The magmatic evolution of Graciosa and Corvo oceanic islands, Azores Archipielago

El archipiélago de las Azores se encuentra localizado en el Océano Atlántico, entre las latitudes 37º y 40º N y las longitudes 25º y 31º O. Está constituido por nueve islas y varios montículos submarinos construidos sobre la plataforma de las Azores. Dos de estas islas han sido objeto de estudio en la presente Tesis Doctoral: Graciosa, al este de la dorsal centro-atlántica, y Corvo, al oeste de la misma. Dado que los estudios previos sobre estas islas son escasos y se han limitado a la descripción geológica y petrológica de las diferentes unidades volcánicas, la presente investigación aborda un completo estudio de la petrología, la mineralogía y la geoquímica de las distintas unidades volcánicas, así como de los procesos magmáticos ocurridos. En la Isla de Graciosa se han estudiado diferentes coladas de lava y xenolitos de gabros (alcalinos y subalcalinos), de sienitas y de dunitas, pertenecientes a los complejos volcánicos de Serra das Fontes, Serra Branca y Vitória - Vulcão Central. Se ha demostrado que las coladas de lava de los tres complejos volcánicos, junto con los gabros de composición alcalina (cumulados) y las sienitas (frozen liquids), están relacionados mediante un proceso de cristalización fraccionada polibárica, que comenzó en una cámara magmática situada a unos 15 km de profundidad. Además, la alternancia temporal de rocas de composición básica y ácida se explica a través de la existencia de varias recargas magmáticas del sistema. Por el contrario, los gabros de composición subalcalina, que son descritos por primera vez en el archipiélago de las Azores, se interpretan como cumulados relacionados con un proceso de fraccionación de fundidos altamente refractarios en niveles más someros (~ 3 km). En la Isla Corvo, se han muestreado también todas las unidades volcanoestratigráficas (Pre-, Sin- y Post-caldera), que incluyen coladas de lava, diques y xenolitos de gabro. Tanto algunas de las coladas, como algunos de los diques, presentan antecristales no cogenéticos que fueron incorporados al fundido previamente a la erupción. Se ha puesto de manifiesto, por primera vez en Azores, que la composición geoquímica de roca total está altamente influenciada por la acumulación de estos antecristales, lo que produce un enmascaramiento de los procesos magmáticos de diferenciación que han dado lugar a la formación de estas rocas. Por ello, para identificar los procesos que han dado lugar a la formación de la isla tan solo se han considerado rocas sin antecristales. De este modo, las coladas de lava y los diques sin antecristales, junto con los xenolitos de gabro (cumulados) están relacionados mediante un proceso de cristalización polibárica, que comenzó en una cámara magmática situada a unos 15 km de profundidad y en la que tuvieron lugar procesos de recarga constantes con fundidos más profundos y de gran carga cristalina. Por lo tanto, se propone que la Isla de Corvo ha sido formada a partir de un complejo sistema magmático en el que los diferentes fundidos y su carga de antecristales provienen de diferentes profundidades y han estado en constante interacción a los largo de toda la evolución de la isla. La Isla de Graciosa ha sido estudiada desde un punto de vista isotópico, para adecuar el conocimiento de la isla con las demás islas del Rift de Terceira. La edades 40Ar/39Ar han permitido establecer la evolución temporal de la isla a lo largo del Pleistoceno y el Holoceno, desde los 1056 ± 28.0 ka hasta los 3.9 ± 1.4 ka, en contraste con las edades previas obtenidas por K-Ar y 14C (620 ka a 2 ka). Las composiciones isotópicas de Sr-Nd-Pb han permitido la caracterización de la fuente del manto de los fundidos, señalando una mezcla entre un componente empobrecido de tipo MORB y un componente enriquecido de tipo HIMU. Estos datos son similares a la composición de manto recientemente redefinida como FOZO, la cual parece estar presente en la signatura isotópica de la mayor parte de islas oceánicas

CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome

Identification of new markers associated with long-term efficacy in patients treated with CAR T cells is a current medical need, particularly in diseases such as multiple myeloma. In this study, we address the impact of CAR density on the functionality of BCMA CAR T cells. Functional and transcriptional studies demonstrate that CAR T cells with high expression of the CAR construct show an increased tonic signaling with up-regulation of exhaustion markers and increased in vitro cytotoxicity but a decrease in in vivo BM infiltration. Characterization of gene regulatory networks using scRNA-seq identified regulons associated to activation and exhaustion up-regulated in CARHigh T cells, providing mechanistic insights behind differential functionality of these cells. Last, we demonstrate that patients treated with CAR T cell products enriched in CARHigh T cells show a significantly worse clinical response in several hematological malignancies. In summary, our work demonstrates that CAR density plays an important role in CAR T activity with notable impact on clinical response

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research