Clinical and genetic factors associated with kidney tubular dysfunction in a real-life single centre cohort of HIV-positive patients

BACKGROUND: Tenofovir (TDF) is one of the most widely used antiretroviral drug. Despite the high degree of tolerability a small percentage of patients experienced alteration in tubular function during TDF use. Intracellular TDF disposition is regulated by ATP-binding cassette (ABC) drug efflux transporters and, a reduced transport activity may be implicated in accumulation of TDF into the cells. The aim of our study was to assess the major determinants of TDF associated tubular dysfunction (KTD) in a real-life setting including the usefulness of single-nucleotide polymorphisms (SNPs) mapping into ABCC2, ABCC4 and ABCC10 genes. METHODS: We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from April 2013 to June 2016. All patients treated with TDF who underwent a genotypization for the functional variants mapping in ABCC2 rs717620 (-24 C > T), ABCC4 rs1751034 (3463 A > G) and ABCC10 rs2125739 (T > C) were evaluated. KTD was defined as the presence of urine phosphate wasting and/or proteinuria at 24 h urine analysis. RESULTS: One hundred fifty-eight patients were genotyped, of which 42 (26.6%) experienced signs of KTD. No statistical significant differences were observed among patients with or without KTD regarding age, gender, ethnicity and comorbidities (hypertension and diabetes). The percentage of patients with KTD was higher among those with "GG" genotype at rs1751034 of ABCC4 compared to patients without KTD [6 (14.3%) vs 4 (3.5%), p = 0.01]. No statistical significant differences were observed regarding the distribution of ABCC2 and ABCC10 SNPs. Carriers of "G" allele in homozygous status at rs1751034 of ABCC4 showed a significant association with KTD (Odds Ratio 4.67, 95% CI 1.25-17.46, p = 0.02) in bivariate analysis, but this association was lost in multivariable analysis. A significant association between bone diseases and KTD was observed (Odds Ratio 3.178, 95%CI 1.529-6.603, p = 0.002). CONCLUSIONS: According to our results ABCC4 rs1751034 could be a genetic determinant of KTD; however validation studies are needed for therapy personalization. Noteworthy, a strong association between bone disease and KTD was also observed

Acute Inflammation and Elevated Cardiac Markers in a Two-Month-Old Infant with Severe Acute Respiratory Syndrome Coronavirus 2 Infection Presenting with Cardiac Symptoms

Severe acute respiratory syndrome coronavirus 2 infection in children mainly shows a milder course. In complicated cases, it is unknown whether inflammation is predictive of disease severity, as in adults. Moreover, cardiac involvement is anecdotally described. We report the case of a 2-month-old infant with severe acute respiratory syndrome coronavirus 2 infection presenting with fever, tachycardia and elevated interleukin-6, who was diagnosed with myocarditis and treated with immunoglobulins

Home Sweet Home: Setting the Best Thriving Conditions for the Ad Hoc Engineered Microbial Consortium in the Zero Mile System

Wastewaters from household appliances, such as dishwashers and washing machines, are an untapped resource of recoverable water and/or nutrients. The Zero Mile system has been developed to reuse/upcycle dishwasher wastewaters through bioremediation activity carried out by an ad hoc engineered phototrophic/heterotrophic microbial consortium. The choice of both suitable microorganisms for engineering consortia and detailed knowledge on their structure, behaviour and interaction are essential to optimising consortium culture conditions and drive the biofilter container design (structure and topology). To these aims, the effect of abiotic conditions (i.e., irradiance, pH and organic load) on the microbial consortium growth and its capability to survive and thrive in different dishwasher wastewater dilutions have been evaluated. At the same time, the crucial interplay between biological and design research has allowed us to define the characteristics of the biofilter container and plan its development for the industrial application of the Zero Mile system, bringing sustainability benefits as it moves household wastewater from a traditional linear model to a more sustainable, circular approach

Role of exosomes released by chronic myelogenous leukemia cells in angiogenesis

The present study is designed to assess if exosomes released from Chronic Myelogenous Leukemia (CML) cells may modulate angiogenesis. We have isolated and characterized the exosomes generated from LAMA84 CML cells and demonstrated that addition of exosomes to human vascular endothelial cells (HUVEC) induces an increase of both ICAM-1 and VCAM-1 cell adhesion molecules and interleukin-8 expression. The stimulation of cell-cell adhesion molecules was paralleled by a dose-dependent increase of adhesion of CML cells to a HUVEC monolayer. We further showed that the treatment with exosomes from CML cells caused an increase in endothelial cell motility accompanied by a loss of VE-cadherin and β-catenin from the endothelial cell surface. Functional characterization of exosomes isolated from CML patients confirmed the data obtained with exosomes derived from CML cell line. CML exosomes caused reorganization into tubes of HUVEC cells cultured on Matrigel. When added to Matrigel plugs in vivo, exosomes induced ingrowth of murine endothelial cells and vascularization of the Matrigel plugs. Our results suggest for the first time that exosomes released from CML cells directly affect endothelial cells modulating the process of neovascularization

Durability of different initial regimens in HIV-infected patients starting antiretroviral therapy with CD4+ counts <200 cells/mm³ and HIV-RNA >5 log₁₀ copies/mL

OBJECTIVES: Our aim was to investigate the durability of different initial regimens in patients starting ART with CD4+ counts 5 log10 copies/mL. METHODS: This was a retrospective study of HIV-infected patients prospectively followed in the ICONA cohort. Those who started ART with boosted protease inhibitors (bPIs), NNRTIs or integrase strand transfer inhibitors (InSTIs), with CD4+ 5 log10 copies/mL, were included. The primary endpoint was treatment failure (TF), a composite endpoint defined as virological failure (VF, first of two consecutive HIV-RNA >50 copies/mL after 6 months of treatment), discontinuation of class of the anchor drug or death. Independent associations were investigated by Poisson regression analysis in a model including age, gender, mode of HIV transmission, CDC stage, HCV and HBV co-infection, pre-treatment HIV-RNA, CD4+ count and CD4+/CD8+ ratio, ongoing opportunistic disease, fibrosis FIB-4 index, estimated glomerular filtration rate, haemoglobin, platelets, neutrophils, calendar year of ART initiation, anchor drug class (treatment group) and nucleos(t)ide backbone. RESULTS: A total of 1195 patients fulfilled the inclusion criteria: 696 started ART with a bPI, 315 with an InSTI and 184 with an NNRTI. During 2759 person-years of follow up, 642 patients experienced TF. Starting ART with bPIs [adjusted incidence rate ratio (aIRR) (95% CI) 1.62 (1.29-2.03) versus starting with NNRTIs; P 5 log10 HIV-RNA copies/mL, the durability of regimens based on InSTIs was longer than that of NNRTI- and bPI-based regimens

microRNAs and Cardiac Cell Fate

The role of small, non-coding microRNAs (miRNAs) has recently emerged as fundamental in the regulation of the physiology of the cardiovascular system. Several specific miRNAs were found to be expressed in embryonic, postnatal, and adult cardiac tissues. In the present review, we will provide an overview about their role in controlling the different pathways regulating cell identity and fate determination. In particular, we will focus on the involvement of miRNAs in pluripotency determination and reprogramming, and specifically on cardiac lineage commitment and cell direct transdifferentiation into cardiomyocytes. The identification of cardiac-specific miRNAs and their targets provide new promising insights into the mechanisms that regulate cardiac development, function and dysfunction. Furthermore, due to their contribution in reprogramming, they could offer new opportunities for developing safe and efficient cell-based therapies for cardiovascular disorders

Generation of human induced pluripotent stem cells (EURACi001-A, EURACi002-A, EURACi003-A) from peripheral blood mononuclear cells of three patients carrying mutations in the CAV3 gene

Caveolinopathies are a heterogeneous family of genetic pathologies arising from alterations of the caveolin-3 gene (CAV3), encoding for the isoform specifically constituting muscle caveolae. Here, by reprogramming peripheral blood mononuclear cells, we report the generation of induced pluripotent stem cells (iPSCs) from three patients carrying the ΔYTT deletion, T78K and W101C missense mutations in caveolin-3. iPSCs displayed normal karyotypes and all the features of pluripotent stem cells in terms of morphology, specific marker expression and ability to differentiate in vitro into the three germ layers. These lines thus represent a human cellular model to study the molecular basis of caveolinopathies

IL4 primes the dynamics of breast cancer progression via DUSP4 inhibition

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4R\uce\ub1 antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24-cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4by inhibiting NF-\uce\ubaB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4activated the ERKand p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFN\uce\ub3-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies

Aptamers against live targets: Is in vivo SELEX finally coming to the edge?

Targeted therapeutics underwent a revolution with the entry of monoclonal antibodies in the medical toolkit. Oligonucleotide aptamers form another family of target agents that have been lagging behind in reaching the clinical arena in spite of their potential clinical translation. Some of the reasons for this might be related to the challenge in identifying aptamers with optimal in vivo specificity, and the nature of their pharmacokinetics. Aptamers usually show exquisite specificity, but they are also molecules that display dynamic structures subject to changing environments. Temperature, ion atmosphere, pH, and other variables are factors that could determine the affinity and specificity of aptamers. Thus, it is important to tune the aptamer selection process to the conditions in which you want your final aptamer to function; ideally, for in vivo applications, aptamers should be selected in an in vivo-like system or, ultimately, in a whole in vivo organism. In this review we recapitulate the implementations in systematic evolution of ligands by exponential enrichment (SELEX) to obtain aptamers with the best in vivo activity