Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Genome-wide transcriptome profiling of ex-vivo precision-cut slices from human pancreatic ductal adenocarcinoma

Ex-vivo tumor tissue culture systems are used as models to test specific anti-cancer drugs. Their main advantage is that they are closely comparable with the in vivo tumor in their host organism. We previously reported that precision-cut organotypic tissue slices of pancreatic ductal adenocarcinoma (PDAC) can be successfully cultured ex-vivo for at least 4 days. In order to study how culturing might affect transcription patterns, we now performed genome-wide transcriptome profiling of both baseline (0 h) and explanted tumors at daily intervals (24, 48 and 72 h) after start of culturing. The total-RNA from five samples of surgically resected human PDAC tumors at baseline and at different time points in culture was sequenced. Differential gene expression analysis of the whole transcriptome, testing 58,713 genes and over 206,000 transcripts, found that only a small number of genes showed significant changes in expression between baseline and cultured samples. The cultured tumor slices showed upregulation of a median of 12, 10 and 15 genes and downregulation of a median of 15, 12 and 25 genes at 24, 48 and 72 h in culture, respectively. One sample had morphologically increasing loss of tissue viability (range 0–18%). The vascular endothelial growth factor A (VEGFA) was significantly upregulated during the entire culture period in this case. Pathway over-representation analysis suggested that VEGFA together with the PTGS2 gene were upregulated at the same time as HIF-1-triggered cell apoptosis via NF-ĸB and the AP-1 activating factor was induced. Indeed, increased areas of apoptotic lesions were visible in this sample after 24 hours of culture. In conclusion, genome-wide transcriptome analysis supports that ex-vivo cultured tissue slices of PDAC may be a representative model of the original tumor. Transcriptome analysis was found to be a valuable complement to morphology for evaluation of ex-vivo cultures of PDAC

Exploration of Patient-Derived Pancreatic Ductal Adenocarcinoma Ex Vivo Tissue for Treatment Response

Patient-derived tissue culture models are valuable tools to investigate drug effects and targeted treatment approaches. Resected tumor slices cultured ex vivo have recently gained interest in precision medicine, since they reflect the complex microenvironment of cancer tissue. In this study, we examined the treatment response to an internally developed ex vivo tissue culture model from pancreatic ductal adenocarcinoma (PDAC) and in vitro analysis. Seven PDAC tissues were cultured and subsequently treated with indole-3-pyruvic acid (IPA). IPA, which is known as an agonist of the aryl hydrocarbon receptor (AHR) pathway, has antioxidant properties. Genome-wide transcriptome sequencing analysis revealed activation of AHR pathway genes (CYP1A1 and CYP1B1, p ≤ 0.05). Additionally, significant upregulation of AHR repressor genes AHRR and TiPARP was also observed (p ≤ 0.05), which is indicative of the negative feedback loop activation of AHR pathway signaling. The overall transcriptomic response to IPA indicated that the tissues are biologically active and respond accordingly to exogenous treatment. Cell culture analysis confirmed the significant induction of selected AHR genes by IPA. A morphological examination of the paraffin-embedded formalin-fixed tissue did not show obvious signs of IPA treatment related to tumor cell damage. This study is a proof of concept that ex vivo patient-derived tissue models offer a valuable tool in precision medicine to monitor the effect of personalized treatments

Ex vivo organotypic culture system of precision-cut slices of human pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, which is mainly due to late diagnosis and profound resistance to treatment. The latter is to a large extent attributed to the tumor stroma that is exceedingly prominent in PDAC and engages in complex interactions with the cancer cells. Hence, relevant preclinical models of PDAC should also include the tumor stroma. We herein describe the establishment and functional validation of an ex vivo organotypic culture of human PDAC that is based on precision-cut tissue slices from surgical specimens and reproducibly recapitulates the complex cellular and acellular composition of PDAC, including its microenvironment. The cancer cells, tumor microenvironment and interspersed remnants of nonneoplastic pancreas contained in these 350 µm thick slices maintained their structural integrity, phenotypic characteristics and functional activity when in culture for at least 4 days. In particular, tumor cell proliferation persisted and the grade of differentiation and morphological phenotype remained unaltered. Cultured tissue slices were metabolically active and responsive to rapamycin, an mTOR inhibitor. This culture system is to date the closest surrogate to the parent carcinoma and harbors great potential as a drug sensitivity testing system for the personalized treatment of PDAC

Efficient Implementation of Application-Aware Spinlock Control in MPSoCs

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotyp