CCL5 secreted by luminal B breast cancer cells induces polarization of M2 macrophages through activation of MEK/STAT3 signaling pathway via CCR5.

In humans, breast cancer affects a large number of females and causes a high rate of mortality worldwide. Chemokine (C-C motif) ligand 5 (CCL5) is one of the cytokines that is highly correlated to the invasive and metastatic stages of breast cancer. Our previous study has suggested the prognostic value of CCL5 expression in luminal B (HER2 - ) breast cancer. In this study, CCL5 expression was upregulated or knockdown in a luminal B breast cancer cell line, ZR7530. Further, we elucidated the effects of CCL5 on the differentiation of THP-1 monocytes into M2 macrophages. Overexpression of CCL5 affected THP-1-M2 differentiation and phosphorylation of MEK1/2, ERK1/2, and STAT2 in the cocultivated cell lines. We report that the knockdown of CCR5, a receptor of CCL5 in THP-1, inhibited the effect of ZR7530 in promoting THP-1-M2 differentiation. Furthermore, our data revealed that the inhibition of MEK1/2 and STAT3 in THP-1 cells produced equivalent results similar to those of CCL5 knockdown. In summary, we revealed the role of CCL5 in the polarization of M2 macrophages. Furthermore, we studied its interaction with CCR5 and MEK/STAT3 signaling members. These targets could be used as key regulatory members in human breast cancer therapy.

Taxifolin retards the D-galactose-induced aging process through inhibiting Nrf2-mediated oxidative stress and regulating the gut microbiota in mice.

Aging and aging-related metabolic complications are global problems that seriously threaten public health. Taxifolin (TAX) is a novel health food and has been widely proved to have a variety of biological activities used in food and medicine. However, the delayed effect of TAX on the aging process has not been investigated. The purpose of this study is to explore the role of TAX as a natural active substance on aging brain tissue induced by D-galactose (D-Gal) and to determine the effect of supplementing TAX on the metabolism of the intestinal flora in aging bodies. The aging model was established by intraperitoneal injection of D-Gal (800 mg kg-1) once per 3 days for 12 weeks, and TAX (20 and 40 mg kg-1) was administered daily by oral gavage after 6 weeks of induction with D-Gal. After testing aging mice in an eight-arm maze, the results showed that TAX treatment significantly restored spatial learning and memory impairment. Moreover, long-term D-Gal treatment incited cholinergic dysfunction of aging mice, and H&E staining revealed obvious histopathological damage and structural disorder in the hippocampus of mouse brain tissue, while TAX treatment significantly reversed these changes. Importantly, supplementing with TAX significantly mitigated oxidative stress injury by alleviating the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) while increasing antioxidant enzymes. Furthermore, TAX decreased the apoptosis of the aging brain by regulating the phosphorylation levels of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and activating nuclear factor-erythroid 2-related factor 2 (Nrf2), nuclear heme oxygenase-1 (HO-1), and NADH dehydrogenase quinone 1 (NQO1) to maximally moderate the oxidative stress injury that occurred after D-Gal induction. In addition, 16S rDNA analysis revealed that TAX treatment decelerated the D-gal-induced aging process by regulating the composition of the intestinal flora and abundance of beneficial bacteria, including Enterorhabdus, Clostridium, Bifidobacterium, and Parvibacter. In conclusion, the results of this study demonstrated that TAX alleviated oxidative stress injury in mice aged by D-Gal and also confirmed that TAX improved the aging process by regulating intestinal microbes, which provides the possibility of prevention and treatment for aging and metabolic disorders through the potential food health factors.

MiR-183-5p Promotes Tumor Progression of Osteosarcoma and Predicts Poor Prognosis in Patients.

BACKGROUND: Although miRNA-183-5p plays a critical role in many cancer types, including gastric cancer, hepatocellular carcinoma, prostate cancer, renal cell cancer and breast cancer, its role in osteosarcoma remains unclear. METHODS: Expression levels of miR-183-5p were detected in osteosarcoma tissues and cell lines using qRT-PCR. The effect of miR-183-5p on the survival and recurrence of osteosarcoma patients was analyzed in a cohort of 80 patients using Kaplan-Meier curves and Cox regression analysis. Effects of miR-183-5p on cell proliferation, migration and invasion abilities were evaluated using CCK-8, crystal violet and transwell assays. RESULTS: The expression of miR-183-5p was found to be upregulated in human osteosarcoma tissues and cell lines. Moreover, miR-183-5p expression was observed to be closely associated with tumor size, TNM stage and lung metastasis. Notably, high expression of miR-183-5p was shown to be able to predict unfavorable clinical prognosis in osteosarcoma patients. Additionally, whilst overexpression of miR-183-5p was observed to significantly promote the proliferation, migration and invasion of osteosarcoma cells; an inhibitory effect was observed with knockdown of miR-183-5p. CONCLUSION: This study demonstrated that miR-183-5p acts as an oncogene and plays a critical role in the regulation of osteosarcoma tumor progression, and our results suggest a novel potential prognostic and therapeutic value of miR-183-5p in osteosarcoma.

Differentiation Antagonizing Non-protein Coding RNA Knockdown Alleviates Lipopolysaccharide-Induced Inflammatory Injury and Apoptosis in Human Chondrocyte Primary Chondrocyte Cells Through Upregulating miRNA-19a-3p.

OBJECTIVE: To confirm the role of long noncoding RNA differentiation antagonizing non-protein coding RNA (DANCR) in chondrocyte inflammatory injury in osteoarthritis (OA) in vitro, as well as its molecular mechanism. METHODS: Human primary chondrocytes were treated with lipopolysaccharide (LPS) to construct a chondrocyte inflammatory injury in human OA cell model. Gene expression was detected using real-time quantitative polymerase chain reaction. Cell inflammatory injury was evaluated by Cell Counting Kit-8 assay, flow cytometry, and enzyme-linked immunosorbent assay. The interplay between miRNA-19a-3p (miR-19a) and DANCR was validated by dual-luciferase reporter assay and RNA immunoprecipitation. RESULTS: Expression of DANCR was upregulated, and miR-19a was downregulated in human OA cartilage and LPS-treated primary chondrocytes in vitro. Moreover, DANCR expression was inversely correlated with miR-19a in OA patients. LPS reduced cell viability and increased the apoptotic rate and secretion of interleukin (IL)-1ß, IL-6, IL-8, as well as tumor necrosis factor (TNF)-α in primary chondrocyte cells in vitro, suggesting an inflammatory injury model of OA. Functionally, knockdown of DANCR could attenuate LPS-induced apoptosis and inflammatory response, as evidenced by improved cell viability, and reduced apoptotic rate and products of IL-1ß, IL-6, IL-8, and TNF-α. Notably, DANCR negatively regulated miR-19a expression, presumably via sponging. Furthermore, miR-19a deletion eliminated the effect of DANCR knockdown on apoptosis and the inflammatory response of primary chondrocytes under LPS stress. CONCLUSION: Differentiation antagonizing non-protein coding RNA silencing could protect human chondrocyte cells against LPS-induced inflammatory injury and apoptosis through targeting miR-19a, suggesting a vital role of the DANCR/miR-19a axis in OA.

Protective Effects of Human Milk-Derived Exosomes on Intestinal Stem Cells Damaged by Oxidative Stress.

Breastfeeding has been shown to have a protective effect on the occurrence of necrotizing enterocolitis (NEC), but the mechanism remains unclear. In the context of NEC pathogenesis, many of the protective properties of exosomes on the intestinal epithelial compartment make it an ideal therapeutic target. In the present study, our hypothesis was that intestinal stem cells (ISCs) would be protected from injury by human milk-derived exosomes (HMDEs). Human breast milk was collected, and exosomes were isolated using ExoQuick reagent. Magnetic-activated cell sorting isolation of prominin-1+ ISCs was performed from small intestines of neonatal rat. ISCs were treated with or without H2O2, and HMDEs, an equal volume of HMDE-free milk, or a control solution [phosphate-buffered solution (PBS)] was added, respectively. In the absence of HMDEs, exposure of ISCs to H2O2 led to decreased cell viability. However, addition of HMDEs to ISCs exposed to H2O2 led to significantly increased ISC viability. There was a significant upregulation of mRNA expression of Axin2, c-Myc, and Cyclin D1 genes of the Wnt/ß-catenin axis in ISCs treated with HMDEs (6.99 ± 2.34, 4.21 ± 1.68, 6.17 ± 2.22, respectively, P < 0.05 for all), as compared to control. In the presence of carnosic acid (a specific Wnt/ß-catenin signaling inhibitor), the cell viability was significantly decreased. Thus, HMDEs protect ISCs from oxidative stress injury in vitro, which were possibly mediated via the Wnt/ß-catenin signaling pathway. Our findings indicate that oral administration of HMDEs might be a promising measure in treating NEC or in preventing the development of NEC in high-risk infants when breast milk is not available.

Network-based proteomic analysis for postmenopausal osteoporosis in Caucasian females.

Menopause is one of the crucial physiological events during the life of a woman. Transition of menopause status is accompanied by increased risks of various health problems such as osteoporosis. Peripheral blood monocytes can differentiate into osteoclasts and produce cytokines important for osteoclast activity. With quantitative proteomics LC-nano-ESI-MS(E) (where MS(E) is elevated-energy MS), we performed protein expression profiling of peripheral blood monocytes in 42 postmenopausal women with discordant bone mineral density (BMD) levels. Traditional comparative analysis showed proteins encoded by four genes (LOC654188, PPIA, TAGLN2, YWHAB) and three genes (LMNB1, ANXA2P2, ANXA2) were significantly down- and upregulated, respectively, in extremely low- versus high-BMD subjects. To study functionally orchestrating groups of detected proteins in the form of networks, we performed weighted gene coexpression network analysis and gene set enrichment analysis. Weighted gene coexpression network analysis showed that the module including the annexin gene family was most significantly correlated with low BMD, and the lipid-binding related GO terms were enriched in this identified module. Gene set enrichment analysis revealed that two significantly enriched gene sets may be involved in postmenopausal BMD variation by regulating pro-inflammatory cytokines activities. To gain more insights into the proteomics data generated, we performed integrative analyses of the datasets available to us at the genome (DNA level), transcriptome (RNA level), and proteome levels jointly.

[Calibration Procedure of Laser Confocal Micro-Raman Spectrometer].

As a common spectral characterization technique, Raman spectroscopy is widely used and has a specified calibration procedure. Based on laser confocal micro-Raman spectrometer, in this paper, we briefly introduced the principle, configuration and main components of Raman spectrometer. In addition, the calibration procedures were also presented, with an emphasis on the calibration of spectrometer (spectrograph) and that of excitation laser wavelength. On the basis of conventional calibration method, a novel and more accurate method was proposed to obtain the actual excitation wavelength, that is, calibration at the point of Raman shift Δν=0. Using this novel calibration method of excitation wavelength, Raman frequency shift values of sulfur were measured, and compared with the standard values from American Society Testing and Materials (ASTM). As a result, the measured values after calibration were consistent with those ASTM values, which indicated that the calibration method is accurate. Thus, a more reasonable calibration procedure of the laser confocal micro-Raman spectrometer was provided.

Chronic Kidney Disease and Carotid Atherosclerosis in Patients With Acute Stroke.

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is increasingly recognized as an independent risk factor for cardiovascular disease and stroke. Our aim was to examine the association between estimated glomerular filtration rate (eGFR) and carotid plaques, stenosis and occlusions, and to assess whether CKD and its severity affect carotid atherosclerosis in a cohort of unselected patients with acute stroke. METHODS: A total of 249 consecutive patients with acute stroke (ischemic or hemorrhagic) were included in this study and baseline eGFR, carotid intima-media thickness (cIMT), and carotid stenosis were evaluated. The eGFR was calculated using the modified Modification of Diet in Renal Disease equation, which was adjusted for data from Chinese CKD patients. An eGFR rate of <60 mL/min/1.73 m was defined as CKD. The cIMT and carotid plaques were detected by carotid ultrasound. RESULTS: CKD, defined as eGFR<60 mL/min/1.73 m, was found in 66 individuals (26.50%). Among the 5 subtypes, the level of low-density lipoprotein cholesterol was significantly higher in the moderate and severe stenosis groups compared with the normal, elevated cIMT and mild stenosis groups (P<0.01). The value of eGFR gradually decreased with increasing degree of carotid stenosis, and the differences between the groups were statistically significant (P<0.01). On linear regression analysis, eGFR was negatively correlated with the degree of carotid stenosis (r=0.03; P<0.05). On ordinal logistic regression analysis, eGFR was an independent risk factor associated with carotid atherosclerosis (1.05; 95% confidence interval, 0.47-1.63). CONCLUSIONS: There was a significant burden of atherosclerosis among individuals with CKD. CKD is an independent predictor of carotid plaques, stenoses, and occlusions in patients with acute stroke.

Association between the nicotinamide adenine dinucleotide phosphate oxidase p22phox gene -A930G polymorphism and intracerebral hemorrhage.

The present study aimed to evaluate whether the ­A930G polymorphism of the nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase p22phox gene is involved in intracerebral hemorrhage (ICH) in the Chinese Han population. In the present case­control investigation, the subjects included 118 patients with ICH and 147 healthy controls. The ­A930G polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. Furthermore, the correlation between the ­A930G gene polymorphism and ICH was evaluated using statistical analyses. The distribution of p22phox ­A930G genotypes differed significantly between the two groups (P=0.003), with the AA, AG and GG genotype frequencies being 61.9, 29.3 and 8.8% in the control group and 40.7, 45.8 and 13.6% in the ICH group, respectively. The G allele frequency was significantly higher in patients with ICH compared with healthy controls (36.4 vs. 23.5%; P<0.05), however, the opposite was observed in the frequency of the A allele (63.6 vs. 76.5%; P<0.05). Binary logistic regression analysis revealed that genetic mutations of the p22phox ­A930G gene were independent risk factors of ICH (odds ratio, 2.196; 95% confidence interval, 1.003­4.586; P=0.009). In addition, certain conventional factors were associated with increased risk of ICH, including elevated blood pressure, increased levels of glucose and triglycerides in the blood, a history of hypertension and smoking. The ­A930G polymorphism of the p22phox gene may affect the susceptibility to ICH and certain haplotypes of the gene may be associated with a higher susceptibility to ICH.

The effect of IGF2BP2 gene polymorphisms on pioglitazone response in Chinese type 2 diabetes patients.

BACKGROUND: Genome-wide association studies identified that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) genetic polymorphisms are related to type 2 diabetes mellitus (T2DM) in several populations. This study aimed to investigate whether the IGF2BP2 gene rs1470579 and rs4402960 polymorphisms were associated with T2DM and pioglitazone efficacy in Chinese T2DM patients. METHODS: A total of 281 T2DM patients and 111 healthy volunteers were enrolled to identify the IGF2BP2 gene rs1470579 and rs4402960 polymorphisms; 86 patients were randomly selected and given a 12-week pioglitazone treatment (30 mg/day). Fasting plasma glucose, postprandial plasma glucose (PPG), glycated hemoglobin, serum triglycerides (TG), total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-C) were determined before and after pioglitazone treatment. RESULTS: The results showed that the IGF2BP2 gene rs1470579 and rs4402960 polymorphisms were associated with T2DM in a Chinese population (OR = 2.002, 95% CI 1.170-3.426, p < 0.05; OR = 1.879, 95% CI 1.110-3.182, p < 0.05). The effect of pioglitazone on PPG (p < 0.05), TG (p < 0.01) and HDL-C (p < 0.05) was lower in patients with the rs1470579 AC+CC genotypes than in AA genotype carriers. Its effect on PPG level was also lower in patients with the GT+TT genotypes of rs4402960 than in patients with the GG genotype (p < 0.05). CONCLUSIONS: The IGF2BP2 gene rs1470579 and rs4402960 polymorphisms were associated with T2DM and therapeutic efficacy of pioglitazone in this Chinese population.

Mutant ZP1 in familial infertility.

The human zona pellucida is composed of four glycoproteins (ZP1, ZP2, ZP3, and ZP4) and has an important role in reproduction. Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in ZP1 in six family members. In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of the zona pellucida around the oocyte.

HindIII polymorphism in the lipoprotein lipase gene and hypertensive intracerebral hemorrhage in the Chinese Han population.

BACKGROUND: To investigate the relationship between the HindIII polymorphism and hypertensive intracerebral hemorrhage (HIH) and lipid metabolism. METHODS: A polymerase chain reaction-restriction fragment length polymorphism assay and the chain termination DNA sequencing method were used to determine the HindIII genotypes of 267 subjects, which included 120 cerebral hemorrhagic patients and 147 controls. The fasting levels of lipids and glucose in the plasma were used to measure the effect of genotype on HIH risk factors. RESULTS: The frequency of the T allele of the HindIII polymorphism in the HIH group was 90.8%. The frequency of the G allele was 9.2%. In the control group, the frequencies were 82.3% T and 17.7% G, which indicated that the proportion of the G allele in the HIH patient group was significantly lower than in the control group (P<.05). The frequency of GG+GT genotypes in HIH patients (P<.05) and the plasma triglyceride (TG) levels in these patients (P<.05) were also lower than in the control group. The levels of plasma TG, low-density lipoprotein cholesterol, glucose, systolic blood pressure, and diastolic blood pressure in the HIH group were higher than in the controls (P<.05). After controlling for risk factors related to HIH, the HindIII G allele was negatively correlated with the incidence of HIH (odds ratio=.417, 95% confidence interval: .193-.901). CONCLUSIONS: The HindIII G allele may be a protective factor against the development of HIH among the Han Chinese population.

Clinical significance of Smac and survivin expression in breast cancer patients treated with anthracycline­based neoadjuvant chemotherapy.

The second mitochondria­derived activator of caspases (Smac), an antagonist of the inhibitor of apoptosis protein (IAP), increases chemosensitivity in vitro. Survivin, an IAP family member, mediates cancer cell survival and chemoresistance. The present study investigated the correlation between Smac and survivin expression in primary breast cancer, and the sensitivity to anthracycline during neoadjuvant chemotherapy (NAC). Pre­treatment biopsies and post­anthracycline treatment tumor sections were analyzed from 98 cases. Biomarker expression was evaluated by immunohistochemistry in tumor samples from clinical stage II and III anthracycline­based NAC­treated breast cancer. A univariate analysis indicated that the estrogen receptor (ER), Smac and survivin were significantly predictive of a pathological complete response (pCR) (P=0.004, 0.001 and 0.037, respectively) in pre­chemotherapy samples. ER, Smac and survivin expression was also significant for pCR on the multivariate analysis (P=0.001, 0.031 and 0.012, respectively). An inverse association was identified between survivin and Smac expression (r=­0.217, P=0.032; and r=­0.335, P=0.003, respectively) prior to and following NAC. The patients with low survivin expression or high Smac expression had significantly longer disease­free survival (DFS; P=0.012 and P=0.020, respectively) and overall survival (OS; P=0.01 and P=0.033, respectively) compared with the patients with high survivin or low Smac expression. Cox regression analyses demonstrated that survivin, Smac and clinical stage were independent predictors for DFS and OS. The present study indicated the significance of Smac and survivin in determining the breast cancer response to anthracycline­based chemotherapy, and may permit further stratifying of pre­chemotherapy patients to undertake more tailored treatments.

Trp64Arg (rs4994) polymorphism of ß3-adrenergic receptor gene is associated with hyperuricemia in a Chinese male population.

BACKGROUND: ß3-Adrenergic receptor (ß3-AR) gene is associated with insulin resistance and may affect serum uric acid levels. Our aim was to determine the possible association between ß3-AR gene Trp64Arg polymorphism (rs4994) and hyperuricemia in a Chinese male population. METHODS: A total of 410 hyperuricemic and 420 normouricemic male subjects were genotyped in this study. The genotypic and allelic frequencies were compared between the two groups. Body mass index (BMI), waist to hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum uric acid, urea nitrogen, creatinine, triglyceride, total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and fasting plasma glucose (FPG) were determined. RESULTS: The frequencies of CC genotype and C allele for Trp64Arg polymorphism were higher in hyperuricemic group than in normouricemic group (p<0.01 and p<0.05, respectively). In both hyperuricemic and normouricemic groups, subjects with mutated C allele of Trp64Arg polymorphism showed significantly higher average uric acid levels than TT genotype carriers (p<0.01 and p<0.01, respectively). Univariate and multivariate logistic regression showed that carrier of mutated C allele of Trp64Arg polymorphism was significantly associated with hyperuricemia occurrence (p=0.003, OR=1.587, 95% CI 1.175-2.145 and p=0.003, OR=1.676, 95% CI 1.051-3.617). CONCLUSIONS: Trp64Arg polymorphism was associated with hyperuricemia in a Chinese male population and should be an independent risk factor for hyperuricemia.

PPAR-γ2 and PTPRD gene polymorphisms influence type 2 diabetes patients' response to pioglitazone in China.

AIM: To investigate the influence of peroxisome proliferator-activated receptor γ2 (PPAR-γ2) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D (PTPRD) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population. METHODS: One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled. Among them, 67 type 2 diabetes patients were administered pioglitazone (30 mg/d, po) for 3 months. All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry. Fasting plasma glucose, postprandial plasma glucose, glycated hemoglobin, serum triglyceride, total cholesterol, low-density and high-density lipoprotein-cholesterol were determined. RESULTS: The PPAR-γ2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility (OR=0.515, 95% CI 0.268-0.990) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes (OR=1.984, 95% CI 1.135-3.469) in a dominant model adjusted for age, gender and BMI. After pioglitazone treatment for 3 months, the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postprandial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype. The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postprandial plasma glucose compared to those with rs17584499 CC genotype. CONCLUSION: Diabetes risk alleles in PPAR-γ2 (rs1801282) and PTPRD (rs17584499) are associated with pioglitazone therapeutic efficacy.

Postmenopausal hormone therapy is associated with in situ breast cancer risk.

BACKGROUND: The relationship between postmenopausal hormone therapy (HT) and invasive breast cancer has been extensively investigated, but that with breast carcinoma in situ (BCIS) has received relatively little attention. The aim of our present study was to review and summarize the evidence provided by longitudinal studies on the association between postmenopausal HT use and BCIS risk. METHODS: A comprehensive literature search for articles published up to May 2012 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risk (RR) or odds ratio (OR) values were calculated using 14 reports (8 case-control studies and 6 cohort studies), published between 1986 and 2012. RESULTS: There was evidence of an association between ever postmenopausal estrogen use and BCIS based on a random-effects model (RR = 1.25, 95% confidence interval (CI) = 1.01, 1.55). However, we found no strong evidence of an association between ever postmenopausal estrogen combined with progesterone use and BCIS using a random- effects model (RR = 1.55, 95% CI = 0.95, 2.51). Furthermore, our analysis showed a strong association between " > 5 years duration" of estrogen or estrogen combined with progesterone use and BCIS. Furthermore, current use of any HT is associated with increased risk of BCIS in cohort studies. Additional well-designed large studies are now required to validate this association in different populations.

Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China.

AIM: To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients. METHODS: One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C(0)) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C(0) (C(0)/dose) based on several clinical indices. RESULTS: The CYP3A5*3C polymorphism influenced the C(0) and C(0)/dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson's correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C(0)/dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C(0)/dose. CONCLUSION: CYP3A5*3C correlates with the C(0)/dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population.

Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients.

BACKGROUND: Mounting clinical and experimental data suggest that the migration of tumor cells into lymph nodes is greatly facilitated by lymphangiogenesis. Vascular endothelial growth factor (VEGF)-C and D have been identified as lymphangiogenic growth factors and play an important role in tumor lymphangiogenesis. The purpose of this study was to investigate the location of lymphangiogenesis driven by tumor-derived VEGF-C/D in breast cancer, and to determine the role of intratumoral and peritumoral lymphatic vessel density (LVD) in lymphangiogenesis in breast cancer. METHODS: The expression levels of VEGF-C/D were determined by immunohistochemistry, and intratumoral LVD and peritumoral LVD were assessed using immunohistochemistry and the D2-40 antibody in 73 patients with primary breast cancer. The associations of intratumoral LVD and peritumoral LVD with VEGF-C/D expression, clinicopathological features and prognosis were assessed. RESULTS: VEGF-C and D expression were significantly higher in breast cancer than benign disease (P < 0.01). VEGF-C (P < 0.001) and VEGF-D (P = 0.005) expression were significantly associated with peritumoral LVD, but not intratumoral LVD. Intratumoral LVD was associated with tumor size (P = 0.01). Peritumoral LVD was significantly associated with lymph node metastasis (LNM; P = 0.005), lymphatic vessel invasion (LVI; P = 0.017) and late tumor,node, metastasis (TNM) stage (P = 0.011). Moreover, peritumoral LVD was an independent risk factor for axillary lymph node metastasis, overall survival and disease-free survival in multivariate analysis. CONCLUSIONS: This study suggests that tumor-derived VEGF-C/D induce peritumoral lymphangiogenesis, which may be one mechanism that leads to lymphatic invasion and metastatic spread. Peritumoral LVD has potential as an independent prognostic factor in breast cancer patients.

Meta-analysis on pharmacogenetics of platinum-based chemotherapy in non small cell lung cancer (NSCLC) patients.

AIM: To determine the pharmacogenetics of platinum-based chemotherapy in Non Small Cell Lung Cancer (NSCLC) patients. METHODS: Publications were selected from PubMed, Cochrane Library and ISI Web of Knowledge. A meta-analysis was conducted to determine the association between genetic polymorphisms and platinum-based chemotherapy by checking odds ratio (OR) and 95% confidence interval (CI). RESULTS: Data were extracted from 24 publications, which included 11 polymorphisms in 8 genes for meta-analysis. MDR1 C3435T (OR = 1.97, 95% CI: 1.11-3.50, P = 0.02), G2677A/T (OR = 2.61, 95% CI: 1.44-4.74, P = 0.002) and GSTP1 A313G (OR = 0.32, 95% CI: 0.17-0.58, P = 0.0002) were significantly correlated with platinum-based chemotherapy in Asian NSCLC patients. CONCLUSION: Attention should be paid to MDR1 C3435T, G2677A/T and GSTP1 A313G for personalized chemotherapy treatment for NSCLC patients in Asian population in the future.

ABCC2 polymorphisms and haplotype are associated with drug resistance in Chinese epileptic patients.

AIMS: Some study found that ATP-binding cassette (ABC) efflux transporters play an important role in antiepileptic drug resistance, especially ABCB1 and ABCC2. The aims of this study were to evaluate the relationship between the genetic polymorphisms of ABCC2 and ABCB1 and the therapeutic efficacy of antiepileptic drugs (AEDs) in Chinese epileptic patients. METHODS: ABCB1 rs1045642 (3435C>T) and ABCC2 rs717620 (-24C>T), rs3740066 (3972C>T), and rs2273697 (1249G>A) polymorphisms loci in 537 Chinese epilepsy patients (217 drug resistant patients and 320 drug responders) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: ABCC2 rs717620 -24TT genotype was significantly associated with drug resistant epilepsy (odds ratio [OR]= 4.06 [1.79-9.20], P= 0.001). The OR values of ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes were markedly higher in drug resistant patients (OR = 1.57 [1.08-2.29], P= 0.018; OR = 1.49 [1.02-2.18], P= 0.038, respectively) compared with responsive patients. ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not associated with drug resistant epilepsy. Linkage disequilibrium (LD) test showed that the ABCC2 rs717620 were in strong LD with rs2273697 (D'= 0.694) and rs3740066 (D'= 0.699). The frequencies of haplotypes TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients was significantly higher than those in responsive patients (21.0% vs. 14.2%, P < 0.05). CONCLUSION: ABCC2-24C>T, 3972C>T polymorphisms and one ABCC2 haplotype is associated with AED resistance; ABCC2 1249G>A and ABCB1 3435C>T polymorphisms are not associated with AED resistance in our study. These data suggest that ABCC2 polymorphisms and haplotype may affect the response of antiepileptic drugs.