Spatiotemporal Delivery of Complementary Proteins for Repair of the Infarcted Myocardium

Ischemic heart disease is a leading cause of morbidity and mortality worldwide. After the onset of myocardial infarction, multiple pathologies develop and progress the disease towards heart failure. Pathologies such as ischemia, inflammation, cardiomyocyte death, ventricular remodeling and dilation, and interstitial fibrosis, develop and involve the signaling of many proteins. Therapeutic proteins can play important roles in limiting or countering pathological changes after infarction. However, they typically have low retention rate and short half-lives in vivo in their free form and can benefit from the advantages offered by controlled release systems to overcome their challenges. Protein-based therapies can be more effective when concerns such as spatiotemporal presentation, bioactivity, and retention are addressed. We tested the efficacy of controlled delivery of different combinations of cardiac-implicated proteins such as VEGF, HGF, PDGF, FGF-2, IL-10, TIMP-3, and SDF-1α. The controlled delivery of an optimal combination of proteins per their physiologic spatiotemporal cues to the infarcted myocardium holds great potential to repair and regenerate the damaged heart muscle. To address this issue, we developed a spatiotemporal delivery vehicle comprised of fibrin gel and heparin-based coacervates. Proteins that should be released relatively quickly are embedded in the fibrin gel, while proteins that should be released over a longer period are embedded in the coacervate and distributed in the same gel. This dissertation describes the process of developing the fibrin gel-coacervate composite for spatiotemporal delivery of therapeutic proteins and demonstrates its potential in triggering a significant cardiac repair process. It explores the ability of the coacervate to co-release different proteins, the development of the fibrin gel-coacervate system to achieve sequential delivery of different proteins, and the optimization of protein combinations and doses, paving the way for a potential comprehensive strategy to treat myocardial infarction

Personalized risk schemes and machine learning to empower genomic prognostication models in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are characterized by variable clinical manifestations and outcomes. Several prognostic systems relying on clinical factors and cytogenetic abnormalities have been developed to help stratify MDS patients into different risk categories of distinct prognoses and therapeutic implications. The current abundance of molecular information poses the challenges of precisely defining patients' molecular profiles and their incorporation in clinically established diagnostic and prognostic schemes. Perhaps the prognostic power of the current systems can be boosted by incorporating molecular features. Machine learning (ML) algorithms can be helpful in developing more precise prognostication models that integrate complex genomic interactions at a higher dimensional level. These techniques can potentially generate automated diagnostic and prognostic models and assist in advancing personalized therapies. This review highlights the current prognostication models used in MDS while shedding light on the latest achievements in ML-based research

A non-cytotoxic regimen of decitabine to treat refractory T-cell large granular lymphocytic leukemia

We report on a novel, successful, non-cytotoxic therapy to treat multiply-refractory T-LGL in an elderly patient

A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges

Simple Summary Risk stratification models, including the European LeukemiaNet 2017 and 2022 guidelines, categorize newly diagnosed acute myeloid leukemia (AML) patients into several subgroups of distinct genetic characteristics and disease outcomes. The intermediate-risk group remains the most heterogenous group, as most AML patients fall into it (i.e., a basket category) by virtue of not fulfilling criteria that identify specific entities (e.g., core-binding factor AML, TP53 mutations, complex karyotypes) of well-recognized prognostic significance. In this review, we aim to discuss the latest updates on intermediate-risk definition and highlight the therapeutic advances and challenges that warrant refining the prognostic classification of this category. Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML

Successful Treatment of Hepatitis C Virus by Ledipasvir/Sofosbuvir in a Cirrhotic Patient with Sickle Cell Disease and Thalassemia Minor

Around 8% of patients diagnosed with sickle cell disease (SCD) are hepatitis C virus (HCV) carriers. Previously, HCV treatment was seldom considered in SCD patients, as the ribavirin-induced hemolysis and interferon-induced cytopenias could lead to more profound anemia. Nowadays, several oral direct-acting antiviral drugs have been developed and approved by the FDA for hepatitis C treatment. While direct-acting antivirals mitigate many of these risks, their safety and efficacy in SCD patients remains insufficiently explored. Here, we report on successfully treating HCV with ledipasvir/sofosbuvir in a compensated cirrhotic patient with SCD and thalassemia minor

Vacuolization of hematopoietic precursors: an enigma with multiple etiologies

Cytoplasmic vacuoles in precursors can be seen in a number of clinical settings, including copper deficiency, zinc toxicity, alcohol abuse, antibiotic treatment, myelodysplasia, and VEXAS syndrome. Gurnari et al asked how common VEXAS syndrome is in patients whose bone marrow aspirates show this distinctive feature, finding 2 diagnoses of VEXAS among 24 cases with vacuoles

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR V beta sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3-based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post-allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post-allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses

Rapporto Finale del Progetto di alta formazione: “Esperti di Idroacustica, Analisi Dati, ICT e Tutela della Biodiversità Marina” (BLU-DATA-BIO)

Questo rapporto di fine progetto presenta i dati relativi al corso di formazione riportato nel titolo e rivolto a giovani laureati in scienze MM.FF.NN., chimiche, biologiche, ma anche ambientali, ingegneristiche e socio-economiche. Il corso è stato concepito come una prima di tappa di chi volesse intraprendere una carriera di ricerca presso Enti di Ricerca, oppure una carriera imprenditoriale nel settore della RS&I applicata alle scienze marine ed in particolare al concetto di “Crescita Blu”. L’ambiente marino con le sue risorse ha costituito il minimo comun denominatore di un’articolata offerta formativa finalizzata a creare nuove professionalità ad alta specializzazione all’interno di 2 macro-ambiti che costituiscono il “core business” del soggetto attuatore e che rappresentato i 2 Profili (A e B) del Progetto: 1. L’acustica marina attiva e passiva, connessa all’analisi dati e alle soluzioni ICT; 2. La tutela della biodiversità marina, connessa alla diffusione della cultura scientifica (Science Communication), collegata all’Osservatorio Regionale delle Biodiversità Siciliana Marina e Terrestre (D.D.G. del Dipartimento Ambiente della Regione Siciliana n. 342 del 10 giugno 2011)