STUDY QUESTION Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficiency (POI) phenotype in young age identify copy number variants (CNVs) with a deleterious effect on ovarian function? SUMMARY ANSWER This approach has proved effective to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms. WHAT IS KNOWN ALREADY POI describes the progression toward the cessation of ovarian function before the age of 40 years. Genetic causes are highly heterogeneous and despite several genes being associated with ovarian failure, most of genetic basis of POI still needs to be elucidated. STUDY DESIGN, SIZE, DURATION The current study included 67 46,XX patients with early onset POI (<19 years) and 134 control females recruited between 2012 and 2016 at the Medical Cytogenetics and Molecular Genetics Lab, IRCCS Istituto Auxologico Italiano. PARTICIPANTS/MATERIALS, SETTING, METHODS High resolution array-CGH analysis was carried out on POI patients’ DNA. Results of patients and female controls were analyzed to search for rare CNVs. All variants were validated and subjected to a gene content analysis and disease gene prioritization based on the present literature to find out new ovary candidate genes. Case-control study with statistical analysis was carried out to validate our approach and evaluate any ovary CNVs/gene enrichment. Characterization of particular CNVs with molecular and functional studies was performed to assess their pathogenic involvement in POI. MAIN RESULTS AND THE ROLE OF CHANCE We identified 37 ovary-related CNVs involving 44 genes with a role in ovary in 32 patients. All except one of the selected CNVs were not observed in the control group. Possible involvement of the CNVs in POI pathogenesis was further corroborated by a case-control analysis that showed a significant enrichment of ovary-related CNVs/genes in patients ( P = 0.0132; P = 0.0126). Disease gene prioritization identified both previously reported POI genes (e.g. BMP15 , DIAPH2 , CPEB1 , BNC1 ) and new candidates supported by transcript and functional studies, such as TP63 with a role in oocyte genomic integrity and VLDLR which is involved in steroidogenesis. LARGE SCALE DATA ClinVar database ( ); accession numbers SCV000787656 to SCV000787743. LIMITATIONS, REASONS FOR CAUTION This is a descriptive analysis for almost all of the CNVs identified. Inheritance studies of CNVs in some non-familial sporadic cases was not performed as the parents’ DNA samples were not available. Addionally, RT-qP...

No abstract

Nuclear expression of the calcium-binding protein S100A4 is a biomarker of increased invasiveness in cholangiocarcinoma (CCA), a primary liver cancer with scarce treatment opportunities and dismal prognosis. In this study, we provide evidence that targeting S100A4 nuclear import by low dose paclitaxel (PTX), a microtubule stabilizing agent, inhibits CCA invasiveness and metastatic spread. Administration of low dose PTX to established (EGI-1) and primary (CCA-TV3) CCA cell lines expressing nuclear S100A4 triggered a marked reduction in nuclear expression of S100A4 without modifying its cytoplasmic levels, an effect associated with a significant decrease in cell migration and invasiveness. While low dose PTX did not affect cellular proliferation, apoptosis or cytoskeletal integrity, it significantly reduced SUMOylation of S100A4, a critical posttranslational modification that directs its trafficking to the nucleus. This effect of lose dose PTX was reproduced by ginkolic acid, a specific SUMOylation inhibitor. Downregulation of nuclear S100A4 by low dose PTX was associated with a strong reduction in RhoA and Cdc42 GTPase activity, MT1-MMP expression and MMP-9 secretion. In a SCID mouse xenograft model, low dose metronomic PTX treatment decreased lung dissemination of EGI-1 cells without significantly affecting their local tumor growth. In the tumor mass, nuclear S100A4 expression by CCA cells was significantly reduced, whereas rates of proliferation and apoptosis were unchanged. Overall, our findings highlight nuclear S100A4 as a candidate therapeutic target in CCA and establish a mechanistic rationale for the use of low dose PTX in blocking metastatic progression of cholangiocarcinoma.

Abomasa of 185 chamois shot during 5 consecutive hunting seasons were collected as part of a health monitoring program in an alpine area of Italy and examined for nematodes. The data were obtained during both the preceding period and that following a severe die-off caused by a pneumonia outbreak. Prevalence, mean abundance, mean intensity, and Thul Importance index were consistently high, in particular for Haemonchus contortus, having a low host specificity and high pathogenic potential. Species typical of cervids were also consistently detected. The abomasal nematode community showed an isolationist structure, suggesting its composition was primarily determined by external factors such as interspecific interaction among host species and environmental conditions. The effect of different factors (host sex, sampling site, and time) on nematode counts and aggregation were analyzed and discussed considering the peculiarities of the study site and the chamois population crash. In the light of parallel results for health monitoring, abomasal parasitism could represent a predisposing factor for the observed die-off.It has been shown that macroparasites play a role in regulating wildlife populations (see Tompkins et al., 2002 for review). However, the effect of parasites on free-ranging ruminant populations remains difficult to evaluate under field conditions due to the wide range of factors that can influence the establishment and abundance of parasite species. Host-parasite interactions may not always be clearly evident, thus leading to contradictory interpretations. Furthermore, the use of macroparasites as an index of population health, in particular, counts of gastrointestinal helminths, has often been criticized (Demarais et al., 1983;Waid et al., 1985;Rossi et al., 1997; Pérez et al., 2003). Nevertheless, different studies have demonstrated that parasites can have an impact on health status in natural ruminant populations (e.g., Gulland, 1992;Stien et al., 2002), and further data, both from an ecological perspective and a management point of view, are needed.If the effect of parasites is considered as the result of various interactions between host, parasite, and environment, studies should ideally focus on (1) the ecological correlates determining the composition and distribution of parasite communities (e.g., climatic conditions and distribution of hosts [Calvete et al., 2003]), (2) the epidemiology and host specificity of the species most likely to exert an impact on hosts (e.g., selected generalist nematodes ), and (3) the pathogenic potential of different parasite species and the contributing factors (e.g., food shortage [Gulland, 1992]). Experimental studies are generally unfeasible in wild populations for ethical and logistical reasons. However, evaluation of the parasite community within a host during particular events such as mortality outbreaks or under extreme conditions may provide an opportunity to correlate parasite populations with predisposing factors.The present study is part of a 5-yr ...

The aim of the study was to perform an investigation on the concentration of 19 minerals and cortisol in red deer (Cervus elaphus) hair, a matrix that is easy to collect with non-invasive and painless sampling, able to represent an integrative values of long-term substance concentrations, and able to give useful information, also when performed on dead animals, given its extreme stability over time. In the study thirty-five animals were included, coming from two different sides of a valley in the Stelvio National Park, where official water analysis had pointed out elevated concentrations of As in one of the two orographic sides. Hair cortisol concentrations were measured using a RIA(Radio Immuno Assay), while minerals were detected using ICP-MS (Inductively Coupled Plasma- Mass Spectrometry). Results showed a negative relationship between cortisol and some mineral concentrations (Li, Co, As, Cd, Cr and Tl) and significant differences in some mineral concentrations between park areas (Al, Co, Cu, Cd and Ni). As, Cr and cortisol differences approached statistical significance. This preliminary study represents a step forward in the study of wildlife allostatic load and a valid method for applications in wildlife management programs, in environmental studies and in public health programs.