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1.
Cell Signal ; 93: 110308, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35301064

RESUMO

The krüppel-like factor (KLF) family is a group of zinc finger transcription factors and contributes to different cellular processes such as differentiation, proliferation, migration, and apoptosis. While different studies show the roles of this family in skeletal development-specifically in chondrocyte and osteocyte development and bone homeostasis-there are few reviews summarizing their importance. To fill this gap, this review discusses current knowledge on different functions of the KLF family during skeletal development, including their roles in stem cell maintenance and differentiation, cell apoptosis, and cell cycle. To understand the importance of the KLF family, we also review genotype-phenotype correlations in different animal models. We also discuss how KLF proteins function through different signaling pathways and display their paramount importance in skeletal development. To highlight their roles in cartilage- or bone-related cells, we also use single-cell RNA sequencing publicly available data on mouse hindlimb. We also challenge our knowledge of how the KLF family is epigenetically regulated-e.g., using DNA methylation, histone modifications, and noncoding RNAs-during chondrocyte and osteocyte development.


Assuntos
Condrócitos , Fatores de Transcrição Kruppel-Like , Animais , Biologia , Cartilagem/metabolismo , Diferenciação Celular/genética , Condrócitos/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Camundongos
2.
Ann N Y Acad Sci ; 1510(1): 18-35, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34982476

RESUMO

Chimeric antigen receptor (CAR) therapy is a method directing T lymphocytes against antigens on the surface of tumors, increasing target cell elimination. Genetic engineering enhances the capability of immune cells to detect new antigens expressed on cell surfaces. CAR T cell therapy is a significant breakthrough for treating human malignancies; however, different side effects (e.g., cytokine release syndrome) restrict its application. Improving design and using various combined receptors enhance the performance of these cells. This review discusses limitations and risk factors associated with CAR T cell therapy. We also review some alternative approaches for developing the next generation of CAR T cells.


Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T
3.
Ir J Med Sci ; 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35031939

RESUMO

BACKGROUND: Microcephaly is a prominent feature of patients with primary autosomal recessive microcephaly 2 (MCPH2) caused by mutations in the WD Repeat Domain 62 (WDR62; OMIM: 613,583). AIM: The study aimed to identify the underlying genetic factor(s) causing microcephaly in two patients in a consanguineous Iranian family. METHODS: Two male patients (11 and 27 years old) were noticed due to microcephaly, neurodevelopmental delay, and occasional seizures. The younger patient (the proband) was subjected to paired-end whole-exome sequencing followed by Sanger sequencing to detect any underlying genetic factor. RESULTS: Upon examination, both patients showed microcephaly as a prominent manifestation; they were under-weighted as well. The patients had a moderate gross motor impairment, severe cognitive disability and speech delay, increased deep tendon reflexes, flexible joint contractures, sensorineural hearing loss, and vertical nystagmus as a new ocular finding. The proband had more severe neurodevelopmental delay symptoms. The brain magnetic resonance imaging series revealed severe structural and cortical brain abnormalities in addition to hemiatrophy. Using Whole-exome Sequencing, a novel homozygous missense variant-NM_001083961.2; c.1598A > G: p.(His533Arg)-was identified in the WDR62. Subsequently, in silico analyses determined the possible impacts of the novel variant on the structure and function of WDR62 protein. CONCLUSIONS: Herein, we identified a novel homozygous missense variant in the WDR62 in two patients with MCPH2. Vertical nystagmus and sensorineural hearing loss were detected as novel neurological findings. The present study expands the phenotype and genotype spectrum of MCPH2.

4.
J Clin Lab Anal ; 36(1): e24150, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34837714

RESUMO

BACKGROUND: Chordoma is a locally aggressive bone tumor with a high capability of recurrence. Because chordoma often occurs at critical locations next to neurovascular structures, there is an urgent need to introduce validated biomarkers. T-box transcription factor T (TBXT; OMIM: 601397) plays an important role in the pathogenesis and survival of chordoma cells. METHODS: Herein, we aimed to show whether rs2305089 polymorphism is correlated with chordoma in the Iranian population. In order to detect rs2305089, tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) was used. In total, 19 chordoma patients and 108 normal healthy individuals were recruited and screened using T-ARMS-PCR. The results were subsequently validated by Sanger sequencing. RESULTS: The genotype distributions and allele frequencies were significantly different among the patient and healthy groups (p-value <0.05). The A allele of rs2305089 showed a significant positive association with chordoma risk (p-value <0.05). DNA sequencing verified the T-ARMS-PCR results as well. This study demonstrated the association between TBXT rs2305089 and chordoma in an Iranian population using a simple, accurate, and cost-effective T-ARMS-PCR assay. CONCLUSIONS: Our results were in line with those of previous studies showing that TBXT rs2305089 is associated with chordoma development. We also developed an efficient T-ARMS-PCR assay to determine the genotype of rs2305089.


Assuntos
Cordoma , Proteínas Fetais/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas com Domínio T/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Neoplasias Ósseas/epidemiologia , Neoplasias Ósseas/genética , Estudos de Casos e Controles , Cordoma/epidemiologia , Cordoma/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Adulto Jovem
5.
J Cell Mol Med ; 26(1): 1-15, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34841647

RESUMO

Different cellular and molecular mechanisms contribute to chondrocyte and osteocyte development. Although vital roles of the mothers against decapentaplegic homolog 4 (also called 'SMAD4') have been discussed in different cancers and stem cell-related studies, there are a few reviews summarizing the roles of this protein in the skeletal development and bone homeostasis. In order to fill this gap, we discuss the critical roles of SMAD4 in the skeletal development. To this end, we review the different signalling pathways and also how SMAD4 defines stem cell features. We also elaborate how the epigenetic factors-ie DNA methylation, histone modifications and noncoding RNAs-make a contribution to the chondrocyte and osteocyte development. To better grasp the important roles of SMAD4 in the cartilage and bone development, we also review the genotype-phenotype correlation in animal models. This review helps us to understand the importance of the SMAD4 in the chondrocyte and bone development and the potential applications for therapeutic goals.


Assuntos
Condrócitos , Osteócitos , Animais , Cartilagem/metabolismo , Diferenciação Celular/genética , Condrócitos/metabolismo , Condrogênese/genética , Osteócitos/metabolismo , Osteogênese/genética , Transdução de Sinais , Células-Tronco
6.
Life Sci ; 285: 119937, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34508764

RESUMO

BACKGROUND: Secreted microRNAs (miRNAs) can serve as promising diagnostic markers for colorectal cancer (CRC). Herein, we evaluated the potential clinical significance of a signature of four circulating serum-derived miRNAs in CRC. We also demonstrated that extracellular vesicles (EVs) containing miR-221-3p could facilitate endothelial cell angiogenesis. METHODS: The expressions of four circulating serum-derived miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) were measured by real-time quantitative PCR, and their associations with lymph node metastasis were determined in CRC patients. Receiver operating characteristic curve analysis was used to determine their diagnostic accuracy. EVs were isolated and characterized from the conditioned media of human CRC cells (HCT116 and Caco2). Cell proliferation, transwell migration, and tube formation assays were performed to investigate the pro-angiogenic effect of miR-221-3p transferred by CRC-EVs into the endothelial cells. In silico analysis was used to show the regulatory functions of miR-221-3p on SOCS3, validated by luciferase and Western blotting assays. RESULTS: The expression levels of serum-derived miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p were significantly higher in CRC than in healthy individuals. The expression of miR-19a-3p, miR-203-3p, and miR-221-3p were positively correlated with the lymph node metastasis status. Moreover, SOCS3 was identified as a direct target of miR-221-3p and the secreted miR-221-3p shuttled by CRC-EVs regulated STAT3/VEGFR-2 signaling axis by targeting SOCS3 in endothelial cells. CRC-EVs promoted endothelial cell proliferation, migration, and the formation of vessel-like structures. The proangiogenic effect of CRC-EVs on the cells was recapitulated by miR-221-3p overexpression, showing the importance of EVs-derived miR-221-3p in promoting endothelial cell angiogenesis. CONCLUSION: We introduced a signature of four-circulating miRNAs (miR-19a-3p, miR-203-3p, miR-221-3p, and let-7f-5p) as a novel diagnostic biomarker for CRC. Besides, we revealed that miR-221-3p induces endothelial cell angiogenesis in vitro by targeting SOCS3.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/patologia , MicroRNAs/metabolismo , Neovascularização Patológica/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Biomarcadores Tumorais/sangue , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Células HCT116 , Células Endoteliais da Veia Umbilical Humana , Humanos , Metástase Linfática , MicroRNAs/sangue , Neovascularização Patológica/genética , Fator de Transcrição STAT3/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética
7.
J Clin Lab Anal ; 35(11): e24010, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34528314

RESUMO

BACKGROUND: Breast cancer (BC) is by far the most common malignancy among women. Epigenetic modulators, microRNAs in particular, may set stages for BC development and its progression. Herein, we aimed to assess the diagnostic potentiality of a signature of six miRNAs (i.e., hsa-miR-25-3p, -29a-5p, -105-3p, -181b1-5p, -335-5p, and -339-5p) in BC and adjacent non-tumor tissues. METHODS: A pair of 50 tumor and adjacent non-tumor samples were taken from BC patients. The expression of each candidate miRNA was measured using quantitative reverse transcription PCR. To investigate the possible roles of each miRNA and their impressions on BC prognosis, in silico tools were used. Receiver operating characteristic (ROC) curves were performed to determine the diagnostic accuracy of each miRNA and the possible association of their expression with clinicopathological characteristics was analyzed. RESULTS: Our findings showed the upregulation of hsa-miR-25-3p, -29a-5p, -105-3p, and -181b1-5p, and the downregulation of hsa-miR-335-5p and -339-5p in BC tumor compared to corresponding adjacent tissues. Except for hsa-miR-339-5p, the up-/down-regulation of the candidate miRNAs was associated with TNM stages. Except for hsa-miR-105-3p, each candidate miRNA was correlated with HER-2 status. ROC curve analysis showed that the signature of six-miRNA is a potential biomarker distinguishing between tumor and non-tumor breast tissue samples. CONCLUSION: We showed that the dysregulation of a novel signature of six-miRNA can be used as a potential biomarker for BC diagnosis.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama , MicroRNAs/genética , Mama/química , Neoplasias da Mama/química , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Transcriptoma/genética
8.
Ann N Y Acad Sci ; 1503(1): 5-22, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34403146

RESUMO

Different cellular mechanisms contribute to osteocyte development. And while critical roles for members of the zinc finger protein SNAI family (SNAIs) have been discussed in cancer-related models, there are few reviews summarizing their importance for chondrocyte-to-osteocyte development. To help fill this gap, we review the roles of SNAIs in the development of mature osteocytes from chondrocytes, including the regulation of chondro- and osteogenesis through different signaling pathways and in programmed cell death. We also discuss how epigenetic factors-including DNA methylation, histone methylation and acetylation, and noncoding RNAs-contribute differently to both chondrocyte and osteocyte development. To better grasp the important roles of SNAIs in bone development, we also review genotype-phenotype correlations in different animal models. We end with comments about the possible importance of the SNAI family in cartilage/bone development and the potential applications for therapeutic goals.


Assuntos
Diferenciação Celular , Condrócitos/citologia , Condrócitos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Osteócitos/citologia , Osteócitos/metabolismo , Fatores de Transcrição da Família Snail/genética , Animais , Desenvolvimento Ósseo/genética , Diferenciação Celular/genética , Condrogênese/genética , Epigênese Genética , Humanos , Osteogênese/genética , Transdução de Sinais , Fatores de Transcrição da Família Snail/metabolismo
9.
Int J Infect Dis ; 111: 295-302, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34343706

RESUMO

INTRODUCTION: Human papillomavirus (HPV) infection is one of the major health concerns of women in developing countries. This study gives an insight into the prevalence and genotype distribution of HPV infection and compares it with Pap smear results among Iranian women. METHODS: In this study, 12 076 Iranian women underwent routine examination from November 2016 to November 2018 using HPV Direct Flow CHIP System for HPV DNA typing. Cytology was undertaken for 5138 samples. RESULTS: Overall HPV prevalence was calculated at 38.68%. The most frequent HPV types were HPV 6, 16, 11, 62/81, 52 and 54. The most high-risk HPV (HR-HPV) types were HPV 16, 52, 18, 39, 31 and 51. These 2 groups represent approximately half of all HPV types detected, 47% and 55%, respectively. Among individuals who underwent cytological tests, 135 individuals (2.63%) were cytologically positive. In this group, 81 individuals (60%) were HPV positive, 62 (76%) of whom were HR-HPV positive, most frequently with HPV 16 (34%). CONCLUSION: This study highlights the urgent need for public education and early diagnosis using HPV screening tests to prevent cervical cancer.


Assuntos
Infecções por Papillomavirus , Neoplasias do Colo do Útero , Colo do Útero , DNA Viral/genética , Feminino , Genótipo , Humanos , Irã (Geográfico)/epidemiologia , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/epidemiologia , Prevalência , Neoplasias do Colo do Útero/epidemiologia
10.
Ir J Med Sci ; 2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34374940

RESUMO

BACKGROUND: Mutations in NARS2 (MIM: 612803) are associated with combined oxidative phosphorylation deficiency 24 (COXPD24; MIM: 616239) that is a rare mitochondrial and a multisystem autosomal recessive disorder. AIMS: We aimed to detect the underlying genetic factors in two siblings with progressive ataxia, epilepsy, and severe-to-profound hearing impairment. METHODS: After doing medical assessments and pertinent tests (i.e., auditory brainstem responses, pure tone otoacoustic emission test, cardiac examinations, computed tomography, and electroencephalogram), because of the clinical and probable genetic heterogeneity, whole-exome sequencing was performed, and co-segregation analysis was confirmed by Sanger sequencing. Biological impacts of the novel variant were evaluated using sequence-to-function bioinformatics tools. RESULTS: A novel homozygous missense variant, NM_024678.6:c.545 T > A; p.(Ile182Lys), in exon 5 of NARS2 was identified in both patients and verified by Sanger sequencing. In silico analyses introduced this variant as pathogenic. Mitral valve prolapses with mild regurgitation, brachymetatarsia, severe hallux valgus, and clubbed fingers were reported as novel manifestations in association with NARS2 gene. By doing a literature review, we also underscored the high heterogeneity of disease phenotype. CONCLUSIONS: Herein, we report some novel phenotype and genotype features of two female patients in an Iranian consanguineous family with COXPD24, caused by a variant in NARS2-NM_024678.6: c.545 T > A; p.(Ile182Lys). Moreover, our data expanded the phenotype and genotype spectrum of NARS2-related disorder and confirmed an unpredictable nature of genotype-phenotype correlation in COXPD24.

11.
J Cell Mol Med ; 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33987950

RESUMO

Different cellular mechanisms contribute to the hearing sense, so it is obvious that any disruption in such processes leads to hearing impairment that greatly influences the global economy and quality of life of the patients and their relatives. In the past two decades, transmembrane inner ear (TMIE) protein has received a great deal of research interest because its impairments cause hereditary deafness in humans. This evolutionarily conserved membrane protein contributes to a fundamental complex that plays role in the maintenance and function of the sensory hair cells. Although the critical roles of the TMIE in mechanoelectrical transduction or hearing procedures have been discussed, there are little to no review papers summarizing the roles of the TMIE in the auditory system. In order to fill this gap, herein, we discuss the important roles of this protein in the auditory system including its role in mechanotransduction, olivocochlear synapse, morphology and different signalling pathways; we also review the genotype-phenotype correlation that can per se show the possible roles of this protein in the auditory system.

12.
BMC Neurol ; 21(1): 180, 2021 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-33910511

RESUMO

BACKGROUND: The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. CASE PRESENTATION: A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant-NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)-in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes. CONCLUSIONS: Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the "RABopathies" term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.


Assuntos
Anormalidades Múltiplas/genética , Catarata/congênito , Córnea/anormalidades , Hipogonadismo/genética , Deficiência Intelectual/genética , Microcefalia/genética , Atrofia Óptica/genética , Proteínas rab3 de Ligação ao GTP/genética , Catarata/genética , Pré-Escolar , Feminino , Humanos , Irã (Geográfico) , Masculino , Mutação , Linhagem , Splicing de RNA , Sequenciamento Completo do Exoma
13.
Acta Neurol Belg ; 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33783721

RESUMO

Progressive myoclonus epilepsies (PMEs) are a group of disorders embracing myoclonus, seizures, and neurological dysfunctions. Because of the genetic and clinical heterogeneity, a large proportion of PMEs cases have remained molecularly undiagnosed. The present study aimed to determine the underlying genetic factors that contribute to the PME phenotype in an Iranian female patient. We describe a consanguineous Iranian family with autosomal recessive PME that had remained undiagnosed despite extensive genetic and pathological tests. After performing neuroimaging and clinical examinations, due to heterogeneity of PMEs, the proband was subjected to paired-end whole-exome sequencing and the candidate variant was confirmed by Sanger sequencing. Various in-silico tools were also used to predict the pathogenicity of the variant. In this study, we identified a novel homozygous missense variant (NM_032737.4:c.472C > T; p.(Arg158Trp)) in the LMNB2 gene (OMIM: 150341) as the most likely disease-causing variant. Neuroimaging revealed a progressive significant generalized atrophy in the cerebral and cerebellum without significant white matter signal changes. Video-electroencephalography monitoring showed a generalized pattern of high-voltage sharp waves in addition to multifocal spikes and waves compatible with mixed type seizures and epileptic encephalopathic pattern. Herein, we introduce the second case of PME caused by a novel variant in the LMNB2 gene. This study also underscores the potentiality of next-generation sequencing in the genetic diagnosis of patients with neurologic diseases with an unknown cause.

14.
Acta Neurol Belg ; 121(3): 737-748, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33783722

RESUMO

Mutations in CLN3 (OMIM: 607042) are associated with juvenile neuronal ceroid lipofuscinoses (JNCL)-a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration. The study aimed to determine the underlying genetic factors justifying the NCL phenotype in a large Iraqi consanguineous family. Four affected individuals with an initial diagnosis of NCL were recruited. By doing neuroimaging and also pertinent clinical examinations, e.g. fundus examination, due to heterogeneity of neurodevelopmental disorders, the proband was subjected to the paired-end whole-exome sequencing to identify underlying genetic factors. The candidate variant was also confirmed by Sanger sequencing. Various in silico predictions were used to show the pathogenicity of the variant. This study revealed a novel homozygous frameshift variant-NM_000086.2: c.1127del; p.(Leu376Argfs*15)-in the exon 14 of the CLN3 gene as the most likely disease-causing variant. Three out of 4 patients showed bilateral vision loss (< 7 years) and retinal degeneration with macular changes in both eyes. Electroencephalography demonstrated the loss of normal posterior alpha rhythm and also low amplitude multifocal slow waves. Brain magnetic resonance imaging of the patients with a high degree of deterioration showed mild cerebral and cerebellar cortical atrophy, mild ventriculomegaly, thinning of the corpus callosum and vermis, and non-specific periventricular white matter signal changes in the occipital area. The novel biallelic deletion variant of CLN3 was identified that most probably led to JNCL with variable expressivity of the phenotype. This study also expanded our understanding of the clinical and genetic spectrum of JNCL.


Assuntos
Encéfalo/diagnóstico por imagem , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Lipofuscinoses Ceroides Neuronais/genética , Deleção de Sequência , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Lipofuscinoses Ceroides Neuronais/diagnóstico por imagem , Fenótipo , Sequenciamento Completo do Exoma , Adulto Jovem
15.
Iran J Child Neurol ; 15(1): 101-106, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33558818

RESUMO

The laminin α2 subunit is a protein encoded by the laminin α2 gene(LAMA2) which has the role of adhesion (attachment of cells to one another). Genetics consideration showed that mutation in LAMA2 caused a collection of muscle-wasting conditions called muscular dystrophy. This disorder causes disconnection of muscular cells and degeneration of the musculoskeletal system. In this study, we defined the molecular consideration of three patients with laminin α2 deficiency by clinical presentations of congenital muscular dystrophy. In this regard, 65 exons of the LAMA2 gene were amplified by polymerase chain reaction. Moreover, multiple ligation-dependent probe amplification and next generation sequencing (NGS) were carried out for all the patients. Because of NGS negativity, gene sequencing was performed. Results of searching for rearrangements of the LAMA2 gene enabled us to recognize homozygous pathogenic mutations c.2049_c.2050del, c.7156-2A>G, and c,1303C>T. These mutations produce an out-of-frame transcript that will be degraded by nonsense mediated decay. Therefore, we think these changes are pathogenic ones.

16.
J Cell Physiol ; 236(9): 6200-6224, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33559213

RESUMO

Posttranscriptional regulation is a mechanism for the cells to control gene regulation at the RNA level. In this process, RNA-binding proteins (RBPs) play central roles and orchestrate the function of RNA molecules in multiple steps. Accumulating evidence has shown that the aberrant regulation of RBPs makes  contributions to the initiation and progression of tumorigenesis via numerous mechanisms such as genetic changes, epigenetic alterations, and noncoding RNA-mediated regulations. In this article, we review the effects caused by RBPs and their functional diversity in the malignant transformation of cancer cells that occurs through the involvement of these proteins in various stages of RNA regulation including alternative splicing, stability, polyadenylation, localization, and translation. Besides this, we review the various interactions between RBPs and other crucial posttranscriptional regulators such as microRNAs and long noncoding RNAs in the pathogenesis of cancer. Finally, we discuss the potential approaches for targeting RBPs in human cancers.


Assuntos
Carcinogênese/metabolismo , Neoplasias/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Processamento Alternativo/genética , Humanos , Neoplasias/patologia , Neoplasias/terapia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo
17.
Life Sci ; 264: 118719, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33159957

RESUMO

AIM: As a natural compound, docosahexaenoic acid (DHA) exerts anti-cancer and anti-angiogenesis functions through exosomes; however, little is known about the molecular mechanisms. MAIN METHODS: Breast cancer (BC) cells were treated with DHA (50 µM) and then tumor cell-derived exosomes (TDEs) were collected and characterized by electron microscopy, dynamic light scattering, and western blot analyses. By the time the cells were treated with DHA, RT-qPCR was used to investigate the expression of vascular endothelial growth factor (VEGF) and the selected pro- and anti-angiogenic microRNAs (miRNAs). The quantification of secreted VEGF protein was measured by enzyme-linked immunosorbent assay (ELISA). The effects of TDEs on endothelial cell angiogenesis were explored by transwell cell migration and in vitro vascular tube formation assays. KEY FINDINGS: DHA treatment caused a significant and time-dependent decrease in the expression and secretion of VEGF in/from BC cells. This also increased expression of anti-angiogenic miRNAs (i.e. miR-34a, miR-125b, miR-221, and miR-222) while decreased levels of pro-angiogenic miRNAs (i.e. miR-9, miR-17-5p, miR-19a, miR-126, miR-130a, miR-132, miR-296, and miR-378) in exosomes derived from DHA-treated BC cells, TDE (DHA+). While treatment with exosomes (100 µg/ml) obtained from untreated BC cells, TDE (DHA-), enhanced the expression of VEGF-A in human umbilical vein endothelial cells (HUVECs), incubation with DHA or TDE (DHA+) led to the significant decrease of VEGF-A transcript level in these cells. We indicated that the incubation with TDE (DHA+) could significantly decrease endothelial cell proliferation and migration and also the length and number of tubes made by HUVECs in comparison with endothelial cells incubated with exosomes obtained from untreated BC cells. SIGNIFICANCE: DHA alters angiogenesis by shifting the up-regulation of exosomal miRNA contents from pro-angiogenic to anti-angiogenic, resulting in the inhibition of endothelial cell angiogenesis. These data can help to figure out DHA's anti-cancer function, maybe its use in cancer therapy.


Assuntos
Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/farmacologia , Exossomos/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
J Mol Endocrinol ; 66(2): R33-R55, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33295879

RESUMO

Autoimmune thyroid disease (AITD) accounts for 90% of all thyroid diseases and affects 2-5% of the population with remarkable familial clustering. Among AITDs, Graves' disease (GD) is a complex disease affecting thyroid function. Over the last two decades, case-control studies using cutting-edge gene sequencing techniques have detected various susceptible loci that may predispose individuals to GD. It has been presumed that all likely associated genes, variants, and polymorphisms might be responsible for 75-80% of the heritability of GD. As a result, there are implications concerning the potential contribution of environmental and epigenetic factors in the pathogenesis of GD, including its initiation, progression, and development. Numerous review studies have summarized the contribution of genetic factors in GD until now, but there are still some key questions and notions that have not been discussed concerning the interplay of genetic, epigenetic, and immunological factors. With this in mind, this review discusses some newly-identified loci and their potential roles in the pathogenicity of GD. This may lead to the identification of new, promising therapeutic targets. Here, we emphasized principles, listed all the reported disease-associated genes and polymorphisms, and also summarized the current understanding of the epigenetic basis of GD.


Assuntos
Epigênese Genética , Predisposição Genética para Doença , Doença de Graves/genética , Animais , Humanos , Sistema Imunitário/metabolismo , Linfócitos T/metabolismo , Hormônios Tireóideos/biossíntese
19.
Biotechnol Appl Biochem ; 68(6): 1250-1256, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33012018

RESUMO

Breast cancer (BC) is one of the most common malignancies among women in the world. There is a global attempt to diagnose BC as early as possible. Long noncoding RNAs (lncRNAs) are emerging as novel targets and biomarkers for BC diagnosis and prognosis. Aberrant expression of lncRNAs is associated with BC development, making them a potential tumor marker for BC. To investigate this possibility, we determined the expression levels of Down syndrome cell adhesion molecule-antisense RNA-1 (DSCAM-AS1) and mitotically-associated long non-coding RNA (MANCR) lncRNAs in BC tissues. This case-control study included 50 paired tumor and adjacent nontumor tissues from female BC patients. The total RNA was isolated and the expression levels of MANCR and DSCAM-AS1 lncRNAs were assessed using quantitative real-time reverse transcription-PCR. Potential correlations between lncRNA levels and clinicopathological characteristics were also analyzed. DSCAM-AS1 and MANCR lncRNAs were significantly upregulated in BC tumor tissues compared with the adjacent nontumor tissues. We also found the significant upregulation of DSCAM-AS1 in advanced tumor-node-metastasis stage (TNM III) of BC tumor tissues. Furthermore, the expression of DSCAM-AS1 and MANCR in HER-2 positive patients was significantly higher than HER-2 negative affected individuals. Receiver operating characteristic curve analysis showed a satisfactory diagnostic efficacy (P value < 0.0001), which means that DSCAM-AS1 and MANCR lncRNAs can potentially serve as a biomarker. The present study might provide further approval for the clinical diagnostic significance of DSCAM-AS1 and MANCR lncRNAs that their high expressions were associated with aggressive clinical parameters of BC.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , RNA Longo não Codificante/metabolismo , Regulação para Cima , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , RNA Longo não Codificante/genética
20.
Mol Genet Genomic Med ; 8(12): e1550, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33205915

RESUMO

BACKGROUND: Hereditary hearing loss (HL) is a heterogeneous and most common sensory neural disorder. At least, 76 genes have been reported in association with autosomal recessive nonsyndromic HL (ARNSHL). Herein, we subjected two patients with bilateral sensorineural HL in two distinct consanguineous Iranian families to figure out the underlying genetic factors. METHODS: Physical and sensorineural examinations were performed on the patients. Imaging also was applied to unveil any abnormalities in anatomical structures of the middle and inner ear. In order to decipher the possible genetic causes of the verified GJB2-negative samples, the probands were subjected to whole-exome sequencing and, subsequently, Sanger sequencing was applied for variant confirmation. RESULTS: Clinical examinations showed ARNSHL in the patients. After doing whole exome sequencing, two novel variants were identified that were co-segregating with HL that were absent in 100 ethnically matched controls. In the first family, a novel homozygous variant, NM_138691.2: c.530T>C; p.(lle177Thr), in TMC1 gene co-segregated with prelingual ARNSHL. In the second family, NM_022124.6: c.2334G>A; p.(Trp778*) was reported as a nonsense variant causing prelingual ARNSHL. CONCLUSION: These findings can, in turn, endorse how TMC1 and CDH23 screening is critical to detecting HL in Iranian patients. Identifying TMC1 and CDH23 pathogenic variants doubtlessly help in the detailed genotypic characterization of HL.


Assuntos
Caderinas/genética , Perda Auditiva Neurossensorial/genética , Proteínas de Membrana/genética , Mutação , Adulto , Proteínas Relacionadas a Caderinas , Criança , Feminino , Genes Recessivos , Perda Auditiva Neurossensorial/patologia , Homozigoto , Humanos , Masculino , Linhagem
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