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Giorgio L Colombo,1,2 Sergio Di Matteo,2 Andrea Antinori,3 Massimo Medaglia,4 Silvia Murachelli,3 Giuliano Rizzardini51Department of Drug Sciences, University of Pavia, Pavia, Italy; 2SAVE – Studi Analisi Valutazioni Economiche, Milan, Italy; 3National Institute for Infectious Diseases L Spallanzani, IRCCS, Rome, Italy; 4Pharmaceutical Department, L. Sacco Hospital, Milan, Italy; 5First Division of Infectious Disease, L. Sacco Hospital, Milan, Italy Introduction: Highly active antiretroviral therapy (HAART) has allowed many HIV-infected patients to enjoy longer survival and a better quality of life. We performed an economic analysis to estimate the cost-effectiveness of HAART regimens in Italy for managing HIV-naïve infected patients with a viral load below 100,000 copies/mL.Patients and methods: The population considered in the model consisted of adult subjects with an HIV viral load below 100,000 copies/mL who received antiretroviral HAART treatment for the first time, according to the Italian National Guidelines with recommendation grade A1. The incremental cost-effectiveness analysis of quality-adjusted life years (QALYs) was carried out by means of a Markov model. Both the outcomes (QALYs) and the costs were discounted by 3.5%. The time horizon adopted in the model was 10 years. The point of view of the analysis was that of the Italian national health service.Results: The tenofovir (TDF)/emtricitabine (FTC)/rilpivirine (RPV) single-tablet regimen (STR) (€7,417.00) revealed the lowest mean treatment cost. TDF/FTC + raltegravir (RAL) showed a better quality of life (0.906 QALY/year), followed by TDF/FTC/RPV (STR; 0.900 QALY/year), TDF/FTC + RPV (multipill regimen) (0.889 QALY/year), and TDF/FTC + atazanavir (ATV/r) (0.886 QALY/year). TDF/FTC/RPV (STR) appeared to be the most cost-effective therapeutic choice (€13,655.00), followed by TDF/FTC + RPV (multipill regimen) (€15,803.00), and TDF/FTC + efavirenz (EFV) (€16,181.00). The sensitivity analysis on the main variables confirmed the validity of the base case scenario.Conclusion: STR (TDF/FTC/RPV) is the most cost-effective treatment strategy compared with the other therapeutic regimens recommended by the Italian guidelines for the treatment of naïve patients with a viral load

In an effort to investigate the molecular determinants of ligand recognition of the C-terminal SH2 domain of the SHP2 protein, we conducted extensive site-directed mutagenesis and kinetic binding experiments with a peptide mimicking a specific portion of a physiological ligand (the scaffold protein Gab2). Obtained data provided an in-depth characterization of the binding reaction, allowing us to pinpoint residues topologically far from the binding pocket of the SH2 domain to have a role in the recognition and binding of the peptide. The presence of a sparse energetic network regulating the interaction with Gab2 was identified and characterized through double mutant cycle analysis, performed by challenging all the designed site-directed variants of C-SH2 with a Gab2 peptide mutated at +3 position relative to its phosphorylated tyrosine, a key residue for C-SH2 binding specificity. Results highlighted non-optimized residues involved in the energetic network regulating the binding with Gab2, which may be at the basis of the ability of this SH2 domain to interact with different partners in the intracellular environment. Moreover, a detailed analysis of kinetic and thermodynamic parameters revealed the role of the residue at +3 position on Gab2 in the early and late events of the binding reaction with the C-SH2 domain., (© 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that may develop at any level of the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) on the basis of its anatomical location. Notably, although these three CCA subtypes have common features, they also have important inter- and intra-tumor differences that can affect their pathogenesis and outcome. A unique feature of CCA is that it manifests in the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, furnished by two distinct stem cell niches: the canals of Hering and the peribiliary glands, respectively. The complexity of CCA pathogenesis highlights the need for a multidisciplinary, translational, and systemic approach to this malignancy. This review focuses on advances in the knowledge of CCA histomorphology, risk factors, molecular pathogenesis, and subsets of CCA., Competing Interests: Conflict of Interest: None

Introduction: Tumors of any histological origin can give rise to cutaneous and subcutaneous metastases during follow-up. This study aims to evaluate the costs and benefits of electrochemotherapy (ECT) with the Cliniporatortrade mark vs other currently used methods in the control and treatment of cutaneous and subcutaneous advanced neoplasms., Materials and Methods: A cost-effectiveness analysis was carried out on ECT using the Cliniporator vs other techniques (radiotherapy, hyperthermia associated with radiotherapy and chemotherapy, interferon-alpha, and isolated limb perfusion) for the control and treatment of cutaneous and subcutaneous neoplasms. The direct health costs were attributed a value according to the Italian National Healthcare System. Resource consumption and clinical outcomes were derived from cost survey data collection and literature review., Results: ECT is cost-effective with an incremental cost effectiveness ratio (ICER) of euro1,571.53 to achieve a further additional response. Radiotherapy and interferon-alpha are the least effective strategies. A combination of hyperthermia, chemotherapy, radiotherapy, and interferon-alpha treatment are dominated by ECT (more costly and less effective). Isolated limb perfusion is the most effective treatment, but is very costly (euro18,530.47) because of the use of antiblastic drugs (TNFalpha), with an ICER of euro92,717.29., Conclusions: After sensitivity analysis, the study results confirm the favorable cost-effectiveness ratio of ECT with the Cliniporator and justify its wider use.