Both baseline clinical factors and genetic polymorphisms influence the development of severe functional status in ankylosing spondylitis

Functional severity in ankylosing spondylitis (AS) patients is variable and difficult to predict early. The aim of our study was to assess whether a combination of baseline clinical factors and genetic markers may predict the development of severe functional status in AS. We performed a cross-sectional association study on AS patients included in the Spanish National Registry of Spondyloarthropathies-REGISPONSER. Bath Ankylosing Spondylitis Functional Index (BASFI) was standardized by adjusting for disease duration since the first symptoms (BASFI/t). We considered as severe functional status the values of BASFI/t in the top of the 60th (p60), 65th (p65), 70th (p70), and 75th (p75) percentile. We selected 384 single nucleotide polymorphisms (SNPs) distributed in 190 genes to be analyzed. The study cohort included 456 patients with mean age 50.8(±10.5) years and with mean disease duration since first symptoms 24.7 (±10.1) years. Older age at disease onset and neck pain at baseline showed statistical significant association with severe BASFI/t. Polymorphisms associated in the allele frequencies test with severe BASFI/t in all classifications were: rs2542151 (p60 [P =.04], p65 [P =.04], p70 [P =.001] and p75 [P =.001]) and rs2254441 (p60 [P =.004], p65 [P =.02], p70 [P =.01] and p75 [P<.001]). Genotype association, after adjustment for covariates, found an association in three of the four patients' classifications for rs2542151 and in two of the classifications for rs2254441.Forward logistic regression did not identify any model with a good predictive power for severe functional development. In our study we identified clinical factors and 24 polymorphisms associated with development of severe functional status in AS patients. Validation of these results in other cohorts is requiredThis work was supported by the Ministerio de Ciencia e Innovación of Spain [Proyect PSE-01000-2006-1] and by Progenika Biopharma S.

A Single Nucleotide Polymorphism in the Il17ra Promoter Is Associated with Functional Severity of Ankylosing Spondylitis

The aim of this study was to identify new genetic variants associated with the severity of ankylosing spondylitis (AS). We sequenced the exome of eight patients diagnosed with AS, selected on the basis of the severity of their clinical parameters. We identified 27 variants in exons and regulatory regions. The contribution of candidate variants found to AS severity was validated by genotyping two Spanish cohorts consisting of 180 cases/300 controls and 419 cases/656 controls. Relationships of SNPs and clinical variables with the Bath Ankylosing Spondylitis Disease Activity and Functional Indices BASDAI and BASFI were analyzed. BASFI was standardized by adjusting for the duration of the disease since the appearance of the first symptoms. Refining the analysis of SNPs in the two cohorts, we found that the rs4819554 minor allele G in the promoter of the IL17RA gene was associated with AS (p<0.005). This variant was also associated with the BASFI score. Classifying AS patients by the severity of their functional status with respect to BASFI/disease duration of the 60th, 65th, 70th and 75th percentiles, we found the association increased from p60 to p75 (cohort 1: p<0.05 to p<0.01; cohort 2: p<0.01 to p<0.005). Our findings indicate a genetic role for the IL17/ILRA axis in the development of severe forms of AS

Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer

Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.This work was funded by the American Association for Cancer Research, Lustgarten Foundation, and Stand Up to Cancer as a Pancreatic Cancer Collective New Therapies Challenge grant (grant no. SU2C-AACR-PCC-01-18)

Red de seguimiento del Grado en Criminología on line

La red tenía por objeto llevar a cabo un especial seguimiento del grupo on line del Grado en Criminología que se imparte en la titulación y para el que son necesarios esfuerzos de coordinación adicionales y métodos docentes específicos a la docencia no presencial. Así, la red ha constituido un espacio de reflexión sobre docencia no presencial, que ha dado como resultado la adopción e implementación de acciones de mejora

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

Contains fulltext : 172380.pdf (publisher's version ) (Open Access

All roads lead to SHP2

It is clear by now that CRISPR screens are a useful tool to identify and validate novel targets for the treatment of various malignancies. Furthermore, genetic screens have allowed the identification of not only the usual kinases but also other genes with different functions in the cell such as epigenetic regulators or phosphatases. SHP2 was discovered in a dropout genetic screen with a phosphatase library as driver of resistance to targeted therapies. As a consequence, SHP2 became an attractive target for BRAF-mutant colorectal tumors that are unresponsive to vemurafenib. Recently, pharmaceutical companies developed specific inhibitors for SHP2. This allowed a more translational investigation of this drug in combination with other approved or experimental targeted therapies. In fact, this thesis titled “All roads lead to SHP2” explores the inhibition and depletion of SHP2 in several tumor types. Specifically, we show that SHP2 suppression in combination with MEK inhibitors, both in vitro and in vivo, improves the tumor control in the context of KRAS-mutant NSCLC tumors. Importantly, we demonstrate here that even though mutant KRAS is overactive, it remains dependent on upstream signaling from growth factor receptors, and thereby SHP2. We validate a different SHP2 inhibitor, RMC-4550, in combination with an ERK inhibitor for the treatment of KRAS-mutant pancreatic adenocarcinomas. This extensive pre-clinical validation with these two specific inhibitors led to the SHERPA phase 1/1b clinical trial, currently testing this combination in patients harboring KRAS-mutant tumors. We seek for mechanisms of resistance to dual blockade of SHP2 and ERK in the context of KRAS-mutant PDAC. Interestingly, we observe two main ways to become resistant to our combination. First, we observed that PTEN deletion can activate the PI3K-AKT-mTOR pathway, and thereby drive survival and proliferation of the tumor cells. Second, depletion of either DET1 or COP1 can lead to resistance to our combination by activating the JUN pathway. Moreover, spontaneously generated resistant cells have increased activity of both mTOR and JUN signaling pathways. We investigate why HCC tumors are unresponsive to mTOR inhibition since 40-50% of these tumors depend on the mTOR pathway. We observe that upregulation of different receptor tyrosine kinases is triggered upon mTOR inhibition. It is important to note that SHP2 is downstream of nearly all receptor tyrosine kinases and upstream of RAS, hence affecting the transduction of signaling from the RTKs to the MAPK pathway as well as the PI3K-AKT-mTOR pathway, two main pathways for cancer cells to proliferate, grow and survive. Following the title of this thesis, we observe SHP2 is commonly activated upon mTOR inhibition. We also combine 3 different SHP2 inhibitors with AZD8055, an mTOR dual kinase inhibitor, in the context of hepatocellular carcinoma. In vivo, we observe greater responses with the combination compared to the monotherapies. Importantly, we show that the combination is effective in a tumor intrinsic manner by downregulating MYC and KRAS signaling. Finally, we summarize and discuss all the findings presented in this thesis. We hypothesize and speculate about the future of SHP2 drugs in cancer therapy

An orphan viral TNF receptor superfamily member identified in lymphocystis disease virus

Background: Lymphocystis disease virus (LCDV) is a large icosahedral dsDNA-containing virus of the Lymphocystivirus genus within the Iridoviridae family that can cause disease in more than 140 marine and freshwater fish species. While several isolates have been charcaterized and classified into distinct genotypes the complete genomic sequence is currently only available from two species, the LCDV-1, isolated from flounder (Platichtys flesus) in Europe and the LCDV-C, isolated from Japanese cultured flounder (Paralichthys olivaceus) in China. Analysis of the genome of LCDV-C showed it to encode a protein named LDVICp016 with similarities to the Tumour necrosis factor receptor (TNFR) superfamily with immunomodulatory potential. Findings. We have expressed and purified the recombinant protein LDVICp016 and screened for potential interaction partners using surface plasmon resonance. Commercially available human and mouse members of the TNF superfamily (TNFSF), along with a representative set of fish-derived TNFSF were tested. We have found the LDVICp016 protein to be secreted and we have identified a second viral TNFR encoded by ORF 095 of the same virus. None of the 42 tested proteins were found to interact with LDVICp016. Conclusions: We show that LDVICp016 is a secreted protein belonging to the TNF receptor family that may be part of a larger gene family in Lymphocystiviruses. While the ligand of this protein remains unknown, possibly due to the species specific nature of this interaction, further investigations into the potential role of this protein in the blockade of immune responses in its fish host are required.Spanish Ministerio de Ciencia e Innovación (AGL 2009-08711, SAF2009-07857)Peer Reviewe

Genetic and compound screens uncover factors modulating cancer cell response to indisulam

Discovering biomarkers of drug response and finding powerful drug combinations can support the reuse of previously abandoned cancer drugs in the clinic. Indisulam is an abandoned drug that acts as a molecular glue, inducing degradation of splicing factor RBM39 through interaction with CRL4DCAF15 Here, we performed genetic and compound screens to uncover factors mediating indisulam sensitivity and resistance. First, a dropout CRISPR screen identified SRPK1 loss as a synthetic lethal interaction with indisulam that can be exploited therapeutically by the SRPK1 inhibitor SPHINX31. Moreover, a CRISPR resistance screen identified components of the degradation complex that mediate resistance to indisulam: DCAF15, DDA1, and CAND1. Last, we show that cancer cells readily acquire spontaneous resistance to indisulam. Upon acquiring indisulam resistance, pancreatic cancer (Panc10.05) cells still degrade RBM39 and are vulnerable to BCL-xL inhibition. The better understanding of the factors that influence the response to indisulam can assist rational reuse of this drug in the clinic