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Diagnosis of myeloid neoplasm is currently performed according to the presence of a predetermined set of clinical, morphological, and molecular diagnostic criteria agreed upon by a consensus of experts. Even strictly adhering to these criteria, it is possible to encounter patients who present features that are not easily ascribable to a single disease category. This is the case, e.g., of patients with de novo myeloid neoplasms with features intermediate between primary myelofibrosis (PMF) and chronic myelomonocytic leukemia (CMML). In this study, we retrospectively searched the pathological database of IRCCS Humanitas Research Hospital to identify cases of chronic myeloid neoplasm with monocytosis with a driver mutation of classic myeloproliferative neoplasms (MPN) and showing morphological MPN features. For each case, we assessed all epidemiological, clinical, histopathological, and molecular data. Then, we carried out a literature review, searching for cases with features similar to those of our patients. We retrieved a total of 13 cases presenting such criteria (9 from the literature review and 4 from our institution); in all of them, there was a coexistence of clinical, histopathological, and molecular myelodysplastic and myeloproliferative features. To date, according to current classifications (World Health Organization and International Consensus Classification), given the presence/absence of essential features for PMF or CMML, these patients should be formally diagnosed as myelodysplastic/myeloproliferative neoplasm unclassified/not otherwise specified (U/NOS). This review aims to summarize the features of these difficult cases and discuss their differential diagnosis and their classification according to the novel classifications and the existing literature on overlapping myeloid neoplasms.

Autosomal-dominant Alport syndrome: Natural history of a disease due to COL4A3 or COL4A4 gene. Alport syndrome is a clinically and genetically heterogeneous nephropathy. The majority of cases are transmitted as an X-linked semidominant condition due to COL4A5 mutations. In this form males are more severely affected than females. Less than 10% of cases are autosomal recessive due to mutation in either COL4A3 or COL4A4. In this rarer form, both males and females are severely affected. Only two cases of autosomal-dominant Alport syndrome have been reported, one due to a COL4A3 mutation and the other due to a COL4A4 mutation. Because of the paucity of the reported families, the natural history of autosomal-dominant Alport syndrome is mostly unknown. Four families with likely autosomal-dominant Alport syndrome were investigated. COL4A3 and COL4A4 genes were analyzed by denaturing high-performance liquid chromatography (HPLC). Automated sequencing was performed to identify the underlying mutation. Two families had a mutation in the COL4A4 gene and two in the COL4A3. Accurate clinical evaluation of family members showed interesting results. Affected individuals (22 persons) had a wide range of phenotypes from end-stage renal disease (ESRD) in the fifth decade to a nonprogressive isolated microhematuria. Finally, three heterozygous individuals (90, 22 and 11years old, respectively) were completely asymptomatic. This paper demonstrated that patients affected by autosomal-dominant Alport syndrome have a high clinical variability. Moreover, a reduced penetrance of about 90% (3 of 25) may be considered for the assessment of recurrence risk during genetic counseling of these families.

Background Chromosomal microarray analysis (CMA) is nowadays widely used in the diagnostic path of patients with clinical phenotypes. However, there is no ascertained evidence to date on how to assemble single/combined clinical categories of developmental phenotypic findings to improve the array‐based detection rate. Methods The Italian Society of Human Genetics coordinated a retrospective study which included CMA results of 5,110 Italian patients referred to 17 genetics laboratories for variable combined clinical phenotypes. Results Non‐polymorphic copy number variants (CNVs) were identified in 1512 patients (30%) and 615 (32%) present in 552 patients (11%) were classified as pathogenic. CNVs were analysed according to type, size, inheritance pattern, distribution among chromosomes, and association to known syndromes. In addition, the evaluation of the detection rate of clinical subgroups of patients allowed to associate dysmorphisms and/or congenital malformations combined with any other single clinical sign to an increased detection rate, whereas non‐syndromic neurodevelopmental signs and non‐syndromic congenital malformations to a decreased detection rate. Conclusions Our retrospective study resulted in confirming the high detection rate of CMA and indicated new clinical markers useful to optimize their inclusion in the diagnostic and rehabilitative path of patients with developmental phenotypes. This study provides a retrospective study coordinated by the Italian Society of Human Genetics (SIGU) of 5,110 patients referred to CMA for variable combined clinical phenotypes, collected by 17 Italian laboratories. The data extrapolated by the present cohort are compared to those of previously reported studies. In addition, the detection rate of single/combined clinical categories of patients sorted out from the overall cohort is evaluated to correctly assess the inclusion of the CMA in the diagnostic path of patients with the developmental clinical phenotypes.

Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome is caused by mutations in the UBA1 gene in myeloid precursors, leading to systemic inflammatory manifestations. We present the case of a 75-year-old man presenting with fever, panniculitis, and macrocytic anemia testing repeatedly negative for UBA1 mutations in peripheral blood samples, but ultimately found positive on bone marrow mononuclear cell DNA. The man has been successfully treated with prednisone and methotrexate.

Rett syndrome is the second most common cause of severe mental retardation in females, with an incidence of approximately 1 out of 10,000 live female births. In addition to the classic form, a number of Rett variants have been described. MECP2 gene mutations are responsible for about 90% of classic cases and for a lower percentage of variant cases. Recently, CDKL5 mutations have been identified in the early onset seizures variant and other atypical Rett patients. While the high percentage of MECP2 mutations in classic patients supports the hypothesis of a single disease gene, the low frequency of mutated variant cases suggests genetic heterogeneity. Since 1998, we have performed clinical evaluation and molecular analysis of a large number of Italian Rett patients. The Italian Rett Syndrome (RTT) database has been developed to share data and samples of our RTT collection with the scientific community (http://www.biobank.unisi.it). This is the first RTT database that has been connected with a biobank. It allows the user to immediately visualize the list of available RTT samples and, using the “Search by” tool, to rapidly select those with specific clinical and molecular features. By contacting bank curators, users can request the samples of interest for their studies. This database encourages collaboration projects with clinicians and researchers from around the world and provides important resources that will help to better define the pathogenic mechanisms underlying Rett syndrome. Hum Mutat 28(4), 329–335, 2007. © 2006 Wiley‐Liss, Inc.

Bisphosphonates (BPs) are drugs used to cure metabolic diseases like osteoporosis and oncological conditions, such as multiple myeloma and bone metastases. The pharmacological activity of these compounds is mediated by their capacity to induce a systemic osteoclast depletion, finally resulting in reduced bone resorption. In spite of their efficacy, the clinical application of BPs is sometimes associated with a frightening side effect known as osteonecrosis of the jaw (ONJ). In principle, a therapeutic approach able to elicit the local re-activation of osteoclast production could counteract the onset of ONJ and promote the healing of its lesions. Using a vitamin D3-dependent model of osteoclast differentiation, it has been previously demonstrated that when used at supra-physiological concentrations, magnesium strongly favors the process under consideration, and its effect is furtherly enhanced by the presence of a BP called zoledronate. Here, we show that similar results can be obtained in a RANKL-dependent model of osteoclast differentiation, suggesting that a topical therapy based on magnesium may be also suitable for ONJ determined by denosumab in light of the ability of this monoclonal antibody to target RANKL.

Bisphosphonates (BPs) are successfully used to cure a number of diseases characterized by a metabolic reduction in bone density, such as Osteoporosis, or a neoplastic destruction of bone tissue, such as multiple myeloma and bone metastases. These drugs exert their therapeutic effect by causing a systemic osteoclast depletion that, in turn, is responsible for reduced bone resorption. Unfortunately, in addition to their beneficial activity, BPs can also determine a frightening side effect known as osteonecrosis of the jaw (ONJ). It is generally believed that the inability of osteoclasts to dispose of inflamed/necrotic bone represents the main physiopathological aspect of ONJ. In principle, a therapeutic strategy able to elicit a local re-activation of osteoclast production could counteract ONJ and promote the healing of its lesions. Using an experimental model of Vitamin D3-dependent osteoclastogenesis, we have previously demonstrated that Magnesium is a powerful inducer of osteoclast differentiation. Here we show that, surprisingly, this effect is greatly enhanced by the presence of Zoledronate, chosen for our study because it is the most effective and dangerous of the BPs. This finding allows us to hypothesize that Magnesium might play an important role in the topical therapy of ONJ.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent an excellent alternative to animals for cardiac studies. However, their immature fetal phenotype represents an important limit to consider. Approaches proposed to overcome this issue are based on better reproducing the native CMs microenvironment. In the present work, a biomimetic environment to enhance hiPSC-CMs maturation was developed by combining a 14-day co-culture of hiPSC-CMs and Human Coronary Artery Endothelial cells (HCAECs) in a 3D Gelatin Methacryloyl (GelMA) hydrogel system. Chemical characterization of custom-synthesized GelMA was performed through Attenuated Total Reflectance Fourier Transformed Infrared (ATR-FTIR) and proton Nuclear Magnetic Resonance ( H NMR) spectroscopies. GelMA degree of methacryloylation (DoM) was estimated through the ninhydrin colorimetric assay. Then, hydrogels were prepared by solubilizing GelMA in presence of phenyl-2,4,6-trimethyl-benzoyl phosphinate (LAP) as photoinitiator (0.05% w/v) and photo-rheological tests were carried out to investigate the photo-polymerization process (at 365 nm, 10 mW/cm ) and the mechanical properties of the resulting gels. Hydrogel swelling ratio was also monitored up to 5 days of incubation in aqueous medium at 37°C. The maturation phenotype was achieved by co-culturing hiPSC-CMs with HCAECs in the 3D model composed of GelMA with around 96% DoM, solubilized at 5% w/v concentration in cell culture medium, added with LAP and crosslinked by UV light (40 s). The expression of specific cardiac maturation markers was investigated through Real-Time PCR (RT-PCR). Omics analyses were carried out to compare terms of biological processes, cellular components, and molecular functions between the 3D model here presented and a classical 2D monoculture of hiPSC-CMs. GelMA was successfully synthesized with two different DoMs (i.e., 30%-40% and 96%-97%) and used to prepare hydrogels at 5%, 7.5% and 10% w/v concentrations. Both GelMA DoM and hydrogel concentration appeared as tuning parameters of gel behavior in aqueous environment at 37°C and mechanical properties, with Young's Modulus of photo-cured gels ranging between 4 and 55 kPa. Within this plethora, photo-cured gels prepared from GelMA with . 96% DoM solubilized at 5% w/v concentration showed prolonged stability over time and E value (8.70 ± 0.12 kPa) similar to the native cardiac tissue and were thus selected to design bioengineered cardiac tissue models upon hiPSC-CMs and HCAECs loading. A direct comparison with the classical 2D monoculture of hiPSC-CMs highlighted the improved maturation profile achieved by hiPSC-CMs in the 3D GelMA system, as demonstrated by the higher expression of cardiac maturation markers (TNNT2, ACTN2, Myl2, MYH 7, CX43 and PPAR-α), in association with proteomics and transcriptomics data, that showed the modulation of specific biological pathways related to cardiac differentiation and contraction processes in the 3D system. A more in-depth investigation of cell health and function also suggested a higher viability and less suffering condition for cells co-cultured in the 3D hydrogel. Our results demonstrated that the 3D bioengineered model proposed here represents a good replica of the native cardiac tissue environment, improving the hiPSC-CMs maturation profile, thus opening the opportunity for its application in disease modeling and toxicological screening studies.