27 research outputs found
Editorial: Human resource management in the COVID-19 era: new insights and management opportunities
Interrelations between Patientsâ Clinicopathological Characteristics and Their Association with Response to Immunotherapy in a Real-World Cohort of NSCLC Patients
Biomarcadores; Eventos adversos relacionados con el sistema inmunitario; InmunoterapiaBiomarcadors; Esdeveniments adversos relacionats amb el sistema immunitari; ImmunoterĂ piaBiomarkers; Immune related adverse events; ImmunotherapyImmune checkpoint inhibitors (ICIs) have transformed non-small cell lung cancer (NSCLC) treatment. Unfortunately, only some patients benefit from these therapies. Thus, certain clinicopathological characteristics of the patients have been proposed as biomarkers of ICIs response. We assembled a retrospective cohort of 262 NSCLC patients treated with ICIs, compiled relevant clinicopathological characteristics, and studied their associations with treatment outcome using Cox proportional-hazards survival models. Additionally, we investigated the interrelations between clinicopathological features and devised a method to create a compendium associated with ICIs response by selecting those that provide non-redundant information. In multivariate analyses, ECOG performance status (hazard ratio (HR) 1.37 (95% CI 1.11 to 1.68), p < 0.005), LDH (HR 1.24 (95% CI 1.03 to 1.48), p = 0.02)) and PD-L1 negativity were associated with decreased progression-free survival (PFS) (HR 1.92 (95% CI 1.03 to 3.58), p = 0.04), whereas presentation of immune-related adverse events (irAEs) (HR 0.35 (95% CI 0.22 to 0.55, p < 0.005) or females (HR 0.52 (95% CI 0.33 to 0.80, p < 0.005) had longer PFS. Additionally, numerous clinicopathological indicators were found to be interrelated. Thus, we searched for features that provide non-redundant information, and found the combination of LDH levels, irAEs, and gender to have a better association with ICIs treatment response (cross-validated c-index = 0.66). We concluded that several clinicopathological features showed prognostic value in our real-world cohort. However, some are interrelated, and compendiums of features should therefore consider these interactions. Joint assessment of LDH, irAEs, and gender may be a good prognostic compendium.None associated with this project
High levels of chromosomal aberrations negatively associate with benefit to checkpoint inhibition in NSCLC
Immunotherapy; Lung neoplasms; Tumor biomarkersImmunoterĂ pia; CĂ ncer de pulmĂł; Biomarcadors tumoralsInmunoterapia; CĂĄncer de pulmĂłn; Biomarcadores tumoralesBackground Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1/programmed death-ligand 1 axis have transformed the management of advanced non-small cell lung cancer (NSCLC). However, many patients do not benefit from this type of treatment, and thus several molecular biomarkers of benefit have been explored. The value of somatic copy number alterations (SCNAs) burden remains elusive.
Patients and methods We assembled a cohort of 109 patients with NSCLC treated with ICIs and available tumor samples. We performed shallow whole-genome sequencing on 89 patients to determine genome-wide SCNAs and targeted gene expression analysis on 63 patients to study immune infiltration. We analyzed SCNAs burden in different ways (ie, the fraction of the genome altered or number of events) and studied their association with ICIs benefit based on survival analysis. We correlated SCNAs burden and immune infiltration on 35 patients of our cohort and on patients with lung adenocarcinoma from The Cancer Genome Atlas (TCGA).
Results High SCNAs burden, computed in diverse ways, is negatively associated with ICIs progression-free survival (PFS), with the fraction of the genome altered (FGA) by arm and chromosome events showing the strongest association with PFS (p=0.002) (n=77). Nevertheless, we found differences in SCNAs across some clinicopathological features (sample site origin). A multivariate analysis adjusted for relevant characteristics showed that the FGA of arm and chromosome alterations was strongly associated with PFS (HR=2.21, p=3.3 x 10â5). Finally, we confirmed that SCNAs burden negatively correlates with tumor immune infiltration (n=35), although this correlation was not found for the males studied. Similar results were observed in the TCGA cohort.
Conclusions SCNAs burden is a potential biomarker of benefit to ICIs in patients with NSCLC, although there appear to be some nuances worth consideration. Further studies will be needed to establish its role as a biomarker of benefit to ICIs.This work was supported by Merck Healthcare KGaA, Darmstadt, Germany (Grant for Oncology Innovation to the Vall dâHebron Institute of Oncology (VHIO), Barcelona, Spain), FundaciĂłn CientiïŹca AsociaciĂłn Española Contra el Cancer-AECC (grant number GCB14142170 to EF); the Catalan Government/AGAUR (2017âSGRâ1738 to EF). Merck Healthcare KGaA reviewed the manuscript for medical accuracy only before journal submission
Neuroprotective coordination of cell mitophagy by the ATPase Inhibitory Factor 1
The mitochondrial ATPase Inhibitory Factor 1 (hereafter referred to as IF1) blocks the reversal of the F1Fo-ATPsynthase to prevent detrimental consumption of cellular ATP and associated demise. Herein, we infer further its molecular physiology by assessing its protective function in neurons during conditions of challenged homeostatic respiration.
By adopting in vitro and in vivo protocols of hypoxia/ischemia and re-oxygenation, we show that a shift in the IF1:F1Fo-ATPsynthase expression ratio occurs in neurons. This increased IF1 level is essential to induce accumulation of the PTEN-induced putative kinase 1 (PINK-1) and recruitment of the mitophagic ubiquitin ligase PARK-2 to promote autophagic âcontrolâ of the mitochondrial population. In IF1 overexpressing neurons ATP depletion is reduced during hypoxia/ischemia and the mitochondrial membrane potential (ÎYm) resilient to re-oxygenation as well as resistant to electrogenic, Ca2+ dependent depolarization.
These data suggest that in mammalian neurons mitochondria adapt to respiratory stress by upregulating IF1, which exerts a protective role by coordinating pro-survival cell mitophagy and bioenergetics resilience
Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer
Corticosteroids; Efficacy; Immune checkpoint inhibitorsCorticosteroides; Eficacia; Inhibidores del punto de control inmunitarioCorticoides; EficĂ cia; Inhibidors del punt de control immunitariIn recent years, immunotherapy-based regimens have been included into the treatment's algorithm of several cancer types. Programmed death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) interact with their ligands found on the surface of antigen presenting cells (APC) or tumor cells (PD-L1/2 and CD80/86). Through these interactions, stimulatory or inhibitory signals are established. Immune checkpoint inhibitors (ICIs), block these interactions, and when administered not only as monotherapy but also as part of combination regimens, have shown to improve survival results in multiple advanced cancers leading to an increasing number of patients treated with ICI and, as a consequence, a rise in the number of patients developing immune-related adverse events (irAEs). Presence of irAEs has been associated with greater benefit from treatment, especially when blocking PD-L1. Recent data suggests that treatment benefit persists after discontinuation of ICIs due to a treatment related adverse event, regardless of the grade. Patients experiencing grade 3-4 irAEs are at risk of toxicity recurrence after reintroducing immunotherapy and therefore, the decision to resume the treatment is challenging. In these cases, a multidisciplinary approach is always needed and several factors should be considered. Management of severe toxicities may require systemic corticosteroids which can impact on T-cell function. Due to their immunosuppressive properties, it is necessary to deeper determine how corticosteroids influence responses. In terms of overall survival (OS), the use of steroids as therapy for irAEs seems not to reduce OS and several studies have reported durable responses in patients experiencing autoimmune toxicities treated with corticosteroids
Efficacy of chemotherapy for malignant pleural mesothelioma according to histology in a real-world cohort
Cancer therapy; MesotheliomaTerapia del cĂĄncer; MesoteliomaTerĂ pia del cĂ ncer; MesoteliomaCheckMate 743 trial demonstrated survival benefit of immunotherapy in first line in MPM with some differences in the efficacy of chemotherapy according to histology. The objective of this study is to characterize the impact of chemotherapy according to histology in patients diagnosed with MPM at our institution. Clinical records of all MPM patients diagnosed at Vall dâHebron University Hospital between November 2002 and April 2020 were reviewed. Associations between clinical variables and outcomes were assessed with Cox regression models. Survival data were calculated by the KaplanâMeier method. 189 patients were included with 76% of tumors classified as epithelioid subtype. First line chemotherapy was offered to 85% of patients. Median survival in overall population was 21.3 months (95% CI 17.2â24.3). We found that patients with epithelioid tumors had better overall survival (OS) and progression free survival (PFS). Median OS of epithelioid patients treated with first line chemotherapy was 26.7 months versus 15.0 months in non-epithelioid patients (HR 2.25 CI 95% 1.4â3.4; pâ<â0.001). Median PFS for patients with epithelioid tumors treated with chemotherapy was 4.8 months versus 3.6 months in non-epithelioid (HR 1.5 CI 95% 1.0â2.3; pâ=â0.03). The improvement of outcomes in patients with epithelioid histology was detected in patients treated with cisplatin or carboplatin. Histology was not a predictive factor for the platinum agent sensitivity (p of interaction PFSâ=â0.09, p of interaction OSâ=â0.65). In our series, patients with non-epithelioid tumors presented worse prognosis. Although epithelioid tumors exposed to cisplatin had higher PFS, histology was not a clear predictor of chemotherapy efficacy
Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer
Altres ajuts: This work was supported by the Fundacion Cientifica Asociación Española Contra el Cancer-AECC [grant number GCB14142170 to LMM, MS-C, and EF].Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs
Expression of TILs and Patterns of Gene Expression from Paired Samples of Malignant Pleural Mesothelioma (MPM) Patients
Gene expression; Immunotherapy; Malignant pleural mesotheliomaExpresión génica; Inmunoterapia; Mesotelioma pleural malignoExpressió gÚnica; Immunoterà pia; Mesotelioma pleural maligneMPM is an aggressive disease with an immunosuppressive tumor microenvironment, and interest in exploring immunotherapy in this disease has been increasing. In the first line of treatment, the combination of nivolumab and ipilimumab demonstrated an improvement in survival over chemotherapy. The presence of TILs has been recognized as a marker of antitumor immune response to chemotherapy in solid tumors. The aim of our study is to identify the effect of treatment on immune cells and the immune gene profile in MPM. We investigated the changes in expression of TILs in 10 human MPM paired tumor tissues using immunohistochemistry and gene expression analysis from paired untreated and treated samples. In this small series, we demonstrated that during the evolution of disease without any treatment there was an increase in the inflammatory component in tumor samples. After systemic treatment there was a decrease in the number of TILs. We observed that after systemic treatment or disease progression immune gene signatures were suppressed. Our integrated analysis of paired samples with immune profile and genomic changes on MPM suggested that during the evolution of the disease the immune system tends to switch, turning off with treatment.The study was partially funded by Project PREDICT-Meso (GEACC19003CED), funded by Fundación AECC
Drivers of population structure of the bottlenose dolphin (Tursiops truncatus) in the Eastern Mediterranean Sea
The drivers of population differentiation in oceanic high dispersal organisms, have been crucial for research in evolutionary biology. Adaptation to different environments is commonly invoked as a driver of differentiation in the oceans, in alternative to geographic isolation. In this study, we investigate the population structure and phylogeography of the bottlenose dolphin (Tursiops truncatus) in the Mediterranean Sea, using microsatellite loci and the entire mtDNA control region. By further comparing the Mediterranean populations with the well described Atlantic populations, we addressed the following hypotheses: (1) bottlenose dolphins show population structure within the environmentally complex Eastern Mediterranean Sea; (2) population structure was gained locally or otherwise results from chance distribution of preexisting genetic structure; (3) strong demographic variations within the Mediterranean basin have affected genetic variation sufficiently to bias detected patterns of population structure. Our results suggest that bottlenose dolphin exhibits population structures that correspond well to the main Mediterranean oceanographic basins. Furthermore, we found evidence for fine scale population division within the Adriatic and the Levantine seas. We further describe for the first time, a distinction between populations inhabiting pelagic and coastal regions within the Mediterranean. Phylogeographic analysis suggests that current genetic structure, results mostly from stochastic distribution of Atlantic genetic variation, during a recent postglacial expansion. Comparison with Atlantic mtDNA haplotypes, further suggest the existence of a metapopulation across North Atlantic/Mediterranean, with pelagic regions acting as source for coastal environments
Regulation of alternative splicing by the p38 SAPK in response to stress
Cells have the ability to respond and adapt to environmental changes through activation of stress-activated protein kinases (SAPKs). Activation of the p38 SAPK is critical to elicit the early gene expression program required for cell adaptation to stress. Alternative splicing (AS) is a crucial mechanism for gene regulation that has been shown to be modulated in response to a wide range of extracellular stimuli. However, the mechanisms behind AS regulation and the functional consequences of differential isoform expression in stress conditions remain largely unknown.
In this study, we identified novel associations between p38 and the splicing machinery, providing mechanisms by which p38 regulates AS. Furthermore, characterization of protein isoforms produced by p38-dependent AS give an insight into the biological relevance of this regulation in adaptation to environmental stresses.
Altogether, the results of this thesis highlight a role for SAPK signaling pathways in adaptation to environmental changes through AS modulation.Les cĂšl·lules tenen l'habilitat de detectar i respondre a les fluctuacions en el seu entorn a travĂ©s de l'activaciĂł de les proteĂŻnes quinasa activades per estrĂšs (SAPKs). L'activaciĂł de la SAPK p38 Ă©s essencial per activar el programa d'expressiĂł gĂšnica necessari perquĂš les cĂšl·lules sâadaptin als estĂmuls extracel·lulars. El processament alternatiu del pre-ARNm Ă©s un mecanisme de regulaciĂł gĂšnica crucial que es regula en resposta a diferents canvis en l'ambient. No obstant, els mecanismes moleculars pels quals es regula, aixĂ com la funciĂł de les diferents isoformes de les proteĂŻnes que s'expressen en resposta a estrĂšs no es coneixen.
En conjunt, els resultats presentats en aquesta tesis proporcionen una nova visió dels mecanismes pels quals p38 modula el processament alternatiu del pre-ARNm en resposta a estrÚs i posen en evidÚncia la importà ncia d'aquest mecanisme per l'adaptació de la cÚl·lula a canvis en l'ambient extracel·lular