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PURPOSE: Isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase gene promoter (TERTp) mutations play crucial roles in glioma biology. Such genetic information is typically obtained invasively from excised tumor tissue; however, these mutations need to be identified preoperatively for better treatment planning. The relative cerebral blood volume (rCBV) information derived from dynamic susceptibility contrast MRI (DSC-MRI) has been demonstrated to correlate with tumor vascularity, functionality, and biology, and might provide some information about the genetic alterations in gliomas before surgery. Therefore, this study aims to predict IDH and TERTp mutational subgroups in gliomas using deep learning applied to rCBV images. METHOD: After the generation of rCBV images from DSC-MRI data, classical machine learning algorithms were applied to the features obtained from the segmented tumor volumes to classify IDH and TERTp mutation subgroups. Furthermore, pre-trained convolutional neural networks (CNNs) and CNNs enhanced with attention gates were trained using rCBV images or a combination of rCBV and anatomical images to classify the mutational subgroups. RESULTS: The best accuracies obtained with classical machine learning algorithms were 83 %, 68 %, and 76 % for the identification of IDH mutational, TERTp mutational, and TERTp-only subgroups, respectively. On the other hand, the best-performing CNN model achieved 88 % accuracy (86 % sensitivity, 91 % specificity) for the IDH-mutational subgroups, 70 % accuracy (73 % sensitivity and 67 % specificity) for the TERTp-mutational subgroups, and 84 % accuracy (86 % sensitivity, 81 % specificity) for the TERTp-only subgroup using attention gates. CONCLUSIONS: DSC-MRI can be utilized to noninvasively classify IDH- and TERTp-based molecular subgroups of gliomas, facilitating preoperative identification of these genetic alterations.
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Neoplasias Encefálicas , Aprendizaje Profundo , Glioma , Humanos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/diagnóstico por imagen , Glioma/genética , Glioma/patología , Isocitrato Deshidrogenasa/genética , Imagen por Resonancia Magnética , MutaciónRESUMEN
Identifying pathogenic missense variants in hereditary cancer is critical to the efforts of patient surveillance and risk-reduction strategies. For this purpose, many different gene panels consisting of different number and/or set of genes are available and we are particularly interested in a panel of 26 genes with a varying degree of hereditary cancer risk consisting of ABRAXAS1, ATM, BARD1, BLM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, and XRCC2. In this study, we have compiled a collection of the missense variations reported in any of these 26 genes. More than a thousand missense variants were collected from ClinVar and the targeted screen of a breast cancer cohort of 355 patients which contributed to this set with 160 novel missense variations. We analyzed the impact of the missense variations on protein stability by five different predictors including both sequence- (SAAF2EC and MUpro) and structure-based (Maestro, mCSM, CUPSAT) predictors. For the structure-based tools, we have utilized the AlphaFold (AF2) protein structures which comprise the first structural analysis of this hereditary cancer proteins. Our results agreed with the recent benchmarks that computed the power of stability predictors in discriminating the pathogenic variants. Overall, we reported a low-to-medium-level performance for the stability predictors in discriminating pathogenic variants, except MUpro which had an AUROC of 0.534 (95% CI [0.499-0.570]). The AUROC values ranged between 0.614-0.719 for the total set and 0.596-0.682 for the set with high AF2 confidence regions. Furthermore, our findings revealed that the confidence score for a given variant in the AF2 structure could alone predict pathogenicity more robustly than any of the tested stability predictors with an AUROC of 0.852. Altogether, this study represents the first structural analysis of the 26 hereditary cancer genes underscoring 1) the thermodynamic stability predicted from AF2 structures as a moderate and 2) the confidence score of AF2 as a strong descriptor for variant pathogenicity.
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Colorectal cancer is the third most common cancer in Turkey. The current guidelines do not provide sufficient information to cover all aspects of the management of rectal cancer. Although treatment has been standardized in terms of the basic principles of neoadjuvant, surgical, and adjuvant therapy, uncertainties in the management of rectal cancer may lead to significant differences in clinical practice. In order to clarify these uncertainties, a consensus program was constructed with the participation of the physicians from the Acibadem Mehmet Ali Aydinlar and Koç Universities. This program included the physicians from the departments of general surgery, gastroenterology, pathology, radiology, nuclear medicine, medical oncology, radiation oncology, and medical genetics. The gray zones in the management of rectal cancer were determined by reviewing the evidence-based data and current guidelines before the meeting. Topics to be discussed consisted of diagnosis, staging, surgical treatment for the primary disease, use of neoadjuvant and adjuvant treatment, management of recurrent disease, screening, follow-up, and genetic counseling. All those topics were discussed under supervision of a presenter and a chair with active participation of related physicians. The consensus text was structured by centralizing the decisions based on the existing data.
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Neoplasias del Recto , Terapia Combinada , Consenso , Humanos , Oncología Médica , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias del Recto/patología , Neoplasias del Recto/terapiaRESUMEN
Assisted reproduction technology has two significant problems: low success rates and multiple pregnancies. Because of these problems, the priority in IVF clinics is to develop a potential diagnostic test that can be used to select the embryos with the ultimate developmental competence. Aneuploidy screening as embryo selection criteria will ensure that the transferred embryos are euploid and high implantation rate. We hypothesize that aneuploidy in human preimplantation embryos could be discriminated by their amino acid metabolism profile in the spent culture media. Preimplantation genetic testing for aneuploidy results and spent embryo culture medium amino acid content were analyzed for 58 couples. The next-generation sequencing technique was used and coupled with TE biopsy. Forty euploid and 71 aneuploid blastocysts were evaluated. Embryos were cultured individually until day 5 or 6 of embryo development. Spent culture medium was collected after finishing the culture. There was no statistical difference between D3 and D5 embryo morphology between euploid and aneuploid embryos (p > .05). Eight amino acids, including SER, GLY, HIS, ARG, THR, ALA, PRO, and TYR, were detected in the culture medium from the blank control group, euploid group, and aneuploid group. Only TYR amino acid concentration was found significantly higher in the aneuploid group compared to the euploid group (p < .003). Tyrosine amino acid levels equal to and above 76.38 µmol/L could be considered aneuploid. Aneuploid embryos demonstrate altered amino acid turnover in vitro relative to euploid counterparts. A noninvasive method of amino acid profiling will be of value as a tool for routine preimplantation embryo selection among all patient groups.
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Diagnóstico Preimplantación , Aminoácidos/metabolismo , Aneuploidia , Blastocisto/metabolismo , Técnicas de Cultivo de Embriones/métodos , Implantación del Embrión , Femenino , Pruebas Genéticas/métodos , Humanos , Embarazo , Diagnóstico Preimplantación/métodosRESUMEN
Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Mutación , Acortamiento del Telómero , Alelos , Proteína BRCA1/química , Proteína BRCA2/química , Femenino , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Modelos Moleculares , Conformación Proteica , Reacción en Cadena en Tiempo Real de la Polimerasa , Medición de Riesgo , Factores de Riesgo , Relación Estructura-ActividadRESUMEN
BACKGROUND: There is a growing interest in noninvasively defining molecular subsets of hemispheric diffuse gliomas based on the isocitrate dehydrogenase (IDH) and telomerase reverse transcriptase gene promoter (TERTp) mutation status, which correspond to distinct tumor entities, and differ in demographics, natural history, treatment response, recurrence, and survival patterns. PURPOSE: To investigate whether metabolite levels detected with short echo time (TE) proton MR spectroscopy (1 H-MRS) at 3T can be used for noninvasive molecular classification of IDH and TERTp mutation-based subsets of gliomas. STUDY TYPE: Retrospective. SUBJECTS: In all, 112 hemispheric diffuse gliomas (70 males/42 females, mean age: 42.1 ± 13.9 years). FIELD STRENGTH/SEQUENCE: Short-TE 1 H-MRS (repetition time (TR) = 2000 msec, TE = 30 msec, number of signal averages = 192) and routine clinical brain tumor MR protocols were acquired at 3T. ASSESSMENT: 1 H-MRS data were quantified using LCModel software. TERTp and IDH1 or IDH2 (IDH1/2) mutations in the tissue were determined by either minisequencing or Sanger sequencing. STATISTICAL TESTS: Metabolic differences between IDH mutant and IDH wildtype gliomas were assessed by a Mann-Whitney U-test. A Kruskal-Wallis test followed by a Tukey-Kramer test was used to analyze metabolic differences between IDH and TERTp mutational molecular subsets of gliomas. A Spearman rank correlation coefficient was used to assess the correlations of metabolite intensities with the Ki-67 index. Furthermore, machine learning was employed to classify the IDH and TERTp mutational status of gliomas, and the accuracy, sensitivity, and specificity values were estimated. RESULTS: Short-TE 1 H-MRS classified the presence of an IDH mutation with 88.39% accuracy, 76.92% sensitivity, and 94.52% specificity, and a TERTp mutation within primary IDH wildtype gliomas with 92.59% accuracy, 83.33% sensitivity, and 95.24% specificity. DATA CONCLUSION: Short-TE 1 H-MRS could be used to identify molecular subsets of hemispheric diffuse gliomas corresponding to IDH and TERTp mutations. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1799-1809.
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Neoplasias Encefálicas , Glioma , Telomerasa , Adulto , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Femenino , Glioma/diagnóstico por imagen , Glioma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Masculino , Persona de Mediana Edad , Mutación , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Telomerasa/genéticaRESUMEN
The geographical location and differences in tumor biology significantly change the management of gastric cancer. The prevalence of gastric cancer ranks fifth and sixth among men and women, respectively, in Turkey. The international guidelines from the Eastern and Western countries fail to manage a considerable amount of inconclusive issues in the management of gastric cancer. The uncertainties lead to significant heterogeneities in clinical practice, lack of homogeneous data collection, and subsequently, diverse outcomes. The physicians who are professionally involved in the management of gastric cancer at two institutions in Istanbul, Turkey, organized a consensus meeting to address current problems and plan feasible, logical, measurable, and collective solutions in their clinical practice for this challenging disease. The evidence-based data and current guidelines were reviewed. The gray zones in the management of gastric cancer were determined in the first session of this consensus meeting. The second session was constructed to discuss, vote, and ratify the ultimate decisions. The identification of the T stage, the esophagogastric area, imaging algorithm for proper staging and follow-up, timing and patient selection for neoadjuvant treatment, and management of advanced and metastatic disease have been accepted as the major issues in the management of gastric cancer. The recommendations are presented with the percentage of supporting votes in the results section with related data.
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Neoplasias Gástricas/terapia , Algoritmos , Medicina Basada en la Evidencia , Humanos , Terapia Neoadyuvante , Estadificación de Neoplasias , Selección de Paciente , Pautas de la Práctica en Medicina , Prevalencia , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patología , Turquía/epidemiologíaRESUMEN
We present three siblings afflicted with a disease characterized by cerebellar ataxia, cerebellar atrophy, pyramidal tract damage with increased lower limb tendon reflexes, and onset of 31 to 57 years, which is not typical for a known disease. In a region of shared homozygosity in patients, exome sequencing revealed novel homozygous c.*240T > C variant in the 3'UTR of STUB1, the gene responsible for autosomal recessive spinocerebellar ataxia 16 (SCAR16). In other genes, such an alteration of the evolutionarily highly conserved polyadenylation signal from AATAAA to AACAAA is known to highly impair polyadenylation. In contrast, RNA sequencing and quantification revealed that neither polyadenylation nor stability of STUB1 mRNA is affected. In silico analysis predicted that the secondary structure of the mRNA is altered. We propose that this change underlies the extremely low amounts of the encoded protein in patient leukocytes.
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Variación Genética , Poli A , Poliadenilación , Ubiquitina-Proteína Ligasas/genética , Regiones no Traducidas 3' , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Ataxia Cerebelosa/diagnóstico , Ataxia Cerebelosa/genética , Análisis Mutacional de ADN , Humanos , Imagen por Resonancia Magnética , LinajeRESUMEN
BACKGROUND: Pathological inflammatory syndromes of unknown etiology are commonly observed in ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in patients with STING-associated vasculopathy in infancy (SAVI). OBJECTIVE: We sought to test the hypothesis that the inflammation-associated manifestations observed in patients with AT and Artemis deficiency stem from increased type I IFN signature leading to neutrophil-mediated pathological damage. METHODS: Cytokine/protein signatures were determined by ELISA, cytometric bead array, or quantitative PCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients' cells were quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy, and flow cytometry. RESULTS: Type I and III IFN signatures were elevated in plasma and peripheral blood cells of patients with AT, Artemis deficiency, and SAVI. Chronic IFN production stemmed from the accumulation of DNA in the cytoplasm of AT and Artemis-deficient cells. Neutrophils isolated from patients spontaneously produced NETs and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFN-α. CONCLUSIONS: Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in patients with AT, Artemis deficiency, and SAVI. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.
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Ataxia Telangiectasia/inmunología , Trampas Extracelulares/inmunología , Síndromes de Inmunodeficiencia/inmunología , Interferón Tipo I/inmunología , Ataxia Telangiectasia/patología , Proteínas de Unión al ADN , Endonucleasas/deficiencia , Endonucleasas/inmunología , Humanos , Síndromes de Inmunodeficiencia/genética , Proteínas de la Membrana/genética , Activación Neutrófila , Neutrófilos/inmunología , Neutrófilos/patología , Proteínas Nucleares/deficiencia , Proteínas Nucleares/inmunología , Vasculitis/genética , Vasculitis/inmunología , Vasculitis/patologíaRESUMEN
BACKGROUND: Jervell and Lange-Nielsen syndrome (JLNS) isa recessive model of long QT syndrome which might also be related to possible hearing loss. Although the syndrome has been demonstrated to be originated from homozygous or compound heterozygous mutations in either the KCNQ1 or KCNE1 genes, additional mutations in other genetic loci should be considered, particularly in malignant course patients. CASE PRESENTATIONS: Three patients were admitted into hospital due to recurrent seizures/syncope, intrauterine and postnatal bradycardia respectively; moreover all three patients had congenital sensorineural hearing-loss. Their electrocardiograms showed markedly prolonged QT interval. Implantable defibrillator was implanted and left cardiac sympathetic denervation was performed due to the progressive disease in case 1. She had countless ventricular fibrillation and appropriate shock while using an implantable defibrillator. The DNA sequencing analysis of the KCNQ1 gene disclosed a homozygous c.728G > A (p.Arg243His) missense mutation in case1. Further targeted next generation sequencing of cardiac panel comprising 68 gene revealed a heterozygous c.1346 T > G (p.Ile449Arg) variant in RYR2 gene and a heterozygous c.809G > A (p.Cys270Tyr) variant in NKX2-5 gene in the same patient. Additional gene alterations in RYR2 and NKX2-5 genes were thought to be responsible for progressive and malignant course of the disease. As a result of DNA sequencing analysis of KCNQ1 and KCNE1 genes, a compound heterozygosity for two mutations had been detected in KCNQ1 gene in case 2: a maternally derived c.477 + 1G > A splice site mutation and a paternally derived c.520C > T (p.Arg174Cys) missense mutation. Sanger sequencing of KCNQ1 and KCNE1 genes displayed a homozygous c.1097G > A (p.Arg366Gln) mutation in KCNQ1 gene in case 3. ß-blocker therapy was initiated to all the index subjects. CONCLUSIONS: Three families of JLNS who presented with long QT and deafness and who carry homozygous, or compound heterozygous mutation in KCNQ1 gene were presented in this report. It was emphasized that broad targeted cardiac panels may be useful to predict the outcome especially in patients with unexplained phenotype-genotype correlation. Clinical presentations and molecular findings will be discussed further to clarify the phenotype genotype associations.
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Pérdida Auditiva Sensorineural/congénito , Síndrome de Jervell-Lange Nielsen/genética , Canal de Potasio KCNQ1/genética , Polimorfismo de Nucleótido Simple , Antagonistas Adrenérgicos beta/uso terapéutico , Preescolar , Electrocardiografía , Femenino , Pérdida Auditiva Sensorineural/etiología , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteína Homeótica Nkx-2.5/genética , Homocigoto , Humanos , Lactante , Síndrome de Jervell-Lange Nielsen/diagnóstico , Síndrome de Jervell-Lange Nielsen/tratamiento farmacológico , Masculino , Linaje , Canales de Potasio con Entrada de Voltaje/genética , Canal Liberador de Calcio Receptor de Rianodina/genética , Análisis de Secuencia de ADN/métodos , TurquíaRESUMEN
BACKGROUND: Meningiomas are one of the most common tumours to affect the central nervous system. Genetic mutations are important in meningeal tumourigenesis, progression and prognosis. In this study, we aimed to examine the effect of 1p/19q deletion on the diagnosis and prognosis of meningioma subtypes using the fluorescence in situ hybridization (FISH) method. METHODS: Twenty-four patients with meningioma were retrospectively studied. Tumour samples were obtained from 10 typical, 11 atypical and three anaplastic malignant meningiomas. The most representative tumour sections were screened for 1p/19q deletion using the FISH method. RESULTS: Of the 24 patients, eight were women (33.3%) and 16 (66.7%) were men. The mean age was 56.6 years. The higher-grade meningioma was usually seen in males and had a higher rate of deletion on 1p (p = 0.001). There was a statistically significant difference between the grades and the rate of deletion on 19q (p = 0.042) and between the grades and the rates of polysomy, monosomy and amplification on 19q (p = 0.002; p = 0.001; p = 0.002, respectively). There was no statistical difference between 1p/19q codeletion and the grades of meningioma (p > 0.05). We detected higher level of Ki-67 in the condition of codeletion but did not find a statistical difference (p = 0.0553). CONCLUSION: Deletion on 1p, as well as deletion, polysomy, monosomy and amplification on 19q, are detected more frequently in high grade meningiomas. This amplification is most likely due to the amplification of oncogenes.
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Deleción Cromosómica , Cromosomas Humanos Par 19/genética , Cromosomas Humanos Par 1/genética , Meningioma/diagnóstico , Meningioma/genética , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Antígeno Ki-67/análisis , Masculino , Meningioma/terapia , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
We report an association between a new causative gene and spastic paraplegia, which is a genetically heterogeneous disorder. Clinical phenotyping of one consanguineous family followed by combined homozygosity mapping and whole-exome sequencing analysis. Three patients from the same family shared common features of progressive complicated spastic paraplegia. They shared a single homozygous stretch area on chromosome 6. Whole-exome sequencing revealed a homozygous mutation (c.853_871del19) in the gene coding the kinesin light chain 4 protein (KLC4). Meanwhile, the unaffected parents and two siblings were heterozygous and one sibling was homozygous wild type. The 19 bp deletion in exon 6 generates a stop codon and thus a truncated messenger RNA and protein. The association of a KLC4 mutation with spastic paraplegia identifies a new locus for the disease.
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Secuencia de Bases , Exones , Genes Recesivos , Enfermedades Genéticas Congénitas/genética , Proteínas Asociadas a Microtúbulos/genética , Paraplejía/genética , Carácter Cuantitativo Heredable , Eliminación de Secuencia , Codón de Terminación/genética , Exoma , Femenino , Humanos , Cinesinas , MasculinoRESUMEN
PURPOSE: Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. METHODS: We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. RESULTS: A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. CONCLUSIONS: Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene.
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Cromosomas Humanos Par 9/genética , Salud de la Familia , Genes Recesivos/genética , Predisposición Genética a la Enfermedad/genética , Defectos del Tubo Neural/genética , Niño , Femenino , Perfilación de la Expresión Génica , Humanos , Hidrocefalia/etiología , Lactante , Defectos del Tubo Neural/complicaciones , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Tomografía Computarizada por Rayos X , TurquíaRESUMEN
BACKGROUND: Klippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported. RESULTS: We identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice. CONCLUSIONS: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans.
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Síndrome de Klippel-Feil/genética , Factores de Transcripción/genética , Adulto , Animales , Cromosomas Humanos Par 17 , Femenino , Ligamiento Genético , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Proteínas de Homeodominio , Homocigoto , Humanos , Síndrome de Klippel-Feil/diagnóstico por imagen , Escala de Lod , Masculino , Ratones , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , Columna Vertebral/anomalías , Tomografía Computarizada por Rayos XRESUMEN
AIM: To evaluate the prevalence of coexisting anal human papillomavirus (HPV) infection and concordance of HPV types in women with cervical HPV infection and to investigate the possible predictors for anal HPV infection. METHODS: Study group was composed of women referred with documented cervical HPV infection. All patients had undergone anal HPV DNA testing. RESULTS: One hundred and six patients presenting with cervical HPV infection were eligible for the study. Overall, 24 and 20 distinct HPV genotypes were detected from cervical and anal specimens, respectively. We observed a considerably high prevalence (51.9 %) of coexisting anal HPV infection in our study group. A majority of the women who were found to have anal HPV infection were infected with oncogenic or probable oncogenic types (64.6 %). There were 20.0 and 58.3 % rate of total and partial concordance between the two sites, respectively. We found that no demographic parameter but history of anal intercourse was related with the risk of anal HPV infection. CONCLUSION(S): Women with cervical HPV infection have a considerable risk for coexisting anal HPV infection. Concordance of HPV types infecting the cervix and anal canal is relatively high. There is no strong predictor for anal HPV infection in this population.
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Enfermedades del Ano/epidemiología , Infecciones por Papillomavirus/epidemiología , Enfermedades del Cuello del Útero/epidemiología , Adulto , Enfermedades del Ano/complicaciones , Enfermedades del Ano/virología , Femenino , Humanos , Papillomaviridae/genética , Prevalencia , Turquía/epidemiología , Enfermedades del Cuello del Útero/complicaciones , Enfermedades del Cuello del Útero/virología , Adulto JovenRESUMEN
microRNA expression and sequence analysis database (http://konulab.fen.bilkent.edu.tr/mirna/) (mESAdb) is a regularly updated database for the multivariate analysis of sequences and expression of microRNAs from multiple taxa. mESAdb is modular and has a user interface implemented in PHP and JavaScript and coupled with statistical analysis and visualization packages written for the R language. The database primarily comprises mature microRNA sequences and their target data, along with selected human, mouse and zebrafish expression data sets. mESAdb analysis modules allow (i) mining of microRNA expression data sets for subsets of microRNAs selected manually or by motif; (ii) pair-wise multivariate analysis of expression data sets within and between taxa; and (iii) association of microRNA subsets with annotation databases, HUGE Navigator, KEGG and GO. The use of existing and customized R packages facilitates future addition of data sets and analysis tools. Furthermore, the ability to upload and analyze user-specified data sets makes mESAdb an interactive and expandable analysis tool for microRNA sequence and expression data.
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Bases de Datos de Ácidos Nucleicos , MicroARNs/química , MicroARNs/metabolismo , Animales , Humanos , Ratones , Análisis de Secuencia de ARN , Programas Informáticos , Integración de Sistemas , Interfaz Usuario-ComputadorRESUMEN
Choroid plexus papilloma (CPP) is a rare, benign epithelial brain tumor of the nervous system seen particularly in infants. Familial cases are extremely uncommon. Some other form of malignant tumors was noted in the relatives of patients with CPPs, and some genetic defects regarding this coincidence were reported in the literature. These neoplasms are occasionally bilateral and hydrocephalus is an associated sign in most of the cases. We report three lateral ventricle CPPs in two siblings, at the age of 7 month and 2 years respectively. All tumors were resected with parietotemporal craniotomy and a superior temporal sulcus approach to the lateral ventricle. To avoid a concomitant need of ventriculoperitoneal shunt insertion, external ventricular drainage was inserted for a week in the postoperative period relieving symptoms of hydrocephalus. Search for a hereditary defect in the p53 gene of the second infant (7 months old) revealed no mutation. Postoperative courses were uneventful and the patients were followed for three years without any recurrence. Bilateral CPPS are rare and unusual in two siblings. A genetic predisposition such as the p53 mutation should be investigated in bilateral CPPs in particular.
Asunto(s)
Papiloma del Plexo Coroideo , Proteína p53 Supresora de Tumor/genética , Derivación Ventriculoperitoneal , Secuencia de Bases , Preescolar , Humanos , Hidrocefalia/genética , Hidrocefalia/patología , Hidrocefalia/cirugía , Lactante , Ventrículos Laterales/patología , Ventrículos Laterales/cirugía , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Papiloma del Plexo Coroideo/genética , Papiloma del Plexo Coroideo/patología , Papiloma del Plexo Coroideo/cirugía , HermanosRESUMEN
Mycoplasma gallisepticum is the primary agent of chronic respiratory disease causing important economic losses in the poultry industry. Serological monitoring is essential to maintain mycoplasma-free breeder flocks and often complicated by the cross-reactions between different mycoplasma species. To overcome serological cross-reactions, a large fragment of the M. gallisepticum PvpA cytadhesin, species-specific surface-exposed protein, was produced in E. coli as a recombinant protein (rPvpA336) and used as a potential diagnostic antigen. The rPvpA336 protein possesses 336 mycoplasma-specific amino acids with relative molecular weight of 44 kDa. A deletion region of 37 amino acids was identified when compared to the wild-type PvpA protein. Immunoreactivity of the rPvpA336 protein has been demonstrated by Western blot analysis with M. gallisepticum-positive and -negative chicken sera. Furthermore, an enzymatic rapid immunofiltration assay (ERIFA) prototype based on the rPvpA336 protein has been developed and its species-specific detection capability has been demonstrated by using M. gallisepticum and/or M. synoviae-positive and -negative chicken sera. In addition to its species-specificity, the ERIFA prototype presents certain advantages such as rapidity, field-applicability and cost-effectiveness. Therefore, these advantages would make the prototype a species-specific rapid diagnostic tool of choice in the field and limited laboratory conditions for screening M. gallisepticum infections.