key genes associated with SCLC biology, and tumours harbouring clonal CREBBP/EP300 alterations underwent genome duplications. Gene-damaging TP53 alterations and co-alterations of TP53 missense mutations with TP73, CREBBP/EP300 or FMN2 were significantly associated with shorter disease relapse following chemotherapy. In summary, we uncover key processes of the genomic evolution of SCLC under therapy, identify the common ancestor as the source of clonal diversity at relapse and show central genomic patterns associated with sensitivity and resistance to chemotherapy.

Music Listening as a Postanesthesia Care Unit (PACU) Nursing Intervention for Laparoscopic Radical Prostatectomy Patients: A Randomized Comparative Clinical Trial.

PURPOSE: Randomized comparative mixed method approach with qualitative inquiry study's aim sought to determine if there was a difference in pre/post-intervention State-Trait Anxiety Inventory (STAI) scores and postanesthesia pain scores between two music listening groups of laparoscopic radical prostatectomy patients. DESIGN: Prospective randomized comparative mixed method approach with a qualitative inquiry. METHODS: Sample size of 77 male participants assigned by a table of random numbers to Spotify patient-preferred music selection Group I (n = 37) or minimalist hypnotic music with guided relaxation breathing (MHMGRB) instructional narrative Group II (n = 40). Outcome measures used patients' STAI questionnaire and reported PACU admission and discharge pain scores. RESULTS: Both Groups I and II had reduced pain scores at discharge as compared to admission; both groups had a significant reduction (P = .046 Group I, and Group II (P = .002), but changes for comparative groups (I and II) were not significant between the two groups (P = .53). CONCLUSIONS: Study revealed that both patient-preferred selected music and MHMGRB can meaningfully reduce patients' anxiety and PACU pain scores.

Mechanochemical control of epidermal stem cell divisions by B-plexins.

The precise spatiotemporal control of cell proliferation is key to the morphogenesis of epithelial tissues. Epithelial cell divisions lead to tissue crowding and local changes in force distribution, which in turn suppress the rate of cell divisions. However, the molecular mechanisms underlying this mechanical feedback are largely unclear. Here, we identify a critical requirement of B-plexin transmembrane receptors in the response to crowding-induced mechanical forces during embryonic skin development. Epidermal stem cells lacking B-plexins fail to sense mechanical compression, resulting in disinhibition of the transcriptional coactivator YAP, hyperproliferation, and tissue overgrowth. Mechanistically, we show that B-plexins mediate mechanoresponses to crowding through stabilization of adhesive cell junctions and lowering of cortical stiffness. Finally, we provide evidence that the B-plexin-dependent mechanochemical feedback is also pathophysiologically relevant to limit tumor growth in basal cell carcinoma, the most common type of skin cancer. Our data define a central role of B-plexins in mechanosensation to couple cell density and cell division in development and disease.

Neurological repercussions of changes in cerebral blood flow in neonates undergoing cardiovascular surgery.

INTRODUCTION: Surgery for congenital heart disease can generate cerebral perfusion-associated alterations with neurological repercussions. OBJECTIVE: To analyze the relationship of peri-surgical cerebrovascular resistance index (RI) with mediate neurological functions after congenital heart disease surgery. METHOD: Prospective cohort study of 34 neonates in whom basilar artery RI, serum oxygen, carbon dioxide and lactate levels were determined before and after palliative or corrective procedures. We related pre-surgical RI with post-surgical ability to initiate the enteral route or to restore unassisted spontaneous breathing. RESULTS: Three groups were formed: 79 neonates with high RI (> 0.73), 73 with normal RI (0.63 to 0.73) and eight with low RI (< 0.63). In the former group, high RI persisted in the postoperative period, with persistent hyperlactatemia and hypoxia; in 86 %, the enteral route could not be initiated, and neither could assisted ventilation be withdrawn. In the second group, RI remained within normal values. In the third group, although RI, serum lactate and arterial oxygen pressure tended to normalize, 71 % had severe neurological damage. CONCLUSIONS: RI changes were common, although neurological damage appears to occur more commonly when RI remains high, possibly associated with low cerebral blood flow.

INTRODUCCIÓN: La cirugía de cardiopatías congénitas puede generar alteraciones perfusorias cerebrales con repercusión neurológica. OBJETIVO: Analizar la relación del índice de resistencia (IR) vascular cerebral periquirúrgico con funciones neurológicas mediatas posteriores a cirugía de cardiopatía congénita. MÉTODO: Estudio de cohorte prospectivo de 34 neonatos en quienes se determinó IR de la arteria basilar, niveles séricos de oxígeno, dióxido de carbono y lactato, antes y después de procedimientos paliativos o correctivos. Relacionamos el IR prequirúrgico con la capacidad posquirúrgica para iniciar la vía enteral o restablecer la respiración espontánea no asistida. RESULTADOS: Se integraron tres grupos: 79 neonatos con IR alto > 0.73, 73 con IR normal de 0.63 a 0.73 y ocho con IR bajo < 0.63. En los primeros persistió IR elevado en el posquirúrgico, con hiperlactatemia e hipoxia persistentes; en 86 % no se logró iniciar la vía enteral ni retirar la ventilación asistida. En los segundos, el IR se mantuvo en valores normales. En los terceros, si bien el IR, el lactato sérico y la presión arterial de oxígeno tendieron a normalizarse, 71 % presentó daño neurológico grave. CONCLUSIONES: Los cambios en el IR fueron frecuentes, aunque el daño neurológico parece presentarse más cuando el IR se mantiene alto, posiblemente asociado con flujos cerebrales bajos.

Repercusión neurológica por cambios en el flujo sanguíneo cerebral en neonatos sometidos a cirugía cardiovascular / Neurological repercussions of changes in cerebral blood flow in neonates undergoing cardiovascular surgery

Resumen Introducción: La cirugía de cardiopatías congénitas puede generar alteraciones perfusorias cerebrales con repercusión neurológica. Objetivo: Analizar la relación del índice de resistencia (IR) vascular cerebral periquirúrgico con funciones neurológicas mediatas posteriores a cirugía de cardiopatía congénita. Método: Estudio de cohorte prospectivo de 34 neonatos en quienes se determinó IR de la arteria basilar, niveles séricos de oxígeno, dióxido de carbono y lactato, antes y después de procedimientos paliativos o correctivos. Relacionamos el IR prequirúrgico con la capacidad posquirúrgica para iniciar la vía enteral o restablecer la respiración espontánea no asistida. Resultados: Se integraron tres grupos: 17 neonatos con IR alto > 0.73, cinco con IR normal de 0.63 a 0.73 y seis con IR bajo < 0.63. En los primeros persistió IR alto en el posquirúrgico, con hiperlactatemia e hipoxia persistentes; en 86 % no se logró iniciar la vía enteral ni retirar la ventilación asistida. En los segundos, el IR se mantuvo en valores normales. En los terceros, si bien el IR, el lactato sérico y la presión arterial de oxígeno tendieron a normalizarse, 71 % presentó daño neurológico grave. Conclusiones: Los cambios en el IR fueron frecuentes, aunque el daño neurológico parece presentarse más cuando el IR se mantiene alto, posiblemente asociado a flujos cerebrales bajos.

Abstract Introduction: Surgery for congenital heart disease can generate cerebral perfusion-associated alterations with neurological repercussions. Objective: To analyze the relationship of peri-surgical cerebrovascular resistance index (RI) with mediate neurological functions after congenital heart disease surgery. Method: Prospective cohort study of 34 neonates in whom basilar artery RI, serum oxygen, carbon dioxide and lactate levels were determined before and after palliative or corrective procedures. We related pre-surgical RI with post-surgical ability to initiate the enteral route or to restore unassisted spontaneous breathing. Results: Three groups were formed: 17 neonates with high RI (> 0.73), five with normal RI (0.63-0.73) and six with low RI (< 0.63). In the former group, high RI persisted in the postoperative period, with persistent hyperlactatemia and hypoxia; in 86%, the enteral route could not be initiated, and neither could assisted ventilation be withdrawn. In the second group, IR remained within normal values. In the third group, although RI, serum lactate and arterial oxygen pressure tended to normalize, 71% had severe neurological damage. Conclusions: RI changes were common, although neurological damage appears to occur more commonly when RI remains high, possibly associated with low cerebral blood flow.