Background::While type 2 diabetes mellitus (T2DM) is considered a putative causal risk factor for coronary artery disease (CAD), the intrinsic link underlying T2DM and CAD is not fully understood. We aimed to highlight the importance of integrated care targeting both diseases by investigating the phenotypic and genetic relationships between T2DM and CAD.Methods::We evaluated phenotypic associations using data from the United Kingdom Biobank ( N = 472,050). We investigated genetic relationships by leveraging genomic data conducted in European ancestry for T2DM, with and without adjustment for body mass index (BMI) (T2DM: Ncase/ Ncontrol = 74,124/824,006; T2DM adjusted for BMI [T2DM adjBMI]: Ncase/ Ncontrol = 50,409/523,897) and for CAD ( Ncase/ Ncontrol = 181,522/984,168). We performed additional analyses using genomic data conducted in multiancestry individuals for T2DM ( Ncase/ Ncontrol = 180,834/1,159,055). Results::Observational analysis suggested a bidirectional relationship between T2DM and CAD (T2DM→CAD: hazard ratio [HR] = 2.12, 95% confidence interval [CI]: 2.01–2.24; CAD→T2DM: HR = 1.72, 95% CI: 1.63–1.81). A positive overall genetic correlation between T2DM and CAD was observed ( rg = 0.39, P = 1.43 × 10 -75), which was largely independent of BMI (T2DM adjBMI–CAD: rg = 0.31, P = 1.20 × 10 –36). This was corroborated by six local signals, among which 9p21.3 showed the strongest genetic correlation. Cross-trait meta-analysis replicated 101 previously reported loci and discovered six novel pleiotropic loci. Mendelian randomization analysis supported a bidirectional causal relationship (T2DM→CAD: odds ratio [OR] = 1.13, 95% CI: 1.11-1.16; CAD→T2DM: OR = 1.12, 95% CI: 1.07-1.18), which was confirmed in multiancestry individuals (T2DM→CAD: OR = 1.13, 95% CI: 1.10-1.16; CAD→T2DM: OR = 1.08, 95% CI: 1.04-1.13). This bidirectional relationship was significantly mediated by systolic blood pressure and intake of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, with mediation proportions of 54.1% (95% CI: 24.9-83.4%) and 90.4% (95% CI: 29.3-151.5%), respectively. Conclusion::Our observational and genetic analyses demonstrated an intrinsic bidirectional relationship between T2DM and CAD and clarified the biological mechanisms underlying this relationship.

The role of intestinal microbiota in mammals and humans are gaining increasing attention. The health of piglets requires a dynamically balanced intestinal microbiota. However, there are temporal and spatial changes in the distri-bution and composition of microbiota from the esophagus to the rectum during the life cycle of the pig. The intestinal micro?biota has various beneficial functions in pig, like nutrient metabolism, intestinal mucosal barrier, immune responses and pathogen infection. A variety of factors play an important role in the formation and stabilization of intestinal microbiota, in?cluding the ways of delivery ( vaginal or caesarean) , the diet during infancy ( breast milk or formula feeds) and the usage of antibiotics or antibiotic-like molecules. In this review, we mainly discussed the relationship between intestinal microbi?ota and the intestinal health of piglets from the aspects of the composition and colonization of intestinal microbiota, as well as the functions and influencing factors of intestinal microbiota, so as to further understanding the importance of intestinal microbiota in intestinal function of piglets.

OBJECTIVETo investigate the effects of crypotanshinone (CPT) on the proliferation and apoptosis of DU145 prostate cancer cells as well as on the metadherin expression and the downstream PI3K/AKT signaling pathway in the DU145 cells.

METHODSWe treated DU145 prostate cancer cells with different concentrations of CPT for 24, 48, and 72 hours followed by evaluation of the proliferation and apoptosis of the cells by MTT assay and TUNEL, respectively. We determined the expressions of metadherin protein and mRNA in the DU145 cells by Western blot and RT-PCR respectively at different time points after CPT treatment. We also detected the expressions of the proteins metadherin, AKT, p-AKT, and Bcl-2 in the CPT-treated DU145 cells at 48 hours.

RESULTSCPT significantly inhibited the proliferation of the DU145 cells in a dose- and time-dependent manner (P < 0.05). After treatment with 10 µmol/L CPT for 24, 48, and 72 hours, the apoptosis rates of the DU145 cells were (29.42 ± 4.51), (55.07 ± 5.67) and (70.84 ± 4.66)%, respectively, significantly higher than (3.1 ± 2.48)% in the control group (P < 0.05). The expression of metadherin was remarkably downregulated at the transcription and translation levels (P < 0.05) and the expressions of the AKT signaling pathway and the Bcl-2 protein were markedly inhibited in the DU145 cells after treated with 10 µmol/L CPT for 48 hours (P < 0.05).

CONCLUSIONCPT can inhibit the proliferation and induce the apoptosis of DU145 prostate cancer cells, which may be associated with its suppression of the downstream PI3K/AKT signaling pathway by reducing the expression of metadherin in the DU145 cells.

Apoptosis ; drug effects ; Cell Adhesion Molecules ; metabolism ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Diterpenes, Abietane ; pharmacology ; Down-Regulation ; Drugs, Chinese Herbal ; pharmacology ; Humans ; In Situ Nick-End Labeling ; Male ; Neoplasm Proteins ; metabolism ; Phosphatidylinositol 3-Kinases ; metabolism ; Prostatic Neoplasms ; metabolism ; pathology ; Proto-Oncogene Proteins c-akt ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; RNA, Messenger ; metabolism ; Signal Transduction ; drug effects ; Time Factors

CYP21A2 gene mutations in a child with congenital adrenal hyperplasia (CAH), and the child's parents, were detected in the study. The clinical features, treatment monitoring and molecular genetic mechanism of CAH are reviewed. In the study, DNA was extracted from peripheral blood samples using the QIAGEN Blood DNA Mini Kit; a highly specific PCR primer for CYP21A2 gene was designed according to the sequence difference between CYP2lA2 gene and its pseudogene; the whole CYP2lA2 gene was amplified with PrimeSTAR DNA polymerase (Takara), and the amplification product was directly sequenced to detect and analyze CYP2lA2 gene mutation. The child was clinically diagnosed with CAH (21-hydroxylase deficiency, 21-OHD) at the age of 36 days, and the case was confirmed by genetic diagnosis at the age of 1.5 years. The proband had a homozygous mutation at c.293-13C in the second intron of CYP21 gene, while the parents had heterozygous mutations. Early diagnosis and standard treatment of CAH (21-OHD) should be performed to prevent salt-wasting crisis and reduce mortality; bone aging should be avoided to increase final adult height (FAH), and reproductive dysfunction due to oligospermia in adulthood should be avoided. These factors are helpful for improving prognosis and increasing FAH. Investigating the molecular genetic mechanism of CAH can improve recognition and optimize diagnosis of this disease. In addition, carrier diagnosis and genetic counseling for the proband family are of great significance.
17-alpha-Hydroxyprogesterone ; blood ; Adrenal Hyperplasia, Congenital ; blood ; genetics ; Humans ; Infant ; Male ; Mutation ; Steroid 21-Hydroxylase ; genetics

OBJECTIVETo evaluate the effect of anthracycline pirarubicin-based regimen in association with different ways of fluorouracil (5-Fu) as neoadjuvant and adjuvant chemotherapy for primary breast cancer.

METHODSTwo hundred and eighty-nine primary breast cancer patients who were to be operated, two to eight cycles of pirarubicin in association with cyclophosphamide and 5-Fu (CTF or CTFci regimen) were given before operation. The pathological response rate, effect and its relation with the infusion routes of 5-Fu were analyzed.

RESULTSThe overall pathological complete remission (pCR) rate was 28.4%. The median follow-up period was 39 months. The 5-year DFS was 87.6% (95% CI:82.1% to 92.7%), 5-year DDFS was 89.9% (95% CI:84.0% to 95.8%), and overall survival was 99.6%. CTFci (5-Fu, continuous infusion) regimen was superior to CTF regimen in pCR rates (32.3% vs. 20.2%, P = 0.037), and 5-year DDFS were 92.9% and 80.1%, respectively (P = 0.015). The pCR group was superior to non-pCR group in 5-year DDFS (92.4% vs. 85.6%, P = 0. 033). The pCR rate of patients with ER/PR-positive tumor was significantly lower than those of ER/PR-negative (P = 0.004). The 5-year DDFS rates of HER-2 (+) and HER-2(-) groups were 75.0% and 91.9%, respectively (P = 0.043). In the ER/PR-positve group, the 5-year DDFS of CTFci regimen was superior to those of CTF regimen, 91.4% vs. 81.4% (P = 0.047).

CONCLUSIONSCTF/CTFci regimen as neoadjuvant and adjuvant chemotherapy is effective for primary breast cancer. CTFci regimen is superior to CTF regimen in pathological complete response rate and 5-year DDFS. CTFci regimen may do better to ER/PR (+) patients' benefits compared with CTF regimen.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Breast Neoplasms ; drug therapy ; pathology ; surgery ; Carcinoma, Ductal, Breast ; drug therapy ; pathology ; surgery ; Chemotherapy, Adjuvant ; Cyclophosphamide ; administration & dosage ; Disease-Free Survival ; Doxorubicin ; administration & dosage ; analogs & derivatives ; Female ; Fluorouracil ; administration & dosage ; Follow-Up Studies ; Humans ; Lymphatic Metastasis ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Metastasis ; Neoplasm Recurrence, Local ; Proportional Hazards Models ; Receptor, ErbB-2 ; metabolism ; Receptors, Estrogen ; metabolism ; Receptors, Progesterone ; metabolism ; Remission Induction ; Retrospective Studies ; Survival Rate

Angioimmunoblastic T-cell lymphoma (AITL) is a rare, distinct subtype of peripheral T-cell lymphoma, possessing an aggressive course and poor prognosis with no standard therapy. Twelve patients who have failed at least two initial CHOP or CHOP-like regimens were enrolled in this study and treated with individualized cyclosporine (CsA), prednisone (PDN), and monthly, high-dose intravenous immunoglobulin (HDIVIG). The dose of CsA was adjusted individually based on the blood trough concentration of CsA and renal function. All patients were examined for response, toxicity and survival. The most significant toxicities (≥ grade 2) were infection (16.7%), renal insufficiency (8.3%), hypertension (8.3%), diabetes (8.3%) and insomnia (16.7%). Discontinuation of treatment occurred in one patient (8.3%) due to grade 3 renal toxicity and subsequent grade 4 pulmonary infection. Treatment-related death was not observed. The overall response rate was 75.0% (complete response, 33.3%; partial response, 41.7%). With a median follow-up of 25.5 months, the median duration of response was 20 months (range, 12 to 49 months) and the median progression-free survival (PFS) was 25.5 months (range, 10 to 56 months). The 2-year PFS rate was 81.5%. Our findings indicate the combination of CsA, PDN and HDIVIG is an effective salvage regimen for refractory or relapsed AITL with predictable and manageable toxicity.
Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Combined Modality Therapy ; Cyclophosphamide ; therapeutic use ; Disease-Free Survival ; Doxorubicin ; therapeutic use ; Female ; Follow-Up Studies ; Humans ; Immunoglobulins ; administration & dosage ; therapeutic use ; Infusions, Intravenous ; Lymphoma, T-Cell, Peripheral ; drug therapy ; therapy ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Prednisolone ; therapeutic use ; Remission Induction ; Salvage Therapy ; Vincristine ; therapeutic use

OBJECTIVETo investigate the prognostic significance of Her-2 expression in node-positive and node-negative breast cancer in Chinese women.

METHODSThe Her-2 expression in breast cancers from 981 patients was detected by immunohistochemistry with anti-Her-2 (CB11) monoclonal antibody. The survival curves were analyzed by Kaplan-Meier method, and Cox regression model was applied to determine whether this factor is an independent predictor of survival in multivariate analysis.

RESULTSNineteen point seven percent of the patients showed positive Her-2 expression in their tumors. Patients with Her-2-positive tumors tended to be younger. The high level Her-2 expression was significantly associated with negative estrogen receptor and progesterone receptor status in their tumors (P < 0.05). Among 387 patients with node-positive disease, the 5-year disease-free survival (DFS) rate and 5-year overall survival (OS) rate were significantly lower in patients with Her-2-positive tumors than in patients with Her-2-negative tumors (DFS: 48.8% vs. 66.9%, P = 0.009; OS: 55.2% vs. 76.4%, P = 0.001), and Her-2 expression was an independent unfavorable prognostic factor for OS, but not for DFS in patients with node-positive disease. Among 591 patients with node-negative disease, Her-2 expression was not significantly associated with DFS and OS (P > 0.05).

CONCLUSIONHer-2 expression is an important prognostic factor in patients with node-positive disease, but not for patients with node-negative disease in Chinese women.

Adult ; Age Factors ; Aged ; Aged, 80 and over ; Breast Neoplasms ; metabolism ; pathology ; Disease-Free Survival ; Female ; Follow-Up Studies ; Gene Expression Regulation, Neoplastic ; Humans ; Lymph Nodes ; pathology ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Staging ; Proportional Hazards Models ; Receptor, ErbB-2 ; metabolism ; Receptors, Progesterone ; metabolism ; Survival Rate

OBJECTIVETo compare and analyze the data of breast cancer recurrence after breast-conserving therapy (BCT), and to find high risk factors that can affect local recurrence.

METHODSA total of 1034 patients in the data base between January 2000 and June 2008 were analyzed retrospectively. The patients aged 23 to 94 years when diagnosed (median age, 48 years). The data was investigated to compare of two different groups in local recurrence rate and survival rate. The high risk factors of recurrence after BCT [estrogen receptor (ER)/progesterone receptor (PR), human epidermal growth factor receptor (HER-2), age, lymph node involvement, tumor diameter, neoadjuvant chemotherapy, pathological status] were studied.

RESULTSThe patients were followed-up to June 2010, and the median period was 42 months (range, 3-126 months). During the period, 35 patients developed ipsilateral breast tumor recurrence (3.3%), 47 patients had metastasis to distant organs (4.5%). The 5-year disease-free survival was 87.7%, 5-year distant disease-free survival was 94.0%. The lymph node status, HER-2 status and age were significant risk factors for ipsilateral breast tumor recurrence on univariate analysis. One peak recurrence period was from the 2nd to 3rd year, and the other was from the 5th to 6th year after the operation. The HER-2 status was independent factors of ipsilateral breast tumor recurrence on multivariate analysis.

CONCLUSIONSThe recurrence happens primarily in the 2nd to 3rd and the 5th to 6th year after the breast-conserving therapy. HER-2 status is an independent factor of ipsilateral breast tumor recurrence. The patients with high risk factors of recurrence should be treated more aggressively.

Adult ; Aged ; Aged, 80 and over ; Breast Neoplasms ; surgery ; Female ; Follow-Up Studies ; Humans ; Kaplan-Meier Estimate ; Mastectomy, Segmental ; Middle Aged ; Neoplasm Recurrence, Local ; etiology ; Prognosis ; Proportional Hazards Models ; Receptor, ErbB-2 ; metabolism ; Retrospective Studies ; Risk Factors ; Young Adult

OBJECTIVETo investigate the correlation of hypermethylation of BRCA1 and APC gene promoters with the response to anthracycline-based neoadjuvant chemotherapy in primary breast cancer.

METHODSOne hundred and forty patients with primary breast cancer received anthracycline-based neoadjuvant chemotherapy, and pretreatment hypermethylation status of BRCA1 and APC genes promoters was detected by methylation-specific PCR.

RESULTSOf the 140 patients, 30 (21.4%) achieved pathological complete response (pCR), and methylation rates of BRCA1 and APC gene promoters were 21.4% (30/140) and 18.3% (24/131), respectively. Among the 110 patients with unmethylated BRCA1 gene, 28 (25.5%) achieved pCR, while in the 30 patients with methylated BRCA1 gene, only 2 (6.7%) had a pCR, with a significant difference between the two groups (chi(2) = 4.94, P = 0.026). However, no statistically significant correlation was found between the methylation of APC gene and pCR to neoadjuvant chemotherapy in this cohort of patients (P > 0.05).

CONCLUSIONPrimary breast cancer with an unmethylated BRCA1 gene is prone to achieve a pathological complete response to anthracycline-based neoadjuvant chemotherapy than those with a methylated BRCA1 gene. BRCA1 methylation status may be a useful predictor for anthracycline-based neoadjuvant chemotherapy in primary breast cancer patients.

Adenomatous Polyposis Coli Protein ; genetics ; metabolism ; Adult ; Aged ; Anthracyclines ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; BRCA1 Protein ; genetics ; metabolism ; Breast Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; CpG Islands ; genetics ; Cyclophosphamide ; therapeutic use ; DNA Methylation ; Epirubicin ; therapeutic use ; Female ; Fluorouracil ; therapeutic use ; Humans ; Middle Aged ; Neoadjuvant Therapy ; Neoplasm Staging ; Remission Induction ; Young Adult

OBJECTIVETo investigate the correlations between Fas-1377 and -670 polymorphisms and survival in Chinese women with breast cancer.

METHODSPolymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP) was used to detect the polymorphism of Fas gene in 310 breast cancer patients with a long-term follow-up (median 10.5 years, range 0.2 - 16.1 years). Survival curves were analyzed by Kaplan-Meier method.

RESULTSThe polymorphism of neither Fas-1377 nor Fas-670 was significantly correlated with the overall survival in this series of 310 cases (P > 0.05). However, among 146 patients without lymph node metastasis, the 5-year overall survival (OS) rate was significantly lower in the patients with Fas-1377 AA genotype than that in the patients with Fas-1377 GA or GG genotype (OS: 66.7% vs. 95.4%, P = 0.03). Among 117 patients with lymph node metastasis, both the Fas-1377 and Fas-670 polymorphisms were not significantly correlated with OS (P = 0.42).

CONCLUSIONAmong breast cancer patients without lymph node metastasis, patients with Fas-1377 AA genotype may have a worse survival, while patients with Fas-1377 GA or GG genotype may not be so.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Apoptosis ; Breast Neoplasms ; genetics ; metabolism ; pathology ; Female ; Follow-Up Studies ; Humans ; Lymphatic Metastasis ; Middle Aged ; Polymorphism, Genetic ; Prognosis ; Survival Rate ; Young Adult ; fas Receptor ; genetics ; metabolism