Efficacy of relative dose intensity of nab-paclitaxel for the short-term outcomes, survival, and quality of life in patients with advanced pancreatic cancer: a retrospective study.

Background: To optimize treatment, choosing the appropriate relative dose intensity (RDI) of nab-paclitaxel is an important way to improve patient tolerance, therapeutic efficacy, and survival. However, few studies have focused on the efficacy of the RDI of nab-paclitaxel in patients with advanced pancreatic cancer, and whether the RDI of nab-paclitaxel could be employed as an index for treatment remains unknown. To explore the relationship between RDI of nab-paclitaxel and chemotherapy efficacy, survival, quality of life (QoL), and adverse effects in patients with advanced pancreatic cancer. Methods: In this retrospective study, a total of 32 patients with advanced pancreatic cancer, ECOG score of 0 to 2 were included from January 2017 to March 2020. The patients were treated with nab-paclitaxel combined with gemcitabine as a first-line treatment and divided into high and low RDI groups. Chemotherapy efficacy, survival, QoL, and adverse effects between two groups were compared. Results: The disease control rate (DCR) was 20.0% in the low RDI group, compared with 81.8% in the high RDI group (P=0.002). A good correlation between nab-paclitaxel RDI and short-term efficacy was observed in all 32 patients (r=0.728, P<0.01). Furthermore, the high RDI group had significantly better median overall survival (mOS: 12 vs. 8 months, P=0.034) and median progression-free survival (mPFS: 5.5 vs. 3 months, P=0.052) compared to that of low RDI patients. Univariate regression analysis showed that longer overall survival was associated with lower ECOG score [hazard ratio (HR): 10.88; 95% confidence interval (CI): 2.54-46.5, P=0.001], tumors located in the body or tail of pancreases (HR: 3.82; 95% CI: 1.4-10.3, P=0.0081), and higher RDI (HR: 0.21; 95% CI: 0.071-0.6, P=0.004). The high RDI group had a significantly better physical function and emotional function improvement compared to the low RDI group (P<0.05). Moreover, high RDI did not increasing the severity and frequency of the adverse events. Conclusions: It is recommended to maintain a sufficient RDI of nab-paclitaxel to ensure that the balance between lerability, therapeutic efficacy, and survival benefits is satisfied in patients with advanced pancreatic cancer.

Development and verification of a hypoxia- and immune-associated prognosis signature for esophageal squamous cell carcinoma.

Background: Esophageal cancer is one of the most common gastrointestinal malignancies worldwide, with high morbidity and mortality in China. The clinical importance of the interaction between hypoxia and immune status in the tumor microenvironment has been established in esophageal squamous cell carcinoma (ESCC). This study aims to develop a new hypoxia- and immune-based gene signature to predict the survival of ESCC patients. Methods: The RNA-sequencing and clinical data of 173 cases of ESCC and 271 normal tissues were obtained from The Cancer Genome Atlas (TCGA) data portal and the Genotype-Tissue Expression (GTEx) database. Hypoxia-related genes (HRGs) and immune-related genes (IRGs) were retrieved from publicly shared data. Differentially expressed gene (DEG) analyses were carried out by the DESeq2 method using the edgeR package in R. Based on the intersection of the DEGs and HRGs/IRGs, differentially expressed HRGs (DEHRGs) and differentially expressed IRGs (DEIRGs) were obtained. DEHRGs and DEIRGs associated with prognosis were evaluated using univariate Cox proportional hazards analysis. A prognostic risk score model was constructed according to the genes acquired through Cox regression. Univariate analysis and Cox proportional hazards analysis were used to determine the independent prognostic factors related to prognosis. A nomogram was developed to predict the 1-, 2-, and 3-year overall survival (OS) probability. Results: A total of 73 intersecting genes were obtained as DEHRGs and a total of 548 intersecting genes were obtained as DEIRGs. The risk score was established using 8 genes (FABP7, TLR1, SYTL1, APLN, OSM, EGFR, IL17RD, MYH9) acquired from univariate Cox analysis. Based on this 8-gene-based risk score, a risk prognosis classifier was constructed to classify the samples into high- and low-risk groups according to the median risk score. The nomogram model was constructed to predict the OS of ESCC patients. Conclusions: The hypoxia- and immune-based gene signature might serve as a prognostic classifier for clinical decision-making regarding individualized management, follow-up plans, and treatment strategies for ESCC patients.

Pattern of distant metastases and predictive nomograms in colorectal mucinous adenocarcinoma: a SEER analysis.

BACKGROUND: We evaluated the metastatic patterns and explored the prognostic value of distant metastasis pattern in patients with metastatic colorectal mucinous adenocarcinoma (MC) using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Between 2010 and 2015, newly diagnosed colorectal MC patients were selected using the SEER database. Patient prognosis was compared based on the clinicopathological parameters, treatment method, and the site and number of metastatic organs. Cox analyses were used to identify factors associated with overall survival (OS). A nomogram was built to predict the patient's survival. Harrell's concordance index (c-index) and calibration curves were used to analyze the discriminative ability of the prognostic factors. RESULTS: Of 3,088 patients diagnosed with colorectal MC, the liver was the only metastatic organ in 78.4% (997/1,271) of all liver metastasis cases, the lung was the only metastatic organ in 41.0% (164/400) of all lung metastasis cases, bone was the only metastatic organ in 26.6% (29/109) of all bone metastasis cases, and the brain was the only metastatic organ in 23.5% (4/17) of all brain metastasis cases. Compared with the untreated cases, those treated with chemotherapy, surgery, and radiotherapy had better OS (P<0.001). There were marked OS differences (P<0.001) between patients with and without liver and bone metastases. Patients with bone metastasis had the best survival, while those with brain metastasis had the worst survival (P<0.001). Patients with one metastatic site had better prognosis compared to those with two or three (P<0.001). Patients with liver metastasis had the best survival, while those with bone and brain metastasis had the worst survival (P<0.001). Multivariate analysis showed that age <65 years, non-black race, grade I, N0 stage, chemotherapy, radiation, surgery, liver metastasis, and bone metastasis were independent prognostic factors. A nomogram was constructed to predict survival probability. The c-index value was up to 0.745. The calibration plot showed that the nomogram was clinically useful. CONCLUSIONS: Metastatic MC (mMC) patients had a characteristic distant metastasis pattern. This study constructed a new and sufficiently accurate prognostic model of mMC based on population-based data. These findings can be utilized to predict prognosis and guide mMC patient management.

A bioinformatics analysis to evaluate the prognostic value of stemness-related genes in gastric cancer.

BACKGROUND: This study aimed to identify potential stemness-related targets in gastric cancer (GC) in order to support the development of new treatment strategies and improve patient survival. METHODS: Using the edgeR package, we identified stemness-related differentially expressed genes (DEGs) using GSE112631 and the stemness-related signaling pathways in the Gene Set Enrichment Analysis (GSEA) database. Lasso-penalized Cox regression analysis and multivariate Cox regression analysis tested by Akaike Information Criterion (AIC) were used to screen out survival genes in order to construct a prognostic model. We verified the accuracy of our prognostic model using a nomogram and receiver operating characteristic (ROC) curve analysis. Patients were divided into two groups based on the median risk score, and functional enrichment analysis was used to explore the differences between the two groups. RESULTS: Eight genes were selected to establish a prognostic model of The Cancer Genome Atlas (TCGA) and a validation model of the GSE84437 dataset from the Genome Expression Omnibus (GEO). In both models, we found that the low risk score group had better overall survival (OS) than the high-risk score group. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways between the two risk groups were totally different. CONCLUSIONS: We used eight stemness-related genes to build a prognostic model. The high-risk score group had a worse prognosis compared to the low-risk score group.

VEGFR2 promotes tumorigenesis and metastasis in a pro-angiogenic-independent way in gastric cancer.

BACKGROUND: VEGF/VEGFR2 pathway is the central therapeutic target in anti-angiogenic treatment in multiple cancers. However, little work has been carried out concerning the pro-malignancy functions of VEGFR2 that are independent of its pro-angiogenesis effects in gastric cancer. Here, we demonstrated that VEGFR2 up-regulation in gastric cancer tissues was a prognostic marker for poor disease-free survival and overall survival of gastric cancer patients. METHODS: Immunohistochemistry was used to detect VEGFR2 and VTN expressions in specimens. Kaplan-Meier curves were constructed for survival analysis. Stably knockdown cell lines and overexpression cell lines were constructed by small interfering RNA and plasmids transfection. Real-time PCR and Western blot were used to confirm the expressions of target genes at both RNA and protein levels. Cell proliferation was measured by using Cell Counting Kit-8 and xenograft models. Microarray and bioinformatic analysis were also performed to identify the relationship between Vitronectin (VTN) and VEGFR2. RESULTS: When overexpressed in gastric cancer cells, VEGFR2 increased cellular proliferation and invasion in vitro and tumor formation in xenograft models. By using integrating microarray and bioinformatic analysis, we identifiedVTN as a downstream of VEGFR2 pathway. In gain- and loss-of function analysis in gastric cancer cells, VTN was further verified in consistent with VEGFR2 in expression levels and in regulating cell growth and motility in vitro and in vivo. Moreover, in gastric cancer samples, VTN was as also revealed as a poor prognostic factor. CONCLUSIONS: Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects. IMPLICATIONS: Our present findings defined a novel activity for VEGFR2 in promoting tumorogenicity, motility and indicating a poor survival in gastric cancer beyond its known pro-angiogenic effects, which may provide a new and valuable target for design of therapies for intervention and a new cognitive perspective for the anti-angiogenesis therapies.

Loss of LKB1 Expression Decreases the Survival and Promotes Laryngeal Cancer Metastasis.

Background: Given recent results indicating that diminished LKB1 expression in laryngeal cancer correlates with shorter survival. We aim to perform an analysis estimate the role of decreased liver kinase B1(LKB1) and in the prognostication of human laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study and evaluate the expression of LKB1 and p16INK4a (p16) in 208 clinical advanced-stage LSCC tissue samples by using immunohistochemistry. The specimens were received at Sun Yat-sen University Cancer Center (Guangzhou, China). To evaluate the independent prognostic relevance of LKB1, univariate and multivariate Cox regression models were used, overall survival (OS) and distant metastasis-free survival (DMFS) were compared using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 80/208 (38.5%) of the LSCC tissue samples expressed high LKB1. Low LKB1 expression was associated with a significantly shorter OS and DMFS than high LKB1 expression (P = 0.041 and 0.028, respectively; log-rank test), and there was a poorer OS in the p16-positive than p16-negative group. In the subgroup stratified by p16 status, the shorter OS were also seen with low LKB1 expression. Multivariate survival analysis indicated that high LKB1 expression was an independent prognostic factor for OS (hazard ratio [HR]: 1.628, 95% confidence interval [CI]: 1.060-2.500, P = 0.026) and DMFS (HR: 2.182, 95% CI: 1.069-4.456, P = 0.032). Conclusions: Our data indicated that low expression of LKB1 was significantly associated with poor prognosis and it may represent a marker of tumor metastasis in patients with LSCC. When combined with p16, LKB1 was also of prognostic value.

DNA-dependent protein kinase catalytic subunit functions in metastasis and influences survival in advanced-stage laryngeal squamous cell carcinoma.

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known to function in several types of cancer. In this study, we investigated the expression and clinicopathologic significance of DNA-PKcs in laryngeal squamous cell carcinoma (LSCC). Methods: We conducted a retrospective study of 208 patients with advanced-stage LSCC treated at Sun Yat-sen University Cancer Center, Guangzhou, China. We assessed DNA-PKcs and p16INK4a (p16) status using immunohistochemistry. We examined the association between DNA-PKcs expression and clinicopathologic features and survival outcomes. To evaluate the independent prognostic relevance of DNA-PKcs, we used univariate and multivariate Cox regression models. We estimated overall survival (OS) and distant metastasis-free survival (DMFS) using the Kaplan-Meier method. Results: Immunohistochemical analyses revealed that 163/208 (78.4%) of the LSCC tissue samples exhibited high DNA-PKcs expression. High DNA-PKcs expression was significantly associated with survival outcomes (P = 0.016) and distant metastasis (P = 0.02; chi-squared test). High DNA-PKcs expression was associated with a significantly shorter OS and DMFS than low DNA-PKcs expression (P = 0.029 and 0.033, respectively; log-rank test), and was associated with poor OS in the p16-positive subgroup (P = 0.047). Multivariate analysis identified DNA-PKcs as an independent prognostic indicator of OS and DMFS in all patients (P = 0.039 and 0.037, respectively). Conclusions: Our results suggest that patients with LSCC in whom DNA-PKcs expression is elevated have a higher incidence of distant metastasis and a poorer prognosis. DNA-PKcs may represent a marker of tumor progression in patients with p16-positive LSCC.

Mean platelet volume provides beneficial diagnostic and prognostic information for patients with resectable gastric cancer.

Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related mortalities worldwide. Platelets play an important and multifaceted role in cancer progression. Elevated mean platelet volume (MPV) detected in peripheral blood has been identified in various types of cancer. In the present study, we investigated the application value of MPV in early diagnostic and prognostic prediction in patients with resectable gastric cancer. In total, 168 patients with resectable gastric cancer were included and separated into the gastric cancer and healthy control groups according to median pre-operatic MPV value (MPV low, <10.51 or MPV high, ≥10.51). The results showed that the pre-operatic MPV level was significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operatic MPV level correlated with improved clinicopathological features, including decreased depth of invasion, less lymphonodus metastasis and early tumor stage. The Kaplan-Meier plots showed that the patients with higher pre-operatic MPV had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant decrease in the MPV level. The patients whose MPV level decreased following surgery had an improved OS. Multivariate Cox regression analysis revealed that the depth of invasion, lymphonodus metastasis, American Joint Committee on Cancer (AJCC) stage, and changes in MPV following surgery were prognostic factors affecting OS, and the AJCC stage and pre-operatic MPV were prognostic factors affecting DFS. In conclusion, MPV measurement can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

Prenatal Maternal Occupational Exposure and Postnatal Child Exposure to Elemental Mercury.

OBJECTIVES: Young children are highly vulnerable to elemental mercury toxicity, and elementary mercury exposure in young children in China unfortunately occurs regularly because of the wide use of fluorescent lamps, glass thermometers, and other mercury-contained items. This study aimed to summarize such recent cases in a referral clinic and to make recommendations for postexposure treatment and prevention of future exposure. METHODS: Patients were evaluated between January 2007 and December 2009 in environmental health facilities throughout China and were referred to our clinic. A total of 6 children younger than 4 years with significant elemental mercury exposure were included in this case series analysis. The total mercury content in blood and hair (fetal hair if necessary) and average 24-hour urine mercury concentrations were analyzed. Meso-2,3-dimercaptosuccinic acid or surgery was prescribed for the patient if necessary. RESULTS: Young children were found to be exposed in 3 ways as follows: prenatal exposure through maternal occupational contact in compact fluorescent-lamp factories (2 cases), broken thermometers (3 cases), and other causes of accidental inhalation of mercury vapor during the embryonic and lactation periods (1 case). For 3 cases caused by broken thermometers, x-ray images helped to identify the position of mercury residues. Local excision was used to remove mercury from the floor of the mouth in 1 case. One child was prescribed oral meso-2,3-dimercaptosuccinic acid, and a good response was received. CONCLUSIONS: Substitution of mercury-in-glass thermometers and vigilance to prevent women of childbearing age from occupational mercury exposure were suggested. Treatment selection should vary according to patient situations.

Application of platelet/lymphocyte and neutrophil/lymphocyte ratios in early diagnosis and prognostic prediction in patients with resectable gastric cancer.

BACKGROUND: Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related deaths worldwide. China has a high incidence of gastric cancer. Inflammation is a critical component of tumor progression. It has been widely accepted that gastric cancer is an inflammation-driven cancer. In this study, we investigated the application value of systemic inflammatory response (SIR) markers, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR), in early diagnosis and prognostic prediction in patients with resectable gastric cancer. MATERIALS AND METHODS: One hundred and sixty-two patients with resectable gastric cancer were included and separated into groups according to median pre-operative PLR or NLR values (PLR low: < 208 or PLR high: ≥ 208, and NLR low: < 4.02 or NLR high: ≥ 4.02, respectively). To evaluate the changes in PLR or NLR values after operation, we introduced the concept of postpre-operative PLR or NLR ratios (< 1 indicated PLR or NLR values were decreased after operation, while ≥ 1 suggested not decreased PLR or NLR values). RESULTS: Pre-operative PLR and NLR levels were significantly higher in gastric cancer patients compared with the healthy subjects. Low pre-operative PLR and NLR levels correlated with better clinicopathological features, including decreased depth of invasion, less lymph node metastasis and early tumor stage. Kaplan-Meier plots illustrated that higher pre-operative NLR and PLR had decreased overall survival (OS) and disease-free survival (DFS). Surgical tumor resection resulted in a significant CONCLUSIONS: PLR and NLR measurements can provide important diagnostic and prognostic results in patients with resectable gastric cancer.

Relationship Between the DPD and TS mRNA Expression and the Response to S-1-Based Chemotherapy and Prognosis in Patients with Advanced Gastric Cancer.

The aim was to determine changes in dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) mRNAs in the blood of advanced gastric cancer (AGC) patients to see whether these enzymes affected the patients' response to S-1-based chemotherapy and prognosis. For this purpose, pretreatment DPD/TS mRNA expressions were determined in 40 AGC patients using RT-PCR. The patients were then administered with S-1-based regimen (S-1 + cisplatin) and toxicities were recorded. The relationship between the DPD/TS mRNA expressions and the chemotherapy response, drug resistance, and prognosis was analyzed. The data show that DPD mRNA expression correlated significantly with Lauren type while TS mRNA expression correlated with distant metastasis. Patients with higher DPD and/or TS mRNA expression(s) showed poor response, while those with low DPD mRNA expression showed better response to the chemotherapy. Pooled analysis showed that the patients with low DPD/TS mRNA expressions had better therapeutic response. The incidence of bone marrow suppression, diarrhea, and oral mucositis was high in patients with low DPD mRNA expression. Median overall survival (OS) in 40 patients was 13.5 months. It was 17 months for low and 10 months for high DPD (P = 0.044) and TS mRNA expression (P = 0.047). Pooled analysis showed that the patients with both low DPD/TS mRNA expressions had longer OS (P = 0.001). In conclusion, the detection of DPD and/or TS mRNA expression can be used to predict the response to S-1-based chemotherapy, drug resistance, and prognosis in AGC patients as well as to help guide the individualized treatment of gastric cancer.

Changes in neutrophil/lymphocyte and platelet/lymphocyte ratios after chemotherapy correlate with chemotherapy response and prediction of prognosis in patients with unresectable gastric cancer.

The aim of the study was to investigate the application value of neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) in the prediction of chemotherapy response and prognosis in patients with advanced gastric cancer. In total, 120 patients with unresectable gastric cancer were included and separated into two groups according to the median values of NLR or PLR (NLR low: <4.62 or NLR high: ≥4.62 and PLR low: <235 or PLR high: ≥235, respectively). Low baseline NLR level correlated with improved clinicopathological characteristics, including smaller tumor size, well differentiation and less metastasis. Low baseline PLR level also associated with less metastasis. Patients with a low baseline level of NLR or PLR had an improved response to chemotherapy. Patients with a higher baseline NLR and PLR had decreased progression-free survival (PFS) and overall survival (OS) ratios. Alterations in the NLR and PLR levels were associated with therapeutic efficacy and prognosis. The patients who remained in or switched to the low NLR level subgroup subsequent to first-line chemotherapy had an improved response and improved OS ratios, compared to the patients remaining in or switching to the high NLR level group. Similar results were observed when the PLR level was investigated. In conclusion, baseline NLR and PLR measurements, as well as changes of NLR and PLR following chemotherapy can predict the prognostic results in patients with unresectable gastric cancer.

Mean platelet volume predicts chemotherapy response and prognosis in patients with unresectable gastric cancer.

Gastric cancer is the fourth most frequent cancer and the second cause of cancer-related mortalities worldwide. Platelets play an important and multifaceted role in cancer progression. Elevated mean platelet volume (MPV) detected in peripheral blood has been identified in various types of cancer. In the present study, we investigated the application value of MPV in the prediction of chemotherapy response and prognosis in patients with unresectable gastric cancer. A total of 128 patients with unresectable gastric cancer were included and divided according to the median values of baseline MPV (low MPV: <11.65 or high MPV: ≥11.65). A low baseline MPV level was correlated with reduced metastasis. The results showed that patients with a low baseline level of MPV improved response to chemotherapy. Changes in MPV were associated with therapeutic efficacy. Patients who remained in or were transferred into the low MPV level subgroup following first-line chemotherapy had improved response, compared to those remaining in or being transferred into the high MPV level group. The patients with a higher baseline MPV had decreased progression-free and overall survival ratios. Univariate and multivariate analyses revealed that baseline MPV was a prognostic factor affecting progression-free survival. In conclusion, the results showed that MPV measurements can provide important prognostic information for gastric cancer patients.

Determination of polychlorinated biphenyls and organochlorine pesticides in human serum by gas chromatography with micro-electron capture detector.

A method for determination of concentrations of polychlorinated biphenyl congeners (PCB-28, 52, 101, 118, 138, 153, 156, and 187) and organochlorine pesticides (hexachlorobenzene, alpha-hexachlorocyclohexane, beta-hexachlorocyclohexane, gamma-hexachlorocyclohexane, delta-hexachlorocyclohexane, p,p'-dichlorodiphenyl dichloroethylene, o,p'-dichlorodiphenyl trichloroethane, p,p'-dichlorodiphenyl dichloroethane, p,p'-dichlorodiphenyl trichloroethane, alpha-chlordane, gamma-chlordane, heptachlor, heptachlor epoxide, and aldrin) in human serum is developed. Recovery is assessed with artificial serum, in which PCBs and OCPs could not be detected. The method is then confirmed with pooled human serum. Experiments are performed by adding two concentrations of analytes (0.5 µg/L and 1.0 µg/L) to both matrices. The sample pretreatment process involves denaturing with a mixture of water-1-propanol (v:v, 85:15), extraction with a C-18 cartridge, and cleanup with an Alumina B cartridge. This process required about 2 mL of serum. The limit of detection ranged from 0.05-0.35 µg/L for all the analytes. Recovery of analytes at low and high spiking concentrations varied from 63-122% and 61-124% for artificial serum and pooled human serum, respectively. Relative standard deviation was lower than 16% and 18% for artificial serum and pooled human serum, respectively. Stability of the method, expressed as relative standard deviation, was lower than 14%. The method has been applied in epidemiological research.

Relationship between serum concentrations of polychlorinated biphenyls and organochlorine pesticides and dietary habits of pregnant women in Shanghai.

The use of most polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) has been restricted in China; however, their use remains a concern because of their adverse effects on human health, especially on fetuses and infants. To date, there is no data regarding the exposure levels of pregnant women to PCBs and OCPs in Shanghai. In order to evaluate PCB and OCP exposure levels and the contribution of dietary habits to these levels, we determined the concentrations of 8 PCBs and 14 OCPs in the umbilical cord blood serum of healthy pregnant women in Shanghai. Dietary habits of the pregnant women were obtained from a self-administered questionnaire. Results showed that p, p'-DDE, HCB and ß-HCH were the major pollutants present in the serum samples; PCBs were detected in a few samples at low concentrations. Age, weight and body mass index before delivery were positively associated with serum levels of p, p'-DDE and ß-HCH. Women and their husbands who had higher education levels, higher income levels, tended to have higher levels of p, p'-DDE and ß-HCH. Spearman correlation analysis results suggested that consumption of foods such as milk, eggs, meat, fish, and shrimp may contribute to higher serum levels of p, p'-DDE and ß-HCH. Furthermore, multiple linear regression analyses indicated that the age and educational levels of the pregnant women and their intake of fried/flamed food and shellfish were positively associated with ß-HCH levels, and that the age and educational levels of the pregnant women and their intake of parity, beef, pork, mutton, and shrimp were positively associated with p, p'-DDE levels. This is the first study to investigate the exposure levels of pregnant women to PCBs and OCPs in Shanghai, and it should provide useful information for future related research.

[Correlation between level of metallic elements in urine and childhood acute leukemia].

OBJECTIVE: To explore the relation between the level of metallic elements in urine and childhood acute leukemia. METHODS: A total of 71 patients under 15 years old who were newly diagnosed with acute leukemia between September 2007 and August 2008 without Downs' syndrome or other tumors, and 113 gender- and age-matched controls without tumors or congenital diseases were enrolled for the case-control study. The general data and potential risk factors were obtained by questionnaires. Inductively coupled plasma mass spectrometry (ICP-MS) was used to determine the metal concentrations in urine, which was collected randomly before chemotherapy. Logistic regression model was performed for univariate and multivariate analysis. RESULTS: The questionnaire showed that there was significant difference in the proportion of children whose mothers had taken iron supplements during or 3 months before pregnancy between case group and control group, which was 28.2% (20/71) and 14.2% (16/113) respectively (Wald χ(2) = 5.438, P = 0.02). Univariate logistic regression analysis showed that levels of vanadium, manganese, iron, cobalt, copper, arsenic, and barium in urine from case group were all higher than those of control group with significant difference. The median values for vanadium in urine from case and control groups were 5.39 and 3.04 ng/mg creatinine (Wald χ(2) = 9.03, P < 0.05); the median values for manganese were respectively 4.46 and 2.44 ng/mg creatinine (Wald χ(2) = 10.57, P < 0.05); the median values for iron were separately 58.69 and 14.09 ng/mg creatinine (Wald χ(2) = 13.41, P < 0.05); the median values for cobalt were respectively 0.98 and 0.77 ng/mg creatinine (Wald χ(2) = 4.46, P < 0.05); the median values for copper were 61.17 and 10.90 ng/mg creatinine (Wald χ(2) = 8.15, P < 0.05); the median values for arsenic were respectively 55.93 and 36.11 ng/mg creatinine (Wald χ(2) = 4.57, P < 0.05); and the median values for barium were 8.55 and 2.87 ng/mg creatinine (Wald χ(2) = 4.82, P < 0.05). Multivariate logistic regression analysis showed that the level of iron in urine had a significantly positive relation with the incidence of childhood acute leukemia (OR = 1.009, 95%CI = 1.002 - 1.016). CONCLUSION: The level of iron in urine might be related to the occurrence of childhood acute leukemia, but its specific role needs further investigation.

The role of metabotropic glutamate receptor 5 in developmental lead neurotoxicity.

A complete explanation of the mechanisms of lead-induced developmental neurotoxicity remains unknown. The glutamate receptor is one of the most important targets of lead. More recently, metabotropic glutamate receptor 5 (mGluR5) has been shown to have a functional relationship with learning and memory. We investigated the impact of developmental lead exposure on hippocampal mGluR5 expression and its potential role in lead neurotoxicity. Both in vitro model of lead exposure with Pb(2+) concentrations of 0, 10 nM, 1 microM, and 100 microM in cultured rat embryonic hippocampal neurons, and the in vivo model of rat maternal lead exposure involving both gestational and lactational exposure with 0, 0.05%, 0.2%, and 0.5% lead acetate were utilized. Immunoperoxidase and immunofluorescent analyses, quantitative PCR and western blotting were used. In vitro studies revealed that expression of mGluR5 mRNA and protein was decreased dose-dependently after lead exposure, which was further confirmed by the results of in vivo studies. These data suggest that mGluR5 might be involved in lead-induced neurotoxicity by disturbing mGluR5-induced long-term depression and decreasing N-methyl-D-aspartic acid receptor (NMDAR)-dependent or protein synthesis-dependent long-term potentiation. These results might improve the understanding of the mechanism and potential treatments for moderate to severe lead poisoning in children.

TRPC1 and STIM1 mediate capacitative Ca2+ entry in mouse pulmonary arterial smooth muscle cells.

Previous studies in pulmonary arterial smooth muscle cells (PASMCs) showed that the TRPC1 channel mediates capacitative Ca(2+) entry (CCE), but the molecular signal(s) that activate TRPC1 in PASMCs remains unknown. The aim of the present study was to determine if TRPC1 mediates CCE through activation of STIM1 protein in mouse PASMCs. In primary cultured mouse PASMCs loaded with fura-2, cyclopiazonic acid (CPA) caused a transient followed by a sustained rise in intracellular Ca(2+) concentration ([Ca(2+)](i)). The transient but not the sustained rise in [Ca(2+)](i) was partially inhibited by nifedipine. In addition, CPA increased the rate of Mn(2+) quench of fura-2 fluorescence that was inhibited by SKF 96365, Ni(2+), La(3+) and Gd(3+), exhibiting pharmacological properties characteristic of CCE. The nifedipine-insensitive sustained rise in [Ca(2+)](i) and the increase in Mn(2+) quench of fura-2 fluorescence caused by CPA were both inhibited in cells pretreated with antibody raised against an extracellular epitope of TRPC1. Moreover, STIM1 siRNA reduced the rise in [Ca(2+)](i) and Mn(2+) quench of fura-2 fluorescence caused by CPA, whereas overexpression of STIM1 resulted in a marked increase in these responses. RT-PCR revealed TRPC1 and STIM1 mRNAs, and Western blot analysis identified TRPC1 and STIM1 proteins in mouse PASMCs. Furthermore, TRPC1 was found to co-immunoprecipitate with STIM1, and the precipitation level of TRPC1 was increased in cells subjected to store depletion. Taken together, store depletion causes activation of voltage-operated Ca(2+) entry and CCE. These data provide direct evidence that CCE is mediated by TRPC1 channel through activation of STIM1 in mouse PASMCs.

Overexpression of PLK1 is associated with poor survival by inhibiting apoptosis via enhancement of survivin level in esophageal squamous cell carcinoma.

PLK1 is essential for the maintenance of genomic stability during mitosis. In our study, we found that overexpression of PLK1 was an independent prognostic factor (RR=4.253, p=0.020) and significantly correlated with survivin, an antiapoptotic protein, in esophageal squamous cell carcinoma (ESCC). Reverse transcription-polymerase chain reaction and fluorescence in situ hybridization (FISH) revealed upregulation of PLK1 mRNA and amplification of PLK1 gene, respectively. Depletion of PLK1 activated the intrinsic apoptotic pathway, which was substantiated by loss of mitochondrial membrane potential, reduction of Mcl-1 and Bcl-2 as well as activation of caspase-9. Coimmunoprecipitation and confocal microscopy displayed that PLK1 was associated with survivin and PLK1 depletion led to downregulation of survivin. Cotransfection of survivin constructs could partially reverse PLK1-depletion-induced apoptosis. These data suggest that PLK1 might be a useful prognostic marker and a potential therapeutic target for ESCC. Survivin is probably involved in antiapoptotic function of PLK1.

Exogenous expression of Esophagin/SPRR3 attenuates the tumorigenicity of esophageal squamous cell carcinoma cells via promoting apoptosis.

Esophagin/SPRR3 is one of the cornified-envelope structural precursor proteins, which is expressed during epithelia cell differentiation. In 1996, another research group discovered, and our own laboratory subsequently confirmed, frequent and dramatic decreased Esophagin/SPRR3 expression in esophageal squamous cell carcinoma (ESCC). However, the role of Esophagin/SPRR3 in tumorigenesis of esophageal epithelium remains undetermined. In this study, we demonstrate that expression of Esophagin/SPRR3 is frequently downregulated in ESCC. In contrast, no correlations between downregulation of Esophagin/SPRR3 expression and clinicopathologic characteristics were observed. Diminished Esophagin/SPRR3 expression was present in dysplastic epithelia, suggesting that Esophagin/SPRR3 alteration could represent an early event in squamous carcinogenesis of the esophagus. Exogenous expression of Esophagin/SPRR3 significantly suppressed the ability of ESCC cells to form colonies in plastic and soft agar, as well as tumor formation in vivo. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end label assay and immunofluorescence analysis of the active form of Caspase 3 indicated that dysregulated apoptosis might contribute to reduced tumorigenicity. In particular, upregulation of CDK11p46 protein was observed in ESCC cells expressing Esophagin/SPRR3, but not in control cells, indicating that Esophagin/SPRR3-induced apoptosis may be due, at least in part, to increased expression of CDK11p46 protein. These findings suggest that Esophagin/SPRR3 may play a role in the maintenance of normal esophageal epithelial homeostasis, and that aberrant expression of Esophagin/SPRR3 may contribute to the tumorigenesis of ESCC.