Endothelial Cell Dysfunction in HIV-1 Infection

Human immunodeficiency virus type 1 (HIV-1) promotes a generalized immune activation that alters the physiology of cells that are not sensitive to viral infection. Endothelial cells (ECs) display heavy dysfunctions in HIV-1-seropositive (HIV+) patients that persist even in patients under successful combined antiretroviral therapy (cART). In vivo studies failed to demonstrate the presence of replicating virus in ECs suggesting that a direct role of the virus in vascular dysfunction is unlikely. This finding paves the way to the hypothesis of a key role of molecules released in the microenvironment by HIV-1-infected cells in sustaining aberrant EC function. Here we review the current understanding regarding the contribution of HIV-1 infection to vascular dysfunction. In particular, we argue that different HIV-1 proteins may play a key role in driving and sustaining inflammation and EC dysregulation, thus underlining the need to target them for therapeutic benefit

identification of amino acid residues critical for the b cell growth promoting activity of hiv 1 matrix protein p17 variants

Abstract Background HIV-1 matrix protein p17 variants (vp17s) detected in HIV-1-infected patients with non-Hodgkin's lymphoma (HIV-NHL) display, differently from the wild-type protein (refp17), B cell growth-promoting activity. Biophysical analysis revealed that vp17s are destabilized as compared to refp17, motivating us to explore structure-function relationships. Methods We used: biophysical techniques (circular dichroism (CD), nuclear magnetic resonance (NMR) and thermal/GuHCL denaturation) to study protein conformation and stability; Surface plasmon resonance (SPR) to study interactions; Western blot to investigate signaling pathways; and Colony Formation and Soft Agar assays to study B cell proliferation and clonogenicity. Results By forcing the formation of a disulfide bridge between Cys residues at positions 57 and 87 we obtained a destabilized p17 capable of promoting B cell proliferation. This finding prompted us to dissect refp17 to identify the functional epitope. A synthetic peptide (F1) spanning from amino acid (aa) 2 to 21 was found to activate Akt and promote B cell proliferation and clonogenicity. Three positively charged aa (Arg15, Lys18 and Arg20) proved critical for sustaining the proliferative activity of both F1 and HIV-NHL-derived vp17s. Lack of any interaction of F1 with the known refp17 receptors suggests an alternate one involved in cell proliferation. Conclusions The molecular reasons for the proliferative activity of vp17s, compared to refp17, relies on the exposure of a functional epitope capable of activating Akt. General significance Our findings pave the way for identifying the receptor(s) responsible for B cell proliferation and offer new opportunities to identify novel treatment strategies in combating HIV-related NHL

Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model

Mesenchymal stromal cells (MSCs) are considered an important therapeutic tool in cancer therapy. They possess intrinsic therapeutic potential and can also be in vitro manipulated and engineered to produce therapeutic molecules that can be delivered to the site of diseases, through their capacity to home pathological tissues. We have recently demonstrated that MSCs, upon in vitro priming with anti-cancer drug, become drug-releasing mesenchymal cells (Dr-MCs) able to strongly inhibit cancer cells growth

The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference

Purpose: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy. Methods: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. Results: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively). Conclusions: Our study demonstrated that BRAF status makes the difference in treatment’s outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis

Cement-Based Mortars with Waste Paper Sludge-Derived Cellulose Fibers for Building Applications

This study assesses the mechanical properties of mortars incorporating waste paper sludge-derived cellulose fibers. Compression and flexural tests were carried out on specimens prepared with cellulose fibers at different proportions, ranging from 0% to 2% of the total weight of the solid mortar constituents (cement, sand, and lime). In addition, a comparative analysis was carried out to evaluate the influence of the preparation method on the mechanical properties of the mortars. To this end, two series of mortars were studied: one prepared following a rigorous control of the preparation parameters and the other made without systematic parameter control to simulate typical on-site conditions. Finally, the applicability of both traditional and eco-friendly mortars in the construction of small-scale masonry walls was assessed through compression tests. Overall, the mechanical properties of mortars with cellulose fibers were comparable to those with 0% waste material, regardless of the production process. Regarding the compressive behavior of masonry walls, experimental tests showed significant similarities between specimens made with traditional and eco-friendly mortar. In conclusion, incorporating cellulose fibers into cement-based mortar shows considerable potential for building applications, enhancing the environmental benefits without compromising the mechanical behavior

HIV-1 matrix protein p17 and its variants promote human triple negative breast cancer cell aggressiveness

BACKGROUND: The introduction of cART has changed the morbidity and mortality patterns affecting HIV-infected (HIV+) individuals. The risk of breast cancer in HIV+ patients has now approached the general population risk. However, breast cancer has a more aggressive clinical course and poorer outcome in HIV+ patients than in general population, without correlation with the CD4 or virus particles count. These findings suggest a likely influence of HIV-1 proteins on breast cancer aggressiveness and progression. The HIV-1 matrix protein (p17) is expressed in different tissues and organs of successfully cART-treated patients and promotes migration of different cells. Variants of p17 (vp17s), characterized by mutations and amino acid insertions, differently from the prototype p17 (refp17), also promote B-cell proliferation and transformation. METHODS: Wound-healing assay, matrigel-based invasion assay, and anchorage-independent proliferation assay were employed to compare the biological activity exerted by refp17 and three different vp17s on the triple-negative human breast cancer cell line MDA-MB 231. Intracellular signaling was investigated by western blot analysis. RESULTS: Motility and invasiveness increased in cells treated with both refp17 and vp17s compared to untreated cells. The effects of the viral proteins were mediated by binding to the chemokine receptor CXCR2 and activation of the ERK1/2 signaling pathway. However, vp17s promoted MDA-MB 231 cell growth and proliferation in contrast to refp17-treated or not treated cells. CONCLUSIONS: In the context of the emerging role of the microenvironment in promoting and supporting cancer cell growth and metastatic spreading, here we provide the first evidence that exogenous p17 may play a crucial role in sustaining breast cancer cell migration and invasiveness, whereas some p17 variants may also be involved in cancer cell growth and proliferation

β-substituted ferrocenyl porphyrins: The role of the spacer and of the number of substituents on their structural and spectroscopic characteristics

Mono and bis ethynyl and ethynylphenyl beta-substituted porphyrins have been synthesized and characterized. Their conformational properties have been analyzed through a combination of NMR experiments and molecular mechanic calculations, while UV-Vis absorption and fluorescence measurements together with electrochemical studies allows us to probe the existence of intramolecular electronic processes. The role of the beta-substituents and of the spacer is underlined