Semiotics of mimesis and communicative relationship among texts: Ekphrasis and replication between Hesiod and Homer

The Shield of Heracles by Hesiod and Homer’s Iliad, XVIII show how mimesis should be considered: it is a process that should be seen different according to the levels that it refers to. There is one object constructed by a craftsman (first level of representation), after that a poet may write about this object and its construction (second level of representation). Then yet another poet could write, on the model of the previous text, his poem with his personal idea. Explaining first, the meaning of representation, arts and mimesis in Plato (Ion, Phaedrus, Cratylus, Sophist, Laws, Republic-Book X) and in Aristotle (Poetics, Nichomachean Ethics), I would like to explain how mimesis was considered according to the terms of form and representation. After that I would carry out a textual analysis of The Shield of Heracles and Iliad, to demonstrate that even if Hesiod’s text is quite similar to Homer’s, the context, the meaning, the background of the authors and the narrative structures are different. The different levels of pertinence and the different points of view demonstrate that mimesis is not a process that produces hierarchy in retrospect, but it is something heading to the direction of what “it is not created yet”

Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse

Limfoma de cèl·lules B; Supervivència lliure de malaltiaLinfoma de células B; Supervivencia libre de enfermedadB-cell lymphoma; Disease-free survivalAlthough methotrexate (MTX) is the most widely used therapy for central nervous system (CNS) prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the optimal regimen remains unclear. We examined the efficacy of different prophylactic regimens in 585 patients with newly diagnosed DLBCL and high-risk for CNS relapse, treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or R-CHOP-like regimens from 2001 to 2017, of whom 295 (50%) received prophylaxis. Intrathecal (IT) MTX was given to 253 (86%) and high-dose MTX (HD-MTX) to 42 (14%). After a median follow-up of 6.8 years, 36 of 585 patients relapsed in the CNS, of whom 14 had received prophylaxis. The CNS relapse risk at 1 year was lower for patients who received prophylaxis than patients who did not: 2% vs. 7.1%. However, the difference became less significant over time (5-year risk 5.6% vs. 7.5%), indicating prophylaxis tended to delay CNS relapse rather than prevent it. Furthermore, the CNS relapse risk was similar in patients who received IT and HD-MTX (5-year risk 5.6% vs. 5.2%). Collectively, our data indicate the benefit of MTX for CNS prophylaxis is transient, highlighting the need for more effective prophylactic regimens. In addition, our results failed to demonstrate a clinical advantage for the HD-MTX regimen.This work was supported in part by research funding from Fundación Alfonso Martín Escudero to SB. Data from this manuscript were presented at the 61st Annual Meeting of the American Society of Hematology, Orlando, FL, December 7th–10th, 2019

Trigeminocardiac reflex by mandibular extension on rat pial microcirculation: Role of nitric oxide

In the present study we have extended our previous findings about the effects of 10 minutes of passive mandibular extension in anesthetized Wistar rats. By prolonging the observation time to 3 hours, we showed that 10 minutes mandibular extension caused a significant reduction of the mean arterial blood pressure and heart rate respect to baseline values, which persisted up to 160 minutes after mandibular extension. These effects were accompanied by a characteristic biphasic response of pial arterioles: during mandibular extension, pial arterioles constricted and after mandibular extension dilated for the whole observation period. Interestingly, the administration of the opioid receptor antagonist naloxone abolished the vasoconstriction observed during mandibular extension, while the administration of Nω-Nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, abolished the vasodilation observed after mandibular extension. Either drug did not affect the reduction of mean arterial blood pressure and heart rate induced by mandibular extension. By qRT-PCR, we also showed that neuronal nitric oxide synthase gene expression was significantly increased compared with baseline conditions during and after mandibular extension and endothelial nitric oxide synthase gene expression markedly increased at 2 hours after mandibular extension. Finally, western blotting detected a significant increase in neuronal and endothelial nitric oxide synthase protein expression. In conclusion mandibular extension caused complex effects on pial microcirculation involving opioid receptor activation and nitric oxide release by both neurons and endothelial vascular cells at different times

Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

Follicular lymphomaLimfoma fol·licularLinfoma folicularIn the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.Was provided by Kite Pharma, a Gilead company, for this study

A 24-month updated analysis of the comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma

Follicular lymphoma; Axicabtagene ciloleucel; Comparative effectivenessLimfoma fol·licular; Axicabtagene ciloleucel; Eficàcia comparativaLinfoma folicular; Axicabtagene ciloleucel; Eficacia comparativaBackground In the ZUMA-5 trial (Clinical trials identification: NCT03105336), axicabtagene ciloleucel (axi-cel; a chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients and clear superiority relative to the SCHOLAR-5 external control cohort. We update this comparison using the ZUMA-5 24-month data. Research design and methods The SCHOLAR-5 cohort is comprised of r/r FL patients who initiated ≥3rd line of therapy after July 2014 and meeting ZUMA-5 eligibility criteria. Groups were balanced for patient characteristics through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. The overall response rate was compared using a weighted logistic regression. Time-to-event outcomes were evaluated using a Cox regression. Results For SCHOLAR-5, the sum of weights for the 143 patients was 85 after SMR weighting, versus 86 patients in ZUMA-5. The median follow-up was 29.4 months and 25.4 months for ZUMA-5 and SCHOLAR-5, respectively. The hazard ratios for overall survival and progression-free survival were 0.52 (95% confidence interval (CI): 0.28–0.95) and 0.28 (95% CI: 0.17–0.45), favoring axi-cel. Conclusion This updated analysis, using a longer minimum follow-up than a previously published analysis, shows that the improved efficacy of axi-cel, relative to available therapies, in r/r FL is durable.This manuscript was funded by Kite, a Gilead Company

Characterization of GECPAR, a noncoding RNA that regulates the transcriptional program of diffuse large B cell lymphoma

Enhancers are regulatory regions of DNA, which play a key role in cell-type specific differentiation and development. Most active enhancers are transcribed into enhancer RNAs (eRNAs) that can regulate transcription of target genes by means of in cis as well as in trans action. eRNAs stabilize contacts between distal genomic regions and mediate the interaction of DNA with master transcription factors. Here, we characterised an enhancer RNA, GECPAR (GErminal Center Proliferative Adapter RNA), that is specifically transcribed in normal and neoplastic germinal center B-cells from the super-enhancer of POU2AF1, a key regulatory gene of the germinal center reaction. Using diffuse large B cell lymphoma cell line models, we demonstrated the tumor suppressor activity of GECPAR, which is mediated via its transcriptional regulation of proliferation and differentiation genes, particularly MYC and the Wnt pathway