90 research outputs found
Molecular genetics of bladder cancer: Targets for diagnosis and therapy
No full textTransitional cell carcinoma of the bladder is a common tumor. While most patients presenting superficial disease can be expected to do well following treatment, still many patients will return to our office with muscle invasive and metastatic disease. Survival in advanced bladder cancer is less than 50%. Tumors of similar histologic grade and stage have variable behavior, suggesting that genetic alterations must be present to explain the diverse behavior of bladder cancer. It is hoped that through the study of the subtle genetic alterations in bladder cancer, important prognostic and therapeutic targets can be exploited. Many new diagnostic tests and gene therapy approaches rely on the identification and targeting of these unique genetic alterations. A review of literature published on the molecular genetics of bladder cancer from 1970 to the present was conducted. A variety of molecular genetic alterations have been identified in bladder cancer. Oncogenes (H-ras, erbB-2, EGFR, MDM2, C-MYC, CCND1), tumor suppressor genes (p53, Rb, p21, p27/KIP1, p16, PTEN, STK15, FHIT, FEZI/LZTS1, bc10), telomerase, and methylation have all been studied in bladder cancer. Several have proven to be potentially useful clinical targets in the prognosis and therapy of bladder cancer such as staining for p53 and gene therapy strategies such as p53 and fezl. Clinical trials targeting HER2/neu and the EGFR pathways are underway. The UroVysion bladder cancer assay relies on FISH to detect genetic alterations in this disease. Continuing identification of the molecular genetic alterations in bladder cancer will enhance future diagnostic and therapeutic approaches to bladder cancer. Capitalizing on these alterations will allow early detection, providing important prognostic information and unique targets for gene therapy and other therapeutic approaches
Whole genome sequencing reveals candidate causal genetic variants for spastic syndrome in Holstein cattle
No full textBovine spastic syndrome (SS) is a progressive, adult-onset neuromuscular disorder (NMD). SS is inherited but the mode of inheritance is unclear. The aim of this study was to characterize the phenotype and to identify a possible genetic cause of SS by whole-genome sequencing (WGS) and focusing on protein-changing variants. Seven affected unrelated Holstein cattle of both sexes were referred for SS at a mean age of 5.3 years (S.D.+/- 1.1) showing intermittent spasm of the skeletal muscles of the pelvic girdle. Assuming monogenic recessive inheritance, analysis of the WGS data did not reveal any private variants common to all cases. Searching for homozygous rare variants considering each case individually, allowed the identification of a rare recessive likely pathogenic missense variant in TOR3A for one case with an allele frequency of 1.69% in a global Holstein population. In the remaining six SS cases, we identified seven potentially dominant de novo mutations or inherited alleles as private heterozygous, mostly missense, variants of uncertain significance involving seven different NMD candidate genes: MPEG1, LHX8, WHAMM, NGRN, TTN, ATP1A1, PCDH1. All eight candidate causal variants identified were predicted to be deleterious. This study describes for the first time WGS findings in confirmed cases of bovine SS and provides evidence for a heterogeneous genetic cause of SS in cattle
Takayasu disease presenting as malignant pyoderma gangrenosum in a child with relapsing polychondritis
No full textA 7-year-old Lebanese girl with recently diagnosed relapsing polychondritis had a 1-month history of several painful ulcerations involving her entire body. Skin biopsy was consistent with the diagnosis of pyoderma gangrenosum. She was hospitalized and started on intravenous steroids with partial improvement. During her hospital stay, she developed right wrist drop. Radiologic studies revealed a large aortic aneurysm and an axillary aneurysm compressing the right brachial nerve plexus. Pathology of the resected aortic anyeurism confirmed the diagnosis of Takayasu's arteritis. The patient was started on infliximab therapy with complete resolution of her skin lesions and improvement in hand function. © 2008 American Academy of Dermatology, Inc.Aoussar A, 2007, ANN DERMATOL VENER, V134, P264, DOI 10.1016-S0151-9638(07)91510-0; Barretto SN, 2002, MAYO CLIN PROC, V77, P971; Bell D, 2007, PLAST RECONSTR SURG, V120, P1087, DOI 10.1097-01.prs.0000278184.60488.8e; Brooklyn TN, 2006, GUT, V55, P505, DOI 10.1136-gut.2005.074815; Cazabon S, 2005, EYE, V19, P222, DOI 10.1038-sj.eye.6701457; Fearfield LA, 1999, BRIT J DERMATOL, V141, P339; Hewitt D, 2007, AUSTRALAS J DERMATOL, V48, P95, DOI 10.1111-j.1440-0960.2007.00344.x; Hoffman GS, 2004, ARTHRITIS RHEUM, V50, P2296, DOI 10.1002-art.20300; Hubbard VG, 2005, BRIT J DERMATOL, V152, P1059, DOI 10.1111-J.1365-2133.2005.06467.x; Jolly M, 2005, JCR-J CLIN RHEUMATOL, V11, P213, DOI 10.1097-01.rhu.0000173218.28013.3e; Kanemitsu S, 2005, ANN THORAC SURG, V80, P1914, DOI 10.1016-j.athoracsur.2004.06.098; Karageorgaki ZT, 2007, CLIN RHEUMATOL, V26, P984, DOI 10.1007-s10067-006-0227-0; Letko E, 2002, SEMIN ARTHRITIS RHEU, V31, P384, DOI 10.1053-sarh.2002.32586; MCADAM LP, 1976, MEDICINE, V55, P193, DOI 10.1097-00005792-197605000-00001; Monsel G, 2007, ANN DERMATOL VENER, V134, P552; Moroki N, 1979, Nihon Naika Gakkai Zasshi, V68, P1133; Mpofu S, 2003, RHEUMATOLOGY, V42, P1117, DOI 10.1093-rheumatology-keg280; Piette JC, 1999, ANN RHEUM DIS, V58, P656, DOI 10.1136-ard.58.10.656; PRESMANES MM, 2001, ACTA DERMOSIFILIOGR, V92, P596; Rapini RP, 2006, CLIN DERMATOL, V24, P482, DOI 10.1016-j.clindermatol.2006.07.018; Rho YH, 2005, J RHEUMATOL, V32, P954; Richez C, 2004, CLIN EXP RHEUMATOL, V22, P629; Saadoun D, 2003, J RHEUMATOL, V30, P1394; Sapienza MS, 2004, DIGEST DIS SCI, V49, P1454, DOI 10.1023-B:DDAS.0000042245.20042.4f; Sasirekha D, 2006, J Assoc Physicians India, V54, P817; Selim AGA, 2001, J CLIN PATHOL, V54, P890; Swale VJ, 2005, CLIN EXP DERMATOL, V30, P134, DOI 10.1111-j.1365-2230.2004.01681.x; Tanaka F, 2006, INTERNAL MED, V45, P313, DOI 10.2169-internalmedicine.45.1377; Ujiie H, 2004, CLIN EXP DERMATOL, V29, P357, DOI 10.1111-j.1365-2230.2004.01514.x; Vounotrypidis P, 2006, RHEUMATOLOGY, V45, P491, DOI 10.1093-rheumatology-kel04185
A frameshift insertion in FA2H causes a recessively inherited form of ichthyosis congenita in Chianina cattle
No full textThe aim of this study was to characterize the phenotype and to identify the genetic etiology of a syndromic form of ichthyosis congenita (IC) observed in Italian Chianina cattle and to estimate the prevalence of the deleterious allele in the population. Sporadic occurrence of different forms of ichthyosis including IC have been previously reported in cattle. However, so far, no causative genetic variant has been found for bovine IC. Nine affected cattle presenting congenital xerosis, hyperkeratosis and scaling of the skin as well as urolithiasis and cystitis associated with retarded growth were examined. Skin histopathology revealed a severe, diffuse orthokeratotic hyperkeratosis with mild to moderate epidermal hyperplasia. The pedigree records indicated a monogenic recessive trait. Homozygosity mapping and whole-genome sequencing allowed the identification of a homozygous frameshift 1 bp insertion in the FA2H gene (c.9dupC; p.Ala4ArgfsTer142) located in a 1.92 Mb shared identical-by-descent region on chromosome 18 present in all cases, while the parents were heterozygous as expected for obligate carriers. These findings enable the selection against this sub-lethal allele showing an estimated frequency of ~ 7.5% in Chianina top sires. A sporadic incidence of mild clinical signs in the skin of heterozygous carriers was observed. So far, pathogenic variants affecting the encoded fatty acid 2-hydroxylase catalyzing the synthesis of 2-hydroxysphingolipids have been associated with myelin disorders. In conclusion, this study represents the first report of an FA2H-related autosomal recessive inherited skin disorder in a mammalian species and adds FA2H to the list of candidate genes for ichthyosis in humans and animals. Furthermore, this study provides a DNA-based diagnostic test that enables selection against the identified pathogenic variant in the Chianina cattle population. However, functional studies are needed to better understand the expression of FA2H in IC-affected Chianina cattle
locus
No full textEar morphology is an important determinant of sheep breeds. It includes different variable traits such as ear size and erectness, suggesting a polygenic architecture. Here, we performed a comprehensive genome-wide analysis to identify regions under selection for ear morphology in 515 sheep from 17 breeds fixed for diverse ear phenotypes using 34k SNP genotyping data. GWASs for two ear type traits, size and erectness, revealed a single genome-wide significant association on ovine chromosome 3. The derived marker alleles were enriched in sheep with large and/or floppy ears. The GWAS signal harboured the MSRB3 gene encoding methionine sulphoxide reductase B3, which has already been found to be associated with different ear types in other species. We attempted whole-genome resequencing to identify causal variant(s) within a 1 Mb interval around MSRB3. This experiment excluded major copy number variants in the interval, but failed to identify a compelling candidate causal variant. Fine-mapping suggested that the causal variant for large floppy ears most likely resides in a 175 kb interval downstream of the MSRB3 coding region
Multiple independent de novo mutations are associated with the development of schistosoma reflexum, a lethal syndrome in cattle
No full textSchistosoma reflexum (SR) is a lethal congenital syndrome characterized by U-shaped dorsal retroflexion of the spine and exposure of abdominal viscera. SR is usually associated with severe dystocia. The syndrome is thought to be inherited as a Mendelian trait. We collected a series of 23 SR-affected calves from four breeds (20 Holstein, one Red Danish, one Limousin, one Romagnola) and performed whole-genome sequencing (WGS). WGS was performed on 51 cattle, including 14 cases with parents (trio-based; Group 1) and nine single cases (solo-based; Group 2). Sequencing-based genome-wide association studies with 20 Holstein cases and 154 controls showed no association (above Bonferroni threshold; P-value<3 ×10-09). Assuming a monogenic recessive inheritance, no region of shared homozygosity was observed, suggesting heterogeneity. Alternatively, the presence of possible dominant acting de novo mutations were assessed. In Group 1, heterozygous private variants, absent in both parents, were found in seven cases. These involved the ACTL6A, FLNA, GLG1, IQSEC2, MAST3, MBTPS2, and MLLT1 genes. In addition, heterozygous private variants affecting the genes DYNC1LI1, PPP2R2B, SCAF8, SUGP1, and UBP1 were identified in five cases from Group 2. The detected frameshift and missense variants are predicted to cause haploinsufficiency. Each of these 12 affected genes belong to the class of haploinsufficient loss-of-function genes or are involved in embryonic and pre-weaning lethality or are known to be associated with severe malformation syndromes in humans and/or mice. This study presents for the first time a detailed genomic evaluation of bovine SR, suggesting that independent de novo mutations may explain the sporadic occurrence of SR in cattle.</p
MITOSTATIN, A NOVEL MITOCHONDRIAL PROTEIN, THAT ACTS AS A TUMOR SUPPRESSOR IN PROSTATE CANCER CELLS
No full textMitostatin is a novel putative tumor suppressor gene at chromosome 12q24.1. The 62-kD Mitostatin protein is expressed in most normal human tissues and its immunohistochemical staining is reduced in advanced stages primary breast and bladder tumors. Mitostatin expression negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27.To determine the role of Mitostatin in prostate cancer we transfected LNCaP, PC3, and DU145 prostate cancer cells with an expression vector encoding Mitostatin -V5 fusion protein or expressing the antisense cDNA of the coding sequence of Mitostatin. In addition, we silenced endogenous Mitostatin by siRNA strategies. Mitostatin expression in primary human prostate tumors was analyzed by immunohistochemistry using three tissue arrays (AccuMax Array - A222, A223 and A302) consisted of 293 0.6-mm cores.Our results demonstrate that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells in addition to induce a reduction in cell growth, significantly inhibits migration and invasion. Moreover, Mitostatin inhibits colony formation in soft-agar in PC3 and LNCaP cells and LNCaP tumorigenicity in nude mice. Conversely, targeting endogenous Mitostatin with siRNA and anti-sense strategies in PC3 and DU145 prostate cancer cells promotes transformation in both cell lines. Mitostatin immunohistochemical staining was absent in 35.5% of prostate tumor samples and its overall reduction was significantly associated with advanced stage disease.Our findings support the hypothesis that Mitostatin acts as a bona fide tumor suppressor and suggest that further investigations of Mitostatin as a useful clinical marker for diagnosis and prognosis in prostate tumors are warranted
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NACA Advanced Restricted Reports
No full text"Three widely different nose shapes were tested on a fuselage alone and on a complete model in the UACA stability tunnel to investigate the effect of cowling shape on stability characteristics. The results are presented in the form of charts which show the variation in the aerodynamic characteristics with the three nose shapes for the propeller-removed condition over a wide range of angles of attack and yaw. The results of the investigation indicated that large changes in the cowling shape produced relatively small changes in the aerodynamic characteristics" (p. 1)
Wind Tunnel Investigation at Low Speed of the Aerodynamic Characteristics of the Army Chemical Corps Model E112 Bomblets
No full textA stability study of transparent conducting WO3/Cu/WO3 coatings with antimicrobial properties
No full textThis study was financially supported by ERDF project No. 1.1.1.1/21/A/050 “Large area deposition technologies of multifunctional antibacterial and antiviral nanocoatings”. The Institute of Solid State Physics, University of Latvia, as a Center of Excellence, has received funding from the European Union's Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART².WO3/Cu/WO3 coatings are transparent electrodes, but conductivity and transmittance have been observed to decrease with time. This paper reports the improved stability of WO3/Cu/WO3 coatings deposited by magnetron sputtering on glass and polyethylene terephthalate substrates. The stability issues due to Cu oxidation and migration can be addressed by adjusting the deposition parameters. Lowering the sputtering pressure results in denser WO3 films, confirmed by spectroscopic ellipsometry, and thus more stable coatings. The coatings retain their properties in an inert atmosphere, indicating that Cu oxidation is the main reason for the decrease in conductivity, rather than its migration observed by X-ray photoelectron spectroscopy. Optical property modeling is used to optimize the thickness of the three-layer coatings to obtain the highest figure-of-merit for a transparent electrode. A structure of glass/WO3 (70 nm)/Cu (10 nm)/WO3 (45 nm) gives a sheet resistance of 14 Ω/sq. and a light transmittance of 65% at 600 nm. In addition, the antimicrobial properties of these coatings are revealed. A decrease up to 105 of the gram-negative Escherichia coli and gram-positive Staphylococcus aureus bacterial colony formation units is found for several WO3/Cu/WO3-based coatings. In the case of the MS2 (Emesvirus zinderi) bacteriophage, a decrease in infectious particles for up to 104 plaque-forming units is obtained. The results indicate that more stable samples also had higher antimicrobial activity. --//-- This is an open access article M. Zubkins, V. Vibornijs, E. Strods, I. Aulika, A. Zajakina, A. Sarakovskis, K. Kundzins, K. Korotkaja, Z. Rudevica, E. Letko, J. Purans, A stability study of transparent conducting WO3/Cu/WO3 coatings with antimicrobial properties,
Surfaces and Interfaces, Volume 41, 2023, 103259, ISSN 2468-0230, https://doi.org/10.1016/j.surfin.2023.103259 published under the CC BY licence.ERDF project No. 1.1.1.1/21/A/050. The Institute of Solid State Physics, University of Latvia, as a Center of Excellence, has received funding from the European Union's Horizon 2020 Framework Programme H2020-WIDESPREAD-01-2016-2017-TeamingPhase2 under grant agreement No. 739508, project CAMART²
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