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Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder with recurrent fever, abdominal pain, serositis, articular manifestations, erysipelas-like erythema, and renal complications as its main features. Caused by the mutations in the MEditerranean FeVer (MEFV) gene, it mainly affects people of Mediterranean descent with a higher incidence in the Turkish, Jewish, Arabic, and Armenian populations. As our understanding of FMF improves, it becomes clearer that we are facing with a more complex picture of FMF with respect to its pathogenesis, penetrance, variant type (gain-of-function vs. loss-of-function), and inheritance. In this study, MEFV gene analysis results and clinical findings of 27,504 patients from 35 universities and institutions in Turkey and Northern Cyprus are combined in an effort to provide a better insight into the genotype-phenotype correlation and how a specific variant contributes to certain clinical findings in FMF patients. Our results may help better understand this complex disease and how the genotype may sometimes contribute to phenotype. Unlike many studies in the literature, our study investigated a broader symptomatic spectrum and the relationship between the genotype and phenotype data. In this sense, we aimed to guide all clinicians and academicians who work in this field to better establish a comprehensive data set for the patients. One of the biggest messages of our study is that lack of uniformity in some clinical and demographic data of participants may become an obstacle in approaching FMF patients and understanding this complex disease.
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Fiebre Mediterránea Familiar , Pirina , Fiebre Mediterránea Familiar/epidemiología , Fiebre Mediterránea Familiar/genética , Genética de Población , Genotipo , Humanos , Mutación , Fenotipo , Pirina/genética , Turquía/epidemiologíaRESUMEN
Oral-facial-digital syndromes (OFDSs) as a subgroup of ciliopathies are rare genetic disorders characterized by the association of abnormalities of the face, oral cavity, and extremities. OFDS XVII is a recently described subtype of OFDS that presents with developmental delay, facial dysmorphism, high palate, tongue nodules, brain malformations, cardiac anomaly, polydactyly, renal malformation, and various other findings. OFDS XVII is caused by biallelic variants in INTU gene and is inherited autosomal recessively. Intu is part of the CPLANE protein module that has an essential role in the ciliary transport system and function. INTU pathogenic variants have been reported in two patients with OFDS XVII, in two patients with short-rib thoracic dysplasia-20 with polydactyly (SRTD20), and one with nephronophthisis so far. We report the third family in the literature with OFDS XVII, with urogenital malformations as an additional finding.
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Síndromes Orofaciodigitales , Enfermedades Renales Poliquísticas , Polidactilia , Cara/anomalías , Humanos , Síndromes Orofaciodigitales/complicaciones , Síndromes Orofaciodigitales/diagnóstico , Síndromes Orofaciodigitales/genética , Polidactilia/complicaciones , ProteínasRESUMEN
Turnpenny-Fry syndrome is a very rare genetic disorder characterized by intellectual disability, developmental delay, facial dysmorphism, and skeletal abnormalities. Mutations of the PCGF2 gene are responsible for Turnpenny-Fry syndrome. This gene encodes the polycomb group ring finger 2 protein that is broadly expressed in various human tissues. To date, only 13 patients with Turnpenny-Fry syndrome have been reported. Our patient was referred to our clinic for neuromotor retardation and dysmorphic features. Whole exome sequencing (WES) was performed from the peripheral blood sample of the patient. WES revealed a heterozygous mutation in the PCGF2 gene. To the best of our knowledge, we reported the 14th patient with Turnpenny-Fry syndrome and the first from Turkey, who had new findings.
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Discapacidad Intelectual , Anomalías Musculoesqueléticas , Humanos , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Mutación , Turquía , Secuenciación del ExomaRESUMEN
Agenesis of Corpus Callosum, Cardiac, Ocular, and Genital Syndrome (ACOGS; OMIM #618929) is a rare genetic disorder characterized by global developmental delay, agenesis or hypoplasia of corpus callosum, craniofacial dysmorphism, ocular, cardiac, and genital anomalies. ACOGS is caused by variations in the CDH2 gene. Our patient had a novel finding besides the classical findings of ACOGS. To the best of our knowledge, only 14 patients with ACOGS have been reported. Here, we reported the fifteenth patient with ACOGS, having a novel de novo nonsense variant in the CDH2 gene, and the first patient from Turkey with a novel finding. Our patient was the first female to have a renal anomaly since only genital malformations were reported in male patients (cryptorchidism, micropenis) so far.
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Anomalías Craneofaciales , Malformaciones del Sistema Nervioso , Anomalías Urogenitales , Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/genética , Antígenos CD , Cadherinas/genética , Cuerpo Calloso , Femenino , Humanos , Masculino , Turquía , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genéticaRESUMEN
OBJECTIVE: Studies on etiopathogenesis of attention deficit/hyperactivity disorder (ADHD) are increasingly focussing on mitochondrial dysfunction. Children diagnosed with ADHD who had significantly higher mitochondrial DNA (mtDNA) copy numbers than healthy children in our first study were re-examined in 1-year follow-up to investigate effects of severity and treatment of ADHD on mtDNA. METHODS: Twenty-eight patients who participated in previous study were included in this follow-up study. Patients were equally divided into two groups according to whether they had been receiving treatment. Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version, and Conners Parent Rating Scale (CPRS) were used. Polymerase chain reaction was performed. RESULTS: Means of the first and second mtDNA copy were similar in all patients. mtDNA copy numbers did not change between two measurements in treated and non-treated groups. There was a correlation between CPRS ADHD index and inattention scores and mtDNA copy number in treated group. mtDNA copy number did not change in patients with ADHD over a period of 1 year regardless of treatment. CONCLUSIONS: There may be a relationship between decreased ADHD severity with treatment and positive effects of mitochondrial functions. Mitochondrial dysfunction may play a role in pathophysiology of ADHD.KEY POINTSThis was the first study to follow up ADHD patients in order to investigate mitochondrial dysfunction by measuring mtDNA copy numbers 1 year after the initial measurements.mtDNA copy number, one of the best markers of mitochondrial dysfunction, did not change in ADHD patients over a period of 1 year regardless of treatment.Mitochondrial dysfunction may play a role in the pathophysiology of ADHD, where it may be involved with or without treatment.In the treated group, there was an association between decreased ADHD severity and reduced mtDNA copy numbers.There may be a relationship between decreased ADHD severity with treatment and the positive effects of mitochondrial functions.
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Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/terapia , ADN Mitocondrial/genética , Enfermedades Mitocondriales/genética , Evaluación de Resultado en la Atención de Salud , Adolescente , Niño , Variaciones en el Número de Copia de ADN/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Índice de Severidad de la EnfermedadRESUMEN
Wilson disease (WD) (OMIM# 277900) is an autosomal recessive inherited disorder characterized by excess copper (Cu) storage in different human tissues, such as the brain, liver, and the corneas of the eyes. It is a rare disorder that occurs in approximately 1 in 30,000 individuals. The clinical presentations of WD are highly varied, primarily consisting of hepatic and neurological conditions. WD is caused by homozygous or compound heterozygous mutations in the ATP7B gene. The diagnosis of the disease is complicated because of its heterogeneous phenotypes. The molecular genetic analysis encourages early diagnosis, treatment, and the opportunity to screen individuals at risk in the family. In this paper, we reported a case with a novel, hotspot-located mutation in WD. We have suggested that this mutation in the ATP7B gene might contribute to liver findings, progressing to liver failure with a loss of function effect. Besides this, if patients have liver symptoms in childhood and/or are children of consanguineous parents, WD should be considered during the evaluation of the patients.
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Proteínas de Transporte de Catión , Degeneración Hepatolenticular , Adenosina Trifosfatasas/genética , Proteínas de Transporte de Catión/genética , Niño , ATPasas Transportadoras de Cobre/genética , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/genética , Humanos , MutaciónRESUMEN
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in children. Several hypotheses have been proposed to explain its etiology. Mitochondrial dysfunction (MD) is suggested to be one of the causes of Attention Deficit Hyperactivity Disorder. The objective of the study was to evaluate the relationship between MD and ADHD by investigating mitochondrial DNA (mtDNA) levels from peripheral blood leukocytes, one of the best biomarkers of mitochondrial dysfunction. SUBJECTS AND METHODS: This study included 56 children aged 6-16 years who were diagnosed with ADHD for the first time and 56 age- and sex-matched children without ADHD. Real-time PCR was performed to determine the relative mtDNA copy number in each study participant. RESULTS: The mean mtDNA copy number of the case group was 57.623±24.827 and that of the control group was 44.204±18.926 (p=0.002). The mtDNA copy number of the case group was higher than that of the control group. Results of ROC curve analysis provided a mtDNA cutoff value of 45. CONCLUSION: Significantly higher mtDNA copy number in ADHD group may suggest mitochondrial dysfunction in the etiopathogenesis of ADHD.
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Trastorno por Déficit de Atención con Hiperactividad , Variaciones en el Número de Copia de ADN , ADN Mitocondrial , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/genética , Niño , Humanos , Mitocondrias , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Vici syndrome (OMIM 242840) is a rare syndrome and since its initial description by Vici et al. [1988], only 29 cases have been reported. We describe two brothers from healthy consanguineous Turkish parents with psychomotor delay, congenital bilateral cataracts, high palate, long philtrum, micrognathia, fair hair, and skin. They both had general hypotonia and elevated muscle enzymes. Magnetic resonance imaging (MRI) of the brain confirmed agenesis of corpus callosum in both patients. Secundum type atrial septal defect (in Patient 1) and mild mitral, tricuspid, and pulmonary insufficiency (in Patient 2) were detected by echocardiographic examination. Immunological studies were normal, as were chromosome karyotype analyses (46, XY). Both children had bilateral cutaneous syndactyly between second and third toes and also bilateral sensorineural hearing loss. Patient 1 had poor feeding and regurgitation necessitating a feeding tube; mild laryngomalacia was subsequently detected by bronchoscopy. Mutation analysis in patient 2 showed a homozygous p.R2483* (c.7447C > T) mutation in EPG5 gene. We report a summary of the clinical findings in our patients and 29 cases from the literature.
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Anomalías Múltiples/genética , Agenesia del Cuerpo Calloso/genética , Encéfalo/anomalías , Catarata/genética , Anomalías Craneofaciales/genética , Atrofia Muscular/genética , Consanguinidad , Familia , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Padres , HermanosRESUMEN
The aim of this study was to investigate the 4977 and 7400 bp deletions of mitochondrial DNA in patients with chronic suppurative otitis media and to indicate the possible association of mitochondrial DNA deletions with chronic suppurative otitis media. Thirty-six patients with chronic suppurative otitis media were randomly selected to assess the mitochondrial DNA deletions. Tympanomastoidectomy was applied for the treatment of chronic suppurative otitis media, and the curettage materials including middle ear tissues were collected. The 4977 and 7400 bp deletion regions and two control regions of mitochondrial DNA were assessed by using the four pair primers. DNA was extracted from middle ear tissues and peripheral blood samples of the patients, and then polymerase chain reactions (PCRs) were performed. PCR products were separated in 2 % agarose gel. Seventeen of 36 patients had the heterozygote 4977 bp deletion in the middle ear tissue but not in peripheral blood. There wasn't any patient who had the 7400 bp deletion in mtDNA of their middle ear tissue or peripheral blood tissue. The patients with the 4977 bp deletion had a longer duration of chronic suppurative otitis media and a higher level of hearing loss than the others (p < 0.01). Long time chronic suppurative otitis media and the reactive oxygen species can cause the mitochondrial DNA deletions and this may be a predisposing factor to sensorineural hearing loss in chronic suppurative otitis media. An antioxidant drug as a scavenger agent may be used in long-term chronic suppurative otitis media.
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ADN Mitocondrial/genética , Eliminación de Gen , Otitis Media Supurativa/genética , Adolescente , Adulto , Anciano , Enfermedad Crónica , Femenino , Pérdida Auditiva Sensorineural/etiología , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
Lithium titanate (Li2TiO3) nanoparticles (LTT NPs; <100 nm) are widely used in battery technology, porcelain enamels, and ceramic insulating bodies. With the increased applications of LTT NPs, the concerns about their potential human toxicity effects and their environmental impact were also increased. However, toxicity data for LTT NPs relating to human health are very limited. Therefore, the purpose of this study was to evaluate whether LTT NPs are able to induce genetic damage in human peripheral lymphocytes in vitro when taking into consideration that DNA damage plays an important role in carcinogenesis. With this aim, the chromosome aberrations (CA), sister chromatid exchanges (SCE), and micronucleus (MN) assays were used as genotoxicity end points. Human peripheral lymphocytes obtained from five healthy male volunteers were exposed to LTT NPs at final dispersed concentrations ranging from 0 to 1000 µg/mL for 72 h at 37°C. The obtained results indicated that LTT NPs compound did not induce DNA damage in human peripheral lymphocytes as depicted by CA/cell, SCE/cell, and MN/1000 cell values in all concentrations tested. In summary, our results revealed that exposure to LTT NPs is not capable of inducing DNA lesions in human peripheral lymphocytes for the first time.
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Carcinógenos Ambientales/toxicidad , Compuestos de Litio/toxicidad , Litio/toxicidad , Linfocitos/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Mutágenos/toxicidad , Titanio/toxicidad , Adulto , Carcinógenos Ambientales/química , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Aberraciones Cromosómicas/inducido químicamente , Cristalografía por Rayos X , Humanos , Litio/química , Compuestos de Litio/química , Linfocitos/citología , Masculino , Nanopartículas del Metal/química , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Mutágenos/química , Tamaño de la Partícula , Intercambio de Cromátides Hermanas/efectos de los fármacos , Titanio/química , Adulto JovenRESUMEN
Oxidative stress is highly damaging to cellular macromolecules and is also considered a main cause of the loss and impairment of neurons in several neurodegenerative disorders. Recent reports indicate that farnesene (FNS), an acyclic sesquiterpene, has antioxidant properties. However, little is known about the effects of FNS on oxidative stress-induced neurotoxicity. We used hydrogen peroxide (H2O2) exposure for 6 h to model oxidative stress. Therefore, this experimental design allowed us to explore the neuroprotective potential of different FNS isomers (α-FNS and ß-FNS) and their mixture (Mix-FNS) in H2O2-induced toxicity in newborn rat cerebral cortex cell cultures for the first time. For this aim, both MTT and lactate dehydrogenase assays were carried out to evaluate cell viability. Total antioxidant capacity (TAC) and total oxidative stress (TOS) parameters were used to assess oxidative alterations. In addition to determining of 8-hydroxy-2-deoxyguanosine (8-OH-dG) levels in vitro, the comet assay was also performed for measuring the resistance of neuronal DNA to H2O2-induced challenge. Our results showed that survival and TAC levels of the cells decreased, while TOS, 8-OH-dG levels and the mean values of the total scores of cells showing DNA damage (comet assay) increased in the group treated with H2O2 alone. But pretreatment of FNS suppressed the cytotoxicity, genotoxicity and oxidative stress, which were increased by H2O2 in clear type of isomers and applied concentration-dependent manners. The order of antioxidant effectiveness for modulating H2O2-induced oxidative stress-based neurotoxicity and genotoxicity is as ß-FNS > Mix-FNS > α-FNS.
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Peróxido de Hidrógeno/toxicidad , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Sesquiterpenos/farmacología , 8-Hidroxi-2'-Desoxicoguanosina , Animales , Antioxidantes/metabolismo , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/patología , Daño del ADN , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/patología , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Ratas , Sesquiterpenos/químicaRESUMEN
3-chloro-1,2-propanediol (3-MCPD) is a member of the group of pollutants known as chloropropanols and is considered a genotoxic carcinogen. Due to the occurrence of 3-MCPD, which cannot be avoided in multiplexed food processes, it is necessary to explore novel agents to reduce or prevent the toxicity of 3-MCPD. Many recent studies on boron compounds reveal their superior biological roles such as antioxidant, anticancer, and antigenotoxic properties. In the current investigation, we have evaluated in vitro cytotoxic, oxidative, and genotoxic damage potential of 3-MCPD on human whole blood cultures and the alleviating effect of boric acid (BA) and borax (BX) for 72 h. In our in vitro experiments, we have treated blood cells with BA and BX (2.5, 5, and 10 mg/L) and 3-MCPD (at IC50 of 11.12 mg/l) for 72 h to determine the cytotoxic damage potential by using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and lactate dehydrogenase (LDH) release assays. Oxidative damage was assessed using total antioxidant capacity (TAC) and malondialdehyde (MDA) levels. Genotoxicity evaluations were performed using chromosome aberrations (CAs) and 8-hydroxy deoxyguanosine (8-OHdG) assays. The result of our experiments showed that the 3-MCPD compound induced cytotoxicity, oxidative stress, and genotoxicity in a clear concentration-dependent manner. BA and BX reduced cytotoxicity, oxidative stress, and genotoxicity induced by 3-MCPD. In conclusion, BA and BX are safe and non-genotoxic under the in vitro conditions and can alleviate cytotoxic, oxidative, and genetic damage induced by 3-MCPD in the human blood cells. Our findings suggest that dietary boron supplements may offer a novel strategy for mitigating hematotoxicity induced by xenobiotics, including 3-MCPD.
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This study was carried out to evaluate the protective role of borax (BX) on genotoxicity induced by aluminum (Al) in rat liver, using liver micronucleus assay as an indicator of genotoxicity. Sprague-Dawley rats were randomly separated into six groups and each group had four animals. Aluminum chloride (AlCl3; 5 mg/kg b.w.) and BX (3.25 and 13 mg/kg b.w.) were injected intraperitoneally to rats. Besides, animals were also treated with Al for 4 consecutive days followed by BX for 10 days. Rats were anesthetized after Al and BX injections and the hepatocytes were isolated for counting the number of micronucleated hepatocytes (MNHEPs). AlCl3 was found to significantly (p < 0.05) increase the number of MNHEPs. Rats treated with BX, however, showed no increase in MNHEPs. Moreover, simultaneous treatments with BX significantly modulated the genotoxic effects of AlCl3 in rats. It can be concluded that BX has beneficial influences and has the ability to antagonize Al toxicity.
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Compuestos de Aluminio/toxicidad , Boratos/farmacología , Cloruros/toxicidad , Daño del ADN/efectos de los fármacos , Hígado/efectos de los fármacos , Cloruro de Aluminio , Animales , Hepatocitos/efectos de los fármacos , Masculino , Pruebas de Micronúcleos , Mutágenos/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: This study investigated the long-term cytotoxic response of thermoplastic polyamide and conventional polymethyle metacrylate (PMMA) denture base materials. MATERIALS AND METHODS: Twenty discs were prepared for each polyamide, heat and cold cured PMMA denture base resins (totally 60) and divided into four sub-groups (n = 5). Cytotoxicity was assessed with the direct cell contact method using cell viability and neutral red (NR) uptake assay. Each sub-group was tested at initial and after being aged for 24 h, 1 week and 8 weeks with artificial saliva according to ISO 10993 standards. RESULTS: There were no significantly difference among the materials and control groups after initial, 24 h and 1 week testing. In 24 h testing, only Deflex was more toxic according to the Control group (p < 0.05). After 8 weeks of aging with artificial saliva, all materials were significantly cytotoxic when compared to the control group. QC20 was more toxic than Deflex and SC Cold Cure (p < 0.05). There were significant differences between the 8 week aging group and the initial, 24 h and 1 week testing for all materials (p < 0.05). CONCLUSIONS: Cytotoxicity of all tested denture base materials increased significantly after the long-term aging. Therefore, long-term aging may be useful to determine a dental material's toxicity. Polyamide denture base material had a similar toxicity profile with conventional heat- and cold-cured PMMA.
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Bases para Dentadura , Fibroblastos/efectos de los fármacos , Nylons/toxicidad , Polimetil Metacrilato/toxicidad , Células Cultivadas , Fibroblastos/citología , Humanos , Técnicas In VitroRESUMEN
Olanzapine (OLZ), risperidone (RPD) and quetiapine (QTP) are atypical antipsychotic drugs and are commonly used for the treatments of schizophrenia and bipolar disorders. However, recent reports indicated that these drugs could exhibit toxic effects on nervous and cardiovascular systems. To our best knowledge, there are scarce data considering the genotoxic damage potentials of OLZ, RPD and QTP on human lymphocyte culture system. Therefore, in this study, the genotoxic potentials of OLZ, RPD and QTP (0-400 mg/L) have been evaluated in human whole blood cultures (WBCs; n = 4). The single cell gel electrophoresis (SCGE) and micronucleus (MN) assays were applied to estimate the DNA damage. The results of the present study indicated that the tested antipsychotic drug did not induce genotoxicity. In fact, the mean values of the total scores of cells showing DNA damage (for SCGE assay) and MN/1000 cell were not found significantly different from the control values (p > 0.05). However, the application of the highest drug concentrations (250 mg/L and above) caused the sterility in lymphocyte cultures. It is concluded that the tested three different atypical antipsychotic drugs can be used safely, but it is necessary to consider the cytotoxic effects that are likely to appear depending on the doses exposed.
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Antipsicóticos/toxicidad , Linfocitos/efectos de los fármacos , Mutágenos/toxicidad , Análisis de Varianza , Benzodiazepinas/toxicidad , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Dibenzotiazepinas/toxicidad , Humanos , Pruebas de Micronúcleos , Pruebas de Mutagenicidad , Olanzapina , Fumarato de Quetiapina , Risperidona/toxicidadRESUMEN
A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the MUTYH, BRCA2, and CHEK2 genes. Nine novel pathogenic/likely pathogenic variants were identified in BRCA1, BRCA2, GALNT12, ATM, MLH1, MSH2, APC, and KIT genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.
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OBJECTIVE: Myeloid malignancies are heterogeneous disorders due to defective hematopoiesis and myeloid differentiation of hematopoietic stem/progenitor cell. The molecular landscape of the diseases is complex. Molecular alterations are used for classification and evaluation of prognosis and treatment. We aimed to evaluate the advantages of the next-generation sequencing panel testing in myeloid malignancies and clinical outcomes. MATERIALS AND METHODS: We evaluated the results of 54 patients who underwent next-generation sequenc- ing myeloid panel testing, with fluorescent in situ hybridization (FISH), polymerase chain reaction results and the clinical outcomes. Target genes in the panel were ASXL1, CALR, CBL, CEBPA, CSF3R, DNMT3A, EZH2, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SH2B3, SRSF2, TET2, TP53, U2AF1, and ZRSR2. RESULTS: Diagnoses were acute myeloid leukemia, essential thrombocytosis, polistemia vera, primary myelo- fibrosis, hypereosinophilic syndrome (HES), chronic myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia. Twenty-eight missense, 8 frameshift, 5 stop gain, and 3 in-frame mutations were detected. A double mutation was detected in JAK-2 with next-generation sequencing in the patient who was given a false negative result due to polymerase chain reaction limitation. CONCLUSION: Screening multiple mutations simultaneously, is time and cost-effective. With the panel test, it is possible to determine the diagnosis, prognosis and targeted treatment options with a single test. Next- generation sequencing myeloid panel tests might be a powerful guide for clinicians.
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Titanium diboride (TiB2) and zinc borate (Zn3BO6) have been utilized in wide spectrum industrial areas because of their favorable properties such as a high melting point, good wear resistance, high hardness and thermal conductivity. On the other hand, the biomedical potentials of TiB2 and Zn3BO6 are still unknown because there is no comprehensive analysis that uncovers their biocompatibility features. Thus, the toxicogenomic properties of TiB2 and Zn3BO6 nanoparticles (NPs) were investigated on human primary alveolar epithelial cell cultures (HPAEpiC) by using different cell viability assays and microarray analyses. Protein-Protein Interaction Networks Functional Enrichment Analysis (STRING) was used to associate differentially expressed gene probes. According to the results, up to 10 mg/L concentration of TiB2 and Zn3BO6 NPs application did not stimulate a cytotoxic effect on the HPAEpiC cell cultures. Microarray analysis revealed that TiB2 NPs exposure enhances cellular adhesion molecules, proteases and carrier protein expression. Furthermore, Zn3BO6 NPs caused differential gene expressions in the cell cycle, cell division and extracellular matrix regulators. Finally, STRING analyses put forth that inflammation, cell regeneration and tissue repair-related gene interactions were affected by TiB2 NPs application. Zn3BO6 NPs exposure significantly altered inflammation, lipid metabolism and infection response activator-related gene interactions. These investigations illustrated that TiB2 and Zn3BO6 NPs exposure may affect different aspects of cellular machineries such as immunogenic responses, tissue regeneration and cell survival. Thus, these types of cellular mechanisms should be taken into account before the use of the related NPs in further biomedical applications.
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Genetic, neuropathological and biochemical investigations have revealed meaningful relationships between aluminum (Al) exposure and neurotoxic and hematotoxic damage. Hence, intensive efforts are being made to minimize the harmful effects of Al. Moreover, boron compounds are used in a broad mix of industries, from cosmetics and pharmaceuticals to agriculture. They affect critical biological functions in cellular events and enzymatic reactions, as well as endocrinal and mineral metabolisms. There are limited dose-related data about boric acid (BA) and other boron compounds, including colemanite (Col), ulexite (UX) and borax (BX), which have commercial prominence. In this study, we evaluate boron compounds' genetic, cytological, biochemical and pathological effects against aluminum chloride (AlCl3)-induced hematotoxicity and neurotoxicity on different cell and animal model systems. First, we perform genotoxicity studies on in vivo rat bone marrow cells and peripheric human blood cultures. To analyze DNA and chromosome damage, we use single cell gel electrophoresis (SCGE or comet assay) and micronucleus (MN) and chromosome aberration (CA) assays. The nuclear division index (NDI) is used to monitor cytostasis. Second, we examine the biochemical parameters (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), total antioxidant capacity (TAC) and total oxidative status (TOS)) to determine oxidative changes in blood and brain. Next, we assess the histopathological alterations by using light and electron microscopes. Our results show that Al increases oxidative stress and genetic damage in blood and brain in vivo and in vitro studies. Al also led to severe histopathological and ultrastructural alterations in the brain. However, the boron compounds alone did not cause adverse changes based on the above-studied parameters. Moreover, these compounds exhibit different levels of beneficial effects by removing the harmful impact of Al. The antioxidant, antigenotoxic and cytoprotective effects of boron compounds against Al-induced damage indicate that boron may have a high potential for use in medical purposes in humans. In conclusion, our analysis suggests that boron compounds (especially BA, BX and UX) can be administered to subjects to prevent neurodegenerative and hematological disorders at determined doses.
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Glioblastoma (GB) is the most common and aggressive primary malignant astrocytoma correlated with poor patient survival. There are no curative treatments for GB, and it becomes resistant to chemotherapy, radiation therapy, and immunotherapy. Resistance in GB cells is closely related to their states of redox imbalance, and the role of reactive oxygen species and its impact on cancer cell survival is still far from elucidation. Boron-containing compounds, especially boric acid (BA) and borax (BX) exhibited interesting biological effects involving antibacterial, antiviral, anti-cancerogenic, anti-mutagenic, anti-inflammatory as well as anti-oxidative features. Recent studies indicated that certain boron compounds could be cytotoxic on human GB. Nevertheless, there is gap of knowledge in the literature on exploring the underlying mechanisms of anti-GB action by boron compounds. Here, we identified and compared the potential anti-GB effect of both BA and BX, and revealed their underlying anti-GB mechanism. We performed cell viability, oxidative alterations, oxidative DNA damage potential assays, and explored the inflammatory responses and gene expression changes by real-time PCR using U-87MG cells. We found that BA and BX led to a remarkable reduction in U-87MG cell viability in a concentration-dependent manner. We also found that boron compounds increased the total oxidative status and MDA levels along with the SOD and CAT enzyme activities and decreased total antioxidant capacity and GSH levels in U-87MG cells without inducing DNA damage. The cytokine levels of cancer cells were also altered. We verified the selectivity of the compounds using a normal cell line, HaCaT and found an exact opposite condition after treating HaCaT cells with BA and BX. BA applications were more effective than BX on U-87MG cell line in terms of increasing MDA levels, SOD and CAT enzyme activities, and decreasing Interleukin-1α, Interleukin-6 and Tumor necrosis factor- α (TNF- α) levels. We finally observed that anticancer effect of BA and BX were associated with the BRAF/MAPK, PTEN and PI3K/AKT signaling pathways in respect of downregulatory manner. Especially, BA application was found more favorable because of its inhibitory effect on PIK3CA, PIK3R1, PTEN and RAF1 genes. In conclusion, our analysis indicated that boron compounds may be safe and promising for effective treatment of GB.