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1.
Artigo em Inglês | MEDLINE | ID: mdl-31494266

RESUMO

To unravel the genetic mechanisms of disease and physiological traits, it requires comprehensive sequencing analysis of large sample size in Chinese populations. Here, we report the primary results of the Chinese Academy of Sciences Precision Medicine Initiative (CASPMI) project launched by the Chinese Academy of Sciences, including the de novo assembly of a northern Han reference genome (NH1.0) and whole genome analyses of 597 healthy people coming from most areas in China. Given the two existing reference genomes for Han Chinese (YH and HX1) were both from the south, we constructed NH1.0, a new reference genome from a northern individual, by combining the sequencing strategies of PacBio, 10× Genomics, and Bionano mapping. Using this integrated approach, we obtained an N50 scaffold size of 46.63 Mb for the NH1.0 genome and performed a comparative genome analysis of NH1.0 with YH and HX1. In order to generate a genomic variation map of Chinese populations, we performed the whole-genome sequencing of 597 participants and identified 24.85 million (M) single nucleotide variants (SNVs), 3.85 M small indels, and 106,382 structural variations. In the association analysis with collected phenotypes, we found that the T allele of rs1549293 in KAT8 significantly correlated with the waist circumference in northern Han males. Moreover, significant genetic diversity in MTHFR, TCN2, FADS1, and FADS2, which associate with circulating folate, vitamin B12, or lipid metabolism, was observed between northerners and southerners. Especially, for the homocysteine-increasing allele of rs1801133 (MTHFR 677T), we hypothesize that there exists a "comfort" zone for a high frequency of 677T between latitudes of 35-45 degree North. Taken together, our results provide a high-quality northern Han reference genome and novel population-specific data sets of genetic variants for use in the personalized and precision medicine.

3.
Forensic Sci Int Genet ; 40: 168-174, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30878720

RESUMO

We previously proposed a prediction model consisting of 9 CpG sites for forensic age estimation with high practical potentials in Chinese males. Here, we further evaluated the performance of this prediction model in two independent batches of time-series bloodstain samples naturally exposed to room temperature conditions. The first batch consists of 30 Han Chinese males (18-59 years of age) whose peripheral blood was converted into bloodstains on Flinders Technology Association (FTA) cards and naturally exposed to room temperature conditions for different time points up to 3 months. The second batch consists of 99 Han Chinese males (21-66 years of age) whose peripheral blood was divided into 3 replicates, converted into bloodstains on gauze, and naturally exposed to room temperature conditions for 3 months. For each time point and each replicate, the methylation levels at the 9 CpG sites were detected using the EpiTYPER system. Applying the 9-CpG age prediction model to these bloodstain samples resulted in highly accurate age predictions for all time points and replicates (0.81

Assuntos
Manchas de Sangue , Ilhas de CpG/genética , Metilação de DNA , Manejo de Espécimes/instrumentação , Adolescente , Adulto , Genética Forense/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Temperatura Ambiente , Fatores de Tempo , Adulto Jovem
5.
Zhonghua Wei Chang Wai Ke Za Zhi ; 21(11): 1291-1295, 2018 Nov 25.
Artigo em Chinês | MEDLINE | ID: mdl-30506542

RESUMO

OBJECTIVE: To investigate the safety of the controllable ileostomy with pipe in view of histology. METHODS: Twenty-eight Beagle dogs undergoing controllable ileostomy with pipe were studied. The special fistula tube with balloon was placed into the hole locating at the cecal root opposing the mesenteric side, and fixed by double knot compression method. RESULTS: The fistula tube was removed 14 days after surgery, then the safety of the procedure was preliminarily evaluated by gastrointestinal radiography and anatomical observation. The small intestine tissue at the compression suture was used as the experimental segment, and the small intestine tissue at the proximal non-compression suture was used as the control segment. The histological staining and the immunohistochemical staining of S-100 protein, c-kit protein and α-smooth muscle actin(α-SMA) protein between two segment were compared, while quantitative comparison of myenteric plexus, intestinal Cajal cell(ICC) and smooth muscle cells in intestinal wall was carried out. After removal of fistula tube at 14 days postoperative, the dogs were normal in feeding and defecation. The digestive tract radiography showed that the intestine was patent without obvious stenosis and obstruction. The dogs were dissected 21 days after operation. The abdominal sinus ostium was well healed and the internal sinus was well formed. Under gross inspection, blood supply, morphology and motor function of experimental intestine segment were similar from the proximal and distal segments of control intestine. S-100 immunohistochemical staining showed that the morphology and distribution of S-100 protein positive cells and "blank area" cells in the experimental and control segments were consistent. Myenteric plexus counting showed that the experimental segment was 3.62±1.82/field and the control segment was 3.27±1.62/field, whose difference was not statistically significant(t=1.30, P=0.20). Immunohistochemical staining of c-kit showed that the distribution of c-kit positive cells in both segments was consistent. Counting of the number of ICCs in myenteric plexus revealed that experimental segment was 2.96±2.57/plexus, and control segment was 2.49±1.80/plexus without significant difference(t=1.81, P=0.07). Immunohistochemical staining of α-SMA showed that the morphology and distribution of smooth muscle cells in whole intestinal wall(muscle layer, longitudinal muscle, ring muscle) in experimental and control segments were consistent. The average absorbance(A) value of α-SMA staining in ring muscle layer was detected and quantified. The experimental segment was 0.15±0.03 and control segment was 0.14±0.04 without significant difference(t=1.16, P=0.25). CONCLUSION: The technique of controllable ileostomy with pipe is safe in view of histology, which may replace the traditional protective ileostomy.

6.
Pharm Biol ; 56(1): 548-558, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30392423

RESUMO

CONTEXT: The plant genus Uncaria (Rubiaceae), also known as Gouteng, is the source of an important traditional Chinese medicine. Misidentification and adulteration of Gouteng affect the safety and efficacy of the medication. Phylogenetic relationships among the species of this genus are unknown. OBJECTIVE: The present study sought to detect the phylogenetic relationships based on internal transcribed spacer (ITS) region of all 12 species of Uncaria recorded in the Flora of China. MATERIALS AND METHODS: Accession of seven species of Uncaria served as reference samples. ITS region was used for polymerase chain reaction (PCR) amplification of the reference samples representing 39 specimens. Distance analysis, species discrimination, and secondary structure of ITS2 were used to assess the ability of ITS sequence in authenticating. The phylogenetic relationships were detected using three methods: Bayesian inference (BI), maximum likelihood (ML), and neighbor joining (NJ). RESULTS: Five species of traditional Chinese medicine Gouteng were well resolved in molecular phylogenetic tree. Besides, Uncaria lancifolia Hutch. was closer to U. rhynchophylloides F.C. How and U. sessilifructus Roxb. was closer to U. laevigata Wall. within the tree. Further, we also found that ITS2 secondary structure can be a candidate tool in distinguishing two closely related species U. yunnanensis K.C.Hsia and U. lanosa Wall. For accurate identification of different species of Uncaria based on species-specific nucleotide sites, a consensus sequences database with all 12 species is established. DISCUSSIONS AND CONCLUSIONS: The results are able to discriminate Uncaria species and illustrate the phylogenetic relationships, which are essential for the investigation of adulterants and misidentifications of Uncaria.

7.
PLoS Genet ; 14(9): e1007640, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30248107

RESUMO

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10-10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10-8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10-11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure.

8.
Twin Res Hum Genet ; 21(5): 361-368, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30064533

RESUMO

Familial monozygotic (MZ) twinning reports are rare around the world, and we report a four-generation pedigree with seven recorded pairs of female MZ twins. Whole-genome sequencing of seven family members was performed to explore the featured genetic factors in MZ twins. For variations specific to MZ twins, five novel variants were observed in the X chromosome. These candidates were used to explain the seemingly X-linked dominant inheritance pattern, and only one variant was exonic, located at the 5'UTR region of ZCCHC12 (chrX: 117958597, G > A). Besides, consistent mitochondrial DNA composition in the maternal linage precluded roles of mitochondria for this trait. In this pedigree, autosomes also contain diverse variations specific to MZ twins. Pathway analysis revealed a significant enrichment of genes carrying novel SNVs in the epithelial adherens junction-signaling pathway (p = .011), contributed by FGFR1, TUBB6, and MYH7B. Meanwhile, TBC1D22A, TRIOBP, and TUBB6, also carrying similar SNVs, were involved in the GTPase family-mediated signal pathway. Furthermore, gene-set enrichment analysis for 533 genes covered by copy number variations specific to MZ twins illustrated that the tight junction-signaling pathway was significantly enriched (p < .001). Therefore, the novel changes in the X chromosome and the provided candidate variants across autosomes may be responsible for MZ twinning, giving clues to increase our understanding about the underlying mechanism.

9.
Cancer Med ; 7(9): 4361-4370, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30062861

RESUMO

BACKGROUND: Gastroesophageal Junction neuroendocrine neoplasms (GEJ-NENs) are rare and heterogeneous tumors. We aim to analyze the clinicopathlogical features and prognostic factors of GEJ-NENs and to compare the outcome of GEJ-NENs with other gastric NENs. METHODS: A total of 297 GEJ-NENs patients were enrolled from 10 Chinese hospitals and 3152 gastric NENs patients, including 274 GEJ-NENs, were retrieved from Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: The clinical characteristics of GEJ-NENs among different races were different. All Chinese patients had GEJ-NENs of grade 3, with 67.7% of poorly differentiated NEC and 32.3% of MANEC. In SEER database, 70.8% of white, 62.5% of black, and 87.5% of AP patients had poorly differentiated/undifferentiated tumors. In Cox multivariate analysis, NEC/MANEC (HR 2.09, 95%CI 1.24-3.56; P = 0.006), lymph node metastasis (HR 3.52, 95%CI 1.68-7.34; P = 0.001), and distant metastases (HR 3.90, 95%CI 2.50-6.08; P < 0.001) are independent predictors of overall survival. Surgical resection showed a median OS improvement of 13.1-73.3 months (HR 0.21, 95% CI 0.14-0.33, P < 0.001). Adjuvant therapy did not improve survival for postoperative GEJ-NEN patients (P = 0.141). GEJ-NENs were larger, higher grade, more distant metastasis, and worse prognosis than other gastric NENs. CONCLUSION: GEJ-NENs were mostly poorly differentiated carcinomas, and all of Chinese patients were NEC/MANEC. The outcome of MANEC was preferable to NECs. Both lymph nodes metastasis and distant disease were independent predictors of prognosis. Surgical resection can improve survival, but postoperative adjuvant therapy had no additional benefit. GEJ-NENs have worse survival than other gastric NENs.

10.
Proc Natl Acad Sci U S A ; 115(30): E7091-E7100, 2018 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-29987045

RESUMO

Worldwide, myopia is the leading cause of visual impairment. It results from inappropriate extension of the ocular axis and concomitant declines in scleral strength and thickness caused by extracellular matrix (ECM) remodeling. However, the identities of the initiators and signaling pathways that induce scleral ECM remodeling in myopia are unknown. Here, we used single-cell RNA-sequencing to identify pathways activated in the sclera during myopia development. We found that the hypoxia-signaling, the eIF2-signaling, and mTOR-signaling pathways were activated in murine myopic sclera. Consistent with the role of hypoxic pathways in mouse model of myopia, nearly one third of human myopia risk genes from the genome-wide association study and linkage analyses interact with genes in the hypoxia-inducible factor-1α (HIF-1α)-signaling pathway. Furthermore, experimental myopia selectively induced HIF-1α up-regulation in the myopic sclera of both mice and guinea pigs. Additionally, hypoxia exposure (5% O2) promoted myofibroblast transdifferentiation with down-regulation of type I collagen in human scleral fibroblasts. Importantly, the antihypoxia drugs salidroside and formononetin down-regulated HIF-1α expression as well as the phosphorylation levels of eIF2α and mTOR, slowing experimental myopia progression without affecting normal ocular growth in guinea pigs. Furthermore, eIF2α phosphorylation inhibition suppressed experimental myopia, whereas mTOR phosphorylation induced myopia in normal mice. Collectively, these findings defined an essential role of hypoxia in scleral ECM remodeling and myopia development, suggesting a therapeutic approach to control myopia by ameliorating hypoxia.


Assuntos
Matriz Extracelular/metabolismo , Hipóxia , Miopia/terapia , Esclera/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Fator de Iniciação 2 em Eucariotos/metabolismo , Matriz Extracelular/patologia , Proteínas do Olho/metabolismo , Cobaias , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Miopia/metabolismo , Miopia/patologia , Esclera/irrigação sanguínea , Esclera/patologia , Serina-Treonina Quinases TOR/metabolismo
11.
Nat Commun ; 9(1): 1684, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29739929

RESUMO

The skin's tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.

12.
Gene ; 668: 121-128, 2018 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-29778423

RESUMO

Although ankylosing spondylitis (AS) is a common, highly heritable arthropathy, the precise genetic mechanism underlying the disease remains elusive. Here, we investigate the disease-causing mutations in a large AS family with distinguished complexity, consisting of 23 patients covering four generations and exhibiting a mixed HLA-B27 (+) and (-) status. Linkage analysis with 32 members using three methods and whole-exome sequencing analysis with three HLA-B27 (+) patients, one HLA-B27 (-) patient, and one healthy individual did not identify a mutation common to all of the patients, strongly suggesting the existence of genetic heterogeneity in this large pedigree. However, if only B27-positive patients were analyzed, the linkage analysis located a 22-Mb region harboring the HLA gene cluster in chromosome 6 (LOD = 4.2), and the subsequent exome analysis identified two non-synonymous mutations in the TREML2 and IP6K3 genes. These genes were resequenced among 370 sporadic AS patients and 487 healthy individuals. A significantly higher mutation frequency of TREML2 was observed in AS patients (1.51% versus 0.21%). The results obtained for the AS pedigree and sporadic patients suggest that mutation of TREML2 is a major factor leading to AS for HLA-B27 (+) members in this large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals.


Assuntos
Antígeno HLA-B27/análise , Mutação , Receptores Imunológicos/genética , Espondilite Anquilosante/genética , Feminino , Ligação Genética , Humanos , Masculino , Fenótipo
13.
Nat Genet ; 50(5): 652-656, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29662168

RESUMO

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.

14.
Forensic Sci Int Genet ; 35: 38-45, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29631189

RESUMO

Estimating individual age from biomarkers may provide key information facilitating forensic investigations. Recent progress has shown DNA methylation at age-associated CpG sites as the most informative biomarkers for estimating the individual age of an unknown donor. Optimal feature selection plays a critical role in determining the performance of the final prediction model. In this study we investigate methylation levels at 153 age-associated CpG sites from 21 previously reported genomic regions using the EpiTYPER system for their predictive power on individual age in 390 Han Chinese males ranging from 15 to 75 years of age. We conducted a systematic feature selection using a stepwise backward multiple linear regression analysis as well as an exhaustive searching algorithm. Both approaches identified the same subset of 9 CpG sites, which in linear combination provided the optimal model fitting with mean absolute deviation (MAD) of 2.89 years of age and explainable variance (R2) of 0.92. The final model was validated in two independent Han Chinese male samples (validation set 1, N = 65, MAD = 2.49, R2 = 0.95, and validation set 2, N = 62, MAD = 3.36, R2 = 0.89). Other competing models such as support vector machine and artificial neural network did not outperform the linear model to any noticeable degree. The validation set 1 was additionally analyzed using Pyrosequencing technology for cross-platform validation and was termed as validation set 3. Directly applying our model, in which the methylation levels were detected by the EpiTYPER system, to the data from pyrosequencing technology showed, however, less accurate results in terms of MAD (validation set 3, N = 65 Han Chinese males, MAD = 4.20, R2 = 0.93), suggesting the presence of a batch effect between different data generation platforms. This batch effect could be partially overcome by a z-score transformation (MAD = 2.76, R2 = 0.93). Overall, our systematic feature selection identified 9 CpG sites as the optimal subset for forensic age estimation and the prediction model consisting of these 9 markers demonstrated high potential in forensic practice. An age estimator implementing our prediction model allowing missing markers is freely available at http://liufan.big.ac.cn/AgePrediction.

15.
Hum Mol Genet ; 27(3): 559-575, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29220522

RESUMO

Shape variation of human head hair shows striking variation within and between human populations, while its genetic basis is far from being understood. We performed a series of genome-wide association studies (GWASs) and replication studies in a total of 28 964 subjects from 9 cohorts from multiple geographic origins. A meta-analysis of three European GWASs identified 8 novel loci (1p36.23 ERRFI1/SLC45A1, 1p36.22 PEX14, 1p36.13 PADI3, 2p13.3 TGFA, 11p14.1 LGR4, 12q13.13 HOXC13, 17q21.2 KRTAP, and 20q13.33 PTK6), and confirmed 4 previously known ones (1q21.3 TCHH/TCHHL1/LCE3E, 2q35 WNT10A, 4q21.21 FRAS1, and 10p14 LINC00708/GATA3), all showing genome-wide significant association with hair shape (P < 5e-8). All except one (1p36.22 PEX14) were replicated with nominal significance in at least one of the 6 additional cohorts of European, Native American and East Asian origins. Three additional previously known genes (EDAR, OFCC1, and PRSS53) were confirmed at the nominal significance level. A multivariable regression model revealed that 14 SNPs from different genes significantly and independently contribute to hair shape variation, reaching a cross-validated AUC value of 0.66 (95% CI: 0.62-0.70) and an AUC value of 0.64 in an independent validation cohort, providing an improved accuracy compared with a previous model. Prediction outcomes of 2504 individuals from a multiethnic sample were largely consistent with general knowledge on the global distribution of hair shape variation. Our study thus delivers target genes and DNA variants for future functional studies to further evaluate the molecular basis of hair shape in humans.

16.
Sci China Life Sci ; 61(1): 68-78, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28795375

RESUMO

Humans have been exposed to many environmental challenges since their evolutionary origins in Africa and subsequent migrations to the rest of the world. A severe environmental challenge to human migrants was hypoxia caused by low barometric oxygen pressure at high altitudes. Several genome-wide scans have elucidated the genetic basis of human high-altitude adaptations. However, the dearth of functional variant information has led to the successful association of only a few candidate genes. In the present study, we employed a candidate gene approach and re-sequenced the EDAR locus in 45 Tibetan individuals to identify mutations involved in hypoxia adaptation. We identified 10 and five quantitative trait-associated mutations for oxygen saturation (SaO2) and blood platelet count, respectively, at the EDAR locus. Among these, rs10865026 and rs3749110 (associated with SaO2 and platelet count, respectively) were identified as functional candidate targets. These data demonstrate that EDAR has undergone natural selection in recent human history and indicate an important role of EDAR variants in Tibetan high-altitude adaptations.


Assuntos
Aclimatação/genética , Altitude , Receptor Edar/genética , Evolução Molecular , Hipóxia/genética , Polimorfismo de Nucleotídeo Único , Estudos de Associação Genética , Genética Populacional , Humanos , Hipóxia/sangue , Oxigênio/sangue , Fenótipo , Contagem de Plaquetas , Seleção Genética , Tibet
17.
Biomed Chromatogr ; 32(3)2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29034541

RESUMO

Uncaria is a multi-source herb and its species identification has become a bottleneck in quality control. To study the identification method of different Uncaria species herbs through HPLC-MS coupled with rDNA Internal Transcribed Spacer (rDNA ITS) sequence, both plant morphological traits and molecular identification were used to determine the species of every collected Uncaria herb. The genetic analysis of different Uncaria species was performed using their rDNA ITS sequence as a molecular marker. Meanwhile, the phylogenetic relationships of 22 samples from six Uncaria species were divided and classified clearly. By optimizing the chromatographic conditions, a practical HPLC method to differentiate various varieties of Uncaria herbs was set up based on a set of characteristic components across each species. A high-performance liquid chromatography-photodiode array detector tandem ion trap and time of flight mass spectrometry technique combined with reference substances was utilized to derive 21 characteristic compounds containing six groups of six Uncaria species in China. Thus, this study provides a feasible method to solve the current problem of confusion in Uncaria species, and makes a significant step forward in the appropriate clinical use, in-depth research and further utilization of different Uncaria species.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , DNA de Plantas/genética , Espectrometria de Massas por Ionização por Electrospray/métodos , Uncaria , DNA Intergênico/genética , DNA de Plantas/análise , Filogenia , Extratos Vegetais/análise , Extratos Vegetais/química , Folhas de Planta/química , Análise de Sequência de DNA , Uncaria/química , Uncaria/classificação , Uncaria/genética
18.
Arch Med Sci ; 13(6): 1255-1261, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29181055

RESUMO

Introduction: This study was designed to investigate the potential function of the activating protein 2α (AP-2α) gene in controlling the proliferation and apoptosis of gastric cancer. Material and methods: Gastric cancer cell line MCG-803 cells and normal cell line GES-1 cells were selected to transfect pcDNA3.1(+)-AP-2α and pcDNA3.1(+) plasmids, respectively. Both mRNA and protein levels of AP-2α in each group transfected with the pcDNA3.1(+)-AP-2α plasmids were up-regulated after 48 h by real-time PCR and Western blotting analysis, leading to marked proliferation inhibition and significant cell cycle arrest. Results: pcDNA3.1(+)-AP-2α reduced tumor tissue growth in a subcutaneous tumor gastric carcinoma nude mouse model. Protein over-expression of AP-2α in the nude mouse model was accompanied by down-regulation of Blc-2 and ErbB2, resulting in the up-regulation of caspase-3, -8, and -9, ERα and p21WAF1/CIP1. Conclusions: The reintroduction of the AP-2α gene by pcDNA3.1 could inhibit gastric tumor growth in vitro and in vivo, which may be an alternative future therapeutic molecular target for human gastric cancer.

19.
Hum Genet ; 136(11-12): 1407-1417, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28921393

RESUMO

Adult height is the most widely genetically studied common trait in humans; however, the trait variance explainable by currently known height-associated single nucleotide polymorphisms (SNPs) identified from the previous genome-wide association studies (GWAS) is yet far from complete given the high heritability of this complex trait. To exam if compound heterozygotes (CH) may explain extra height variance, we conducted a genome-wide analysis to screen for CH in association with adult height in 10,631 Dutch Europeans enriched with extremely tall people, using our recently developed method implemented in the software package CollapsABEL. The analysis identified six regions (3q23, 5q35.1, 6p21.31, 6p21.33, 7q21.2, and 9p24.3), where multiple pairs of SNPs as CH showed genome-wide significant association with height (P < 1.67 × 10-10). Of those, 9p24.3 represents a novel region influencing adult height, whereas the others have been highlighted in the previous GWAS on height based on analysis of individual SNPs. A replication analysis in 4080 Australians of European ancestry confirmed the significant CH-like association at 9p24.3 (P < 0.05). Together, the collapsed genotypes at these six loci explained 2.51% of the height variance (after adjusting for sex and age), compared with 3.23% explained by the 14 top-associated SNPs at 14 loci identified by traditional GWAS in the same data set (P < 5 × 10-8). Overall, our study empirically demonstrates that CH plays an important role in adult height and may explain a proportion of its "missing heritability". Moreover, our findings raise promising expectations for other highly polygenic complex traits to explain missing heritability identifiable through CH-like associations.


Assuntos
Estatura/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Heterozigoto , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Grupos Étnicos/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos
20.
Zhonghua Wei Chang Wai Ke Za Zhi ; 20(8): 919-922, 2017 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-28836255

RESUMO

OBJECTIVE: To study the management for the perineal incision after laparoscopic-assisted abdominoperineal resection for rectal cancer. METHODS: Clinical data of 87 patients undergoing laparoscopic Miles operation for lower rectal cancer from June 2009 to February 2014 were collected and studied. Presacral space drainage group: presacral space drainage tube was applied in 42 patients. Combined drainage group: presacral space drainage tube combined with subcutaneous vacuum pressure suction was applied in 45 cases. In combined drainage group, except the presacral drainage tube, another drainage tube was placed subcutaneously and connected to a negative pressure ball, which was fixed on the lateral anterior of perineal wound by the further incision and drainage. After subcutaneous tube was placed for 2 weeks, as drainage fluid was limpid and <15 ml/d for 3 days, meanwhile no obvious pelvic fluid was detected by ultrasound, and the wound healed quite well without redness and edema, then the subcutaneous tube with the negative pressure ball could be removed. RESULTS: There were 51 males and 36 females with the mean age of 26-78(56.9±10.8) years old. The laparoscopic Miles operation was successfully completed in all the cases without death and complications. The drainage tube was placed for 4-13(8.0±2.5) days in presacral space drainage group, and for 4-14(6.7±2.4) days in combined drainage group. The subcutaneous tube was placed for 14-24(15.8±3.0) days. The primary healing rate of perineal wound in presacral space drainage group and combined drainage group was 66.7%(28/42) and 91.1%(41/45) respectively, while the perineal wound infection rate was 21.4%(9/42) and 4.4%(2/45) respectively, whose differences between two groups were both significant (χ2=7.911, P=0.005 and χ2=5.674, P=0.017). CONCLUSION: Presacral space drainage tube combined with subcutaneous vacuum pressure suction in laparoscopic-assisted abdominoperineal resection for rectal cancer has better efficacy and lower infection rate for perineal incision, which is worth wide application.

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