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1.
Ann Hum Genet ; 88(5): 382-391, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38624263

RESUMO

To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.


Assuntos
Alelos , Transtorno do Deficit de Atenção com Hiperatividade , Éxons , Repetições Minissatélites , Receptores de Dopamina D4 , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Receptores de Dopamina D4/genética , Masculino , Feminino , Criança , Hong Kong , Genótipo , Desequilíbrio de Ligação , Adolescente , Predisposição Genética para Doença
2.
J Biomed Sci ; 31(1): 72, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-39010070

RESUMO

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) has been widely studied as a tumor antigen due to its expression in varieties of solid tumors. Moreover, the glycoprotein contributes to critical cancer-associated cellular functionalities via its extracellular (EpEX) and intracellular (EpICD) domains. In colorectal cancer (CRC), EpCAM has been implicated in the Wnt signaling pathway, as EpICD and ß-Catenin are coordinately translocated to the nucleus. Once in the nucleus, EpICD transcriptionally regulates EpCAM target genes that; however, remains unclear whether Wnt signaling is modulated by EpICD activity. METHODS: Patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and various CRC cell lines were used to study the roles of EpCAM and EpICD in Wnt receptor expression. Fluorescence and confocal microscopy were used to analyze tumors isolated from PDX and other xenograft models as well as CRC cell lines. EpCAM signaling was intervened with our humanized form of EpCAM neutralizing antibody, hEpAb2-6. Wnt receptor promoters under luciferase reporters were constructed to examine the effects of EpICD. Luciferase reporter assays were performed to evaluate promoter, γ-secretase and Wnt activity. Functional assays including in vivo tumor formation, organoid formation, spheroid and colony formation experiments were performed to study Wnt related phenomena. The therapeutic potential of EpCAM suppression by hEpAb2-6 was evaluated in xenograft and orthotopic models of human CRC. RESULTS: EpICD interacted with the promoters of Wnt receptors (FZD6 and LRP5/6) thus upregulated their transcriptional activity inducing Wnt signaling. Furthermore, activation of Wnt-pathway-associated kinases in the ß-Catenin destruction complex (GSK3ß and CK1) induced γ-secretase activity to augment EpICD shedding, establishing a positive-feedback loop. Our hEpAb2-6 antibody blocked EpICD-mediated upregulation of Wnt receptor expressions and conferred therapeutic benefits in both PDX and orthotopic models of human CRC. CONCLUSIONS: This study uncovers relevant functions of EpCAM where Wnt receptors are upregulated via the transcriptional co-factor activity of EpICD. The resultant enhancement of Wnt signaling induces γ-secretase activity further stimulating EpICD cleavage and its nuclear translocation. Our humanized anti-EpCAM antibody hEpAb2-6 blocks these mechanisms and may thereby provide therapeutic benefit in CRC.


Assuntos
Neoplasias Colorretais , Molécula de Adesão da Célula Epitelial , Via de Sinalização Wnt , Humanos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Molécula de Adesão da Célula Epitelial/metabolismo , Molécula de Adesão da Célula Epitelial/genética , Camundongos , Animais , Linhagem Celular Tumoral , Progressão da Doença
3.
J Transl Med ; 21(1): 530, 2023 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-37543570

RESUMO

BACKGROUND: Epithelial cell adhesion molecule (EpCAM) is known to highly expression and promotes cancer progression in many cancer types, including colorectal cancer. While metastasis is one of the main causes of cancer treatment failure, the involvement of EpCAM signaling in metastatic processes is unclear. We propose the potential crosstalk of EpCAM signaling with the HGFR signaling in order to govern metastatic activity in colorectal cancer. METHODS: Immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA), and fluorescence resonance energy transfer (FRET) was conducted to explore the extracellular domain of EpCAM (EpEX) and HGFR interaction. Western blotting was taken to determine the expression of proteins in colorectal cancer (CRC) cell lines. The functions of EpEX in CRC were investigated by proliferation, migration, and invasion analysis. The combined therapy was validated via a tail vein injection method for the metastasis and orthotopic colon cancer models. RESULTS: This study demonstrates that the EpEX binds to HGFR and induces downstream signaling in colon cancer cells. Moreover, EpEX and HGF cooperatively mediate HGFR signaling. Furthermore, EpEX enhances the epithelial-to-mesenchymal transition and metastatic potential of colon cancer cells by activating ERK and FAK-AKT signaling pathways, and it further stabilizes active ß-catenin and Snail proteins by decreasing GSK3ß activity. Finally, we show that the combined treatment of an anti-EpCAM neutralizing antibody (EpAb2-6) and an HGFR inhibitor (crizotinib) significantly inhibits tumor progression and prolongs survival in metastatic and orthotopic animal models of colon cancer. CONCLUSION: Our findings illuminate the molecular mechanisms underlying EpCAM signaling promotion of colon cancer metastasis, further suggesting that the combination of EpAb2-6 and crizotinib may be an effective strategy for treating cancer patients with high EpCAM expression.


Assuntos
Neoplasias do Colo , Animais , Molécula de Adesão da Célula Epitelial/metabolismo , Crizotinibe , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Transdução de Sinais , Transição Epitelial-Mesenquimal , Movimento Celular
4.
J Lipid Res ; 61(1): 116-126, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31712249

RESUMO

The brain is highly enriched in the long-chain omega-3 (n-3) PUFA DHA. Due to the limited capacity for local DHA synthesis in the brain, it relies on a continual supply from the circulation to replenish metabolized DHA. Previous studies investigating brain DHA turnover and metabolism have relied on isotope tracers to determine brain fatty acid kinetics; however, this approach is cumbersome and costly. We applied natural abundance carbon isotope ratio analysis via high-precision gas chromatography combustion isotope ratio mass spectrometry, without the use of labeled tracers, to determine the half-life of brain DHA in mice following a dietary switch experiment. Mice fed diets containing either α-linolenic acid (ALA) or DHA as the sole dietary n-3 PUFA were switched onto diets containing ALA, DHA, or ALA + DHA at 6 weeks of age, while control mice were maintained on their respective background diet. We measured brain DHA carbon isotope ratios (reported as δ13CDHA signatures) over a 168-day time course. Brain δ13CDHA signatures of control mice maintained on background diets over the time course were stable (P > 0.05). Brain δ13CDHA signatures of mice switched to the DHA or ALA + DHA diet from the ALA diet changed over time, yielding brain incorporation half-lives of 40 and 34 days, respectively. These half-lives determined by natural abundance carbon isotope ratio analysis were consistent with estimates from kinetic isotope tracer studies. Our results demonstrate the feasibility of natural abundance carbon isotope ratio analysis in the study of fatty acid metabolism without the use of isotopically labeled fatty acid tracers.


Assuntos
Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/análise , Animais , Isótopos de Carbono , Dieta , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/metabolismo , Ácidos Graxos Ômega-3/administração & dosagem , Ácidos Graxos Ômega-3/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ácido alfa-Linolênico/administração & dosagem , Ácido alfa-Linolênico/metabolismo
5.
J Biol Chem ; 294(19): 7769-7786, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-30926604

RESUMO

Mesenchymal stem cells (MSCs) are widely considered to be an attractive cell source for regenerative therapies, but maintaining multipotency and self-renewal in cultured MSCs is especially challenging. Hence, the development and mechanistic description of strategies that help promote multipotency in MSCs will be vital to future clinical use. Here, using an array of techniques and approaches, including cell biology, RT-quantitative PCR, immunoblotting, immunofluorescence, flow cytometry, and ChIP assays, we show that the extracellular domain of epithelial cell adhesion molecule (EpCAM) (EpEX) significantly increases the levels of pluripotency factors through a signaling cascade that includes epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), and Lin-28 homolog A (LIN28) and enhances the proliferation of human bone marrow MSCs. Moreover, we found that EpEX-induced LIN28 expression reduces the expression of the microRNA LET7 and up-regulates that of the transcription factor high-mobility group AT-hook 2 (HMGA2), which activates the transcription of pluripotency factors. Surprisingly, we found that EpEX treatment also enhances osteogenesis of MSCs under differentiation conditions, as evidenced by increases in osteogenic markers, including Runt-related transcription factor 2 (RUNX2). Taken together, our results indicate that EpEX stimulates EGFR signaling and thereby context-dependently controls MSC states and activities, promoting cell proliferation and multipotency under maintenance conditions and osteogenesis under differentiation conditions.


Assuntos
Molécula de Adesão da Célula Epitelial/metabolismo , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/biossíntese , Transdução de Sinais , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Molécula de Adesão da Célula Epitelial/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Humanos , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Proteínas de Ligação a RNA/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo
6.
J Biomed Sci ; 27(1): 1, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31894001

RESUMO

It has been more than three decades since the first monoclonal antibody was approved by the United States Food and Drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically evolved. Current antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeutic antibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top ten bestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued at approximately US$115.2 billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and $300 billion by 2025. Thus, the market for therapeutic antibody drugs has experienced explosive growth as new drugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolic and infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but there is still significant growth potential. This review summarizes the latest market trends and outlines the preeminent antibody engineering technologies used in the development of therapeutic antibody drugs, such as humanization of monoclonal antibodies, phage display, the human antibody mouse, single B cell antibody technology, and affinity maturation. Finally, future applications and perspectives are also discussed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Doenças Transmissíveis/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Neoplasias/tratamento farmacológico , Humanos , Estados Unidos , United States Food and Drug Administration
8.
Exp Mol Pathol ; 99(1): 7-15, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25952364

RESUMO

The crown-of-thorns starfish Acanthaster planci is a venomous starfish whose venom provokes strong cytotoxicity. In the present study, the purified cytotoxic toxin of A. planci venom (CAV) was identified as plancitoxin I protein by mass spectrum analyses. This study aims to investigate the molecular mechanism underlying the cytotoxicity function of plancitoxin I by focusing on the oxidative stress, mitochondrial dysfunction and endoplasmic reticulum (ER) stress pathway in human melanoma A375.S2 cells. The results indicated that after being treated with CAV toxin, A375.S2 cells significantly decreased viability in a dose-dependent manner. The CAV was found to reduce the cellular antioxidant enzymes such as SOD and CAT, and there was a significant decrease in total thiol level and mtDNA integrity, and it enhanced the lipid peroxidation. In addition, CAV increased cytosolic Ca(2+) concentration, and enhanced the expression of the ER molecular chaperones GRP78 and CHOP in a dose-dependent manner. CAV significantly elevated the activity of caspase-3, -8 and -9, and reduced the ratio of Bcl-2/Bax. The cells exhibited apoptosis were determined by using propidium iodide (PI) staining of DNA fragmentation (sub-G1 peak). In summary, the results demonstrated that plancitoxin I inhibits the proliferation of A375.S2 cells through induction of oxidative stress, mitochondrial dysfunction and ER stress associated apoptosis.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Toxinas Marinhas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estrelas-do-Mar/química , Peçonhas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Caspase 3/genética , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Caspase 9/genética , Caspase 9/metabolismo , Linhagem Celular Tumoral/efeitos dos fármacos , Fragmentação do DNA , DNA Mitocondrial/química , Chaperona BiP do Retículo Endoplasmático , Humanos , Melanoma/metabolismo , Peçonhas/química , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
9.
J Appl Toxicol ; 35(4): 407-17, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25047904

RESUMO

This study reports on a cytotoxic toxin derived from the venom of the crown-of-thorns starfish Acanthaster planci (CAV). The protein toxin was isolated through both ion-exchange and gel-filtration chromatography, and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrum analyzes. The CAV was identified as plancitoxin I protein. The mechanistic role of the CAV toxin was explored in human malignant melanoma A375.S2 cell death. The results indicated that after incubation with CAV toxin, cells significantly decreased in A375.S2 cell viability and increased in the lactate dehydrogenase (LDH) level in a dose-dependent manner. The assays indicated that CAV toxin promoted reactive oxygen species (ROS) production, induced nitric oxide (NO) formation, lost mitochondrial membrane potential (ΔΨm) and induced inter-nucleosomal DNA fragmentation in A375.S2 cells. The molecular cytotoxicity of the CAV toxin was tested through evaluation of the apoptosis/necrosis ratio by double staining with annexin V-FITC and a propidium iodide (PI) assay. The results suggested that CAV toxin induced a cytotoxic effect in A375.S2 cells via the apoptotic procedure, and may be associated with the regulation of the p38 pathways.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Descoberta de Drogas , Toxinas Marinhas/farmacologia , Melanoma/tratamento farmacológico , Estrelas-do-Mar/química , Peçonhas/química , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Toxinas Marinhas/química , Toxinas Marinhas/isolamento & purificação , Melanoma/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Óxido Nítrico/agonistas , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oceano Pacífico , Mapeamento de Peptídeos , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Estrelas-do-Mar/crescimento & desenvolvimento , Taiwan
10.
Front Neurosci ; 16: 1058359, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36711134

RESUMO

Background: Schizophrenia (SCZ) is a heterogeneous psychiatric disorder, with significant contribution from genetic factors particularly for chronic cases with negative symptoms and cognitive deficits. To date, Genome Wide Association Studies (GWAS) and exome sequencing have associated SCZ with a number of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs), but there is still missing heritability. Medium-sized structural variants (SVs) are difficult to detect using SNP arrays or second generation sequencing, and may account for part of the missing heritability of SCZ. Aims and objectives: To identify SVs associated with severe chronic SCZ across the whole genome. Study design: 10 multiplex families with probands suffering from chronic SCZ with negative symptoms and cognitive deficits were recruited, with all their affected members demonstrating uni-lineal inheritance. Control subjects comprised one affected member from the affected lineage, and unaffected members from each paternal and maternal lineage. Methods: Third generation sequencing was applied to peripheral blood samples from 10 probands and 5 unaffected controls. Bioinformatic tools were used to identify SVs from the long sequencing reads, with confirmation of findings in probands by short-read Illumina sequencing, Sanger sequencing and visual manual validation with Integrated Genome Browser. Results: In the 10 probands, we identified and validated 88 SVs (mostly in introns and medium-sized), within 79 genes, which were absent in the 5 unaffected control subjects. These 79 genes were enriched in 20 biological pathways which were related to brain development, neuronal migration, neurogenesis, neuronal/synaptic function, learning/memory, and hearing. These identified SVs also showed evidence for enrichment of genes that are highly expressed in the adolescent striatum. Conclusion: A substantial part of the missing heritability in SCZ may be explained by medium-sized SVs detectable only by third generation sequencing. We have identified a number of such SVs potentially conferring risk for SCZ, which implicate multiple brain-related genes and pathways. In addition to previously-identified pathways involved in SCZ such as neurodevelopment and neuronal/synaptic functioning, we also found novel evidence for enrichment in hearing-related pathways and genes expressed in the adolescent striatum.

11.
Adv Sci (Weinh) ; : e2205451, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36373710

RESUMO

Deciphering signaling mechanisms critical for the extended pluripotent stem cell (EPSC) state and primed pluripotency is necessary for understanding embryonic development. Here, a membrane protein, podocalyxin-like protein 1 (PODXL) as being essential for extended and primed pluripotency, is identified. Alteration of PODXL expression levels affects self-renewal, protein expression of c-MYC and telomerase, and induced pluripotent stem cell (iPSC) and EPSC colony formation. PODXL is the first membrane protein reported to regulate de novo cholesterol biosynthesis, and human pluripotent stem cells (hPSCs) are more sensitive to cholesterol depletion than fibroblasts. The addition of exogenous cholesterol fully restores PODXL knockdown-mediated loss of pluripotency. PODXL affects lipid raft dynamics via the regulation of cholesterol. PODXL recruits the RAC1/CDC42/actin network to regulate SREBP1 and SREBP2 maturation and lipid raft dynamics. Single-cell RNA sequencing reveals PODXL overexpression enhanced chimerism between human cells in mouse host embryos (hEPSCs 57%). Interestingly, in the human-mouse chimeras, laminin and collagen signaling-related pathways are dominant in PODXL overexpressing cells. It is concluded that cholesterol regulation via PODXL signaling is critical for ESC/EPSC.

12.
Psychiatry Res ; 190(2-3): 172-6, 2011 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-21856020

RESUMO

Deficits in facial emotion recognition have been recognised in Chinese patients diagnosed with schizophrenia. This study examined the relationship between chronicity of illness and performance of facial emotion recognition in Chinese with schizophrenia. There were altogether four groups of subjects matched for age and gender composition. The first and second groups comprised medically stable outpatients with first-episode schizophrenia (n=50) and their healthy controls (n=26). The third and fourth groups were patients with chronic schizophrenic illness (n=51) and their controls (n=28). The ability to recognise the six prototypical facial emotions was examined using locally validated coloured photographs from the Japanese and Caucasian Facial Expressions of Emotion. Chinese patients with schizophrenia, in both the first-episode and chronic stages, performed significantly worse than their control counterparts on overall facial emotion recognition, (P<0.001), with specific impairment in identifying surprise, fear and disgust. The level of deficit was similar at the two stages of illness. Findings suggest that impaired recognition of facial emotion did not appear to have worsened over the course of disease progression, suggesting that recognition of facial emotion is a rather stable trait of the illness. The emotion-specific deficit may have implications for understanding the social difficulties in schizophrenia.


Assuntos
Expressão Facial , Transtornos da Memória/etiologia , Reconhecimento Psicológico/fisiologia , Esquizofrenia/complicações , Psicologia do Esquizofrênico , Adolescente , Adulto , Análise de Variância , Povo Asiático , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estatística como Assunto , Adulto Jovem
13.
J Pers Med ; 11(8)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34442404

RESUMO

Infertility is one of the important problems in the modern world. Male infertility is characterized by several clinical manifestations, including low sperm production (oligozoospermia), reduced sperm motility (asthenozoospermia), and abnormal sperm morphology (teratozoospermia). WDR4, known as Wuho, controls fertility in Drosophila. However, it is unclear whether WDR4 is associated with clinical manifestations of male fertility in human. Here, we attempted to determine the physiological functions of WDR4 gene. Two cohorts were applied to address this question. The first cohort was the general population from Taiwan Biobank. Genomic profiles from 68,948 individuals and 87 common physiological traits were applied for phenome-wide association studies (PheWAS). The second cohort comprised patients with male infertility from Wan Fang Hospital, Taipei Medical University. In total, 81 male participants were recruited for the genetic association study. Clinical records including gender, age, total testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), total sperm number, sperm motility, and sperm morphology were collected. In the first cohort, results from PheWAS exhibited no associations between WDR4 genetic variants and 87 common physiological traits. In the second cohort, a total of four tagging single-nucleotide polymorphisms (tSNPs) from WDR4 gene (rs2298666, rs465663, rs2248490, and rs3746939) were selected for genotyping. We found that SNP rs465663 solely associated with asthenozoospermia. Functional annotations through the GTEx portal revealed the correlation between TT or TC genotype and low expression of WDR4. Furthermore, we used mouse embryonic fibroblasts cells from mwdr4 heterozygous (+/‒) mice for functional validation by western blotting. Indeed, low expression of WDR4 contributed to ROS-induced DNA fragmentation. In conclusion, our results suggest a critical role of WDR4 gene variant as well as protein expression in asthenozoospermia.

14.
Front Neurosci ; 15: 649588, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33986640

RESUMO

Background: Recent findings indicated a high comorbidity between attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), as well as shared genetic influences on them. The latter might contribute at least partly to the former clinical scenario. This study aimed at investigating whether SHANK genes were potential pleiotropic genes to the two said disorders, underlying their genetic overlap. Methods: This study recruited 298 boys with ADHD (including 256 family trios of 1 ADHD boy and his 2 biological parents), 134 boys with ASD, 109 boys with both ADHD and ASD, and 232 typically developing boys as community controls. They were aged between 6 and 11 years old. Results: There was no significant difference in allele frequency of a number of single nucleotide polymorphisms (SNPs) in SHANK2/SHANK3 between the three clinical groups (ADHD, ASD, and ADHD + ASD) and between the two control groups (community controls and pseudo-controls), respectively. The three clinical groups and the two control groups were thus, respectively, combined. A comparison between the two aggregated samples identified significant evidence of disease association for three SHANK2 SNPs with both ADHD and ASD, even after multiple testing correction: rs11236616 (OR = 0.762, permuted p = 0.0376), rs7106631 (OR = 0.720, permuted p = 0.0034), and rs9888288 (OR = 0.770, permuted p = 0.0407). Comparisons among individual groups pointed to a similar trend of findings. Conclusion: SHANK2 could be considered a potential pleiotropic gene underlying the genetic overlap between ADHD and ASD. This might contribute partly to their high comorbidity in the afflicted children.

15.
Br J Psychiatry ; 194(2): 123-9, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19182173

RESUMO

BACKGROUND: Children with attention-deficit hyperactivity disorder (ADHD) have difficulties with executive function and impulse control which may improve with age. AIMS: To map the brain correlates of executive function in ADHD and determine age-related changes in reaction times and brain volumes. METHOD: Attention-deficit hyperactivity disorder and control groups were compared on the change task measures of response inhibition (stop signal reaction time, SSRT) and shifting (change response reaction time, CRRT). Voxel-wise magnetic resonance imaging (MRI) correlations of reaction times and grey matter volume were determined, along with bivariate correlations of reaction times, brain volumes and age. RESULTS: Individuals in the ADHD group had longer SSRTs and CRRTs. Anterior cingulate, striatal and medial temporal volumes highly correlated with SSRT. Striatal and cerebellar volumes strongly correlated with CRRT. Older children had faster reaction times and larger regional brain volumes. In controls, orbitofrontal, medial temporal and cerebellar volumes correlated with CRRT but not SSRT. Neither reaction times nor regional brain volumes were strongly age-dependent. CONCLUSIONS: Our evidence supports delayed brain maturation in ADHD and implies that some features of ADHD improve with age.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/patologia , Cérebro/patologia , Tempo de Reação , Fatores Etários , Estudos de Casos e Controles , Cerebelo/patologia , Cérebro/crescimento & desenvolvimento , Criança , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos
16.
Eur Child Adolesc Psychiatry ; 17(7): 452-61, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18427862

RESUMO

PURPOSE: To provide preliminary prevalence estimates of common DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-4th Edition) disorders in a sample of Hong Kong Chinese adolescents. METHODS: 541 Chinese adolescents were recruited from Grades 7, 8 and 9 of 28 mainstream high schools in Hong Kong (mean age=13.8 years; SD=1.2). The adolescents and their parents were separately administered the Youth and Parent versions of DISC-IV (Diagnostic Interview Schedule for Children-Version 4), respectively. RESULTS: Based upon both symptom and impairment criteria, as required by DSM-IV, the overall prevalence estimate of DSM-IV disorders in our sample of Chinese adolescents was 16.4%. Estimates for such individual disorders/diagnostic groupings as anxiety disorders, depressive disorders, attention deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), conduct disorder (CD), and substance use disorders were 6.9, 1.3, 3.9, 6.8, 1.7, and 1.1%, respectively. These rates were largely compatible with those reported in previous studies with perhaps lower rates of generalized anxiety disorder (GAD), depressive disorders, CD, and substance use disorders, but a higher rate of ODD. The rate of ADHD was somewhat higher, but this might reflect the current DSM-IV diagnostic practice. The rate of anxiety disorders was not as high as predicted from some previous questionnaire surveys. The application of an impairment criterion had discernible impacts on prevalence estimates, greater on anxiety and substance use disorders, but smaller on depressive and disruptive behavior disorders. There was a lack of gender difference in rates of ODD and CD. DISCUSSION AND CONCLUSION: While the findings reported here are broadly compatible with those of other studies, there may be cross-cultural differences in rates of some individual disorders, e.g., GAD, depressive disorders, ODD, CD, and substance use disorders, as well as in gender difference regarding rates of ODD and CD. However, exact comparison between studies is confounded by methodological differences in sample characteristics, measures, and case definition. Standardization of methodology in epidemiological surveys should allow more precise identification of any within- or between-culture variations in prevalence estimation.


Assuntos
Comportamento do Adolescente/psicologia , Transtornos Mentais/epidemiologia , Adolescente , Criança , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Hong Kong/epidemiologia , Humanos , Masculino , Transtornos Mentais/diagnóstico , Razão de Chances , Projetos Piloto , Prevalência , Escalas de Graduação Psiquiátrica , Instituições Acadêmicas , Distribuição por Sexo
17.
Cell Signal ; 47: 16-26, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29574139

RESUMO

Wuho known as WDR4 encodes a highly conserved WD40-repeat protein, which has known homologues of WDR4 in human and mouse. Wuho-FEN1 interaction may have a critical role in the growth and development, and in the maintenance of genome stability. However, how Wuho gene deletion contributes to cell growth inhibition and apoptosis is still unknown. We utilized CAGGCre-ER transgenic mice have a tamoxifen-inducible cre-mediated recombination cassette to prepare primary mouse embryonic fibroblasts (MEFs) with Wuho deficiency. We have demonstrated that Wuho deficiency would induces γH2AX protein level elevation, heterochromatin relaxation and DNA damage down-stream sequences, including p53 activation, caspase-mediated apoptotic pathway, and p21-mediated G2/M cell cycle arrest.


Assuntos
Apoptose , Proliferação de Células , Dano ao DNA , Proteínas de Ligação ao GTP/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/deficiência , Proteínas de Ligação ao GTP/metabolismo , Histonas/metabolismo , Camundongos , Camundongos Knockout , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Tamoxifeno/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
PLoS One ; 12(3): e0173748, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28282463

RESUMO

The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Metilfenidato/farmacologia , Polimorfismo Genético , Receptores de Dopamina D4/genética , Adolescente , Povo Asiático/genética , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Éxons , Família , Feminino , Frequência do Gene , Humanos , Masculino , Repetições Minissatélites
19.
Neuropsychiatr Dis Treat ; 13: 1071-1080, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28442911

RESUMO

BACKGROUND: Methylphenidate (MPH) has been found to be an effective medication for attention-deficit/hyperactivity disorder (ADHD). However, there are neither consistent nor sufficient findings on whether psychiatric comorbidities and associated cognitive functions of ADHD are related to treatment response to MPH in ADHD children. OBJECTIVES: This study investigated whether psychiatric comorbidities, IQ, and neurocognitive deficits are related to treatment response to MPH in ADHD children. In some ways, it is preferable to have a drug that the effectiveness of which to a disorder is not affected by its associated cognitive functions and psychiatric comorbidities. On the other hand, it is likely that the baseline symptom severity of ADHD is associated with the effectiveness of MPH treatment on the symptoms post treatment. METHODS: A total of 149 Chinese boys (aged 6-12 years) with ADHD, combined type, and normal IQ participated in this study. Assessment of ADHD symptom severity was conducted pre and post MPH treatment, while assessment of psychiatric comorbidities, IQ, and neurocognitive deficits was performed in a non-medicated condition. Treatment response was defined as the ADHD symptom severity post MPH treatment. RESULTS: Results indicated that MPH treatment was effective, significantly improving the ADHD condition. Yet, comorbid disorders, IQ, and neurocognitive deficits were not related to MPH treatment response on ADHD symptoms. These findings indicated that the effectiveness of MPH was not affected by psychiatric comorbidities and associated cognitive functions of ADHD. Instead, as expected, it was the baseline symptom severity that was mainly related to the treatment response, ie, the milder the baseline condition, the better the treatment response. CONCLUSION: The current findings positively endorse the widespread clinical use of MPH for treating ADHD. It improves the behavioral symptoms of ADHD regardless of varying psychiatric comorbidities, IQ, and neurocognitive deficits.

20.
Clin Transl Med ; 5(1): 18, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27271878

RESUMO

BACKGROUND: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong. METHODS: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array. RESULTS: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort). CONCLUSIONS: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

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