Epidemiology, risk factors and therapy of candidemia in pediatric hematological patients

Invasive fungal infections (IFI) are an important cause of morbidity, increased hospitalization and healthcare costs in critically ill or immunocompromised children. The mortality is comprised between 5 and 20%. In the last 2 decades, the epidemiology of candidemia has changed with an increase of episodes caused by non-Candida albicans species. Central venous catheter, diagnosis of malignancy, and receipt of either vancomycin or antimicrobials with activity against anaerobic organisms for >3 days have been associated with the development of candidemia in the pediatric intensive care unit (PICU). Additional risk factors found in hematological patients were the diagnosis of aplastic anemia, performing an unrelated bone marrow or cord blood transplant, the occurrence of a graft versus host disease and the use of steroids. Early antifungal treatment is recommended to reduce mortality. In neutropenic patients, liposomal amphotericin B, an echinocandin (caspofungin, micafungin), and voriconazole are considered the best option especially for C. glabrata and C. krusei. Fluconazole remains a valid option for infection by Candida albicans in patients not exposed to fluconazole prophylaxis. Amphotericn B deoxy-cholate is generally not recommended because of its nephrotoxicity

Reverting Immune Suppression to Enhance Cancer Immunotherapy.

Tumors employ strategies to escape immune control. The principle aim of most cancer immunotherapies is to restore effective immune surveillance. Among the different processes regulating immune escape, tumor microenvironment-associated soluble factors, and/or cell surface-bound molecules are mostly responsible for dysfunctional activity of tumor-specific CD

Clonal chromosome anomalies and propensity to myeloid malignancies in congenital amegakaryocytic thrombocytopenia (OMIM 604498).

Congenital amegakaryocytic thrombocytopenia (CAMT, OMIM 604498) is an autosomal recessive disorder characterized by absent or reduced number of megakaryocytes in the bone marrow (BM) since birth, elevated serum levels of thrombopoietin (TPO), and very low platelet count. Prognosis of CAMT patient

Molecular analysis of Fanconi anemia: the experience of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Onco-Hematology

Fanconi anemia is an inherited disease characterized by congenital malformations, pancytopenia, cancer predisposition, and sensitivity to cross-linking agents. The molecular diagnosis of Fanconi anemia is relatively complex for several aspects including genetic heterogeneity with mutations in at least 16 different genes. In this paper, we report the mutations identified in 100 unrelated probands enrolled into the National Network of the Italian Association of Pediatric Hematoly and Oncology. In approximately half of these cases, mutational screening was carried out after retroviral complementation analyses or protein analysis. In the other half, the analysis was performed on the most frequently mutated genes or using a next generation sequencing approach. We identified 108 distinct variants of the FANCA, FANCG, FANCC, FANCD2, and FANCB genes in 85, 9, 3, 2, and 1 families, respectively. Despite the relatively high number of private mutations, 45 of which are novel Fanconi anemia alleles, 26% of the FANCA alleles are due to 5 distinct mutations. Most of the mutations are large genomic deletions and nonsense or frameshift mutations, although we identified a series of missense mutations, whose pathogenetic role was not always certain. The molecular diagnosis of Fanconi anemia is still a tiered procedure that requires identifying candidate genes to avoid useless sequencing. Introduction of next generation sequencing strategies will greatly improve the diagnostic process, allowing a rapid analysis of all the genes

Omega-3 fatty acid-rich fish oil supplementation prevents rosiglitazone-induced osteopenia in aging mice

Rosiglitazone is an effective insulin-sensitizer, however, associated with bone loss mainly due to increased bone resorption, and bone marrow adiposity, and decreased bone formation. We investigated the effect of the co-administration of fish oil (FO) rich in omega-3 fatty acids (FAs) on rosiglitazone (RSG)-induced bone loss in aging C57BL/6 mice and the mechanisms underlying potential preventive effect. Mice fed the iso-caloric diet supplemented with fish oil exhibited significantly higher levels of bone density in different regions compared to the other groups. In the same cohort of mice, reduced activity of COX-2, enhanced activity of alkaline phosphatase, lower levels of cathepsin k, PPAR-?, and pro-inflammatory cytokines, and a higher level of anti-inflammatory cytokines were observed. Moreover, fish oil restored rosiglitazone-induced down-regulation of osteoblast differentiation and up-regulation of adipocyte differentiation in C3H10T1/2 cells and inhibited the up-regulation of osteoclast differentiation of RANKL-treated RAW264.7 cells. We finally tested our hypothesis on human Mesenchymal Stromal Cells (MSCs) differentiated to osteocytes and adipocytes confirming the beneficial effect of docosahexaenoic acid (DHA) omega-3 FA during treatment with rosiglitazone, through the down-regulation of adipogenic genes, such as adipsin and FABP4 along the PPARg/FABP4 axis, and reducing the capability of osteocytes to switch toward adipogenesis. Our findings demonstrate that fish oil may prevent rosiglitazone-induced bone loss by inhibiting inflammation, osteoclastogenesis, and adipogenesis and by enhancing osteogenesis in the bone microenvironment. Further clinical studies will be undertaken to establish this treatment regimen for the successful treatment of diabetic patients with rosiglitazone without adverse side effects on bone

Conjugated Linoleic Acid (CLA) co-treatment alleviates antidiabetic drug, rosiglitazone associated deterioration of bone remodeling

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia due to decreased insulin secretion, defective action or both. The rosiglitazone (RSG) is one of the oral antidiabetic drug used in type 2 (T2) DM and has a unique insulin-sensitizing capacity. However, RSG has a negative side effect on the bone as it stimulates the differentiation of bone marrow-mesenchymal stromal cells (BM-MSCs) into adipocytes at the expense of osteoblasts in the bone marrow microenvironment, disturbing the normal balance of bone remodeling and causing BM adiposity. On the other hand, the trans-10,cis-12 conjugated linoleic acid (CLA), a fatty acid is known as anti-adipogenic, pro-osteogenic. Therefor, this study was designed to assess whether CLA can alleviate the negative effect of RSG on bone. We used adipose tissue derived-mesenchymal stem cells (AT-MSCs) as a human in vitro model to study the effect of CLA, RSG and combined treatment (RSG+CLA) on the osteoblastogenic and adipogenic differentiation of AT-MSCs. Osteoblastogenesis was assessed by Alizarin Red Staining and bone mineralization was assessed by ?"OsteoImage" ?^TMassays, whereas adipogenesis was assessed by Oil Red O Staining and LipidTOX assays. Besides, the level of expression of osteogenic and adipogenic markers was measured on treated osteo- and adipo-differentiated MSCs using real time RT-PCR, immunohistochemistry (IHC) and western blot analysis. Compared to RSG group, the combined treatment group stimulates osteoblastogenesis, as evidenced by increased mineralization and upregulation of osteogenic markers OPN and RUNX2 and inhibits adipogenesis in osteogenic media as showed by decreased lipid content and downregulation of adipogenic markers FABP4, LPL and adipsin. In conclusion, the use of CLA as an adjunctive treatment reversed the effects of RSG on osteogenesis and adipogenesis. Further preclinical and clinical studies will be undertaken to establish this treatment regimen for the successful treatment of diabetic patients with rosiglitazone without adverse side effects on bone

A curated transcriptome dataset collection to investigate the functional programming of human hematopoietic cells in early life [version 1; referees: 2 approved]

Compendia of large-scale datasets made available in public repositories provide an opportunity to identify and fill gaps in biomedical knowledge. But first, these data need to be made readily accessible to research investigators for interpretation. Here we make available a collection of transcriptome datasets to investigate the functional programming of human hematopoietic cells in early life. Thirty two datasets were retrieved from the NCBI Gene Expression Omnibus (GEO) and loaded in a custom web application called the Gene Expression Browser (GXB), which was designed for interactive query and visualization of integrated large-scale data. Quality control checks were performed. Multiple sample groupings and gene rank lists were created allowing users to reveal age-related differences in transcriptome profiles, changes in the gene expression of neonatal hematopoietic cells to a variety of immune stimulators and modulators, as well as during cell differentiation. Available demographic, clinical, and cell phenotypic information can be overlaid with the gene expression data and used to sort samples. Web links to customized graphical views can be generated and subsequently inserted in manuscripts to report novel findings. GXB also enables browsing of a single gene across projects, thereby providing new perspectives on age- and developmental stage-specific expression of a given gene across the human hematopoietic system. This dataset collection is available at: http://developmentalimmunology.gxbsidra.org/dm3/geneBrowser/list

Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis

The role of the mesenchymal stromal cell- (MSC-) derived secretome is becoming increasingly intriguing from a clinical perspective due to its ability to stimulate endogenous tissue repair processes as well as its effective regulation of the immune system, mimicking the therapeutic effects produced by the MSCs. The secretome is a composite product secreted by MSC in vitro (in conditioned medium) and in vivo (in the extracellular milieu), consisting of a protein soluble fraction (mostly growth factors and cytokines) and a vesicular component, extracellular vesicles (EVs), which transfer proteins, lipids, and genetic material. MSC-derived secretome differs based on the tissue from which the MSCs are isolated and under specific conditions (e.g., preconditioning or priming) suggesting that clinical applications should be tailored by choosing the tissue of origin and a priming regimen to specifically correct a given pathology. MSC-derived secretome mediates beneficial angiogenic effects in a variety of tissue injury-related diseases. This supports the current effort to develop cell-free therapeutic products that bring both clinical benefits (reduced immunogenicity, persistence in vivo, and no genotoxicity associated with long-term cell cultures) and manufacturing advantages (reduced costs, availability of large quantities of off-the-shelf products, and lower regulatory burden). In the present review, we aim to give a comprehensive picture of the numerous components of the secretome produced by MSCs derived from the most common tissue sources for clinical use (e.g., AT, BM, and CB). We focus on the factors involved in the complex regulation of angiogenic processes