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1. Sobrerol in Managing Acute Respiratory Infections in Clinical Practice During the “Cold” Season: An Italian Primary Care Experience

Author

Varricchio A and Ciprandi G

Subjects
acute upper respiratory infections, combined therapy, nebulization, oral formulation, primary care, sobrerol., Medicine (General), R5-920
Abstract

Attilio Varricchio,1 Giorgio Ciprandi,2 Study Group on respiratory infection management in clinical practice included:Francesco Paolo Brunese, Luigi Costanzo, Lorenzo Cresta, Maurizio Daccò, Donatella Del Gaizo, Carla Dominici, Cosimo Lanza, Michele Lisco, Anastasia Matteucig, Carlotta Moretti On behalf of the Study Group on respiratory infection management in clinical practice1Department of Otolaryngology, University of Molise, Campobasso, Italy; 2Allergy Clinic, Casa di Cura Villa Montallegro, Genoa, ItalyCorrespondence: Giorgio Ciprandi, Casa di Cura Villa Montallegro, Genoa, Italy, Email gio.cip@libero.itPurpose: Acute upper respiratory infections (AURI) represent a daily challenge in primary care practice. Mucus production may impair during AURI. Sobrerol is a muco-active agent that improves rheological characteristics and exerts other ancillary activities. The aim of this retrospective case–series study was to compare the efficacy and safety of different uses of sobrerol (only oral, only nebulized, and combined or standard treatment for infections alone) in patients with AURIs.Patients and Methods: The present clinical experience retrospectively collected clinical data of patients with AURIs visited by ten primary care doctors (pediatricians and general practitioners) over a long period. Patients could take standard therapy for infections, or as add-on: oral sobrerol, nebulized sobrerol, or combined oral and nebulized aerosol during the infection for 3 days.Results: Patients treated with combined oral and nebulized sobrerol experienced less intense symptoms, mainly concerning cough (p < 0.001) and nasal complaints (p = 0.043). In addition, the patients taking the combined therapy reported a more rapid disappearance of cough and nasal symptoms at day 7 than patients treated with the other options (OR 4.47 and 3.16, respectively).Conclusion: The current retrospective and observational study showed that a three-day combined (oral and nebulized) sobrerol course may represent a valuable add-on option in patients with AURIs.Keywords: acute upper respiratory infections, combined therapy, nebulization, oral formulation, primary care, sobrerol

Published
2024

3. Bacteriotherapy with Streptococcus salivarius 24SMB and Streptococcus oralis 89a nasal spray for preventing recurrent acute otitis media in children: a real-life clinical experience

Author

La Mantia I, Varricchio A, and Ciprandi G

Subjects
recurrent acute otitis media, bacteriotherapy, Streptococcus salivarius 24SMB, Streptococcus oralis 89a, nasal spray, children., Medicine (General), R5-920
Abstract

Ignazio La Mantia, Attilio Varricchio, Giorgio Ciprandi Associazione Italiana Vie Aeree Superiori, Naples, Italy Abstract: Recurrence of acute otitis media (RAOM) is a relevant issue in the clinical practice. “Bacteriotherapy” has been proposed as an option in children with RAOM. Streptococcus salivarius 24SMB nasal spray has been previously demonstrated to reduce the risk of acute otitis media (AOM) in otitis-prone children. The current retrospective and observational study aimed to confirm this outcome in a real-life setting, such as the common pediatric practice. Group A (108 children) served as control; group B (159 children) was treated with S. salivarius 24SMB and Streptococcus oralis 89a nasal spray after the first AOM episode. Active treatment consisted of 3 monthly courses: 2 puffs per nostril twice/day for a week. Group B showed a significant reduction of AOM episodes in comparison with group A (p

Published
2017

4. Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL

Author

Sergio, Ilaria, Varricchio, Claudia, Patel, Sandesh Kumar, Del Gaizo, Martina, Russo, Eleonora, Orlando, Andrea, Peruzzi, Giovanna, Ferrandino, Francesca, Tsaouli, Georgia, Coni, Sonia, Peluso, Daniele, Besharat, Zein Mersini, Campolo, Federica, Venneri, Mary Anna, Del Bufalo, Donatella, Lai, Silvia, Indraccolo, Stefano, Minuzzo, Sonia, La Starza, Roberta, Bernardini, Giovanni, Screpanti, Isabella, Campese, Antonio Francesco, and Felli, Maria Pia

Published
2024
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5. $\varepsilon$-fractional Core Stability in Hedonic Games

Author

Fioravanti, Simone, Flammini, Michele, Kodric, Bojana, and Varricchio, Giovanna

Subjects
Computer Science - Computer Science and Game Theory, Computer Science - Artificial Intelligence
Abstract

Hedonic Games (HGs) are a classical framework modeling coalition formation of strategic agents guided by their individual preferences. According to these preferences, it is desirable that a coalition structure (i.e. a partition of agents into coalitions) satisfies some form of stability. The most well-known and natural of such notions is arguably core-stability. Informally, a partition is core-stable if no subset of agents would like to deviate by regrouping in a so-called core-blocking coalition. Unfortunately, core-stable partitions seldom exist and even when they do, it is often computationally intractable to find one. To circumvent these problems, we propose the notion of $\varepsilon$-fractional core-stability, where at most an $\varepsilon$-fraction of all possible coalitions is allowed to core-block. It turns out that such a relaxation may guarantee both existence and polynomial-time computation. Specifically, we design efficient algorithms returning an $\varepsilon$-fractional core-stable partition, with $\varepsilon$ exponentially decreasing in the number of agents, for two fundamental classes of HGs: Simple Fractional and Anonymous. From a probabilistic point of view, being the definition of $\varepsilon$-fractional core equivalent to requiring that uniformly sampled coalitions core-block with probability lower than $\varepsilon$, we further extend the definition to handle more complex sampling distributions. Along this line, when valuations have to be learned from samples in a PAC-learning fashion, we give positive and negative results on which distributions allow the efficient computation of outcomes that are $\varepsilon$-fractional core-stable with arbitrarily high confidence., Comment: Accepted as poster at NeurIPS 2023

Published
2023

6. Solving Woeginger's Hiking Problem: Wonderful Partitions in Anonymous Hedonic Games

Author

Constantinescu, Andrei, Lenzner, Pascal, Reiffenhäuser, Rebecca, Schmand, Daniel, and Varricchio, Giovanna

Subjects
Computer Science - Computer Science and Game Theory, Computer Science - Data Structures and Algorithms
Abstract

A decade ago, Gerhard Woeginger posed an open problem that became well-known as "Woeginger's Hiking Problem": Consider a group of $n$ people that want to go hiking; everyone expresses preferences over the size of their hiking group in the form of an interval between $1$ and $n$. Is it possible to efficiently assign the $n$ people to a set of hiking subgroups so that every person approves the size of their assigned subgroup? The problem is also known as efficiently deciding if an instance of an anonymous Hedonic Game with interval approval preferences admits a wonderful partition. We resolve the open problem in the affirmative by presenting an $O(n^5)$ time algorithm for Woeginger's Hiking Problem. Our solution is based on employing a dynamic programming approach for a specific rectangle stabbing problem from computational geometry. Moreover, we propose natural, more demanding extensions of the problem, e.g., maximizing the number of satisfied participants and variants with single-peaked preferences, and show that they are also efficiently solvable. Last but not least, we employ our solution to efficiently compute a partition that maximizes the egalitarian welfare for anonymous single-peaked Hedonic Games., Comment: To appear in ICALP 2024; contains omitted material and small writing improvements

Published
2023

8. NMNAT2 is a druggable target to drive neuronal NAD production

Author

Tribble, James R., Jöe, Melissa, Varricchio, Carmine, Otmani, Amin, Canovai, Alessio, Habchi, Baninia, Daskalakis, Evangelia, Chaleckis, Romanas, Loreto, Andrea, Gilley, Jonathan, Wheelock, Craig E., Jóhannesson, Gauti, Wong, Raymond C. B., Coleman, Michael P., Brancale, Andrea, and Williams, Pete A.

Published
2024
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10. Targeted Reversible Covalent Modification of a Noncatalytic Lysine of the Krev Interaction Trapped 1 Protein Enables Site-Directed Screening for Protein–Protein Interaction Inhibitors

Author

Francisco, Karol R, Bruystens, Jessica, Varricchio, Carmine, McCurdy, Sara, Wu, Jian, Lopez-Ramirez, Miguel A, Ginsberg, Mark, Caffrey, Conor R, Brancale, Andrea, Gingras, Alexandre R, Hixon, Mark S, and Ballatore, Carlo

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences, protein-protein interaction, noncatalytic lysine, targeted covalent modification, covalent reversibleligand, inhibition kinetics, Biochemistry and cell biology, Medical biochemistry and metabolomics, Pharmacology and pharmaceutical sciences
Abstract

The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys720) of the Krev interaction trapped 1 (KRIT1) protein. We show that the interaction of HNA with KRIT1 is highly specific, results in prolonged residence time of >8 h, and inhibits the Heart of glass 1 (HEG1)-KRIT1 protein-protein interaction (PPI). Screening of HNA derivatives identified analogs exhibiting similar binding modes as the parent fragment but faster target engagement and stronger inhibition activity. These results demonstrate that HNA is an efficient site-directing fragment with promise in developing HEG1-KRIT1 PPI inhibitors. Further, the aldimine chemistry, when coupled with templating effects that promote proximity, can produce a long-lasting reversible covalent modification of noncatalytic lysines.

Published
2023

11. Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis.

Author

Monti, Ludovica, Liu, Lawrence, Varricchio, Carmine, Lucero, Bobby, Alle, Thibault, Yang, Wenqian, Bem-Shalom, Ido, Gilson, Michael, Brunden, Kurt, Brancale, Andrea, Caffrey, Conor, and Ballatore, Carlo

Subjects
Triazolopyrimidines, Trypanosoma brucei, drug discovery, human African trypanosomiasis, microtubules, Humans, Mice, Animals, Trypanosomiasis, African, Tubulin, Pyrimidines, Microtubules, Structure-Activity Relationship, Trypanosoma brucei brucei, Trypanocidal Agents, Mammals
Abstract

Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT-active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T. brucei-infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses at 10 mg/kg of a candidate TPD significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.

Published
2023

12. NMNAT2 is a druggable target to drive neuronal NAD production

Author

James R. Tribble, Melissa Jöe, Carmine Varricchio, Amin Otmani, Alessio Canovai, Baninia Habchi, Evangelia Daskalakis, Romanas Chaleckis, Andrea Loreto, Jonathan Gilley, Craig E. Wheelock, Gauti Jóhannesson, Raymond C. B. Wong, Michael P. Coleman, Andrea Brancale, and Pete A. Williams

Subjects
Science
Abstract

Abstract Maintenance of NAD pools is critical for neuronal survival. The capacity to maintain NAD pools declines in neurodegenerative disease. We identify that low NMNAT2, the critical neuronal NAD producing enzyme, drives retinal susceptibility to neurodegenerative insults. As proof of concept, gene therapy over-expressing full length human NMNAT2 is neuroprotective. To pharmacologically target NMNAT2, we identify that epigallocatechin gallate (EGCG) can drive NAD production in neurons through an NMNAT2 and NMN dependent mechanism. We confirm this by pharmacological and genetic inhibition of the NAD-salvage pathway. EGCG is neuroprotective in rodent (mixed sex) and human models of retinal neurodegeneration. As EGCG has poor drug-like qualities, we use it as a tool compound to generate novel small molecules which drive neuronal NAD production and provide neuroprotection. This class of NMNAT2 targeted small molecules could have an important therapeutic impact for neurodegenerative disease following further drug development.

Published
2024
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13. PAC learning and stabilizing Hedonic Games: towards a unifying approach

Author

Fioravanti, Simone, Flammini, Michele, Kodric, Bojana, and Varricchio, Giovanna

Subjects
Computer Science - Computer Science and Game Theory, Computer Science - Artificial Intelligence
Abstract

We study PAC learnability and PAC stabilizability of Hedonic Games (HGs), i.e., efficiently inferring preferences or core-stable partitions from samples. We first expand the known learnability/stabilizability landscape for some of the most prominent HGs classes, providing results for Friends and Enemies Games, Bottom Responsive, and Anonymous HGs. Then, having a broader view in mind, we attempt to shed light on the structural properties leading to learnability/stabilizability, or lack thereof, for specific HGs classes. Along this path, we focus on the fully expressive Hedonic Coalition Nets representation of HGs. We identify two sets of conditions that lead to efficient learnability, and which encompass all of the known positive learnability results. On the side of stability, we reveal that, while the freedom of choosing an ad hoc adversarial distribution is the most obvious hurdle to achieving PAC stability, it is not the only one. First, we show a distribution independent necessary condition for PAC stability. Then, we focus on $\W$-games, where players have individual preferences over other players and evaluate coalitions based on the least preferred member. We prove that these games are PAC stabilizable under the class of bounded distributions, which assign positive probability mass to all coalitions. Finally, we discuss why such a result is not easily extendable to other HGs classes even in this promising scenario. Namely, we establish a purely computational property necessary for achieving PAC stability., Comment: Accepted paper at AAAI 2023

Published
2023

14. Testes de atividade inseticida e juvenil do látex de Euphorbia tirucalli em larvas de Aedes aegypti. Micropropagação e novo potencial para atividade biológica

Author

Varricchio, Márcia Cristina Braga Nunes, primary, Gaspar, Sandra Villa, additional, Rebelo, Rayssa de Macedo, additional, Branco, Morgana Teixeira Lima Castelo, additional, Pyrrho, Alexandre dos Santos, additional, Silva, Simone da, additional, Lage, Celso Luiz Salgueiro, additional, and Brioso, Paulo Sérgio Torres, additional

Published
2024
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15. Potential plastic digestor of Euphorbia Tirucalli

Author

Gaspar, Sandra Ávila, primary, Rebelo, Rayssa de Macedo, additional, Pyrrho, Alexandre dos Santos, additional, Silva, Simone da, additional, Varricchio, Marcia Cristina Braga Nunes, additional, and Brioso, Paulo Sérgio Torres, additional

Published
2024
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17. Telomerase activity, telomere length, and the euploidy rate of human embryos

Author

Maria Longo, Ermanno Greco, Ilaria Listorti, Maria Teresa Varricchio, Katerina Litwicka, Cristiana Arrivi, Cecilia Mencacci, and Pierfrancesco Greco

Subjects
Telomere, telomerase, aneuploidies, telomere length, granulosa cell, Gynecology and obstetrics, RG1-991, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Background Telomeres maintain chromosome stability, while telomerase counteracts their progressive shortening. Telomere length varies between cell types, with leukocyte telomere length (LTL) decreasing with age. Reduced telomerase activity has been linked to reproductive issues in females, such as low pregnancy rates and premature ovarian failure, with recent studies indicating correlations between telomere length in granulosa cells and IVF outcomes.Objectives The study aims to explore the relationship between telomere length, telomerase activity, and euploid blastocyst rate in infertile women undergoing IVF/ICSI PGT-A cycles.Methods This prospective study involves 108 patients undergoing controlled ovarian stimulation and PGT-A. Telomere length and telomerase activity were measured in peripheral mononuclear cells and granulosa cells (GC), respectively.Results The telomere repeat copy number to single gene copy number ratio (T/S) results respectively 0.6 ± 0.8 in leukocytes and 0.7 ± 0.9 in GC. An inverse relationship was found between LTL and the patient’s age (p

Published
2024
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18. A deep learning model to predict Ki-67 positivity in oral squamous cell carcinoma

Author

Francesco Martino, Gennaro Ilardi, Silvia Varricchio, Daniela Russo, Rosa Maria Di Crescenzo, Stefania Staibano, and Francesco Merolla

Subjects
OSCC, Ki-67, Prediction, Deep learning, Computer applications to medicine. Medical informatics, R858-859.7, Pathology, RB1-214
Abstract

Anatomical pathology is undergoing its third revolution, transitioning from analogical to digital pathology and incorporating new artificial intelligence technologies into clinical practice. Aside from classification, detection, and segmentation models, predictive models are gaining traction since they can impact diagnostic processes and laboratory activity, lowering consumable usage and turnaround time. Our research aimed to create a deep-learning model to generate synthetic Ki-67 immunohistochemistry from Haematoxylin and Eosin (H&E) stained images. We used 175 oral squamous cell carcinoma (OSCC) from the University Federico II’s Pathology Unit’s archives to train our model to generate 4 Tissue Micro Arrays (TMAs). We sectioned one slide from each TMA, first stained with H&E and then re-stained with anti-Ki-67 immunohistochemistry (IHC). In digitised slides, cores were disarrayed, and the matching cores of the 2 stained were aligned to construct a dataset to train a Pix2Pix algorithm to convert H&E images to IHC. Pathologists could recognise the synthetic images in only half of the cases in a specially designed likelihood test. Hence, our model produced realistic synthetic images. We next used QuPath to quantify IHC positivity, achieving remarkable levels of agreement between genuine and synthetic IHC.Furthermore, a categorical analysis employing 3 Ki-67 positivity cut-offs (5%, 10%, and 15%) revealed high positive-predictive values. Our model is a promising tool for collecting Ki-67 positivity information directly on H&E slides, reducing laboratory demand and improving patient management. It is also a valuable option for smaller laboratories to easily and quickly screen bioptic samples and prioritise them in a digital pathology workflow.

Published
2024
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20. Robotic Treatment of Splenic Diseases

Author

Annecchiarico, Mario, Varricchio, Antonio, Milone, Marco, editor, Agresta, Ferdinando, editor, Guerrieri, Mario, editor, Petz, Wanda, editor, Arezzo, Alberto, editor, and Casarano, Salvatore, editor

Published
2024
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22. Attitude to food supplement use: a survey promoted by the Italian Society of Pediatric Allergy and Immunology

Author

Giorgio Ciprandi, Maria Daglia, Giulia Brindisi, Francesco Paolo Brunese, Giulio Dinardo, Alessandra Gori, Cristiana Indolfi, Matteo Naso, Enrico Tondina, Chiara Trincianti, Attilio Varricchio, Anna Maria Zicari, Michele Miraglia del Giudice, and Lorenzo Drago

Subjects
Food supplements, Nutraceuticals, Survey, Pediatricians, Scientific society, Pediatrics, RJ1-570
Abstract

Abstract Food supplements are defined as foodstuffs the purpose of which is to supplement the normal diet and which are concentrated sources of nutrients or other substances with a nutritional or physiological effect, often referred to as nutraceuticals, may exert benefit to the human body. Their use is increasing worldwide, including Europe and in Italy. However, some doctors are skeptical about their effectiveness and safety. This reluctance may depend on poor knowledge of the mechanisms of action and clinical evidence in literature. The Italian Society of Pediatric Allergy and Immunology (SIAIP) promoted the institution of an ad hoc Committee. The first initiative performed by this Committee was the administration of a questionnaire to the members of SIAIP. The results of this survey provided interesting results. Most pediatricians know the food supplement concept but frequently need help understanding the mechanisms of action. Most prescribe food supplements, mainly for preventing infections or enhancing immune defense. In addition, they prefer to use food supplements as cycles or add-on therapy. Finally, most participants like to attend events on this issue and contribute to new evidence through trials. In conclusion, this survey underscores the relevance of food supplement issues and attests to interest in this topic. However, there is a need to provide information and promote studies on this matter.

Published
2024
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23. Certainty and uncertainty in the biological activities of resveratrol

Author

Lorenzo Drago, Giorgio Ciprandi, Giulia Brindisi, Francesco Paolo Brunese, Giulio Dinardo, Alessandra Gori, Cristiana Indolfi, Matteo Naso, Enrico Tondina, Chiara Trincianti, Attilio Varricchio, Anna Maria Zicari, Hammad Ullah, Maria Daglia, and the Nutraceutical and Medical Device Task Force of the Italian Society of Pediatric Allergy, Immunology (SIAIP)

Subjects
clinical trials, health effects, preclinical studies, resveratrol, safety, Nutrition. Foods and food supply, TX341-641, Food processing and manufacture, TP368-456
Abstract

Abstract Resveratrol is a nonflavonoid polyphenolic compound with a chemical structure consisting of two aromatic rings linked by a methylene bridge. It exists in two primary isomers and has a broad range of desirable biological activities, including antioxidant, anti‐inflammatory, antidiabetic, cardioprotective, and antitumor activities. Some antioxidant properties of resveratrol are known with certainty, such as its potential to positively impact cardiovascular health, inflammation, and the metabolism. On the other hand, many uncertainties and controversies plague its efficacy, including issues related to its bioavailability, dosing, human clinical trial results, interactions with other food components and drugs, and individual variability. In brief, although promising results have been observed in in vitro and in vivo studies, the translation of these findings to human health remains uncertain. Many human clinical trials on resveratrol are ongoing or have proven inconclusive, making it challenging to definitively determine its efficacy for specific health conditions and its dose and duration of treatment. Resveratrol may interact with medications and have varying effects on individuals. In conclusion, it is essential to approach resveratrol with a balanced perspective, consulting with healthcare professionals, and considering the evolving scientific evidence when making decisions regarding its clinical use.

Published
2024
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24. Best of Both Worlds: Agents with Entitlements

Author

Hoefer, Martin, Schmalhofer, Marco, and Varricchio, Giovanna

Subjects
Computer Science - Computer Science and Game Theory
Abstract

Fair division of indivisible goods is a central challenge in artificial intelligence. For many prominent fairness criteria including envy-freeness (EF) or proportionality (PROP), no allocations satisfying these criteria might exist. Two popular remedies to this problem are randomization or relaxation of fairness concepts. A timely research direction is to combine the advantages of both, commonly referred to as Best of Both Worlds (BoBW). We consider fair division with entitlements, which allows to adjust notions of fairness to heterogeneous priorities among agents. This is an important generalization to standard fair division models and is not well-understood in terms of BoBW results. Our main result is a lottery for additive valuations and different entitlements that is ex-ante weighted envy-free (WEF), as well as ex-post weighted proportional up to one good (WPROP1) and weighted transfer envy-free up to one good (WEF(1,1)). It can be computed in strongly polynomial time. We show that this result is tight - ex-ante WEF is incompatible with any stronger ex-post WEF relaxation. In addition, we extend BoBW results on group fairness to entitlements and explore generalizations of our results to instances with more expressive valuation functions.

Published
2022

25. Maximizing Nash Social Welfare in 2-Value Instances: Delineating Tractability

Author

Akrami, Hannaneh, Chaudhury, Bhaskar Ray, Hoefer, Martin, Mehlhorn, Kurt, Schmalhofer, Marco, Shahkarami, Golnoosh, Varricchio, Giovanna, Vermande, Quentin, and van Wijland, Ernest

Subjects
Computer Science - Computer Science and Game Theory
Abstract

We study the problem of allocating a set of indivisible goods among a set of agents with \emph{2-value additive valuations}. In this setting, each good is valued either $1$ or $\sfrac{p}{q}$, for some fixed co-prime numbers $p,q\in \NN$ such that $1\leq q < p$. Our goal is to find an allocation maximizing the \emph{Nash social welfare} (\NSW), i.e., the geometric mean of the valuations of the agents. In this work, we give a complete characterization of polynomial-time tractability of \NSW\ maximization that solely depends on the values of $q$. We start by providing a rather simple polynomial-time algorithm to find a maximum \NSW\ allocation when the valuation functions are \emph{integral}, that is, $q=1$. We then exploit more involved techniques to get an algorithm producing a maximum \NSW\ allocation for the \emph{half-integral} case, that is, $q=2$. Finally, we show it is \classNP-hard to compute an allocation with maximum \NSW\ whenever $q\geq3$.

Published
2022

26. Microtubule-Stabilizing 1,2,4-Triazolo[1,5‑a]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure–Activity Insights

Author

Alle, Thibault, Varricchio, Carmine, Yao, Yuemang, Lucero, Bobby, Nzou, Goodwell, Demuro, Stefania, Muench, Megan, Vuong, Khoa D, Oukoloff, Killian, Cornec, Anne-Sophie, Francisco, Karol R, Caffrey, Conor R, Lee, Virginia M-Y, Smith, Amos B, Brancale, Andrea, Brunden, Kurt R, and Ballatore, Carlo

Subjects
Neurodegenerative, Alzheimer's Disease, Dementia, Neurosciences, Aging, Acquired Cognitive Impairment, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Neurological, Humans, Neurodegenerative Diseases, Pyrimidines, Microtubules, Alzheimer Disease, Tubulin, Structure-Activity Relationship, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry
Abstract

Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.

Published
2023

28. Case report: Potential role of immunotherapy in thymic malignancies: a unique case of a durable and complete response upon an immune checkpoint inhibitor

Author

Angelo Luciano, Erica Pietroluongo, Margaret Ottaviano, Angela Grieco, Annarita Peddio, Pietro De Placido, Alberto Servetto, Massimo Mascolo, Silvia Varricchio, Roberto Bianco, Giovannella Palmieri, and Mario Giuliano

Subjects
immune-related adverse events, autoimmunity, Good’s syndrome, thymomas, immunotherapy, Immunologic diseases. Allergy, RC581-607
Abstract

Thymic epithelial tumors are rare malignancies with an incidence of 1.7 cases per million people per year. They pose significant management challenges due to their association with autoimmune disorders. In this case report, we present the 21-year history of a patient diagnosed with advanced B2/B3 thymoma and Good’s syndrome. The patient achieved a complete and durable response after receiving only two cycles of the immune checkpoint inhibitor Nivolumab. However, this positive outcome was accompanied by the development of severe immune-related myocarditis complicated by reactivation of cytomegalovirus. Moreover, the patient developed a highly uncommon subdiaphragmatic pararectal dissemination of the thymic tumor, which is a condition rarely described in the literature. Despite the success in achieving complete and durable response with immune checkpoint inhibitors, the emergence of immune-related adverse events highlights the potential challenges associated with these treatments, emphasizing the need for careful monitoring and a comprehensive understanding of the intricate interplay between cancer, immune system dysregulations and immunotherapy.

Published
2024
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30. Existence and Computation of Epistemic EFX Allocations

Author

Caragiannis, Ioannis, Garg, Jugal, Rathi, Nidhi, Sharma, Eklavya, and Varricchio, Giovanna

Subjects
Computer Science - Computer Science and Game Theory
Abstract

We consider the problem of allocating indivisible goods among $n$ agents in a fair manner. For this problem, one of the best notions of fairness is envy-freeness up to any good (EFX). However, it is not known if EFX allocations always exist. Hence, several relaxations of EFX allocations have been studied. We propose another relaxation of EFX, called epistemic EFX (EEFX). An allocation is EEFX iff for every agent $i$, it is possible to shuffle the goods of the other agents such that agent $i$ does not envy any other agent up to any good. We show that EEFX allocations always exist for additive valuations, and give a polynomial-time algorithm for computing them. We also show how EEFX is related to some previously-known notions of fairness., Comment: Edit: include additional authors and some minor changes

Published
2022

31. Correction: Notch3-regulated microRNAs impair CXCR4-dependent maturation of thymocytes allowing maintenance and progression of T-ALL

Author

Sergio, Ilaria, Varricchio, Claudia, Patel, Sandesh Kumar, Del Gaizo, Martina, Russo, Eleonora, Orlando, Andrea, Peruzzi, Giovanna, Ferrandino, Francesca, Tsaouli, Georgia, Coni, Sonia, Peluso, Daniele, Besharat, Zein Mersini, Campolo, Federica, Venneri, Mary Anna, Del Bufalo, Donatella, Lai, Silvia, Indraccolo, Stefano, Minuzzo, Sonia, La Starza, Roberta, Bernardini, Giovanni, Screpanti, Isabella, Campese, Antonio Francesco, and Felli, Maria Pia

Published
2024
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33. Effects of the supplementation of single and multi-strain probiotics, alone or in combination with other treatments, on asthma in children: A systematic review of the randomized, placebo-controlled clinical studies

Author

Daglia, Maria, Drago, Lorenzo, Ullah, Hammad, Di Minno, Alessandro, Brindisi, Giulia, Brunese, Francesco Paolo, Dinardo, Giulio, Gori, Alessandra, Indolfi, Cristiana, Naso, Matteo, Tondina, Enrico, Trincianti, Chiara, Varricchio, Attilio, Zicari, Anna Maria, and Ciprandi, Giorgio

Published
2024
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39. Investigation of the antifungal action of natural products on seeds of Euterpe oleraceae: Bioproduct Potential

Author

Gaspar, Sandra Ávila, primary, Silva, Felipe Freire Souza, additional, Alves, Elvira, additional, Varricchio, Marcos Tadeu, additional, Nigri, Armando Isaac, additional, Bolognani, Fábio de Almeida, additional, Pyrrho, Alexandre dos Santos, additional, Silva, Simone da, additional, and Varricchio, Marcia Cristina Braga Nunes, additional

Published
2023
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40. Human serum albumin binds spike protein and protects cells from SARS-CoV-2 infection by modulating the RAS pathway

Author

Romualdo Varricchio, Giovanna De Simone, Gian Marco Vita, Walter Nocera Cariola, Maurizio Viscardi, Sergio Brandi, Gerardo Picazio, Verena Zerbato, Raffaella Koncan, Ludovica Segat, Stefano Di Bella, Giovanna Fusco, Paolo Ascenzi, and Alessandra di Masi

Subjects
ACE2, Human serum albumin, Renin-angiotensin pathway, SARS-CoV-2, S1 domain, Spike, Medicine
Abstract

Since the start of the pandemic, scientists have directed their research towards identifying COVID-19 risk factors and predictive elements. Numerous clinical studies have established a strong connection between hypoalbuminemia and an unfavorable prognosis for COVID-19. Here, we aim to explore the impact of human serum albumin (HSA) on SARS-CoV-2 infection. Our findings indicate that HSA plays a role in reducing the replication rate of SARS-CoV-2 in Vero E6 cells. This protective effect is due to HSA ability to bind to the S1 domain of the spike protein, effectively competing with ACE2. Moreover, we show that the protective role of HSA is dependent also on its ability to activate the protective axis within the RAS system pathway, which is responsible for inducing vasodilation and promoting anti-inflammatory, anti-fibrotic, and anti-apoptotic responses. In summary, the data presented in this study support the idea that reduced levels of circulating HSA in hypoalbuminemic patients may heighten their susceptibility to SARS-CoV-2 infection, as the spike protein is unhindered in its ability to bind to ACE2 and penetrate human cells. Besides, hypoalbuminemia exacerbates the imbalance of the RAS pathway towards the classical “detrimental” axis. This could potentially contribute to the increased severity and elevated mortality rate observed in individuals with low levels of circulating albumin.

Published
2024
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41. Decoding the historical tale: COVID-19 impact on haematological malignancy patients—EPICOVIDEHA insights from 2020 to 2022Research in context

Author

Jon Salmanton-García, Francesco Marchesi, Francesca Farina, Barbora Weinbergerová, Federico Itri, Julio Dávila-Valls, Sonia Martín-Pérez, Andreas Glenthøj, Ditte Stampe Hersby, Maria Gomes da Silva, Raquel Nunes Rodrigues, Alberto López-García, Raúl Córdoba, Yavuz M. Bilgin, Iker Falces-Romero, Shaimaa El-Ashwah, Ziad Emarah, Caroline Besson, Milena Kohn, Jaap Van Doesum, Emanuele Ammatuna, Monia Marchetti, Jorge Labrador, Giovanni Paolo Maria Zambrotta, Luisa Verga, Ozren Jaksic, Marcio Nucci, Klára Piukovics, Alba Cabirta-Touzón, Moraima Jiménez, Elena Arellano, Ildefonso Espigado, Ola Blennow, Anna Nordlander, Stef Meers, Jens van Praet, Tommaso Francesco Aiello, Carolina Garcia-Vidal, Nicola Fracchiolla, Mariarita Sciumè, Guldane Cengiz Seval, Pavel Žák, Caterina Buquicchio, Carlo Tascini, Stefanie K. Gräfe, Martin Schönlein, Tatjana Adžić-Vukičević, Valentina Bonuomo, Chiara Cattaneo, Summiya Nizamuddin, Martin Čerňan, Gaëtan Plantefeve, Romane Prin, Tomas Szotkovski, Graham P. Collins, Michelina Dargenio, Verena Petzer, Dominik Wolf, Natasha Čolović, Lucia Prezioso, Toni Valković, Francesco Passamonti, Gustavo-Adolfo Méndez, Uluhan Sili, Antonio Vena, Martina Bavastro, Alessandro Limongelli, Rafael F. Duarte, Marie-Pierre Ledoux, Milche Cvetanoski, Zlate Stojanoski, Marina Machado, Josip Batinić, Gabriele Magliano, Monika M. Biernat, Nikola Pantić, Christian Bjørn Poulsen, Annarosa Cuccaro, Maria Ilaria Del Principe, Austin Kulasekararaj, Irati Ormazabal-Vélez, Alessandro Busca, Fatih Demirkan, Marriyam Ijaz, Nikolai Klimko, Igor Stoma, Sofya Khostelidi, Noemí Fernández, Ali S. Omrani, Rui Bergantim, Nick De Jonge, Guillemette Fouquet, Milan Navrátil, Ghaith Abu-Zeinah, Michail Samarkos, Johan Maertens, Cristina De Ramón, Anna Guidetti, Ferenc Magyari, Tomás José González-López, Tobias Lahmer, Olimpia Finizio, Natasha Ali, László Imre Pinczés, Esperanza Lavilla-Rubira, Alessandra Romano, Maria Merelli, Mario Delia, Maria Calbacho, Joseph Meletiadis, Darko Antić, José-Ángel Hernández-Rivas, Joyce Marques de Almeida, Murtadha Al-Khabori, Martin Hoenigl, Maria Chiara Tisi, Nina Khanna, Aleksandra Barać, Noha Eisa, Roberta Di Blasi, Raphaël Liévin, Carolina Miranda-Castillo, Nathan C. Bahr, Sylvain Lamure, Mario Virgilio Papa, Ayel Yahya, Avinash Aujayeb, Jan Novák, Nurettin Erben, María Fernández-Galán, José-María Ribera-Santa Susana, Ikhwan Rinaldi, Rita Fazzi, Monica Piedimonte, Rémy Duléry, Yung Gonzaga, Andrés Soto-Silva, Giuseppe Sapienza, Alexandra Serris, Ľuboš Drgoňa, Ana Groh, Laura Serrano, Eleni Gavriilaki, Athanasios Tragiannidis, Juergen Prattes, Nicola Coppola, Vladimir Otašević, Miloš Mladenović, Mirjana Mitrović, Bojana Mišković, Pavel Jindra, Sofia Zompi, Maria Vittoria Sacchi, Carolin Krekeler, Maria Stefania Infante, Daniel García-Bordallo, Gökçe Melis Çolak, Jiří Mayer, Marietta Nygaard, Michaela Hanáková, Zdeněk Ráčil, Matteo Bonanni, Philipp Koehler, Laman Rahimli, Oliver A. Cornely, Livio Pagano, Francisco Javier Martín-Vallejo, Przemyslaw Zdziarski, Hossein Zarrinfer, Jana Wittig, Sein Win, Vivien Wai-Man, Benjamín Víšek, Donald C. Vinh, Maria Vehreschild, Gina Varricchio, Panagiotis Tsirigotis, Ana Torres-Tienza, Alina Daniela Tanase, Agostino Tafuri, Maria Stamouli, Jiří Sramek, Carole Soussain, Ayten Shirinova, Jörg Schubert, Enrico Schalk, Mohammad Reza Salehi, Modar Saleh, Giorgio Rosati, Elisa Roldán, Florian Reizine, Mayara Rêgo, Isabel Regalado-Artamendi, Marina Popova, Fernando Pinto, Laure Philippe, Hans Martin Orth, Hans-Beier Ommen, Aleš Obr, Lucía Núñez-Martín-Buitrago, Nicolas Noël, Julia Neuhann, Gianpaolo Nadali, Julia A. Nacov, Ana M. Munhoz Alburquerque, Maria Enza Mitra, Malgorzata Mikulska, Sibylle Mellinghoff, Ben Mechtel, Juan-Alberto Martín-González, Sandra Malak, Jorge Loureiro-Amigo, Lisset Lorenzo De La Peña, Giulia Liberti, Marianne Landau, Ira Lacej, Martin Kolditz, Chi Shan Kho, Reham Abdelaziz Khedr, Meinolf Karthaus, Linda Katharina Karlsson, María-Josefa Jiménez-Lorenzo, Macarena Izuzquiza, Baerbel Hoell-Neugebauer, Raoul Herbrecht, Christopher H. Heath, Fabio Guolo, Jan Grothe, Antonio Giordano, Sergey Gerasymchuk, Ramón García-Sanz, Nicole García-Poutón, Vaneuza Araújo Moreira Funke, Monica Fung, Charlotte Flasshove, Luana Fianchi, Jenna Essame, Matthias Egger, Bernard Drenou, Giulia Dragonetti, Maximilian Desole, Roberta Della Pepa, Bénédicte Deau Fischer, Elizabeth De Kort, Erik De Cabo, François Danion, Etienne Daguindau, Tania Cushion, Louise Cremer, Marianna Criscuolo, Gregorio Cordini, Antonella Cingolani, Fabio Ciceri, Fazle Rabbi Chowdhury, Ekaterina Chelysheva, Adrien Chauchet, Louis Yi Ann Chai, M. Mansour Ceesay, Elena Busch, Mathias Brehon, Davimar M.M. Borducchi, Stephen Booth, Serge Bologna, Caroline Berg Venemyr, Rebeca Bailén-Almorox, Anastasia Antoniadou, Amalia N. Anastasopoulou, and Fevzi Altuntaş

Subjects
Vaccination, ICU, COVID-19, Haematological malignancy, Immunosuppression, Medicine (General), R5-920
Abstract

Summary: Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe COVID-19 cases. Funding: Not applicable.

Published
2024
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42. Dexamethasone treatment for COVID-19 is related to increased mortality in hematologic malignancy patients: results from the EPICOVIDEHA Registry

Author

Tommaso Francesco Aiello, Jon Salmanton-Garcia, Francesco Marchesi, Barbora Weinbergerova, Andreas Glenthoj, Jens Van Praet, Francesca Farina, Julio Davila-Valls, Sonia Martin-Perez, Shaimaa El-Ashwah, Martin Schonlein, Iker Falces-Romero, Jorge Labrador, Uluhan Sili, Caterina Buquicchio, Antonio Vena, Gaetan Plantefeve, Verena Petzer, Monika M. Biernat, Tobias Lahmer, Ildefonso Espigado, Jaap Van Doesum, Ola Blennow, Klara Piukovics, Carlo Tascini, Michail Samarkos, Yavuz M. Bilgin, Luana Fianchi, Federico Itri, Toni Valković, Nicola S. Fracchiolla, Michelina Dargenio, Moraima Jimenez, Ferenc Magyari, Alberto Lopez-Garcia, Lucia Prezioso, Natasha Čolović, Evgenii Shumilov, Ghaith Abu-Zeinah, Carolin Krekeler, Esperanza Lavilla-Rubira, Mario Virgilio Papa, Tomas Jose Gonzalez-Lopez, Laszlo Imre Pinczes, Fatih Demirkan, Natasha Ali, Caroline Besson, Guillemette Fouquet, Alessandra Romano, Jose-Angel Hernandez-Rivas, Maria Ilaria Del Principe, Avinash Aujayeb, Maria Merelli, Sylvain Lamure, Joyce Marques De Almeida, Maria Gomes Da Silva, Noha Eisa, Joseph Meletiadis, Ikhwan Rinaldi, Olimpia Finizio, Ozren Jaksic, Mario Delia, Summiya Nizamuddin, Monia Marchetti, Marriyam Ijaz, Marina Machado, Rebeca Bailen-Almorox, Martin Čerňan, Nicola Coppola, Eleni Gavriilaki, Chiara Cattaneo, Ana Groh, Zlate Stojanoski, Nurettin Erben, Nicola Pantic, Gustavo-Adolfo Mendez, Roberta Di Blasi, Stef Meers, Cristina De Ramon, Nathan C. Bahr, Ziad Emarah, Gina Varricchio, Milche Cvetanoski, Ramon Garcia-Sanz, Mirjana Mitrovic, Raphael Lievin, Michaela Hanakova, Zdeněk Račil, Maria Vehreschild, Athanasios Tragiannidis, Raquel Nunes Rodrigues, Daniel Garcia-Bordallo, Raul Cordoba, Alba Cabirta, Anna Nordlander, Emanuele Ammatuna, Elena Arellano, Dominik Wolf, Romane Prin, Alessandro Limongelli, Martina Bavastro, Gokce Melis Colak, Stefanie Grafe, Ditte Stampe Hersby, Laman Rahimli, Oliver A. Cornely, Carolina Garcia-Vidal, Livio Pagano, and EPICOVIDEHA study group

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2024
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44. Maximizing Nash Social Welfare in 2-Value Instances

Author

Akrami, Hannaneh, Chaudhury, Bhaskar Ray, Hoefer, Martin, Mehlhorn, Kurt, Schmalhofer, Marco, Shahkarami, Golnoosh, Varricchio, Giovanna, Vermande, Quentin, and van Wijland, Ernest

Subjects
Computer Science - Computer Science and Game Theory
Abstract

We consider the problem of maximizing the Nash social welfare when allocating a set $\mathcal{G}$ of indivisible goods to a set $\mathcal{N}$ of agents. We study instances, in which all agents have 2-value additive valuations: The value of every agent $i \in \mathcal{N}$ for every good $j \in \mathcal{G}$ is $v_{ij} \in \{p,q\}$, for $p,q \in \mathbb{N}$, $p \le q$. Maybe surprisingly, we design an algorithm to compute an optimal allocation in polynomial time if $p$ divides $q$, i.e., when $p=1$ and $q \in \mathbb{N}$ after appropriate scaling. The problem is \classNP-hard whenever $p$ and $q$ are coprime and $p \ge 3$. In terms of approximation, we present positive and negative results for general $p$ and $q$. We show that our algorithm obtains an approximation ratio of at most 1.0345. Moreover, we prove that the problem is \classAPX-hard, with a lower bound of $1.000015$ achieved at $p/q = 4/5$.

Published
2021

45. Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings

Author

Giuseppe Rossi, Jon Salmanton-García, Chiara Cattaneo, Francesco Marchesi, Julio Dávila-Valls, Sonia Martín-Pérez, Federico Itri, Alberto López-García, Andreas Glenthøj, Maria Gomes da Silva, Caroline Besson, Monia Marchetti, Barbora Weinbergerová, Ozren Jaksic, Moraima Jiménez, Yavuz M. Bilgin, Jaap Van Doesum, Francesca Farina, Pavel Žák, Luisa Verga, Graham P. Collins, Valentina Bonuomo, Jens Van Praet, Marcio Nucci, Stef Meers, Ildefonso Espigado, Nicola S. Fracchiolla, Toni Valković, Christian Bjørn Poulsen, Natasha Čolović, Giulia Dragonetti, Marie-Pierre Ledoux, Carlo Tascini, Caterina Buquicchio, Ola Blennow, Francesco Passamonti, Marina Machado, Jorge Labrador, Rafael F. Duarte, Martin Schönlein, Lucia Prezioso, Iker Falces-Romero, Austin Kulasekararaj, Carolina Garcia-Vidal, Noemí Fernández, Ghaith Abu-Zeinah, Irati Ormazabal-Vélez, Tatjana Adžić-Vukičević, Klára Piukovics, Igor Stoma, Annarosa Cuccaro, Gabriele Magliano, Tomáš Szotkowski, Tomás-José González-López, Shaimaa El-Ashwah, Rui Bergantim, Uluhan Sili, Johan Maertens, Fatih Demirkan, Cristina De Ramón, Verena Petzer, Maria Ilaria Del Principe, Milan Navrátil, Michelina Dargenio, Guldane Cengiz Seval, Michail Samarkos, Zdeněk Ráčil, László Imre Pinczés, Tobias Lahmer, Alessandro Busca, Gustavo-Adolfo Méndez, Antonio Vena, Monika M. Biernat, Maria Merelli, Maria Calbacho, Aleksandra Barać, Martina Bavastro, Alessandro Limongelli, Osman Ilhan, Dominik Wolf, Gökçe Melis Çolak, Ramón García-Sanz, Ziad Emarah, Bojana Mišković, Stefanie K. Gräfe, Miloš Mladenović, Tommaso Francesco Aiello, Lucía Núñez-Martín-Buitrago, Anna Nordlander, Elena Arellano, Giovanni Paolo Maria Zambrotta, Emanuele Ammatuna, Alba Cabirta, Maria Vittoria Sacchi, Raquel Nunes Rodrigues, Ditte Stampe Hersby, Michaela Hanakova, Laman Rahimli, Raul Cordoba, Oliver A. Cornely, Livio Pagano, Joyce MARQUES DE ALMEIDA, José-Ángel HERNÁNDEZ-RIVAS, Anna GUIDETTI, Olimpia FINIZIO, Zlate STOJANOSKI, Milche CVETANOSKI, Joseph MELETIADIS, Nick DE JONGE, Darko ANTIĆ, Natasha ALI, Maria Chiara TISI, Laura SERRANO, Gaëtan PLANTEFEVE, Nina KHANNA, Martin HOENIGL, Martin ČERŇAN, Carolina MIRANDA-CASTILLO, María FERNÁNDEZ-GALÁN, Alexandra SERRIS, Nurettin ERBEN, Rémy DULÉRY, Avinash AUJAYEB, Mario Virgilio PAPA, Jan NOVÁK, Mario DELIA, Giuseppe SAPIENZA, Florian REIZINE, Ali S. OMRANI, Roberta DI BLASI, Sylvain LAMURE, Ľuboš DRGOŇA, Nicola COPPOLA, Josip BATINIĆ, Murtadha AL-KHABORI, José-María RIBERA-SANTA SUSANA, Monica PIEDIMONTE, Jorge LOUREIRO-AMIGO, Guillemette FOUQUET, Rita FAZZI, François DANION, Jörg SCHUBERT, Baerbel HOELL-NEUGEBAUER, Nathan C. BAHR, Ayel Omar YAHIA, Ana TORRES-ATIENZA, Ikhwan RINALDI, Marina POPOVA, Hans-Beier OMMEN, Maria Enza MITRA, Malgorzata MIKULSKA, Ira LACEJ, Sofya KHOSTELIDI, Sein WIN, Donald VINH, Modar SALEH, Juergen PRATTES, Pavel JINDRA, Fabio GUOLO, Roberta DELLA PEPA, Ekaterina CHELYSHEVA, Przemyslaw ZDZIARSKI, Vivien WAI-MAN, Andrés SOTO-SILVA, Hans Martin ORTH, Sandra MALAK, Lisset LORENZO DE LA PEÑA, Martin KOLDITZ, Chi Shan KHO, Christopher H. HEATH, Ana GROH, Eleni GAVRIILAKI, Monica FUNG, Matthias EGGER, Elizabeth DE KORT, Erik DE CABO, Tania CUSHION, Fazle Rabbi CHOWDHURY, M. Mansour CEESAY, Mathias BREHON, Gina VARRICCHIO, Agostino TAFURI, María-Josefa JIMÉNEZ-LORENZO, Nikolai KLIMKO, Panagiotis TSIRIGOTIS, Anastasia ANTONIADOU, and Maria VEHRESCHILD

Subjects
Elderly, SARS-CoV-2, Hematological malignancy, High-risk patient, COVID-19, Infectious and parasitic diseases, RC109-216
Abstract

Objectives: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail. Methods: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy. Results: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment. Conclusion: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts.

Published
2023
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47. Decoding the historical tale: COVID-19 impact on haematological malignancy patients—EPICOVIDEHA insights from 2020 to 2022

Author

Martín-Vallejo, Francisco Javier, Zdziarski, Przemyslaw, Zarrinfer, Hossein, Wittig, Jana, Win, Sein, Wai-Man, Vivien, Víšek, Benjamín, Vinh, Donald C., Vehreschild, Maria, Varricchio, Gina, Tsirigotis, Panagiotis, Torres-Tienza, Ana, Tanase, Alina Daniela, Tafuri, Agostino, Stamouli, Maria, Sramek, Jiří, Soussain, Carole, Shirinova, Ayten, Schubert, Jörg, Schalk, Enrico, Salehi, Mohammad Reza, Saleh, Modar, Rosati, Giorgio, Roldán, Elisa, Reizine, Florian, Rêgo, Mayara, Regalado-Artamendi, Isabel, Popova, Marina, Pinto, Fernando, Philippe, Laure, Orth, Hans Martin, Ommen, Hans-Beier, Obr, Aleš, Núñez-Martín-Buitrago, Lucía, Noël, Nicolas, Neuhann, Julia, Nadali, Gianpaolo, Nacov, Julia A., Munhoz Alburquerque, Ana M., Mitra, Maria Enza, Mikulska, Malgorzata, Mellinghoff, Sibylle, Mechtel, Ben, Martín-González, Juan-Alberto, Malak, Sandra, Loureiro-Amigo, Jorge, Lorenzo De La Peña, Lisset, Liberti, Giulia, Landau, Marianne, Lacej, Ira, Kolditz, Martin, Kho, Chi Shan, Khedr, Reham Abdelaziz, Karthaus, Meinolf, Karlsson, Linda Katharina, Jiménez-Lorenzo, María-Josefa, Izuzquiza, Macarena, Hoell-Neugebauer, Baerbel, Herbrecht, Raoul, Heath, Christopher H., Guolo, Fabio, Grothe, Jan, Giordano, Antonio, Gerasymchuk, Sergey, García-Sanz, Ramón, García-Poutón, Nicole, Funke, Vaneuza Araújo Moreira, Fung, Monica, Flasshove, Charlotte, Fianchi, Luana, Essame, Jenna, Egger, Matthias, Drenou, Bernard, Dragonetti, Giulia, Desole, Maximilian, Della Pepa, Roberta, Deau Fischer, Bénédicte, De Kort, Elizabeth, De Cabo, Erik, Danion, François, Daguindau, Etienne, Cushion, Tania, Cremer, Louise, Criscuolo, Marianna, Cordini, Gregorio, Cingolani, Antonella, Ciceri, Fabio, Chowdhury, Fazle Rabbi, Chelysheva, Ekaterina, Chauchet, Adrien, Chai, Louis Yi Ann, Ceesay, M. Mansour, Busch, Elena, Brehon, Mathias, Borducchi, Davimar M.M., Booth, Stephen, Bologna, Serge, Berg Venemyr, Caroline, Bailén-Almorox, Rebeca, Antoniadou, Anastasia, Anastasopoulou, Amalia N., Altuntaş, Fevzi, Salmanton-García, Jon, Marchesi, Francesco, Farina, Francesca, Weinbergerová, Barbora, Itri, Federico, Dávila-Valls, Julio, Martín-Pérez, Sonia, Glenthøj, Andreas, Hersby, Ditte Stampe, Gomes Da Silva, Maria, Nunes Rodrigues, Raquel, López-García, Alberto, Córdoba, Raúl, Bilgin, Yavuz M., Falces-Romero, Iker, El-Ashwah, Shaimaa, Emarah, Ziad, Besson, Caroline, Kohn, Milena, Van Doesum, Jaap, Ammatuna, Emanuele, Marchetti, Monia, Labrador, Jorge, Zambrotta, Giovanni Paolo Maria, Verga, Luisa, Jaksic, Ozren, Nucci, Marcio, Piukovics, Klára, Cabirta-Touzón, Alba, Jiménez, Moraima, Arellano, Elena, Espigado, Ildefonso, Blennow, Ola, Nordlander, Anna, Meers, Stef, Vian Praet, Jens, Aiello, Tommaso Francesco, Garcia-Vidal, Carolina, Fracchiolla, Nicola S., Sciumè, Mariarita, Seval, Guldane Cengiz, Žák, Pavel, Buquicchio, Caterina, Tascini, Carlo, Gräfe, Stefanie K., Schönlein, Martin, Adžić-VUKIČEVIĆ, Tatjana, Bonuomo, Valentina, Cattaneo, Chiara, Nizamuddin, Summiya, Čerňan, Martin, Plantefeve, Gaëtan, Prin, Romane, Szotkovski, Tomas, Collins, Graham P., Dargenio, Michelina, Petzer, Verena, Wolf, Dominik, Čolović, Natasha, Prezioso, Lucia, Valković, Toni, Passamonti, Francesco, Méndez, Gustavo-Adolfo, Sili, Uluhan, Vena, Antonio, Bavastro, Martina, Limongelli, Alessandro, Duarte, Rafael F., Ledoux, Marie-Pierre, Cvetanoski, Milche, Stojanoski, Zlate, Machado, Marina, Batinić, Josip, Magliano, Gabriele, Biernat, Monika M., Pantić, Nikola, Poulsen, Christian Bjørn, Cuccaro, Annarosa, Del Principe, Maria Ilaria, Kulasekararaj, Austin, Ormazabal-Vélez, Irati, Busca, Alessandro, Demirkan, Fatih, Ijaz, Marriyam, Klimko, Nikolai, Stoma, Igor, Khostelidi, Sofya, Fernández, Noemí, Omrani, Ali S., Bergantim, Rui, De Jonge, Nick, Fouquet, Guillemette, Navrátil, Milan, Abu-Zeinah, Ghaith, Samarkos, Michail, Maertens, Johan, De Ramón, Cristina, Guidetti, Anna, Magyari, Ferenc, González-López, Tomás José, Lahmer, Tobias, Finizio, Olimpia, Ali, Natasha, Pinczés, László Imre, Lavilla-Rubira, Esperanza, Romano, Alessandra, Merelli, Maria, Delia, Mario, Calbacho, Maria, Meletiadis, Joseph, Antić, Darko, Hernández-Rivas, José-Ángel, Marques De Almeida, Joyce, Al-Khabori, Murtadha, Hoenigl, Martin, Tisi, Maria Chiara, Khanna, Nina, Barać, Aleksandra, Eisa, Noha, Di Blasi, Roberta, Liévin, Raphaël, Miranda-Castillo, Carolina, Bahr, Nathan C., Lamure, Sylvain, Papa, Mario Virgilio, Yahya, Ayel, Aujayeb, Avinash, Novák, Jan, Erben, Nurettin, Fernández-Galán, María, Ribera-Santa Susana, José-María, Rinaldi, Ikhwan, Fazzi, Rita, Piedimonte, Monica, Duléry, Rémy, Gonzaga, Yung, Soto-Silva, Andrés, Sapienza, Giuseppe, Serris, Alexandra, Drgoňa, Ľuboš, Groh, Ana, Serrano, Laura, Gavriilaki, Eleni, Tragiannidis, Athanasios, Prattes, Juergen, Coppola, Nicola, Otašević, Vladimir, Mladenović, Miloš, Mitrović, Mirjana, Mišković, Bojana, Jindra, Pavel, Zompi, Sofia, Sacchi, Maria Vittoria, Krekeler, Carolin, Shumilov, Evgenii, Infante, Maria Stefania, García-Bordallo, Daniel, Çolak, Gökçe Melis, Mayer, Jiří, Nygaard, Marietta, Hanáková, Michaela, Ráčil, Zdeněk, Quattrone, Martina, Bonanni, Matteo, Koehler, Philipp, Rahimli, Laman, Cornely, Oliver A., and Pagano, Livio

Published
2024
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48. Identification of SARS-CoV-2 inhibitors targeting Mpro and PLpro using in-cell-protease assay

Author

Narayanan, Anoop, Narwal, Manju, Majowicz, Sydney A, Varricchio, Carmine, Toner, Shay A, Ballatore, Carlo, Brancale, Andrea, Murakami, Katsuhiko S, and Jose, Joyce

Subjects
Infectious Diseases, Lung, Pneumonia, Prevention, Emerging Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Coronavirus 3C Proteases, Coronavirus Papain-Like Proteases, Drug Evaluation, Preclinical, Drug Repositioning, HEK293 Cells, Humans, Molecular Docking Simulation, Molecular Targeted Therapy, SARS-CoV-2, Viral Protease Inhibitors, COVID-19 Drug Treatment
Abstract

SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.

Published
2022

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