SGLT2 inhibitors and new frontiers in heart failure treatment regardless of ejection fraction and setting.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to reduce cardiovascular (CV) mortality and heart failure (HF) hospitalizations, independently from left ventricular ejection fraction (EF). Their efficacy has been assessed both in patients with reduced and preserved EF, with notable benefits in renal outcomes as well. The initiation of SGLT2i in the early phase of hospitalization for acute HF has proven to be safe and beneficial.

MitraClip Procedure in Advanced Heart Failure and Severe Mitral Regurgitation: Case Report and Literature Review.

Mitral regurgitation (MR) is a common valvular disorder often seen in a severely dilated left ventricle (LV) and reduced LV function. In chronic heart failure (HF), severe functional MR increases preload, wall tension, LV workload, and worsening prognosis. The MitraClip device offers a percutaneous treatment option in HF, although its safety and efficacy in advanced and acute HF remain a gray zone.

The Therapy and Management of Heart Failure with Preserved Ejection Fraction: New Insights on Treatment.

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterised by the presence of diastolic dysfunction and elevated left ventricular filling pressure, in the setting of a left ventricular ejection fraction of at least 50%. Despite the epidemiological prevalence of HFpEF, a prompt diagnosis is challenging and many uncertainties exist. HFpEF is characterised by different phenotypes driven by various cardiac and non-cardiac comorbidities.

Right Ventricular Dysfunction before and after Cardiac Surgery: Prognostic Implications.

Right ventricular dysfunction is a prognostic factor for morbidity and mortality across a broad spectrum of cardiovascular diseases. While the role of the right ventricle in surgical patients has emerged, the prognostic impact of right ventricular dysfunction remains unclear in a large cardiac surgery population. We reviewed the existing literature about the role of right ventricular dysfunction in adults undergoing different kinds of cardiac surgery either present before or developed after surgery itself.

Prognostic Value of sST2 in Heart Failure.

In recent years, there has been growing interest in the risk stratification for heart failure, and the use of multiple biomarkers to identify different pathophysiological processes associated with this condition. One such biomarker is soluble suppression of tumorigenicity-2 (sST2), which has shown some potential for integration into clinical practice. sST2 is produced by both cardiac fibroblasts and cardiomyocytes in response to myocardial stress.

Enalaprilat and losartan decrease erythroid precursors frequency in cells from patients with polycythemia vera.

Objective: Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by the overproduction of red blood cells. First-line therapies are directed at lowering hematocrit levels. After the discovery of a mutation in the Janus kinase 2 (2), JAK2 inhibitors have been tested as second-line therapies.

Selective cell cycle arrest in glioblastoma cell lines by quantum molecular resonance alone or in combination with temozolomide.

Background: Glioblastoma is the most aggressive form of brain cancer, characterised by high proliferation rates and cell invasiveness. Despite advances in surgery and radio-chemotherapy, patients continue to have poor prognoses, with a survival rate of 14-15 months. Thus, new therapeutic strategies are needed.

Logistics of an advanced therapy medicinal product during COVID-19 pandemic in Italy: successful delivery of mesenchymal stromal cells in dry ice.

Background: During the coronavirus disease-2019 (COVID-19) pandemic, Italian hospitals faced the most daunting challenges of their recent history, and only essential therapeutic interventions were feasible. From March to April 2020, the Laboratory of Advanced Cellular Therapies (Vicenza, Italy) received requests to treat a patient with severe COVID-19 and a patient with acute graft-versus-host disease with umbilical cord-derived mesenchymal stromal cells (UC-MSCs). Access to clinics was restricted due to the risk of contagion.

Regulation of DNA repair pathway choice in S and G2 phases by the NHEJ inhibitor CYREN.

Classical non-homologous end joining (cNHEJ) and homologous recombination compete for the repair of double-stranded DNA breaks during the cell cycle. Homologous recombination is inhibited during the G1 phase of the cell cycle, but both pathways are active in the S and G2 phases. However, it is unclear why cNHEJ does not always outcompete homologous recombination during the S and G2 phases.

A BARF1-specific mAb as a new immunotherapeutic tool for the management of EBV-related tumors.

The use of monoclonal antibodies (mAb) for the diagnosis and treatment of malignancies is acquiring an increasing clinical importance, thanks to their specificity, efficacy and relative easiness of use. However, in the context of Epstein-Barr virus (EBV)-related malignancies, only cancers of B-cell origin can benefit from therapeutic mAb targeting specific B-cell lineage antigens. To overcome this limitation, we generated a new mAb specific for BARF1, an EBV-encoded protein with transforming and immune-modulating properties.

Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4 T Cells.

CD4 T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4 T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4 T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach.

Role of VHL, HIF1A and SDH on the expression of miR-210: Implications for tumoral pseudo-hypoxic fate.

The hypoxia-inducible factor 1α (HIF-1α) and its microRNA target, miR-210, are candidate tumor-drivers of metabolic reprogramming in cancer. Neuroendocrine neoplasms such as paragangliomas (PGLs) are particularly appealing for understanding the cancer metabolic adjustments because of their associations with deregulations of metabolic enzymes, such as succinate dehydrogenase (SDH), and the von Hippel Lindau (VHL) gene involved in HIF-1α stabilization. However, the role of miR-210 in the pathogenesis of SDH-related tumors remains an unmet challenge.

A site-selective hyaluronan-interferonα2a conjugate for the treatment of ovarian cancer.

While interferon alpha (IFNα) is used in several viral and cancer contexts, its efficacy against ovarian cancer (OC) is far from being incontrovertibly demonstrated and, more importantly, is hindered by heavy systemic side effects. To overcome these issues, here we propose a strategy that allows a targeted delivery of the cytokine, by conjugating IFNα2a with an aldehyde-modified form of hyaluronic acid (HA). The resulting HA-IFNα2a bioconjugate was biochemically and biologically characterized.

Reverse immunoediting: When immunity is edited by antigen.

Immune selective pressure occurring during cancer immunoediting shapes tumor features revealed at clinical presentation. However, in the "Escape" phase, the tumor itself has the chance to influence the immunological response. Therefore, the capacity of the immune response to sculpt the tumor characteristics is only one side of the coin and even the opposite is likely true, i.

Drug conjugation to hyaluronan widens therapeutic indications for ovarian cancer.

Management of ovarian cancer still requires improvements in therapeutic options. A drug delivery strategy was tested that allows specific targeting of tumor cells in combination with a controlled release of a cytotoxic molecule. To this aim, the efficacy of a loco-regional intraperitoneal treatment with a bioconjugate (ONCOFID-S) derived by chemical linking of SN-38, the active metabolite of irinotecan (CPT-11), to hyaluronan was assessed in a mouse model of ovarian carcinomatosis.

Peritoneal tumor carcinomatosis: pharmacological targeting with hyaluronan-based bioconjugates overcomes therapeutic indications of current drugs.

Peritoneal carcinomatosis still lacks reliable therapeutic options. We aimed at testing a drug delivery strategy allowing a controlled release of cytotoxic molecules and selective targeting of tumor cells. We comparatively assessed the efficacy of a loco-regional intraperitoneal treatment in immunocompromised mice with bioconjugates formed by chemical linking of paclitaxel or SN-38 to hyaluronan, against three models of peritoneal carcinomatosis derived from human colorectal, gastric and esophageal tumor cell xenografts.

PSMA-specific CAR-engineered T cells eradicate disseminated prostate cancer in preclinical models.

Immunology-based interventions have been proposed as a promising curative chance to effectively attack postoperative minimal residual disease and distant metastatic localizations of prostate tumors. We developed a chimeric antigen receptor (CAR) construct targeting the human prostate-specific membrane antigen (hPSMA), based on a novel and high affinity specific mAb. As a transfer method, we employed last-generation lentiviral vectors (LV) carrying a synthetic bidirectional promoter capable of robust and coordinated expression of the CAR molecule, and a bioluminescent reporter gene to allow the tracking of transgenic T cells after in vivo adoptive transfer.

Functional avidity-driven activation-induced cell death shapes CTL immunodominance.

Immunodominance is a complex phenomenon that relies on a mere numerical concept, while being potentially influenced at every step of the immune response. We investigated the mechanisms leading to the establishment of CTL immunodominance in a retroviral model and found that the previously defined subdominant Env-specific CD8(+) T cells are endowed with an unexpectedly higher functional avidity than is the immunodominant Gag-recognizing counterpart. This high avidity, along with the Env Ag overload, results in a supraoptimal TCR engagement.

In vitro study of normoxic epidermal growth factor receptor-induced hypoxia-inducible factor-1-alpha, vascular endothelial growth factor, and BNIP3 expression in head and neck squamous cell carcinoma cell lines: Implications for anti-epidermal growth factor receptor therapy.

Background: We previously showed that activation of epidermal growth factor receptor (EGFR) induces hypoxia inducible factor-1α (HIF-1α) in head and neck squamous cell carcinoma (HNSCC) cells. In this study, we have furthered this by investigating the mechanism of HIF-1α activation by epidermal growth factor (EGF) and its association with the sensitivity to gefitinib.

Methods: EGFR/HIF-1α signaling was tested by immunoblot, polymerase chain reaction (PCR), cell proliferation, and apoptosis assays.

Survivin expression and prognostic significance in pediatric malignant peripheral nerve sheath tumors (MPNST).

Malignant peripheral nerve sheath tumors (MPNST) are very aggressive malignancies comprising approximately 5-10% of all soft tissue sarcomas. In this study, we focused on pediatric MPNST arising in the first 2 decades of life, as they represent one the most frequent non-rhabdomyosarcomatous soft tissue sarcomas in children. In MPNST, several genetic alterations affect the chromosomal region 17q encompassing the BIRC5/SURVIVIN gene.

Identification of somatic VHL gene mutations in sporadic head and neck paragangliomas in association with activation of the HIF-1α/miR-210 signaling pathway.

Context: Head and neck paragangliomas (HNPGLs) arise from parasympathetic paraganglias and 35% to 45% are hereditary caused by mutations in succinate dehydrogenase (SDH) genes. The connection between SDH and tumor development is unclear. The most accepted hypothesis proposes a central role for the pseudohypoxic (pHx) pathway activated by hypoxia-inducible factor (HIF).

Identification of TRPC6 as a possible candidate target gene within an amplicon at 11q21-q22.2 for migratory capacity in head and neck squamous cell carcinomas.

Background: Cytogenetic and gene expression analyses in head and neck squamous cell carcinomas (HNSCC) have allowed identification of genomic aberrations that may contribute to cancer pathophysiology. Nevertheless, the molecular consequences of numerous genetic alterations still remain unclear.

Methods: To identify novel genes implicated in HNSCC pathogenesis, we analyzed the genomic alterations present in five HNSCC-derived cell lines by array CGH, and compared high level focal gene amplifications with gene expression levels to identify genes whose expression is directly impacted by these genetic events.