NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function

Inter-Method Differences in the Measurement of Some Specific Plasma Proteins: Commutability of Control Materials

Peer Reviewe

La Diffusione del genere <i>Alexandrium</i> (Dinophyceae) nelle acque costiere mediterranee è correlata alle attività umane? = Is the spreading of the <i>genus Alexandrium</i> (Dinophyceae) in Mediterranean coastal waters related to human activity?

The spreading of the dinoflagellates Alexandrium spp. in Mediterranean coastal waters, as well as the possible relationships with water trophic status and anthropic influence, were studied in the framework of a recent European project. Extensive monitoring, carried out along the coast of Spain (Catalonia and Balearic Islands), Greece (Aegean regions) and Italy (Sardinia and Sicily), indicated that the major HAB (Harmful Algal Blooms) problems are in the Catalan area which is characterized by the highest nutrient local and marked human intervention along the coast

Hyperexpression of HOXC13, located in the 12q13 chromosomal region, in well-differentiated and dedifferentiated human liposarcomas

Liposarcoma (LPS) is the most common soft tissue neoplasm in adults and is characterized by neoplastic adipocyte proliferation. Some subtypes of LPSs show aberrations involving the chromosome 12. The most frequent are t(12;16) (q13;p11) present in more than 90% of myxoid LPSs and 12q13-15 amplification in well-differentiated and dedifferentiated LPSs. In this region, there are important oncogenes such as CHOP (DDIT3), GLI, MDM2, CDK4, SAS, HMGA2, but also the HOXC locus, involved in development and tumor progression. In this study, we evaluated the expression of HOXC13, included in this chromosomal region, in a series of adipocytic tumors. We included 18 well-differentiated, 4 dedifferentiated, 11 myxoid and 6 pleomorphic LPSs as well as 13 lipomas in a tissue microarray. We evaluated the HOXC13 protein and gene expression by immunohistochemistry and quantitative PCR. Amplification/translocation of the 12q13-15 region was verified by FISH. Immunohistochemical HOXC13 overexpression was observed in all well-differentiated and dedifferentiated LPSs, all characterized by the chromosome 12q13-15 amplification, and confirmed by quantitative PCR analysis. In conclusion, our data show a deregulation of the HOXC13 marker in well-differentiated and dedifferentiated LPSs, possibly related to 12q13-15 chromosomal amplification

Pattern of Hepatitis A Virus Epidemiology in Nursing Students and Adherence to Preventive Measures at Two Training Wards of a University Hospital

Background: Nursing students can be exposed to patients with hepatitis A virus (HAV) and can represent a vehicle of transmission both for health personnel, patients and relatives. Objectives: The aim of this study was to assess the risk of HAV infection in nursing students during their internship. Patients and Methods: A seroprevalence survey on HAV infection was performed on nursing students at the Cagliari university-hospital, together with the assessment of the compliance to preventive measures to decrease the risk of infection during their internship. Blood specimens were obtained from 253 students. All serum samples were tested for anti-HAV antibodies (IgG) by the enzyme-linked immunosorbent assay (ELISA). Compliance to preventive measures was recorded by trained personnel. Results: Overall HAV seropositivity in nursing students (mean age 24, range 17 - 45 years) was 3%. Compliance to preventive measures was not uniform (6% - 76%) and extremely low in some specific measures targeted to decrease the oral-fecal transmission. Conclusions: The high proportion of susceptible nursing students can contribute to an increase in the risk of nosocomial transmission, especially when specific preventive measures are not completely applied. Nursing education packages, before starting medical internship, should be implemented in order to increase their compliance to preventive measures, especially in wards at higher risk. Vaccination should be considered in wards at higher risk

Pattern of hepatitis A virus epidemiology in nursing students and adherence to preventive measures at two training wards of a university hospital

Background: Nursing students can be exposed to patients with hepatitis A virus (HAV) and can represent a vehicle of transmission both for health personnel, patients and relatives. Objectives: The aim of this study was to assess the risk of HAV infection in nursing students during their internship. Patients and Methods: A seroprevalence survey on HAV infection was performed on nursing students at the Cagliari university-hospital, together with the assessment of the compliance to preventive measures to decrease the risk of infection during their internship. Blood specimens were obtained from 253 students. All serum samples were tested for anti-HAV antibodies (IgG) by the enzyme-linked immunosorbent assay (ELISA). Compliance to preventive measures was recorded by trained personnel. Results: Overall HAV seropositivity in nursing students (mean age 24, range 17 - 45 years) was 3%. Compliance to preventive measures was not uniform (6% - 76%) and extremely low in some specific measures targeted to decrease the oral-fecal transmission. Conclusions: The high proportion of susceptible nursing students can contribute to an increase in the risk of nosocomial transmission, especially when specific preventive measures are not completely applied. Nursing education packages, before starting medical internship, should be implemented in order to increase their compliance to preventive measures, especially in wards at higher risk. Vaccination should be considered in wards at higher risk

Genomic classification of serous ovarian cancer with adjacent borderline differentiates RAS pathway and TP53-mutant tumors and identifies NRAS as an oncogenic driver

Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinumbased chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors.We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies.Experimental Design: We reviewed >1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling.Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC.Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents

Genomic Classification of Serous Ovarian Cancer with Adjacent Borderline Differentiates RAS Pathway and TP53-Mutant Tumors and Identifies NRAS as an Oncogenic Driver.

PURPOSE: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. EXPERIMENTAL DESIGN: We reviewed \u3e1,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. RESULTS: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC; however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first example of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. CONCLUSION: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res; 20(24); 6618-30. ©2014 AACR. Clin Cancer Res 2014 Dec 15; 20(24):6618-30