Cytogenetics of Premature Ovarian Failure: An Investigation on 269 Affected Women

The importance of X chromosome in the aetiology of premature ovarian failure (POF) is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause

Cytogenetics of Premature Ovarian Failure: An Investigation on 269 Affected Women

The importance of X chromosome in the aetiology of premature ovarian failure (POF) is well-known but in many cases POF still remains idiopathic. Chromosome aneuploidy increase is a physiological phenomenon related to aging, but the role of low-level sex chromosome mosaicism in ovarian function is still undiscovered. Standard cytogenetic analysis was carried out in a total of 269 patients affected by POF: 27 chromosomal abnormalities were identified, including X chromosome and autosomal structural and numerical abnormalities. In 47 patients with 46,XX karyotype we performed interphase FISH using X alpha-satellite probe in order to identify X chromosome mosaicism rate. Aneuploidy rate in the patient group was significantly higher than the general population group. These findings underline the importance of X chromosome in the aetiology of POF and highlight the potential role of low-level sex chromosome mosaicism in ovarian aging that may lead to a premature onset of menopause

Effectiveness of omalizumab in patients with severe allergic asthma with and without chronic rhinosinusitis with nasal polyps: a PROXIMA study post hoc analysis

Abstract Background A significant proportion of patients with severe asthma may also suffer from nasal polyposis, which is commonly defined as chronic rhinosinusitis with nasal polyps (CRSwNP), the presence of which may adversely affect asthma treatment outcomes. The biologic agent omalizumab is effective as add-on therapy in patients with severe allergic asthma. The aim of this post hoc analysis of the PROXIMA study was to compare the efficacy of omalizumab between patients with severe allergic asthma, with and without comorbid CRSwNP. Methods PROXIMA was a prospective observational 2-part study conducted in Italy in adult patients with severe allergic asthma, where, in the second part, patients eligible for add-on omalizumab initiated treatment for 12 months. Patient baseline data such as comorbidities and history of exacerbations were collected. Outcomes were asthma control (Asthma Control Questionnaire [ACQ]), lung function (forced expiratory volume in 1 s [FEV1]) and exacerbation rate. The post hoc analysis compared these outcomes between the cohort with comorbid CRSwNP and the cohort without CRSwNP. Results Of 123 patients included in this analysis, 17 (13.8%) were in the CRSwNP cohort. There was no significant difference between cohorts in baseline clinical characteristics or in change from baseline at 12 months in ACQ values,  % of predicted FEV1 or annual asthma exacerbation rate, although results were numerically in favor of the CRSwNP cohort versus the non-CRSwNP cohort. The proportion of patients who achieved an improvement in all three outcomes was numerically greater in the CRSwNP cohort (35.7% vs 23.0%). Conclusions In an observational real-world setting, add-on omalizumab for severe allergic asthma was effective in improving asthma control, lung function and in reducing exacerbations, including in those patients with CRSwNP

TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells

Skin cancers are the most commonly diagnosed cancers. Understanding what are the factors contributing to skin tumour development can be instrumental to identify preventive therapies. The myeloid differentiation primary response gene (MyD)88, the downstream adaptor protein of most Toll-like receptors (TLR), has been shown to be involved in several mouse tumourigenesis models. We show here that TLR4, but not TLR2 or TLR9, is upstream of MyD88 in skin tumourigenesis. TLR4 triggering is not dependent on lipopolysaccharide associated to skin-colonizing bacteria, but on the high mobility group box-1 protein (HMGB1), an endogenous ligand of TLR4. HMGB1 is released by necrotic keratinocytes and is required for the recruitment of inflammatory cells and for the initiation of inflammation. The expression of TLR4 on both bone marrow-derived and radioresistant cells is necessary for carcinogenesis. Consistently, a human tissue microarray analysis showed that melanoma and colon cancer display an over-expression of TLR4 and its downstream adaptor protein MyD88 within tumours. Together, our results suggest that the initial release of HMGB1 triggers a TLR4-dependent inflammatory response that leads to tumour development

Constitutional de novo deletion of the FBXW7 gene in a patient with focal segmental glomerulosclerosis and multiple primitive tumors

Multiple primary malignant neoplasms are rare entities in the clinical setting, but represent an important issue in the clinical management of patients since they could be expression of a genetic predisposition to malignancy. A high resolution genome wide array CGH led us to identify the first case of a de novo constitutional deletion confined to the FBXW7 gene, a well known tumor suppressor, in a patient with a syndromic phenotype characterized by focal segmental glomerulosclerosis and multiple primary early/atypical onset tumors, including Hodgkin's lymphoma, Wilms tumor and breast cancer. Other genetic defects may be associated with patient's phenotype. In this light, constitutional mutations at BRCA1, BRCA2, TP53, PALB2 and WT1 genes were excluded by performing sequencing and MLPA analysis; similarly, we ruled out constitutional abnormalities at the imprinted 11p15 region by methylation specific -MLPA assay. Our observations sustain the role of FBXW7 as cancer predisposition gene and expand the spectrum of its possible associated diseases

The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide

Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of "pathogenic" T helper 17 (pT(H)17) cells and memory T(H)1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT(H)17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT(H)17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response