The use of computational tools to identify biological targets of natural products with anticancer properties and unknown modes of action is gaining momentum. We employed self-organizing maps to deconvolute the phenotypic effects of piperlongumine (PL) and establish a link to modulation of the human transient receptor potential vanilloid 2 (hTRPV2) channel. The structure of the PL-bound full-length rat TRPV2 channel was determined by cryo-EM. PL binds to a transient allosteric pocket responsible for a new mode of anticancer activity against glioblastoma (GBM) in which hTRPV2 is overexpressed. Calcium imaging experiments revealed the importance of Arg539 and Thr522 residues on the antagonistic effect of PL and calcium influx modulation of the TRPV2 channel. Downregulation of hTRPV2 reduces sensitivity to PL and decreases ROS production. Analysis of GBM patient samples associates hTRPV2 overexpression with tumor grade, disease progression, and poor prognosis. Extensive tumor abrogation and long term survival was achieved in two murine models of orthotopic GBM by formulating PL in an implantable scaffold/hydrogel for sustained local therapy. Furthermore, in primary tumor samples derived from GBM patients, we observed a selective reduction of malignant cells in response to PL ex vivo . Our results establish a broadly applicable strategy, leveraging data-motivated research hypotheses for the discovery of novel means tackling cancer.
ObjectivesTo compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs).MethodsPatients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models.ResultsOf the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI<4 was much larger than the opposite (ie, ASDAS <2.1, if BASDAI≥4): 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most ‘stringent’ outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months: 61% vs 25% and at 6 months: 42% vs 25%).ConclusionThe ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally ‘captured’ patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions.
Background: To investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA). Methods: Patients with axSpA from the Rheumatic Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models. Results: In total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 [95%CI 1.9; 27.7]), adverse events (OR 9.1 [2.5; 33.3]), or other reasons (OR 7.7 [1.6; 37.9]) compared to primary failure. Conclusion: Patients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the gene encoding the Thymidine Phosphorylase (TP). It is clinically characterized by severe gastrointestinal dysmotility, cachexia, palpebral ptosis, ophthalmoparesis, sensorimotor polyneuropathy and leukoencephalopathy. The diagnosis is established by the presence of typical clinical and neuroimaging features, positive family history, and abnormal genetic test. A 19-year-old Cape Verdean patient with a history since childhood of recurrent episodes of nausea, vomiting, diarrhoea and painful abdominal distension associated with progressive motor disability with difficulty in climbing stairs and running and clumsiness with her hands. The diagnostic workup was suggestive of MNGIE. Genetic screening of the TYMP gene identified a novel mutation (c. 1283 G>A). Patients with MNGIE have significant comorbidity and mortality, and they are frequently misdiagnosed. A better acknowledgment of this disorder is essential to permit an earlier diagnosis and to improve disease management.
Background Identifying predictors of response to biological therapies in patients with Ankylosing Spondylitis (AS) is of utmost importance, especially in view of the costs and potential side effects of these agents. Objectives To determine baseline predictive factors of response to biological therapies at 12 weeks in patients with AS in daily clinical practice. Methods Patients with AS under biological therapy and followed in the Rheumatic Diseases Portuguese Register (Reuma.pt) were included in this analysis. Reuma.pt is used as an electronic medical record and assessments are performed by rheumatologists. Patients with information at baseline and 12 weeks of follow-up were included in the analysis (n=197). Univariable logistic regression analysis of baseline predictors of ASDAS (improvement ≥1.1) and BASDAI response (improvement ≥2 units or ≥50%) were performed. Variables with a p-value<0.1 were re-tested in multivariable models. When both ASDAS and CRP (or ASDAS and BASDAI) were significant in the univariable analysis, they were included in separate multivariable models, in order to avoid collinearity-problems. Forward selection was performed until the best-fit model was obtained, taking confounding effects into account. Interactions were tested. Results ASDAS response at 12 weeks was predicted by male gender, higher educational level, lower back pain and higher ASDAS (table). When ASDAS was removed from the baseline predictors, both a younger age and higher CRP were significant predictors of ASDAS response. A BASDAI response was independently predicted by age (<40), gender (male), baseline BASDAI (per unit) or ASDAS (per unit) (depending on which was tested in the model). Table 1 ΔASDAS ≥1.1ΔBASDAI ≥2 or ≥50 OR (95%CI)OR (95% CI)OR (95% CI)OR (95% CI) (n=166)(n=135)(n=174)(n=193) Age at start of first biologic (<40 vs ≥40)**4.04 (1.86; 8.78)3.02 (1.56; 5.84)3.43 (1.82; 6.44) Gender (male vs female)3.01 (1.20; 7.57)**2.39 (1.21; 4.74)2.73 (1.36; 5.45) BMI (kg/m2)******** Educational level (years)1.11 (1.01; 1.21)**§§ Patient’s pain (≥4 vs <4; 0-10)0.27 (0.09; 0.84)**§§ ASDAS3.98 (2.19; 7.21)†1.47 (1.03; 2.10)† BASDAI (0-10)§§§1.20 (1.01; 1.43) CRP (≥5mg/l vs <5mg/l)†9.33 (3.89; 22.35)§§ §Not included in the multivariable model **Not selected during multivariable regression analysis (p≥0.05). †Excluded from the model due to collinearity; the same model is repeated with this variable included. Conclusions CRP is as an important predictor of ASDAS response, but not of BASDAI response. A better response can be expected in male- and younger patients. Baseline disease activity predicts a response at 12 weeks. The ASDAS predicts both ASDAS- and BASDAI response and the BASDAI only predicts the BASDAI response. Disclosure of Interest None Declared
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