RESUMEN
To determine whether recent genome-wide association studies that reported 45 susceptibility loci in European women are also risk factors for breast cancer in Chinese women. We selected and genotyped 40 single nucleotide polymorphisms (SNPs) using the Sequenom iPlex platform in a female Chinese cohort of 2,901 breast cancer cases and 2,789 healthy controls. We evaluated these SNPs with the risk of breast cancer and further by estrogen receptor (ER) status, progestin (PR) status, human epidermal growth factor receptor-2 (HER-2) status, and four breast cancer subtypes (Luminal A type, Luminal B type, HER-2 overexpression type and Basal-like type). We first confirmed that the SNP rs9693444 on 8p12 was associated with breast cancer in Chinese women (P = 6.44 × 10(-4)). Furthermore, we identified four susceptibility loci that were associated with specific tumor subtypes. Statistically significant differences were detected with the association of rs6828523 (4q34.1/ADAM29) with ER-positive breast cancer (P = 1.27 × 10(-3)) and the association of rs4849887 (2q14.2) with PR-positive breast cancer (P = 1.29 × 10(-3)). Of the four breast cancer subtypes, the associations of rs12493607 (3p24.1/TGFBR2) with HER-2 overexpression in breast cancer (P = 1.09 × 10(-3)) and rs11075995 (16q12.2/FTO) with basal-like breast cancer (P = 1.64 × 10(-4)) were statistically significant. This study is the first to show that these 5 susceptibility loci (8p12, 4q34.1/ADAM29, 2q14.2, 3p24.1/TGFBR2, and 16q12.2/FTO) correlate with breast cancer (overall and specific subtypes) in Chinese women, which has improved our understanding of the genetic basis of specific breast cancer subtypes.
Asunto(s)
Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Receptor ErbB-2/biosíntesis , Adulto , Pueblo Asiatico , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Proteínas de Neoplasias , Polimorfismo de Nucleótido Simple , Receptor ErbB-2/genética , Factores de RiesgoRESUMEN
To search for factors promoting bone fracture repair, we investigated the effects of extracorporeal shock wave (ESW) on the adhesion, spreading, and migration of osteoblasts and its specific underlying cellular mechanisms. After a single period of stimulation by 10 kV (500 impulses) of shock wave (SW), the adhesion rate was increased as compared with the vehicle control. The data from both wound healing and transwell tests confirmed an acceleration in the migration of osteoblasts by SW treatment. RT-PCR, flow cytometry, and Western blotting showed that SW rapidly increased the surface expression of α5 and ß1 subunit integrins, indicating that integrin ß1 acted as an early signal for ESW-induced osteoblast adhesion and migration. It has also been found that a significant elevation occurred in the expression of phosphorylated ß-catenin and focal adhesion kinase (FAK) at the site of tyrosine 397 in response to SW stimulation after the increasing expression of the integrin ß1 molecule. When siRNAs of integrin α5 and ß1 subunit were added, the level of FAK phosphorylation elevated by SW declined. Interestingly, the adhesion and migration of osteoblasts were decreased when these siRNA reagents as well as the ERK1/2 signaling pathway inhibitors, U0126 and PD98059, were present. Further studies demonstrated that U0126 could inhibit the downstream integrin-dependent signaling pathways, such as the FAK signaling pathway, whereas it had no influence on the synthesis of integrin ß1 molecule. In conclusion, these data suggest that ESW promotes the adhesion and migration of osteoblasts via integrin ß1-mediated expression of phosphorylated FAK at the Tyr-397 site; in addition, ERK1/2 are also important for osteoblast adhesion, spreading, migration, and integrin expression.
Asunto(s)
Adhesión Celular/efectos de la radiación , Movimiento Celular/efectos de la radiación , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Ondas de Choque de Alta Energía , Integrina beta1/metabolismo , Osteoblastos/fisiología , Animales , Células Cultivadas , Femenino , Proteína-Tirosina Quinasas de Adhesión Focal/genética , Expresión Génica , Integrina alfa5/genética , Integrina alfa5/metabolismo , Integrina beta1/genética , Sistema de Señalización de MAP Quinasas , Masculino , Osteoblastos/metabolismo , Osteoblastos/efectos de la radiación , Fosforilación , Cultivo Primario de Células , Procesamiento Proteico-Postraduccional/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Cráneo/citología , Vía de Señalización Wnt , beta Catenina/metabolismoRESUMEN
Genome-wide association studies have identified more than 90 susceptibility loci for breast cancer. However, the missing heritability is evident, and the contributions of coding variants to breast cancer susceptibility have not yet been systematically evaluated. Here, we present a large-scale whole-exome association study for breast cancer consisting of 24,162 individuals (10,055 cases and 14,107 controls). In addition to replicating known susceptibility loci (e.g., ESR1, FGFR2, and TOX3), we identify two novel missense variants in C21orf58 (rs13047478, Pmeta = 4.52 × 10-8) and ZNF526 (rs3810151, Pmeta = 7.60 × 10-9) and one new noncoding variant at 7q21.11 (P < 5 × 10-8). C21orf58 and ZNF526 possessed functional roles in the control of breast cancer cell growth, and the two coding variants were found to be the eQTL for several nearby genes. rs13047478 was significantly (P < 5.00 × 10-8) associated with the expression of genes MCM3AP and YBEY in breast mammary tissues. rs3810151 was found to be significantly associated with the expression of genes PAFAH1B3 (P = 8.39 × 10-8) and CNFN (P = 3.77 × 10-4) in human blood samples. C21orf58 and ZNF526, together with these eQTL genes, were differentially expressed in breast tumors versus normal breast. Our study reveals additional loci and novel genes for genetic predisposition to breast cancer and highlights a polygenic basis of disease development.Significance: Large-scale genetic screening identifies novel missense variants and a noncoding variant as predisposing factors for breast cancer. Cancer Res; 78(11); 3087-97. ©2018 AACR.
Asunto(s)
Pueblo Asiatico/genética , Neoplasias de la Mama/genética , Exoma/genética , Predisposición Genética a la Enfermedad/genética , Sitios de Carácter Cuantitativo/genética , Adulto , Estudios de Casos y Controles , Femenino , Estudio de Asociación del Genoma Completo/métodos , Humanos , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Intramedullary nails had been widely used in the treatment of long-bone fractures because of less interference of fractures and center bearing biomechanical advantage. However, it had been also found many shortcomings such as broken nails, delayed healing and was modified in order to achieve better efficacy and reduce complications. The aim of the present study is to compare the efficacy of rotary self-locking intramedullary nails (RSIN) with that of interlocking intramedullary nails (IIN) in the treatment of long-bone fractures. METHODS: A retrospective study investigated 129 cases with long-bone fractures (36 with femoral fracture, 81 with tibial fracture, and 12 with humeral fracture). The fractures were fixed using either an RSIN or IIN. All patients underwent followup for 12-30 months. RESULTS: All patients in both groups achieved a clinical fracture healing standard and the postoperative affected limb muscle strength and joint function were well restored. The RSIN group required a shorter operative time and the fracture healed faster. There was no significant difference in the hospital stay, intraoperative blood loss or postoperative complications between the two groups. CONCLUSIONS: RSIN is used to treat long-bone fractures. Its healing efficacy is equivalent to the IIN. Moreover, the RSIN method is simpler and causes less tissue damage than the IIN, therefore having the advantage of accelerated healing.