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Item does not contain fulltext OBJECTIVE: Real-world studies are needed to identify factors associated with response to biologic therapies in patients with axial spondyloarthritis (SpA). The objective was to assess sex differences in response to tumor necrosis factor inhibitors (TNFi) and to explore possible risk factors associated with TNFi efficacy. METHODS: A total of 969 patients with axial SpA (315 females, 654 males) enrolled in the BIOBADASER registry (2000-2019) who initiated a TNFi (first, second, or further lines) were studied. Statistical and artificial intelligence (AI)-based data analyses were used to explore the association of sex differences and other factors to TNFi response, using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), to calculate the BASDAI50, with an improvement of at least 50% of the BASDAI score, and using the Ankylosing Spondylitis Disease Activity Score, calculated using the C-reactive protein level (ASDAS-CRP). RESULTS: Females had a lower probability of reaching a BASDAI50 response with a first line TNFi treatment at the second year of follow-up (P = 0.018) and a lesser reduction of the ASDAS-CRP at this time point. The logistic regression model showed lower BASDAI50 responses to TNFi in females (P = 0.05). Other factors, such as older age (P = 0.004), were associated with unfavorable responses. The AI data analyses reinforced the idea that age at the beginning of the treatment was the main factor associated with an unfavorable response. The combination of age with other clinical characteristics (female sex or cardiovascular risk factors and events) potentially contributed to an unfavorable response to TNFi. CONCLUSION: In this national multicenter registry, female sex was associated with less response to a first-line TNFi by the second year of follow-up. A higher age at the start of the TNFi was the main factor associated with an unfavorable response to TNFi. 01 januari 2023

Embryo implantation is one of the most inefficient steps in assisted reproduction, so the identifying drugs with a potential clinical application to improve it has a strong interest. This work applies artificial intelligence and systems biology-based mathematical modeling strategies to unveil potential treatments by computationally analyzing and integrating available molecular and clinical data from patients. The mathematical models of embryo implantation computationally generated here simulate the molecular networks underneath this biological process. Once generated, these models were analyzed in order to identify potential repositioned drugs (drugs already used for other indications) able to improve embryo implantation by modulating the molecular pathways involved. Interestingly, the repositioning analysis has identified drugs considering two endpoints: (1) drugs able to modulate the activity of proteins whose role in embryo implantation is already bibliographically acknowledged, and (2) drugs that modulate key proteins in embryo implantation previously predicted through a mechanistic analysis of the mathematical models. This second approach increases the scope open for examination and potential novelty of the repositioning strategy. As a result, a list of 23 drug candidates to improve embryo implantation after IVF was identified by the mathematical models. This list includes many of the compounds already tested for this purpose, which reinforces the predictive capacity of our approach, together with novel repositioned candidates (e.g., Infliximab, Polaprezinc, and Amrinone). In conclusion, the present study exploits existing molecular and clinical information to offer new hypotheses regarding molecular mechanisms in embryo implantation and therapeutic candidates to improve it. This information will be very useful to guide future research. Abbreviations: IVF: in vitro fertilization; EI: Embryo implantation; TPMS: Therapeutic Performance Mapping System; MM: mathematical models; ANN: Artificial Neuronal Networks; TNFα: tumour necrosis factor factor-alpha; HSPs: heat shock proteins; VEGF: vascular endothelial growth factor; PPARA: peroxisome proliferator activated receptor-α PXR: pregnane X receptor; TTR: transthyretin; BED: Biological Effectors Database; MLP: multilayer perceptron

From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches. The drug combination of pirfenidone and melatonin has been identified as a candidate treatment that may contribute to reduce the virus infection. Starting from different drug targets the effect of the drugs converges on human proteins with a known role in SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server has been used as an alternative method to corroborate the effect of pirfenidone and melatonin against the infection of SARS-CoV-2. We have also predicted a potential therapeutic effect of the drug combination over the respiratory associated pathology, thus tackling at the same time two important issues in COVID-19. These evidences, together with the fact that from a medical point of view both drugs are considered safe and can be combined with the current standard of care treatments for COVID-19 makes this combination very attractive for treating patients at stage II, non-severe symptomatic patients with the presence of virus and those patients who are at risk of developing severe pulmonary complications. LA, MC, PMF, JF, RV and JMM have commercial affiliation to Anaxomics Biotech SL. The funders provided support in the form of salaries for authors JAP, NFF and PMF, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. JAP, NFF and BO acknowledge support from the Spanish Ministry of Economy (MINECO) [BIO2017-85329-R] [RYC-2015-17519]; Unidad de Excelencia María de Maeztu”, funded by the Spanish Ministry of Economy [ref: MDM-2014-0370].PMF has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 765912.

Numerous studies suggest that the increased activity of p38MAPK plays an important role in the abnormal immune and inflammatory response observed in the course of neurodegenerative diseases such as Alzheimer's disease. On the other hand, High levels of p38MAPK are present in the brain during normal aging, suggesting the existence of mechanisms that keep the p38MAPK-regulated pro-inflammatory activity within physiological limits. In this study, we show that high p38MAPK activity in the hippocampus of old mice is in part due to the reduction in membrane cholesterol that constitutively occurs in the aging brain. Mechanistically, membrane cholesterol reduction increases p38MAPK activity through the stimulation of a subset of tyrosine kinase receptors (RTKs). In turn, activated p38MAPK increases the expression and activity of the phosphatase DUSP2, which is known to reduce the activity of different MAPKs, including p38MAPK. These results suggest that the loss of membrane cholesterol that constitutively occurs with age takes part in a negative-feedback loop that keeps p38MAPK activity levels within physiological range. Thus, conditions that increase p38MAPK activity such as cellular stressors or that inhibit DUSP2 will amplify inflammatory activity with its consequent deleterious functional changes., Ministry of Economy and Competitiveness grants Consolider CSD2010-00064 and SAF2013-45392 and SAF201676722 to CD. AN was supported by the Consolider grant CSD2010-0045. PF is the recipient of a Ramon y Cajal Award RYC-2014-16410 from the Spanish Ministry of Economy and Competitiveness.

e15108 Background: VAN is a novel bispecific mAb targeting VEGF & ANG-2. A randomized phase 2 study (McCAVE) investigating VAN & BEV, each combined with chemotherapy (mFOLFOX-6), in 1L metastatic colorectal cancer patients was completed. Reported gastrointestinal perforation (GIP) events (including GI fistula & abdominal abscess) in both arms (approx. 10%) exceeded those expected with BEV+CTx. The present work focused on identifying the explicit molecular pathways mediating VAN/BEV associated GIP. Methods: Clinical data from McCave (safety outcomes & gene expression profiling) was integrated with data from other clinical/preclinical VAN/BEV studies. Machine learning was applied to the dataset to computationally infer GIP mechanisms. The methodology was constrained by relevant biological & clinical knowledge. Literature reviews & database queries mapped 194 unique proteins to 8 biological processes previously hypothesized to play a role in GIP. Identified proteins guided construction of a GIP protein interaction network which was transformed into an artificial neural network and was fitted to the dataset to predict molecular pathways/biological processes most likely linking VEGF-A and/or ANG-2 inhibition to GIP. Results: VAN/BEV were predicted to enhance GIP risk via 4 out of 8 previously suggested biological effects: (i) reduced GI mucosal integrity; (ii) impaired wound healing; (iii) inhibition of angiogenesis (iv) increased thromboembolic risk. The specific proteins & associated interactions predicted to mediate these 4 effects were identified as solely VEGF-A inhibition driven. These effects may drive increased susceptibility to GIP triggered by secondary insults, e.g. preclinical ulcer & intramural lesion. Candidate GIP biomarkers for monitoring these effects were identified, e.g., aPTT, citrulline & I-FABP. Conclusions: The molecular pathways mediating GIP in VAN/BEV treated patients are likely driven by VEGF inhibition with no contribution from ANG-2 inhibition. It is proposed, that in addition to VAN/BEV, one or more secondary insults to the GI tract wall are required to drive perforation.