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La gestació subrogada: reflexions i propostes per a una possible regulació
Full text linkGestació subrogada; Reflexions; BioèticaGestación subrogada; Reflexiones; BioéticaSurrogacy; Reflections; BioethicsAquest document sobre la gestació subrogada presenta una línia de pensament i una proposta d'acció que pretén acomodar sensibilitats ètiques diverses que tinguin com a eix axiològic l’atenció suprema al menor i, a la vegada, excloguin conductes d’opressió o de qualsevol explotació a les persones implicades, en especial a la dona gestant.Este documento sobre la gestación subrogada presenta una línea de pensamiento y una propuesta de acción que pretende acomodar sensibilidades éticas diversas que tengan como eje axiológico la atención suprema al menor y, al mismo tiempo, excluyan conductas de opresión o cualquier explotación de las personas implicadas, en especial de la mujer gestante.This document on surrogacy presents a line of thought and a proposed course of action aimed at accommodating diverse ethical sensitivities that have the supreme well-being of the child as their axiological focus while also excluding any form of oppression or exploitation of the individuals involved, especially the gestational mother
Homologous recombination repair status in metastatic prostate cancer by next-generation sequencing and functional immunofluorescence
Full text linkGenomics; Immunofluorescence; Prostate cancerGenòmica; Immunofluorescència; Càncer de pròstataGenómica; Inmunofluorescencia; Cáncer de próstataMetastatic prostate cancer (mPC) is enriched for homologous recombination repair (HRR) gene alterations, which have prognostic and predictive value. Routine clinical implementation of next-generation sequencing (NGS) is still limited. We investigated the association between genomic and functional loss of HRR, using NGS and RAD51 immunofluorescence (RAD51-IF) in 219 primary or metastatic biopsies from 187 patients with stage IV prostate cancer. NGS showed frequent genomic alterations in TP53 (40%), AR (15%), PTEN (14%), FOXA1 (12%), MYC (10%), BRCA2 (9%), ATM (8%), and BRCA1 (2%). We pursued RAD51-IF in 206 samples; of those, 139/206 (67%) were evaluable. 21% of samples had RAD51-low score compatible with HRR deficiency (HRD). RAD51-IF showed high sensitivity (71%) and specificity (86%) for BRCA1/2 alterations. Patients with RAD51-low scores experienced longer progression-free survival (PFS) on poly(ADP-ribose) polymerase inhibitors (PARPi) or platinum chemotherapy. RAD51-IF is feasible in routine clinical samples from patients with mPC and is associated with clinically relevant HRR gene alterations.This work was funded by an Impact Award from the Department of Defense CDMRP (PC170510P1) and a grant from AstraZeneca (ESR-21-21360). The funders had no role in the design or conduction of the study and were not involved in the analysis or interpretation of results. CRIS Cancer Foundation (grant TCL_2020-10) and Fundación AECC (LABAE20019MATE) and a Department of Defense Physician Science Award to J.M. (PC220307). S.A.-G. was supported by Instituto de Salud Carlos III (FI19/00280). P.C.M. was supported by an ESMO Translational Research Fellowship, funded by BMS (any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the authors and do not necessarily reflect those of ESMO or BMS). I.C.-S. was supported by a Prostate Cancer Foundation YIA (24YOU12). A.L.-G. was supported by an AECC grant (INVES20095LLOP), and V.S. received funding from an ERA PerMed grant (ERAPERMED2019-215). The VHIO authors would like to acknowledge the Spanish State Agency for Research (Agencia Estatal de Investigación) for its financial support as a Center of Excellence Severo Ochoa (CEX2020-001024-S/AEI/10.13039/501100011033), the Cellex Foundation for providing research facilities and equipment, and the CERCA Program from the Generalitat de Catalunya for their support of this research
Peroxidase (POD) Mimicking Activity of Different Types of Poly(ethyleneimine)-Mediated Prussian Blue Nanoparticles
Full text linkPrussian blue nanoparticles; Nanozyme; Peroxidase mimeticNanopartículas de azul de Prusia; Nanozima; Mimética peroxidasaNanopartícules de blau de Prussia; Nanozima; Mimètica peroxidasaPrussian blue nanoparticles (PBNPs) have been identified as a promising candidate for biomimetic peroxidase (POD)-like activity, specifically due to the metal centres (Fe3+/Fe2+) of Prussian blue (PB), which have the potential to function as catalytically active centres. The decoration of PBNPs with desired functional polymers (such as amino- or carboxylate-based) primarily facilitates the subsequent linkage of biomolecules to the nanoparticles for their use in biosensor applications. Thus, the elucidation of the catalytic POD mimicry of these systems is of significant scientific interest but has not been investigated in depth yet. In this report, we studied a series of poly(ethyleneimine) (PEI)-mediated PBNPs (PB/PEI NPs) prepared using various synthesis protocols. The resulting range of particles with varying size (~19–92 nm) and shape combinations were characterised in order to gain insights into their physicochemical properties. The POD-like nanozyme activity of these nanoparticles was then investigated by utilising a 3,3′,5,5′-tetramethylbenzidine (TMB)/H2O2 system, with the catalytic performance of the natural enzyme horseradish peroxidase (HRP) serving as a point of comparison. It was shown that most PB/PEI NPs displayed higher catalytic activity than the PBNPs, with higher activity observed in particles of smaller size, higher Fe content, and higher Fe2+/Fe3+ ratio. Furthermore, the nanoparticles demonstrated enhanced chemical stability in the presence of acid, sodium azide, or high concentrations of H2O2 when compared to HRP, confirming the viability of PB/PEI NPs as a promising nanozymatic material. This study disseminates fundamental knowledge on PB/PEI NPs and their POD-like activities, which will facilitate the selection of an appropriate particle type for future biosensor applications.The authors would like to express their gratitude for the financial support provided by the ’QUPID’ EuroNanoMed-JTC2021-110 project, which is funded by the European Union through the Instituto de Salud Carlos III (ISCIII, grant AC21_2/00021) and the Agence Nationale de la Recherche (ANR)
DNA damage response signatures are associated with frontline chemotherapy response and routes of tumor evolution in extensive stage small cell lung cancer
Full text linkDNA damage; Frontline chemotherapy; Small cell lung cancerDaño del ADN; Quimioterapia de primera línea; Cáncer de pulmón de células pequeñasDany de l'ADN; Quimioteràpia de primera línia; Càncer de pulmó de cèl·lules petitesIntroduction
A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.
Methods
To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is associated with SCLC biology, chemotherapy response, and tumor evolution following therapy.
Results
Using multi-omic profiling, we demonstrate that SCLC tumors cluster into three DDR phenotypes with unique molecular features. Hallmarks of these DDR clusters include differential expression of DNA repair genes, increased replication stress, and heightened G2/M cell cycle arrest. SCLCs with elevated DDR phenotypes exhibit increased neuroendocrine features and decreased “inflamed” biomarkers, both within and across SCLC subtypes. Clinical analyses demonstrated treatment naive DDR status was associated with different responses to frontline chemotherapy. Using longitudinal liquid biopsies, we found that DDR Intermediate and High tumors exhibited subtype switching and coincident emergence of heterogenous phenotypes following frontline treatment.
Conclusions
We establish that SCLC can be classified into one of three distinct, clinically relevant DDR clusters. Our data demonstrates that DDR status plays a key role in shaping SCLC phenotypes and may be associated with different chemotherapy responses and patterns of tumor evolution. Future work targeting DDR specific phenotypes will be instrumental in improving patient outcomes.This work was supported by: NIH/NCI CCSG P30-CA016672 (MD Anderson Bioinformatics Shared Resource, and the MD Anderson Institutional Tissue bank (ITB)); The University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE P50-CA070907 (JW, JVH, CMG, LAB); NIH/NCI R01-CA207295 (LAB); NIH/NCI U01-CA213273 (JVH, LAB); NIH/NCI R50-CA243698 (CAS); NIH/NCI U01-CA256780 (JVH, LAB); NIH/NCI U24-CA213274 (LAB); The Department of Defense LC210510 (LAB); the LUNGevity Foundation 2020–02 (CMG); CPRIT RP210159 (CMG); Andrew Sabin Family Foundation (CMG); NETRF (CMG); NIH/NCI T32-CA009666 (KC); Rexanna’s Foundation for Fighting Lung Cancer (JVH, LAB, CMG); Jeffrey Lee Cousins Endowed Fellowship in Lung Cancer Research (BBM); and generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (JVH, CMG, LAB). BBM is a TRIUMPH Fellow in the CPRIT Research Training Program (RP210028). This research includes work performed in the Single Cell Genomics Core Facility, which is supported in part by CPRIT Single Core grant RP180684. LAB also acknowledges philanthropic support from A.R.K., L.W.Y., M.J.A., R.B.N., K.E.N., J.O., J.K.R., B. & B.N, C.K., P.C.B., S.S., S.R., and W.A.B
Recerca en atenció primària: del finançament a l’impacte; anàlisi de l’impacte dels projectes finançats en el marc del PERIS 2016-2020
Full text linkPERIS 2016-2020; Recerca finançada; Atenció primàriaPERIS 2016-2020; Funded research; Primary carePERIS 2016-2020; Investigación financiada; Atención primariaAquest monogràfic forma part d’una sèrie de diferents documents que avaluen l’impacte de les propostes finançades en el marc del PERIS 2016-2020. S’avalua l’impacte de la recerca finançada en la convocatòria de projectes en l’àmbit d’atenció primària SLT002 on es van atorgar dos milions d’euros a 24 projectes de recerca amb un finançament per a tres anys. Amb l’objectiu de retre comptes sobre els ajuts atorgats i de fomentar els casos on es demostren els retorns de la recerca, s’han analitzat els canvis assolits més enllà de l’àmbit acadèmic seguint el camí d’impacte en cadascuna de les fases (recursos, processos i productes primaris, aplicacions i impactes finals) i partint d’una anàlisi de context. Els factors de context posen el focus en aspectes operatius, tecnològics, estructurals i polítics L’anàlisi de context ens mostra una recerca en atenció primària que, tot i el desenvolupament incremental que ha tingut en els últims anys, on ha guanyat un seguit de fortaleses i oportunitats (recerca orientada a les persones, disponibilitat de grans bases de dades o avenç global i tecnològic, entre d’altres), encara té unes debilitats i amenaces que s’han de seguir treballant (elevada pressió assistencial, manca d’intensificacions, dificultat per fer una recerca mediàtica o la manca de recanvi generacional, per exemple). Inclou resum
Pain Management in Burned Patients Treated with Bromelain-Based Enzymatic Debridement
Full text linkBurn; Enzymatic debridement; PainCremada; Desbridament enzimàtic; DolorQuemadura; Desbridamiento enzimático; DolorBackground/Objectives: Enzymatic debridement with bromelain is a treatment option for deep partial thickness and full thickness burns. This procedure is associated with significant pain, necessitating the use of anesthesia techniques. However, there is limited evidence on the optimal strategy to achieve effective pain control. To detail the anesthetic approach in patients undergoing bromelain-based enzymatic debridement for burn injuries. Methods: A retrospective observational study was conducted by analysing the medical records of burn patients treated with enzymatic debridement using bromelain. The study included patients admitted to the Burn Unit of Vall d’Hebron University Hospital between January 2015 and December 2019. Results: A total of 112 patients met the inclusion criteria. The average burned total body surface area (TBSA) was 10.7% ± 11.4, and the median Abbreviated Burn Severity Index (ABSI) was 5 (range: 2–12). The most commonly burned and treated regions were the upper limbs (73%), followed by the lower limbs (30%) and the abdomen (8%). Regional anesthesia was the predominant technique, utilised in 96% of cases. Among these, axillary nerve block was performed in 47% of patients, with continuous catheter placement in 31%. Pain control was achieved in 61% of patients during the first 48 h following enzymatic debridement. Opioids were required for post-procedure pain relief in 12.5% of cases, and repeat anesthesia was necessary in 2.7%. There was no significant difference in pain management outcomes between single nerve blocks and catheter-based approaches (p = 0.809). Complications were reported in nine patients and included hypotension, nausea, and urinary retention. Conclusions: Bromelain-based enzymatic debridement is a painful intervention requiring specialised anesthetic management. Regional anesthesia techniques offer a safe and effective strategy for pain control, though achieving optimal analgesia during the initial 48 h remains a clinical challenge
The role of miR-150-5p/E2F3/survivin axis in the pathogenesis of plasmablastic lymphoma and its therapeutic potential
Full text linkPathogenesis; Plasmablastic lymphomaPatogènesi; Limfoma plasmablàsticPatogénesis; Linfoma plasmablásticoPlasmablastic lymphoma (PBL) is an uncommon and aggressive B-cell lymphoma with a poor prognosis. Some studies have described genetic alterations in PBL, but its transcriptome has been scarcely studied, and molecular mechanisms driving lymphomagenesis remain poorly understood. Our goal was to delineate transcriptomic profiles to identify potential biomarkers for novel targeted therapy in PBL. RNA sequencing uncovered an enrichment of cell cycle-related genes, including MYC and E2F targets, and genes involved in G2/M checkpoint in PBL. Microarray analyses discovered 2 microRNA expression signatures depending on the presence of MYC translocation. Interestingly, miR-150-5p was downregulated, whereas E2F3 and BIRC5 (survivin), a cell cycle activator and an antiapoptotic regulator, respectively, were upregulated. Increasing miR-150-5p in PBL-1 cells induced G1 cell cycle arrest, suppressed proliferation by transcriptionally repressing E2F3, and promoted apoptosis by the downregulation of BIRC5. Interestingly, the miR-150-5p tumor suppressor activity was diminished in E2F3-knockdown cells. The combined inhibition of E2F3 and survivin attenuated lymphomagenesis in PBL cells and suppressed tumor growth in a chorioallantoic membrane-derived xenograft model of PBL. Overall, our study highlights the pivotal role of the miR-150-5p/E2F3/survivin axis in boosting PBL lymphomagenesis and unveils new therapeutic targets for this lymphoma.This study was supported by a grant from Instituto de Salud Carlos III, Ministerio de Economia y Competitividad (PI19/01588) and by the Josep Carreras Foundation, Spain
Genomic Profiling of Extensive Stage Small-Cell Lung Cancer Patients Identifies Molecular Factors Associated with Survival
Full text linkImmunotherapy; Small-cell lung cancer; Tumor mutation burdenInmunoterapia; Cáncer de pulmón de células pequeñas; Carga de mutación tumoralImmunoteràpia; Càncer de pulmó de cèl·lules petites; Càrrega de mutació tumoralObjective: Extensive stage Small-Cell Lung Cancer (ES-SCLC) is the most lethal lung cancer, and the addition of immunotherapy conferred a slight survival benefit for patients. Extensive molecular profiling of patients treated with chemotherapy (CT) or chemotherapy plus immunotherapy (CT+IO) would be able to identify molecular factors associated with patients' survival.
Material and methods: In this retrospective study, 99 ES-SCLC patients were considered. Of the 79 includible patients, 42 received CT (median age 71 y/o, I-IIIQ: 65-76), and 37 received CT+IO (median age 71 y/o, I-IIIQ 66-75). The FoundationOne CDx assay was performed on patients' tumor tissues.
Results: The most mutated genes were TP53 (99%), RB1 (78%), PTEN (23%) and MLL2 (20%), with no significant differences between the treatment groups. As a continuous variable, Tumor Mutation Burden (TMB) had an effect on patients' progression-free survival (PFS) by type of treatment (HR 1.81 (95%, CI: 0.99-3.31) and HR 0.84 (95%, CI: 0.56-1.26) for patients treated with CT and CT+IO, respectively). TMB was also computed and dichotomized using two different cut-offs: considering cut-offs of 10 mut/Mb and >16 mut/Mb, 45 patients (57%) and 68 patients (86.1%) had a low TMB, respectively. A high TMB (cut-off 10 mut/Mb) predicted worse PFS in patients treated with CT (p=0.046); even though not statistically significant, a high TMB (cut-off 16 mut/Mb) predicted a better survival in patients treated with CT+IO. Moreover, at univariate analysis, MLL2 mutations were associated with better prognosis in the overall case series (HRPFS = 0.51, 95% CI: 0.28-0.94), and overall survival (HROS = 0.52, 95% CI: 0.28-0.97).
Conclusion: In ES-SCLC, TMB is associated with worse survival in patients treated with CT alone, and with better survival in patients treated with CT+IO, whether considered as a continuous or a dichotomized variable, at different cut-offs. Alterations in epigenetic factors are also associated to better patient prognosis
Evolving epidemiology of HCC in Spain
Full text linkEtiology; Liver cancer; SurveillanceEtiología; Cáncer de hígado; VigilanciaEtiologia; Càncer de fetge; VigilànciaBackground & Aims
The epidemiological landscape of hepatocellular carcinoma (HCC) in Europe is evolving. This study aims to provide an updated description of the current epidemiology of liver cancer in Spain.
Methods
This multicenter prospective study collected demographic and clinical data on primary liver cancer between October 2022 and January 2023. We conducted descriptive and comparative analyses with data collected in 2008 and 2014.
Results
Of the 767 cases of primary liver cancer collected from 52 centers, 91% were diagnosed as HCC. The majority of patients were male (83.3%), average age 68 years, 80.7% had cirrhosis. The primary causes were alcohol (29.9% alone, 55% combined with other etiologies), liver disease related to metabolic syndrome (LDrMS, 23%) and hepatitis C (17.3%). Treatments included ablation (15.7%), systemic therapy (14.7%), and chemoembolization (14.6%). Data from 29 centers (n = 1,351) across three registries revealed a significant increase in LDrMS (from 4.9% to 24%) and HCC in non-cirrhotic livers (from 4.2% to 7.9%). Meanwhile, hepatitis C decreased sharply (from 43% to 17.5%). Alcohol-related cases remained stable. There was a slight increase in male patients and hypertension, diabetes, and obesity. Patients with cirrhosis diagnosed outside of screening programs presented with larger tumors and more advanced disease. This led to fewer evaluations for curative treatments.
Conclusions
Alcohol accounts for 30% of HCC cases and is the main etiology. The registry shows a decrease in hepatitis C-related HCC, an increase in LDrMS and HCC in non-cirrhotic livers. Surveillance was implemented in ∼80% of the recommended population. There is a need for improved screening and prevention strategies, particularly for alcohol abuse and LDrMS, to enhance HCC management.
Impact and implications
Our study showcases the involvement of numerous reference centers across Spain and examines over 1,300 patients to track the changing epidemiology of hepatocellular carcinoma (HCC) over 14 years. In patients with known liver cirrhosis, more than 80% of HCC diagnoses were made through screening leading to early-stage identification and curative treatment opportunities. Notably, there has been a shift in HCC etiology within the registries from hepatitis C to liver disease related to metabolic syndrome, with an increase in cases without cirrhosis. Findings indicate a need for the prevention and early detection of HCC, particularly focusing on alcohol and liver disease related to metabolic syndrome, along with greater involvement of health authorities, to improve the participation of at-risk patients in screening programs.The Spanish Association for the Study of the Liver (AEEH) has supported the design of the database in the online digital platform (REDCap®) and the storage in an electronic file (https://aeeh.es/politica-de-privacidad/). Elena Avanzas, Ph.D, expert medical writer has reviewed all the content to ensure that the grammar and style sound natural in British English. BM received competitive grants from Instituto de Salud Carlos III (grant numbers PI18/00961 and PI21/00714) cofounded by the EU and a research grant from Laboratorios Viñas S.L. MR received grant support from Instituto de Salud Carlos III (PI18/0358 and PI22/01427), from Centro de Investigación Biomédica en Red - CIBER (Immune4Al, S2300092_3) and from the Spanish Association Against Cancer (AECC, PRYCO234831)
Preferences on the Use of Prokinetic Agents in Adult Intensive Care Unit Patients-An International Survey
Full text linkIntensive care; Prokinetic agents; SurveyCures intensives; Agents procinètics; EnquestaCuidados intensivos; Agentes procinéticos; EncuestaIntroduction
Feeding intolerance complicates enteral nutrition in intensive care unit (ICU) patients but is poorly defined. Prokinetic agents are administered to facilitate the uptake of enteral nutrition, but preferences for their use among clinicians in ICUs are unknown.
Methods
We conducted an international electronic survey targeting ICU doctors. The survey included 76 questions that focused on symptoms considered when assessing feeding intolerance, preferences for using prokinetic agents, and willingness to participate in a future randomised trial on prokinetic agents.
Results
We received 830 responses from 17 countries, with an overall response rate of 29%. Most respondents were specialists working in mixed ICUs. Feeding intolerance was assessed by 90% of respondents in their clinical work, though only 36% considered it well defined. Gastric residual volume and vomiting were symptoms most frequently used for defining feeding intolerance. Metoclopramide was the preferred prokinetic agent (54% of respondents), followed by erythromycin (42%). Four out of five considered using combination therapy, primarily a combination of metoclopramide and erythromycin (89%). Concerns about side effects were reported for all agents, with extrapyramidal symptoms and QT prolongation being the most common across agents. The majority (91%) of respondents supported a future randomised trial comparing prokinetic agents to placebo.
Conclusion
This international survey found practice variations in the symptoms reportedly used to assess feeding intolerance. Metoclopramide was the preferred prokinetic agent, followed by erythromycin. Most respondents supported a future randomised trial