In Vivo Models of Human Immunodeficiency Virus Persistence and Cure Strategies

Current HIV therapy is not curative regardless of how soon after infection it is initiated or how long it is administered, and therapy interruption almost invariably results in robust viral rebound. Human immunodeficiency virus persistence is therefore the major obstacle to a cure for AIDS. The testing and implementation of novel yet unproven approaches to HIV eradication that could compromise the health status of HIV-infected individuals might not be ethically warranted. Therefore, adequate in vitro and in vivo evidence of efficacy is needed to facilitate the clinical implementation of promising strategies for an HIV cure. Animal models of HIV infection have a strong and well-documented history of bridging the gap between laboratory discoveries and eventual clinical implementation. More recently, animal models have been developed and implemented for the in vivo evaluation of novel HIV cure strategies. In this article, we review the recent progress in this rapidly moving area of research, focusing on the two most promising model systems: humanized mice and nonhuman primates

in Vitro and in Vivo Models to Decipher Intra-tumor Heterogeneity

Recent advances in next-generation sequencing and other omics technologies capable to map cell fate provide increasing evidence on the crucial role of intra-tumor heterogeneity (ITH) for cancer progression. The different facets of ITH, from genomic to microenvironmental heterogeneity and the hierarchical cellular architecture originating from the cancer stem cell compartment, contribute to the range of tumor phenotypes. Decoding these complex data resulting from the analysis of tumor tissue complexity poses a challenge for developing novel therapeutic strategies that can counteract tumor evolution and cellular plasticity. To achieve this aim, the development of in vitro and in vivo cancer models that resemble the complexity of ITH is crucial in understanding the interplay of cells and their (micro)environment and, consequently, in testing the efficacy of new targeted treatments and novel strategies of tailoring combinations of treatments to the individual composition of the tumor. This challenging approach may be an important cornerstone in overcoming the development of pharmaco-resistances during multiple lines of treatment. In this paper, we report the latest advances in patient-derived 3D (PD3D) cell cultures and patient-derived tumor xenografts (PDX) as in vitro and in vivo models that can retain the genetic and phenotypic heterogeneity of the tumor tissue

Rock-face temperature at high-elevation sites: a new measuring approach

The Alpine environment and in particular the cryosphere, is responding quickly and with great intensity to climate change. Temperature increase observed in the Alps urge the scientific community to study not only air temperature but also rock temperature, to deepen the knowledge about thermal properties of the potentially unstable geological materials. The metrological traceability of measurements is fundamental for data comparability in space and in time and this can be achieved by the use of calibrated instruments and with the evaluation of measurement uncertainties. Here we present some preliminary results of rock-face temperature analysis based on data acquired at high-elevation sites, by means of sensors with documented traceability to International System of Units Standards and evaluated measurement uncertainty. We found and quantified a strong difference in the hourly rate of temperature increase between air and rock. During summer rock temperature grows more than 8 times over air temperature

Stress–Strain Investigation of the Rock Mass Based on Overcoring with CSIRO HI Cell Test and Numerical Modeling: A Case Study from an Italian Underground Marble Quarry

The present research illustrates the application of a methodological approach to studying the stress–strain distribution in a marble quarry of the Apuan Alps mining area (Italy). This study has been carried out in the framework of a project involving the University of Siena and the UOC Ingegneria Mineraria—USL Toscana Nord-Ovest, Tuscany Region. This stress–strain analysis aims foremost to monitor the slope stability conditions to guarantee a safe workplace for the personnel involved in mining activities, and to enable more sustainable long-term planning for excavation and production. The involved survey activities are as follows: (i) terrestrial laser scanning; (ii) engineering–geological data mapping; and (iii) in situ marble stress measuring through four CSIRO-type cell tests executed in different locations and at various depths within the underground excavation walls. The gathered data converged into numerical models of the quarry, both in 2D (DEM) and 3D (FEM), calibrated by in situ stress results through a rigorous back analysis assessment using least squares procedures. The created models represent a valuable tool for the identification and securing of risk areas and for future excavation planning in respect of the site efficiency and safety

Increase of plasma IL-9 and decrease of plasma IL-5, IL-7, and IFN-γ in patients with chronic heart failure

BACKGROUND: Several cytokines are associated with the development and/or progression of chronic heart failure (CHF). Our aim was to look more closely at the cytokine networks involved in CHF, and to assess whether disease etiology affects cytokine expression. The study population was comprised of a) 69 patients with stable CHF, New York Heart Association (NYHA) II/IV classes, secondary to ischaemic (ICM) and non ischaemic dilated (NIDCM) cardiomyopathy and b) 16 control subjects. We analyzed and compared the plasma levels of 27 pro- and anti-inflammatory mediators, in the study population and assessed for any possible correlation with echocardiographic parameters and disease duration. METHODS: 27 cytokines and growth factors were analyzed in the plasma of ICM- (n = 42) and NIDCM (n = 27) NYHA class II-IV patients vs age- and gender-matched controls (n = 16) by a beadbased multiplex immunoassay. Statistical analysis was performed by ANOVA followed by Tukey post-hoc test for multiple comparison. RESULTS: Macrophage inflammatory protein (MIP)-1\u3b2, Vascular endothelial growth factor (VEGF), interleukin (IL)-9, Monocyte chemotactic protein (MCP)-1, and IL-8 plasma levels were increased in both ICM and NIDCM groups vs controls. In contrast, IL-7, IL-5, and Interferon (IFN)-\u3b3 were decreased in both ICM and NIDCM groups as compared to controls. Plasma IL-6 and IL-1 \u3b2 were increased in ICM and decreased in NIDCM, vs controls, respectively.IL-9 levels inversely correlated, in ICM patients, with left ventricular ejection fraction (LVEF) while IL-5 plasma levels inversely correlated with disease duration, in NYHA III/IV ICM patients.This is the first time that both an increase of plasma IL-9, and a decrease of plasma IL-5, IL-7 and IFN-\u3b3 have been reported in ICM as well as in NIDCM groups, vs controls. Interestingly, such cytokines are part of a network of genes whose expression levels change during chronic heart failure. The altered expression levels of MIP-1 \u3b2, VEGF, MCP-1, IL-1 \u3b2, IL-6, and IL-8, found in this study, are in keeping with previous reports. CONCLUSIONS: The increase of plasma IL-9, and the decrease of plasma IL-5, IL-7 and IFN-\u3b3 in ICM as well as in NIDCM groups vs controls may contribute to get further insights into the inflammatory pathways involved in CHF

Novel TOP3A Variant Associated With Mitochondrial Disease: Expanding the Clinical Spectrum of Topoisomerase III Alpha-Related Diseases

ObjectivesTopoisomerase III alpha plays a key role in the dissolution of double Holliday junctions and is required for mitochondrial DNA (mtDNA) replication and maintenance. Sequence variants in the TOP3A gene have been associated with the Bloom syndrome-like disorder and described in an adult patient with progressive external ophthalmoplegia. The purpose of this report is to expand the clinical phenotype of the TOP3A-related diseases and clarify the role of this gene in primary mitochondrial disorders.MethodsA 44-year-old woman was referred to our hospital because of exercise intolerance and creatine kinase increase. Muscle biopsy and a targeted next-generation sequencing (NGS) analysis were performed.ResultsA histopathologic assessment documented a mitochondrial myopathy, and a molecular analysis revealed a novel homozygous variant in the TOP3A gene associated with multiple mtDNA deletions.DiscussionThis case suggests that TOP3A is one of the several nuclear genes associated with mtDNA maintenance disorder and expands the spectrum of its associated phenotypes, ranging from a clinical condition defined Bloom syndrome-like disorder to canonical mitochondrial syndromes