Η επίδραση της υπερλιπιδαιμίας και της αθηρωμάτωσης στην επαγόμενη καρδιοτοξικότητα από την καρφιλζομίμπη

Εισαγωγή: Το πολλαπλό μυέλωμα αποτελεί τη συχνότερη κυτταροπλασματική δυσκρασία και εκδηλώνεται κυρίως σε άτομα τρίτης ηλικίας τα οποία παράλληλα πάσχουν από καρδιαγγειακές συννοσηρότητες. Η καρφιλζομίμπη χρησιμοποιείται ως θεραπεία πρώτης γραμμής έναντι του υποτροπιάζοντος/ανθεκτικού πολλαπλού μυελώματος, ωστόσο παρουσιάζει σημαντική καρδιαγγειακή τοξικότητα. Καθώς η υπερλιπιδαιμία αποτελεί μια συχνά απαντούμενη συννοσηρότητα στους ασθενείς υπό θεραπεία με καρφιλζομίμπη και αποτελεί έναν ανεξάρτητο παράγοντα κινδύνου για την εκδήλωση καρδιαγγειακών συμβαμάτων. Σκοπός της παρούσας εργασίας είναι η διερεύνηση i) της επίδρασης της υπερλιπιδαιμίας-αθηρωμάτωσης στην επαγόμενη-καρδιοτοξικότητα της καρφιλζομίμπης (Cfz) ii) της καρδιοπροστατευτικής δράσης της μετφορμίνης (Met) η οποία έχει προταθεί ως πιθανή προφυλακτική θεραπεία iii) της πιθανής καρδιοπροστατευτικής δράσης της ατορβαστατίνης στον παρατηρούμενο φαινότυπο in vivo. Μέθοδοι: Aρσενικοί ApoE-/- μύες τυχαιοποιήθηκαν ως εξής: Οξύ πρωτόκολλο: Apoe-/- 5 μηνών: 1. Control (Ν/S 0.9%) 2. Cfz για 2 ημέρες Υπο-οξύ πρωτόκολλο: Apoe -/- 5 μηνών: 1. Control (Ν/S 0.9%) 2. Cfz για 6 ημέρες. Στη συνέχεια το υπο-οξύ πρωτόκολλο επαναλήφθηκε σε ApoE-/- πειραματόζωα στα οποία χορηγήθηκε διατροφή δυτικού τύπου (HFD), ενώ επίσης ελέγχθηκε η καρδιοπροστατευτική δράση της μετφορμίνης παρουσία ή απουσία ατορβαστατίνης. Έτσι τα πειραματόζωα τυχαιοποιήθηκαν στις παρακάτω ομάδες: Apoe-/- HFD: 1. Control (Ν/S 0.9%) 2. Cfz 3. Cfz+Met για 6 ημέρες και Apoe-/- HFD+ατορβαστατίνη: 1. Control (Ν/S 0.9%) 2. Cfz 3. Cfz+Met για 6 ημέρες. Το Cfz (8 mg/kg, ενδοπεριτοναϊκά) στο πρωτόκολλο των δύο δόσεων χορηγήθηκε και τις δύο ημέρες, ενώ στα υπόλοιπα πρωτόκολλα χορηγήθηκε ανά 48 ώρες. Η Met (140 mg/kg, per os) χορηγήθηκε κάθε 24 ώρες. Η ατορβαστατίνη χορηγήθηκε στο νερό των μυών σε συγκέντρωση 20mg/kg/ημερησίως. Στη γραμμή βάσης και στο καταληκτικό σημείο των πειραμάτων, έγινε υπερηχογραφική αξιολόγηση, ενώ στη συνέχεια οι μύες θυσιάστηκαν και πραγματοποιήθηκε λήψη αίματος και καρδιακού ιστού. Πραγματοποιήθηκε προσδιορισμός των λιπιδίων στο πλάσμα, μέτρηση της ενεργότητας του πρωτεασώματος τόσο στα πολυμορφοπύρηνα κύτταρα του αίματος όσο και στο μυοκάρδιο, ενώ τμήμα του μυοκαρδίου υποβλήθηκε σε ανάλυση Western Blot. Αποτελέσματα: Η χορήγηση Cfz μείωσε την ενεργότητα του πρωτεασώματος καθώς και το κλάσμα συστολικής βράχυνσης (FS%) σε όλα τα πρωτόκολλα. Στα πρωτόκολλα της συγχορήγησης Cfz+Met παρατηρήθηκε επαναφορά του FS% στις τιμές των ομάδων ελέγχου. Στους ApoE-/- μύες 5 μηνών, η Cfz μείωσε τη φωσφορυλίωση της eNOS και του Raptor μετά από 2 δόσεις, ενώ μετά από 4 δόσεις μείωσε τη φωσφορυλίωση της Akt και ανέστειλε τον άξονα AMPKα/Raptor. Στους ApoE-/- υπό διατροφή HFD η Cfz ανέστειλε τον άξονα Akt/eNOS, ενώ η συγχορήγηση Cfz+Met οδήγησε σε αύξηση της φωσφορυλίωσης της AMPKα και της έκφρασης της LC3B. Επιπρόσθετα, οι ApoE-/- εμφάνισαν διαταραγμένη λιπιδική ομοιόσταση, η οποία επιδεινώθηκε από τη χορήγηση HFD όπως υποδηλώνεται από τα αυξημένα επίπεδα ολικής χοληστερόλης και λιποπρωτεΐνης χαμηλής πυκνότητας (LDL). H μετφορμίνη στην ομάδα της συγχορήγησης αύξησε τα επίπεδα HDL στο πλάσμα. Τέλος, η ατορβαστατίνη βελτίωσε το λιπιδαιμικό προφίλ των πειραματόζωων χωρίς να επιφέρει καρδιοπροστασία έναντι της Cfz-επαγόμενης καρδιοτοξικότητας. Συμπεράσματα: Η χορήγηση Cfz επάγει καρδιοτοξικότητα σε όλα τα ανωτέρω μοντέλα σε συμφωνία με προηγούμενα αποτελέσματα του εργαστηρίου μας. Η Met διατηρεί τη καρδιοπροστατευτική της δράση σε καταστάσεις υπερλιπιδαιμίας και υπερέχει της ατορβαστατίνης πιθανώς μέσω της μεταβολικής δράσης της επί του μυοκαρδίου.Introduction: Multiple myeloma is the most common hematological dyscrasia and is primarily manifested in the elderly patients who also suffer from cardiovascular comorbidities. Carfilzomib is used as a first-line treatment for relapsed/refractory multiple myeloma, but exhibits a significant cardiovascular toxicity. Taking under consideration that hyperlipidemia is a common comorbidity in patients treated with carfilzomib and stands as an independent risk factor for cardiovascular events manifestation, the aim of the present study was to investigate (i) the effect of hyperlipidemia-atherosclerosis in terms of carfilzomib-induced cardiotoxicity (ii) the cardioprotective effect of metformin (Met) which has been recently suggested as a potential prophylactic treatment act (iii) the potential cardioprotective effect of atorvastatin in the observed phenotype in vivo. Methods: Male ApoE -/- mice were randomized as follows: Acute protocol: ApoE -/- 5 months of age: 1. Control (N/S 0.9%) 2. Cfz for 2 days. Sub-aute protocol: ApoE -/- 5 months of age: 1. Control (N / S 0.9%) 2. Cfz for 6 days. The sub-acute protocol was then repeated in ApoE -/- mice fed with Western diet (HFD), and the cardioprotective potential of metformin was evaluated in the presence or absence of atorvastatin. Thus, ApoE -/- mice were randomized as follows: ApoE -/- HFD: 1. Control (N/S 0.9%) 2. Cfz 3. Cfz + Met for 6 days, ApoE -/- HFD + atorvastatin: 1. Control (N/S 0.9%) 2. Cfz 3. Cfz + Met for 6 days. Cfz (8 mg / kg, intraperitoneally) in the two-dose protocol was administered daily, while in the sub-acute setting Cfz was administered on alternate days. Met (140 mg / kg, per os) and atorvastatin (20mg/kg per os) were administered every 24 hours. At the baseline and at the end of the experiments, ultrasound evaluation was performed and mice were sacrificed for blood and heart tissue collection. Plasma lipids were determined, proteasome activity was measured in both polymorphonuclear cells of the blood (PBMCs) and myocardium, and a part of the myocardium was subjected to Western Blot analysis. Results: Cfz reduced proteasome activity as well as the fractional shortening (FS%) in all protocols. Cfz+Met co-administration led to a restoration of cardiac contractily. In ApoE -/- mice, Cfz decreased eNOS and Raptor phosphorylation after 2 doses, while 4 doses of Cfz reduced Akt phosphorylation and inhibited the AMPKα / Raptor axis. In ApoE -/- mice on HFD, Cfz inhibited the Akt/eNOS axis, while co-administration of Cfz + Met resulted in increased AMPKα phosphorylation and LC3B expression. In addition, ApoE -/- showed impaired lipid homeostasis, which was exacerbated by HFD as indicated by elevated levels of total cholesterol and low-density lipoprotein (LDL). Metformin co-administration increased plasma HDL levels. Finally, atorvastatin improved the lipid profile of experimental animals without providing cardioprotection against Cfz-induced cardiotoxicity. Conclusions: Cfz administration induces cardiotoxicity in all the above models in compliance with our previous findings. Met retains its cardioprotective action despite hyperlipidemia and is superior to atorvastatin possibly through its metabolic action on the myocardium

Synergetic and performance characteristics of a high-speed pre-cooled propulsion concept

Pre-cooled air-breathing cycles are promising candidates to power future high-speed flight as well as Single-Stage-To-Orbit vehicles, due to their increased efficiency over contemporary propulsion systems and launch vehicles. These concepts usually feature complex interactions in the synergy of their thermodynamic cycles. In this study, a performance model of such a cycle is developed for its air-breathing mode of operation. One-dimensional thermodynamic modeling is employed within a component-level approach, to evaluate the performance and operation of the cycle under investigation in the range of 1.35 = ≤ 8 = 5 and conditions of up to 26 kilometers altitude. The model is validated quantitatively and qualitatively for both design and off-design conditions. The specific impulse Isp and specific thrust, as predicted by the model, agree within less than 5% for both design and off-design point conditions, while it captures the trend of Isp for the range modeled. Moreover the maximum gross thrust point is predicted correctly at M∞ = 4. The fundamental operating principles and synergetic characteristics of the engine at design and off-design conditions are investigated and reported. A model which does not feature a bypass duct is created and compared for the same inflow conditions and mission profile. It is found that the engine without the bypass duct exhibits reduced specific impulse up to 32% lower at off-design conditions while the overall trend of engine efficiency cannot be properly captured without modeling of the bypass duct, especially at the region of M∞ < 3.5.Journal of Engineering for Gas Turbines and Powe

A Water Futures approach on water demand forecasting with online ensemble learning

This study presents a collaborative framework developed by the Water Futures team of researchers for the “Battle of the Water Demand Forecasting” challenge at the 3rd International WDSA-CCWI Joint Conference. The framework integrates an ensemble of machine learning forecasting models into a deterministic outcome consistent with the competition formulation. The water demand trajectory over a week exhibits complex overlapping patterns and non-linear dependencies to multiple features and time-dependent events that a single model cannot accurately predict. As such, the reconciled forecast from an ensemble of models exceeds the performance of the individual ones and exhibits higher stability across the weeks of the year and district metered areas considered

Trends in Indications and Techniques of Corneal Transplantation from 1999 through 2015 at a Tertiary Referral Center in Athens, Greece.

During the past decade, novel techniques of corneal transplantation allowing faster and better restoration of vision have emerged. The present cohort study describes a shift of indications and techniques that has occurred in the field of corneal transplantation over a 17-year period in Greece. All patients undergoing keratoplasty between January 1999 and December 2015 at an academic tertiary referral center in Athens, Greece, were retrospectively reviewed. The annual incidence of keratoplasty indications and techniques was recorded and analyzed. A total of 1382 keratoplasty procedures were included. Leading indications were bullous keratopathy (BK) (37.5%), followed by allograft rejection (17.7%), corneal scar (12%), keratoconus (KC) (10.3%), and Fuchs endothelial dystrophy (FED) (8.8%). A decreasing trend was observed for KC ( <i>P</i> =0.009) and an increasing trend for BK ( <i>P</i> =0.003) and FED ( <i>P</i> =0.001). In 2015, the incidence of penetrating keratoplasty (PK) had decreased from 100% (1999 to 2009) to 21.4%; for cases with isolated pathology of the corneal endothelium, DSAEK was the preferred technique (59.8%), while the respective rate of DMEK was 18.8%. Herein, we observed an increasing trend of endothelial pathology among keratoplasty indications as well as a major shift in preferred techniques due to a wide adoption of the new EK procedures

Does COVID-19 Vaccination Warrant the Classical Principle " ofelein i mi vlaptin"?

The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic warrants an imperative necessity for effective and safe vaccination, to restrain Coronavirus disease 2019 (COVID-19) including transmissibility, morbidity, and mortality. In this regard, intensive medical and biological research leading to the development of an arsenal of vaccines, albeit incomplete preconditioned evaluation, due to emergency. The subsequent scientific gap raises some concerns in the medical community and the general public. More specifically, the accelerated vaccine development downgraded the value of necessary pre-clinical studies to elicit medium- and long-term beneficial or harmful consequences. Previous experience and pathophysiological background of coronaviruses' infections and vaccine technologies, combined with the global vaccines' application, underlined the obligation of a cautious and qualitative approach, to illuminate potential vaccination-related adverse events. Moreover, the high SARS-CoV-2 mutation potential and the already aggregated genetical alterations provoke a rational vagueness and uncertainty concerning vaccines' efficacy against dominant strains and the respective clinical immunity. This review critically summarizes existing evidence and queries regarding SARS-CoV-2 vaccines, to motivate scientists' and clinicians' interest for an optimal, individualized, and holistic management of this unprecedented pandemic

Battle of Water Demand Forecasting

As part of the Battle of Water Networks competition series, the Battle of Water Demand Forecasting (BWDF) was organized in the context of the 3rd Water Distribution Systems Analysis and Computing and Control in the Water Industry (WDSA-CCWI) joint conference held in Ferrara (Italy) in 2024. In line with the previous editions of the Battle of Water Networks—the main objective of which was to address a specific problem related to the design and operation of water distribution networks—the BWDF aims to compare the effectiveness of methods for the short-term forecast of urban water demand in a set of real district metered areas. During the conference, 31 teams across the world participated in the BWDF and presented their approaches. The results obtained demonstrate the importance of (1) considering integrated approaches for short-term water demand forecasting; and (2) evaluating their performance in relation to more than one metric, case study, and period