A novel nomogram for predicting cancer-specific survival in women with uterine sarcoma: a large population-based study.

BACKGROUND: Uterine sarcoma (US) is a rare malignant uterine tumor with aggressive behavior and rapid progression. The purpose of this study was to constructa comprehensive nomogram to predict cancer-specific survival (CSS) of patients with US-based on the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: A retrospective population-based study was conducted using data from patients with US between 2010 and 2015 from the SEER database. They were randomly divided into a training cohort and a validation cohort ata 7-to-3 ratio. Multivariate Cox analysis was performed to identify independent prognostic factors. Subsequently, a nomogram was established to predict patient CSS. The discrimination and calibration of the nomogram were evaluated by the concordance index (C-index) and the area under the curve (AUC). Finally, net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration plotting, and decision-curve analysis (DCA) were used to evaluate the benefits of the new prediction model. RESULTS: A total of 3861 patients with US were included in our study. As revealed in multivariate Cox analysis, age at diagnosis, race, marital status, insurance record, tumor size, pathology grade, histological type, SEER stage, AJCC stage, surgery status, radiotherapy status, and chemotherapy status were found to be independent prognostic factors. In our nomogram, pathology grade had strongest correlation with CSS, followed by age at diagnosis and surgery status. Compared to the AJCC staging system, the new nomogram showed better predictive discrimination with a higher C-index in the training and validation cohorts (0.796 and 0.767 vs. 0.706 and 0.713, respectively). Furthermore, the AUC value, calibration plotting, NRI, IDI, and DCA also demonstrated better performance than the traditional system. CONCLUSION: Our study validated the first comprehensive nomogram for US, which could provide more accurate and individualized survival predictions for US patients in clinical practice.

The association of ADORA2A and ADORA2B polymorphisms with the risk and severity of chronic heart failure: a case-control study of a northern Chinese population.

The causes of chronic heart failure (CHF) and its progression are likely to be due to complex genetic factors. Adenosine receptors A2A and A2B (ADORA2A and ADORA2B, respectively) play an important role in cardio-protection. Therefore, polymorphisms in the genes encoding those receptors may affect the risk and severity of CHF. This study was a case-control comparative investigation of 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls. Four common single-nucleotide polymorphisms (SNPs) of ADORA2A (rs2236625, rs2236624, rs4822489, and rs5751876) and one SNP of ADORA2B (rs7208480) were genotyped and an association between SNPs and clinical outcomes was evaluated. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association. The rs4822489 was significantly associated with the severity of CHF after adjustment for traditional cardiovascular risk factors (p = 0.040, OR = 1.912, 95% CI = 1.029-3.550). However, the five SNPs as well as the haplotypes were not found to be associated with CHF susceptibility. The findings of this study suggest that rs4822489 may contribute to the severity of CHF in the northern Chinese. However, further studies performed in larger populations and aimed at better defining the role of this gene are required.

Glutathione S-transferase gene polymorphisms and susceptibility to chronic myeloid leukemia.

Glutathione S-transferase (GST), a phase II metabolizing enzyme, plays an important role in the cellar defense system, and its activity may modulate leukemia risk. A large body of evidence has shown the possible relevance of functional polymorphisms of the genes that encode GSTs µ, π, and θ (GSTM1, GSTP1, and GST1, respectively) to the genetic susceptibility of chronic myeloid leukemia (CML). Because of the lack of available conclusive data, we performed a meta-analysis of all relevant available studies to derive a more precise estimation of the relationship. A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until December 20, 2013, and the extracted data were statistically analyzed using Review Manager version 5.2. Finally, 16 eligible studies were identified in the literature. The GSTT1 null genotype was associated with an increased risk of CML, as were the double null GSTT1 and GSTM1 genotypes. These findings suggest that heritable GST status influences the risk of developing CML and that more attention should be paid to carriers of these susceptibility genes.

Glutathione S-transferase gene polymorphisms and susceptibility to acute myeloid leukemia: meta-analyses.

OBJECTIVE: A large body of evidence has shown the possible relevance of polymorphisms of the genes that encode glutathione S-transferase µ, π and θ (GSTM1, GSTP1 and GST1, respectively) to the susceptibility of acute myeloid leukemia, but the exact association still remains uncertain. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship. METHODS: A comprehensive literature search of PubMed and Web of Knowledge electronic databases was conducted to collect relevant studies until 20 February 2014. References of the retrieved articles were also screened. The extracted data were statistically analyzed, and pooled odds ratios with 95% confidence intervals were calculated to estimate the association strength using Review Manager version 5.2. RESULTS: Twenty-nine studies were included in the meta-analysis. The pooled analyses revealed that the GSTM1-null genotype was associated with an increased risk of acute myeloid leukemia in East Asians (P = 0.01; odds ratio = 1.22; 95% confidence interval = 1.05-1.42), and GSTT1-null genotype in Caucasians (P < 0.0001; odds ratio = 1.48; 95% confidence interval = 1.29-1.69). There was also a predilection towards the female gender for both of these polymorphisms. For GSTP1 Ile105Val polymorphism, no significant association was found under any contrast model. In addition, the presence of the double-null genotypes increased the risk of acute myeloid leukemia in both Caucasians and East Asians. CONCLUSIONS: This meta-analysis suggested that heritable GST status could influence the risk of developing acute myeloid leukemia.

Combined application of plasma mutagenesis and gene engineering leads to 5-oxomilbemycins A3/A4 as main components from Streptomyces bingchenggensis.

Milbemycin oxime has been commercialized as effective anthelmintics in the fields of animal health, agriculture, and human infections. Currently, milbemycin oxime is synthesized by a two-step chemical reaction, which involves the ketonization of milbemycins A3/A4 to yield the intermediates 5-oxomilbemycins A3/A4 using CrO3 as catalyst. Due to the low efficiency and environmental unfriendliness of the ketonization of milbemycins A3/A4, it is imperative to develop alternative strategies to produce 5-oxomilbemycins A3/A4. In this study, the atmospheric and room temperature plasma (ARTP) mutation system was first employed to treat milbemycin-producing strain Streptomyces bingchenggensis, and a mutant strain BC-120-4 producing milbemycins A3, A4, B2, and B3 as main components was obtained, which favors the construction of genetically engineered strains producing 5-oxomilbemycins. Importantly, the milbemycins A3/A4 yield of BC-120-4 reached 3,890 ± 52 g/l, which was approximately two times higher than that of the initial strain BC-109-6 (1,326 ± 37 g/l). The subsequent interruption of the gene milF encoding a C5-ketoreductase responsible for the ketonization of milbemycins led to strain BCJ60 (∆milF) with the production of 5-oxomilbemycins A3/A4 and the elimination of milbemycins A3, A4, B2, and B3. The high 5-oxomilbemycins A3/A4 yield (3,470 ± 147 g/l) and genetic stability of BCJ60 implied the potential use in industry to prepare 5-oxomilbemycins A3/A4 for the semisynthesis of milbemycins oxime.

The adenosine deaminase gene polymorphism is associated with chronic heart failure risk in Chinese.

Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10-2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.

Genetic engineering of Streptomyces bingchenggensis to produce milbemycins A3/A4 as main components and eliminate the biosynthesis of nanchangmycin.

Milbemycins A3/A4 are important 16-membered macrolides which have been commercialized and widely used as pesticide and veterinary medicine. However, similar to other milbemycin producers, the production of milbemycins A3/A4 in Streptomyces bingchenggensis is usually accompanied with undesired by-products such as C5-O - methylmilbemycins B2/B3 (α-class) and ß1/ß2 (ß-class) together with nanchangmycin. In order to obtain high yield milbemycins A3/A4-producing strains that produce milbemycins A3/A4 as main components, milD, a putative C5-O-methyltransferase gene of S. bingchenggensis , was biofunctionally investigated by heterologous expression in Escherichia coli . Enzymatic analysis indicated that MilD can catalyze both α-class (A3/A4) and ß-class milbemycins (ß11) into C5-O-methylmilbemycins B2/B3 and ß1, respectively, suggesting little effect of furan ring formed between C6 and C8a on the C5-O-methylation catalyzed by MilD. Deletion of milD gene resulted in the elimination of C5-Omethylmilbemycins B2/B3 and ß1/ß2 together with an increased yield of milbemycins A3/A4 in disruption strain BCJ13. Further disruption of the gene nanLD encoding loading module of polyketide synthase responsible for the biosynthesis of nanchangmycin led to strain BCJ36 that abolished the production of nanchangmycin. Importantly, mutant strain BCJ36 (ΔmilDΔnanLD) produced milbemycins A3/A4 as main secondary metabolites with a yield of 2312 ± 47 µg/ml, which was approximately 74 % higher than that of the initial strain S. bingchenggensis BC-109-6 (1326 ± 37 µg/ml).

[Effects of magnetic c-erbB-2 antisense probe of different concentrations on morphology and expression of SK-Br-3 cancer cell lines in vitro].

OBJECTIVE: To explore the effects of the magnetic c-erbB-2 antisense probe of different concentrations on the morphology and expression of SK-Br-3 cancer cells in vitro. METHODS: Breast cancer SK-Br-3 cells were transfected for 24 h by antisense probe at an iron concentration of 5, 10, 25, 50, and 100 mg/L, respectively. The distribution and content of iron particles in SK-Br-3 cells was determined by Prussian blue staining, electron microscopy, and atomic absorption spectrometry. Cell viability was observed by trypan-blue exclusion and CCK-8 test. The protein expression of c-erbB-2 was assessed by the Western blot analysis. The changes of the signal strength were considered by magnetic resonance imaging (MRI). RESULTS: c-erbB-2 antisense probe was uptake by SK-Br-3 cells in a concentration-dependence manner within a certain range (5, 10, and the Medicine Scientific Research Project of Chongqing Health Bureau (062025)25 mg/L). When the probe concentration was 25 mg/L, iron content in cells was (18.38±0.28) pg, the cell vitality, survival, and c-erbB-2 protein expression were reduced significantly (all P<0.05), and the T2 value was lower significantly (P<0.05). However, the results of 50 mg/L or 100 mg/L group showed no significant difference with the 25 mg/L group (P>0.05). CONCLUSION: The magnetic c-erbB-2 antisense probe can effectively transfect and specifically inhibit the expression of SK-Br-3 cell lines at the iron concentration of 25 mg/L.

[Optimal time for MRI scanning of tumors in BALB/c mice using c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles].

OBJECTIVE: To determine the optimal time for MRI scanning of tumors in BALB/c mice using c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles. METHODS: SK-Br-3 tumor-bearing BALB/c mice (n= 30) were injected with antisense probe (12.0 mg Fe/kg). MRI scanning was performed on 5 mice before the injection and 60 min, 180 min, 360 min, 720 min and 1 440 min after the injection, respectively. Tumor tissues were taken immediately after the scanning and fixed with 10% formalin and paraffin-embedded sections. The MRI signal strength of the tumors and adjacent muscles were compared with changes detected under a microscope using HE and Prussian blue staining. RESULTS: SK-Br-3 tumors were introduced to the BALB/c mice successfully. The strongest signal intensity was detected by the MRI 360 min after injection with the antisense probe. The pathological examination revealed structural disorders of the tumor issues, with a large number of special-shaped cells arranged in a cancer nest shape. Punctuate blue iron particles were observed in all of the tumor issues, with the greatest density occurring at 360 min after the injection with the antisense probe. CONCLUSION: The MR4 optimal time for MRI scanning of tumors in BALB/c mice using c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles should be set at 360 min after injection.

You are what you eat: Microplastics in the feces of young men living in Beijing.

PURPOSE: Microplastics have been widely detected in the environment and marine organisms. However, few studies have investigated the presence of microplastics in humans. This preliminary study identified and quantified the microplastic content in human feces. METHODS: A total of 26 young male students aged 18-25 years were recruited from Beijing, China. A self-administered 7-day 24-h fluid intake record was used to document fluid intake, and food intake was recorded for 3 days. Feces were collected by participants using a sterile fecal collector. Microplastics in the remaining fecal residues were measured and identified using fourier transform infrared micro-spectroscopy. RESULTS: Eventually, twenty-four participants completed the study. The fecal samples of 23 (95.8%) participants tested positive for microplastics. In these 23 samples, the abundance of microplastics varied from 1 particle/g to 36 particles/g (size 20 to 800 µm). The summed mass of all microplastic particles per participant ranged from 0.01 to 14.6 mg. Qualitative analysis of the microplastics indicated the presence of one to eight types of microplastics in each sample, with polypropylene (PP) being the most abundant; it was found in 95.8% of fecal samples. We examined associations between water intake habits and the abundance of microplastics in their feces. A moderate correlation was observed between packaged water and beverage intake and microplastic abundance in feces (r = 0.445, P = 0.029). CONCLUSION: Various types of microplastics were detected in human feces, with PP being found in the highest proportion. There may be an association between water intake habits and microplastic abundance in feces.

Structure and absolute configuration assignments of ochracines F-L, chamigrane and cadinane sesquiterpenes from the basidiomycete Steccherinum ochraceum HFG119.

Ochracines F-L (1-7), seven previously undescribed chamigrane and cadinane sesquiterpenoids, together with four known chamigranes were isolated from cultures of the wood-decaying fungus Steccherinum ochraceum HFG119. Ochracines F-L were structurally characterized by extensive analysis of HRMS and NMR spectroscopic data. The relative configurations were assigned through a combination of NOE correlations and J-based configuration analysis (JBCA), while the absolute configurations were determined by X-ray single-crystal diffraction, and calculated methods (ECD, [α], 13C NMR). All the new isolates were evaluated for their cytotoxicity against five human cancer cell lines HL-60, SMMC-7721, A549, MCF-7, and SW-480, and inhibitory activity on NO production in RAW 264.7 macrophages.

Global and regional burdens of oral cancer from 1990 to 2017: Results from the global burden of disease study.

BACKGROUND: Data on the incidence, mortality, and other burden of oral cancer as well as their secular trends are necessary to provide policy-makers with the information needed to allocate resources appropriately. The purpose of this study was to use the Global Burden of Disease (GBD) 2017 results to estimate the incidence, mortality, and disability-adjusted life years (DALYs) for oral cancer from 1990 to 2017. METHODS: We collected detailed data on oral cancer from 1990 to 2017 from the GBD 2017. The global incidence, mortality, and DALYs attributable to oral cancer as well as the corresponding age-standardized rates (ASRs) were calculated. The estimated annual percentage changes in the ASRs of incidence (ASRI) and mortality (ASRM) and age-standardized DALYs of oral cancer were also calculated according to regions and countries to quantify the secular trends in these rates. RESULTS: We tracked the incidence, mortality, and DALYs of oral cancer in 195 countries/territories over 28 years. Globally, the incidence, mortality, and DALYs of oral cancer increased by about 1.0-fold from 1990 to 2017. The ASRI of oral cancer showed a similar trend, increasing from 4.41 to 4.84 per 100,000 person-years during the study period. The ASRM remained approximately stable at about 2.4 per 100,000 from 1990 to 2017, as did the age-standardized DALYs, at about 64.0 per 100,000 person-years. ASRI was highest in Pakistan (27.03/100,000, 95% CI = 22.13-32.75/100,000), followed by Taiwan China, and lowest in Iraq (0.96/100,000, 95% CI = 0.86-1.06/100,000). ASRM was highest in Pakistan (16.85/100,000, 95% CI = 13.92-20.17/100,000) and lowest in Kuwait (0.51/100,000, 95% CI = 0.45-0.58/100,000). CONCLUSIONS: The ASRI of oral cancer has increased slightly worldwide, while the ASRM and age-standardized DALY have remained stable. However, these characteristics vary between countries, suggesting that current prevention strategies should be reoriented, and much more targeted and specific strategies should be established in some countries to forestall the increase in oral cancer.

The Polymorphism in ADORA3 Decreases Transcriptional Activity and Influences the Chronic Heart Failure Risk in the Chinese.

AIM: To investigate the genetic contribution of adenosine A3 receptor (ADORA3) gene polymorphisms in the pathogenesis of chronic heart failure (CHF). METHODS: Firstly, a case-control study was performed to investigate the association of ADORA3 polymorphisms with CHF risk. Three hundred northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls were included. Four polymorphisms were genotyped. This case-control study was also replicated in 304 CHF patients and 402 controls from southern China. Finally, the functional variability of positive polymorphism was analyzed using luciferase reporter assay and real-time PCR. RESULTS: Overall, the rs1544223 was significantly associated with CHF risk under the dominant model (P = 0.046, OR = 1.662, 95% CI = 1.009-2.738). But it did not affect disease severity. These results were also consistent in replicated population. In addition, the transcriptional activity for promoter with the A allele was lower than that with the G allele (n = 3, 4.501 ± 0.308 versus 0.571 ± 0.114, P < 0.01) and ADORA3 mRNA levels were significantly higher in GG homozygotes than subjects carrying GA (n = 6, 0.058 ± 0.01 versus 0.143 ± 0.068, P = 0.004) or AA genotypes (n = 6, 0.065 ± 0.01 versus 0.143 ± 0.068, P = 0.008). CONCLUSIONS: Should the findings be validated by further studies with larger patient samples and in different ethnicities, they may provide novel insight into the pathogenesis of CHF.

The effect of reintubation on ventilator-associated pneumonia and mortality among mechanically ventilated patients with intubation: A systematic review and meta-analysis.

OBJECTIVES: This meta-analysis summarized the risks that reintubation impose on ventilator-associated pneumonia (VAP) and mortality. BACKGROUND: Extubation failure increases the probability of poor clinical outcomes pertaining to mechanical ventilation. METHODS: Literature published during a 15-year period was retrieved from PubMed, Web of Knowledge databases, the Embase (Excerpa Medica database), and the Cochrane Library. Data involving reintubation, VAP, and mortality were extracted for a meta-analysis. RESULTS: Forty-one studies involving 29,923 patients were enrolled for the analysis. The summary odds ratio (OR) between VAP and reintubation was 7.57 (95% confidence interval [CI] = 3.63-15.81). The merged ORs for mortality in hospital and intensive care unit were 3.33 (95% CI = 2.02-5.49) and 7.50 (95% CI = 4.60-12.21), respectively. CONCLUSIONS: Reintubation can represent a threat to survival and increase the risk of VAP. The risk of mortality after reintubation differs between planned and unplanned extubation. Extubation failure is associated with a higher risk of VAP in the cardiac surgery population than in the general population.

Iptakalim hydrochloride protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models.

Iptakalim hydrochloride (Ipt), a novel antihypertensive drug, exhibits K(ATP) channel activation. Here, we report that Ipt remarkably protects cells against neurotoxin-induced glutamate transporter dysfunction in in vitro and in vivo models. Chronic exposure of cultured PC12 cells to neurotoxins, such as 6-OHDA, MPP+, or rotenone, decreased overall [3H]-glutamate uptake in a concentration-dependent manner. Pre-treatment using 10 microM Ipt significantly protected cells against neurotoxin-induced glutamate uptake diminishment, and this protection was abolished by the K(ATP) channel blocker glibenclamide (20 microM), suggesting that the protective mechanisms may involve the opening of K(ATP) channels. In 6-OHDA-treated rats (as an in vivo Parkinson's disease model), [3H]-glutamate uptake was significantly lower in synaptosomes isolated from the striatum and cerebral cortex, but not the hippocampus. Pre-conditioning using 10, 50, and 100 microM Ipt significantly restored glutamate uptake impairment and these protections were abolished by blockade of K(ATP) channels. It is concluded that Ipt exhibits substantial protection of cells against neurotoxicity in in vitro and in vivo models. The cellular mechanisms of this protective effect may involve the opening of K(ATP) channels. Collectively, Ipt may serve as a novel and effective drug for PD therapy.

The association between XRCC1 Arg399Gln polymorphism and risk of leukemia in different populations: a meta-analysis of case-control studies.

BACKGROUND: Associations between Arg399Gln single-nucleotide polymorphism (SNP) in the XRCC1 gene and leukemia susceptibility have been studied extensively, however, the results are inconsistent. The aim of this study was to determine these associations using meta-analytical methods. METHODS: A meta-analysis was performed to examine the associations between XRCC1 Arg399-Gln SNP and leukemia risk. A literature search of PubMed and Web of Science databases was conducted to identify relevant studies published up to March 10, 2015. The references of the retrieved articles were also screened. All the statistical analyses were conducted using Review Manager software. RESULTS: The XRCC1 Arg399Gln SNP was found to be associated with increased childhood risk of acute lymphoblastic leukemia among Asians under the dominant (odds ratio [OR] 2.11, 95% confidence interval [CI] 1.50-2.97, P<0.0001), allele contrast (OR 1.72, 95% CI 1.33-2.23, P<0.0001), and homozygote contrast (OR 2.34, 95% CI 1.25-4.36, P=0.008) models. However, no association was found in Caucasians between the SNP and risk of either chronic myeloid leukemia or chronic lymphocytic leukemia under any contrast model. CONCLUSION: The findings of the current meta-analysis indicate that the XRCC1 Arg399Gln SNP is a risk factor for childhood lymphoblastic leukemia in Asians.

Genetic polymorphisms of CYP1A1 and risk of leukemia: a meta-analysis.

The associations between CYP1A1 polymorphisms and risk of leukemia have been studied extensively, but the results have been inconsistent. Therefore, in this study, we performed a meta-analysis to clarify associations of three CYP1A1 polymorphisms (T3801C, A2455G, and C4887A) with the risks of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Medline, EMBASE, and China National Knowledge Infrastructure databases were searched to collect relevant studies published up to April 20, 2015. The extracted data were analyzed statistically, and pooled odds ratios with 95% confidence intervals were calculated to quantify the associations. Overall, 26 publications were included. Finally, T3801C was associated with an increased risk of AML in Asians under the dominant model. For A2455G, the risk of ALL was increased among Caucasians in the recessive model and the allele-contrast model; A2455G was also associated with an increased risk of CML among Caucasians under the recessive model, dominant model, and allele-contrast model. For C4887A, few of the included studies produced data. In conclusion, the results suggest that Asians carrying the T3801C C allele might have an increased risk of AML and that Caucasians with the A2455G GG genotype might have an increased risk of ALL. Further investigations are needed to confirm these associations.

[Relationship between neurotoxicity of 6-hydroxydopamine and glutamate transport].

AIM: To study the relationship of neurotoxicity of 6-hydroxydopamine (6-OHDA) and the function of glutamate transporter. METHODS: Using in vivo microdialysis together with high performance liquid chromatography (HPLC) to detect the alteration of glutamate in the striatum and extracellular fluid of the PC12 cell. The rate of apoptosis and the activity of PC12 cells are read in a flow cytometer and a photometer for enzyme-labeled assays. The function of glutamate transporter is decided by detecting the ability of L-[3H]-glutamate uptake. RESULTS: 6-OHDA was shown to induce apoptosis and decrease the activity of PC12 cells. Increased release of glutamate was also found in PC12 cells and the injured striatum of the PD rats. But glutamate uptake in PC12 cells and rat striatum synaptosomes are inhibited obviously. CONCLUSION: The neurotoxicity of 6-hydroxydopamine is associated with declined function of glutamate transporters, which may be one important pathogenesis mechanisms of Parkinson's disease.

Association between reduced folate carrier G80A polymorphism and methotrexate toxicity in childhood acute lymphoblastic leukemia: a meta-analysis.

Abstract Methotrexate (MTX) is a key component of chemotherapeutic regimens for childhood acute lymphoblastic leukemia (ALL), and enters the cell via active transport mediated by the reduced folate carrier (RFC1). A major single-nucleotide polymorphism of the RFC1 gene, G80A, which affects the activity of RFC1, may influence MTX toxicity in pediatric ALL. We collected all studies that investigated the association of RFC1 G80A polymorphism and MTX toxicity in pediatric ALL, and found inconsistency among their results. The aim of this meta-analysis was to summarize all of these studies in order to clarify the correlation between the RFC1 G80A polymorphism and MTX toxicity in pediatric ALL. A recessive model demonstrated no influence of the RFC1 G80A genotype on MTX toxicity. In conclusion, the RFC1 G80A polymorphism does not seem to be a good marker of MTX-related toxicity in pediatric ALL.

Establishment of paclitaxel-resistant breast cancer cell line and nude mice models, and underlying multidrug resistance mechanisms in vitro and in vivo.

BACKGROUND: Breast cancer is a common malignant tumor which affects health of women and multidrug resistance (MDR) is one of the main factors leading to failure of chemotherapy. This study was conducted to establish paclitaxel-resistant breast cancer cell line and nude mice models to explore underlying mechanisms of MDR. METHODS: The breast cancer drug-sensitive cell line MCF-7 (MCF-7/S) was exposed in stepwise escalating paclitaxel (TAX) to induce a resistant cell line MCF-7/TAX. Cell sensitivity to drugs and growth curves were measured by MTT assay. Changes of cell morphology and ultrastructure were examined by optical and electron microscopy. The cell cycle distribution was determined by flow cytometry. Furthermore, expression of proteins related to breast cancer occurrence and MDR was tested by immunocytochemistry. In Vivo, nude mice were injected with MCF-7/S and MCF-7/TAX cells and weights and tumor sizes were observed after paclitaxel treatment. In addition, proteins involved breast cancer and MDR were detected by immunohistochemistry. RESULTS: Compared to MCF-7/S, MCF-7/TAX cells had a higher resistance to paclitaxel, cross-resistance and prolonged doubling time. Moreover, MCF-7/TAX showed obvious alterations of ultrastructure. Estrogen receptor (ER) expression was low in drug resistant cells and tumors while expression of human epidermal growth factor receptor 2 (HER2) and Ki-67 was up-regulated. P-glycoprotein (P-gp), lung resistance-related protein (LRP) and glutathione-S-transferase-π (GST-π) involved in the MDR phenotype of resistant cells and tumors were all overexpressed. CONCLUSION: The underlying MDR mechanism of breast cancer may involve increased expression of P-gp, LRP and GST-π.