Modulating the Electrolyte Microenvironment in Electrical Double Layer for Boosting Electrocatalytic Nitrate Reduction to Ammonia.

Electrochemical nitrate reduction reaction (NO3RR) is a promising approach to achieve remediation of nitrate-polluted wastewater and sustainable production of ammonia. However, it is still restricted by the low activity, selectivity and Faraday efficiency for ammonia synthesis. Herein, we propose an effective strategy to modulate the electrolyte microenvironment in electrical double layer (EDL) by mediating alkali metal cations in the electrolyte to enhance the NO3RR performance. Taking bulk Cu as a model catalyst, the experimental study reveals that the NO3 --to-NH3 performance in different electrolytes follows the trend Li+

FgPfn participates in vegetative growth, sexual reproduction, pathogenicity, and fungicides sensitivity via affecting both microtubules and actin in the filamentous fungus Fusarium graminearum.

Fusarium head blight (FHB), caused by Fusarium graminearum species complexes (FGSG), is an epidemic disease in wheat and poses a serious threat to wheat production and security worldwide. Profilins are a class of actin-binding proteins that participate in actin depolymerization. However, the roles of profilins in plant fungal pathogens remain largely unexplored. Here, we identified FgPfn, a homolog to profilins in F. graminearum, and the deletion of FgPfn resulted in severe defects in mycelial growth, conidia production, and pathogenicity, accompanied by marked disruptions in toxisomes formation and deoxynivalenol (DON) transport, while sexual development was aborted. Additionally, FgPfn interacted with Fgα1 and Fgß2, the significant components of microtubules. The organization of microtubules in the ΔFgPfn was strongly inhibited under the treatment of 0.4 µg/mL carbendazim, a well-known group of tubulin interferers, resulting in increased sensitivity to carbendazim. Moreover, FgPfn interacted with both myosin-5 (FgMyo5) and actin (FgAct), the targets of the fungicide phenamacril, and these interactions were reduced after phenamacril treatment. The deletion of FgPfn disrupted the normal organization of FgMyo5 and FgAct cytoskeleton, weakened the interaction between FgMyo5 and FgAct, and resulting in increased sensitivity to phenamacril. The core region of the interaction between FgPfn and FgAct was investigated, revealing that the integrity of both proteins was necessary for their interaction. Furthermore, mutations in R72, R77, R86, G91, I101, A112, G113, and D124 caused the non-interaction between FgPfn and FgAct. The R86K, I101E, and D124E mutants in FgPfn resulted in severe defects in actin organization, development, and pathogenicity. Taken together, this study revealed the role of FgPfn-dependent cytoskeleton in development, DON production and transport, fungicides sensitivity in F. graminearum.

FgMet3 and FgMet14 related to cysteine and methionine biosynthesis regulate vegetative growth, sexual reproduction, pathogenicity, and sensitivity to fungicides in Fusarium graminearum.

Fusarium graminearum is a destructive filamentous fungus, which widely exists in wheat and other cereal crops. Cysteine and Methionine are unique sulfur-containing amino acids that play an essential role in protein synthesis and cell life, but their functions and regulation in F. graminearum remain largely unknown. Here we identified two proteins, FgMet3 and FgMet14 in F. graminearum, which are related to the synthesis of cysteine and methionine. We found FgMet3 and FgMet14 were localized to the cytoplasm and there was an interaction between them. FgMet3 or FgMet14 deletion mutants (ΔFgMet3 and ΔFgMet14) were deficient in vegetative growth, pigment formation, sexual development, penetrability and pathogenicity. With exogenous addition of cysteine and methionine, the vegetative growth and penetrability could be completely restored in ΔFgMet3 and ΔFgMet14, while sexual reproduction could be fully restored in ΔFgMet3 and partially restored in ΔFgMet14. ΔFgMet3 and ΔFgMet14 exhibited decreased sensitivity to Congo red stress and increased sensitivity to SDS, NaCl, KCl, Sorbitol, Menadione, and Zn ion stresses. Moreover, FgMet3 and FgMet14 nonspecifically regulate the sensitivity of F. graminearum to fungicides. In conclusion, FgMet3 and FgMet14 interacted to jointly regulate the development, pathogenicity, pigment formation, sensitivity to fungicides and stress factors in F. graminearum.

Tensile behaviors of layer-to-layer 2.5D angle-interlock woven composites with/without a center hole at various temperatures.

The temperature-dependent mechanical behaviors of open-hole composite plates are essential for composite design and structures. Here, tensile experiments of shallow straight-link-shaped 2.5D woven composites (abbr. 2.5DWC) with/without a center hole are first conducted at different temperatures (20 °C, 180 °C and 240 °C). Failure modes are examined by scanning electron microscope (SEM). Thermal property of QY8911-IV resin is investigated by DMA analysis. It is noted for samples without the center hole that with the increase of temperature, the tensile stress-strain curves exhibit a linear response until that a slight nonlinearity at the end stage. The strength retention rates at 180 °C and 240 °C are totally equal. For the open-hole samples, it is interestingly found that the strength retention rates are higher than that of samples without the hole at 180 °C, resulting from the stress concentration accommodation and fiber-dominated failure mode. Even at 240 °C, there is no necking phenomenon for all the failed samples, but more broom-like damage extent is observed in the cross-section. Due to the primary load-bearing warp yarns and hole-edge stress concentration, obvious pull-out warp yarns emerge near the hole edge.

Enhancing Delithiation Reversibility of Li15Si4 Alloy of Silicon Nanoparticles-Carbon/Graphite Anode Materials for Stable-Cycling Lithium Ion Batteries by Restricting the Silicon Particle Size.

Silicon nanoparticles (SiNPs) with a median size of 51 nm are prepared by the sand mill from waste silicon, and then carbon-interweaved SiNPs/graphite anode materials are designed. Because of the size of SiNPs is restricted below a critical fracture size of 150 nm as well as the rational decoration of carbon and graphite, fracture of SiNPs, and volume deformation of active materials are highly alleviated, leading to low impedance, enhanced electrochemical reaction kinetics, and good electronic connection between active materials and current collector. Furthermore, delithiation reversibility of the formed crystalline Li15Si4 alloy is enhanced. As a result, the anode with 10.5 wt % content of Si (including SiOx) delivers a properly high initial reversible capacity of 505 mA h g-1, high cycling stability with capacity retentions of 86.3%, and 91.5% at 0.1 and 1 A g-1 after 500 cycles, respectively. After cycling at a series of higher current densities, the reversible capacity recovers to the original level completely (100% recovery) when the current density is set back to the original value, exhibiting outstanding rate performance. The results indicate that the silicon-carbon anode can achieve high cycling performances with enhanced delithiation reversibility of the formed crystalline Li15Si4 alloy by restricting size of SiNPs and decoration of carbon materials, which are discussed systematically. The SiNPs are recycled from waste Si, and synthetic strategy of anode materials is very facile, cost-effective, and nontoxic, which has potential for industrial production.

Preparation of Si-SiOx nanoparticles from volatile residue produced by refining of silicon.

Residual Si was produced on a furnace wall when upgraded metallurgical grade Si was refined by electron beam melting. It was then recycled to prepare Si-SiOx nanoparticles with an average size of 100 nm by planetary ball milling. The obtained Si-SiOx nanoparticles mainly consist of amorphous Si, crystalline Si and amorphous SiOx, which was confirmed by XRD, FTIR, XPS and TEM. SiOx is mainly composed of SiO2 and SiO1.35. Distilled water used as a grinding aid not only enhances milling efficiency, but also plays a key role in obtaining SiOx. During refining of upgraded metallurgical grade Si, the deposition pattern of residual Si on furnace wall agrees with model of three-dimension growth. Growth of Si-SiOx nanoparticles is the mutual effect of distilled water and ball milling. Si-SiOx nanoparticles were doped into phenolic resin pyrolysis carbon as anode materials for lithium ion batteries, and 10% doping was observed to improve the specific capacity. After 500 cycles, specific capacity of delithiation remained around 550 mA h/g. It suggests the residual Si is a value-added by-product, and it can be recycled as anode materials for lithium ion batteries.

Concordant effects of aromatase inhibitors on gene expression in ER+ Rat and human mammary cancers and modulation of the proteins coded by these genes.

Aromatase inhibitors are effective in therapy/prevention of estrogen receptor-positive (ER⁺) breast cancers. Rats bearing methylnitrosourea (MNU)-induced ER⁺ mammary cancers were treated with the aromatase inhibitor vorozole (1.25 mg/kg BW/day) for five days. RNA expression showed 162 downregulated and 180 upregulated (P < 0.05 and fold change >1.5) genes. Genes modulated by vorozole were compared with published data from four clinical neoadjuvant trials using aromatase inhibitors (anastrozole or letrozole). More than 30 genes and multiple pathways exhibited synchronous changes in animal and human datasets. Cell-cycle genes related to chromosome condensation in prometaphase [anaphase-prometaphase complex (APC) pathway, including Aurora-A kinase, BUBR1B, TOP2, cyclin A, cyclin B CDC2, and TPX-2)] were downregulated in animal and human studies reflecting the strong antiproliferative effects of aromatase inhibitors. Comparisons of rat arrays with a cell culture study where estrogen was removed from MCF-7 cells showed decreased expression of E2F1-modulated genes as a major altered pathway. Alterations of the cell cycle and E2F-related genes were confirmed in a large independent set of human samples (81 pairs baseline and two weeks anastrozole treatment). Decreases in proliferation-related genes were confirmed at the protein level for cyclin A2, BuRB1, cdc2, Pttg, and TPX-2. Interestingly, the proteins downregulated in tumors were similarly downregulated in vorozole-treated normal rat mammary epithelium. Finally, decreased expression of known estrogen-responsive genes (including TFF, 1,3, progesterone receptor, etc.) were decreased in the animal model. These studies demonstrate that gene expression changes (pathways and individual genes) are similar in humans and the rat model.

Chemopreventive effect of a mixture of Chinese Herbs (antitumor B) on chemically induced oral carcinogenesis.

In this study, we evaluated chemopreventive efficacy of Antitumor B, a Chinese herbal mixture of six plants (Sophora tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus arvensis L., Dictamnus dasycarpus, and Dioscorea bulbifera) on the development of 4-nitroquinoline-1-oxide (4NQO) induced oral squamous cell carcinomas in A/J mice. Antitumor B, delivered through diet, inhibited 4NQO-induced oral cancer development by 59.19%. The reduction of cell proliferation appears to be associated with efficacy of Antitumor B against 4NQO-induced oral cancer in A/J mice. The expression of epidermal growth factor receptor (EGFR) and phosphorylated EGFR (Tyr1173) were down-regulated by Antitumor B. Tissue distribution of Antitumor B was determined using obacunone, matrine, and maackiain as marker chemicals. We found significant amounts of obacunone, matrine, and maackiain in the blood after 1-wk treatment. The concentrations of these three compounds did not increase further at 18 wk, suggesting that plasma concentrations had reached a steady-state level at 1 wk. There was no significant body weight loss and there was no other obvious sign of toxicity in Antitumor B-treated mice. These results suggest that Antitumor B is a promising agent for human oral cancer chemoprevention.

Functional characterization of CLPTM1L as a lung cancer risk candidate gene in the 5p15.33 locus.

Cleft Lip and Palate Transmembrane Protein 1-Like (CLPTM1L), resides in a region of chromosome 5 for which copy number gain has been found to be the most frequent genetic event in the early stages of non-small cell lung cancer (NSCLC). This locus has been found by multiple genome wide association studies to be associated with lung cancer in both smokers and non-smokers. CLPTM1L has been identified as an overexpressed protein in human ovarian tumor cell lines that are resistant to cisplatin, which is the only insight thus far into the function of CLPTM1L. Here we find CLPTM1L expression to be increased in lung adenocarcinomas compared to matched normal lung tissues and in lung tumor cell lines by mechanisms not exclusive to copy number gain. Upon loss of CLPTM1L accumulation in lung tumor cells, cisplatin and camptothecin induced apoptosis were increased in direct proportion to the level of CLPTM1L knockdown. Bcl-xL accumulation was significantly decreased upon loss of CLPTM1L. Expression of exogenous Bcl-xL abolished sensitization to apoptotic killing with CLPTM1L knockdown. These results demonstrate that CLPTM1L, an overexpressed protein in lung tumor cells, protects from genotoxic stress induced apoptosis through regulation of Bcl-xL. Thus, this study implicates anti-apoptotic CLPTM1L function as a potential mechanism of susceptibility to lung tumorigenesis and resistance to chemotherapy.

MicroRNA profiling and prediction of recurrence/relapse-free survival in stage I lung cancer.

About 30% stage I non-small cell lung cancer (NSCLC) patients undergoing resection will recur. Robust prognostic markers are required to better manage therapy options. MicroRNAs (miRNAs) are a class of small non-coding RNAs of 19-25 nt and play important roles in gene regulation in human cancers. The purpose of this study is to identify miRNA expression profiles that would better predict prognosis of stage I NSCLC. MiRNAs extracted from 527 stage I NSCLC patients were profiled on the human miRNA expression profiling v2 panel (Illumina). The expression profiles were analyzed for their association with cancer subtypes, lung cancer brain metastasis and recurrence/relapse free survival (RFS). MiRNA expression patterns between lung adenocarcinoma and squamous cell carcinoma differed significantly with 171 miRNAs, including Let-7 family members and miR-205. Ten miRNAs associated with brain metastasis were identified including miR-145*, which inhibit cell invasion and metastasis. Two miRNA signatures that are highly predictive of RFS were identified. The first contained 34 miRNAs derived from 357 stage I NSCLC patients independent of cancer subtype, whereas the second containing 27 miRNAs was adenocarcinoma specific. Both signatures were validated using formalin-fixed paraffin embedded and/or fresh frozen tissues in independent data set with 170 stage I patients. Our findings have important prognostic or therapeutic implications for the management of stage I lung cancer patients. The identified miRNAs hold great potential as targets for histology-specific treatment or prevention and treatment of recurrent disease.

Modulation of gene expression and cell-cycle signaling pathways by the EGFR inhibitor gefitinib (Iressa) in rat urinary bladder cancer.

The epidermal growth factor receptor inhibitor Iressa has shown strong preventive efficacy in the N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) model of bladder cancer in the rat. To explore its antitumor mechanism, we implemented a systems biology approach to characterize gene expression and signaling pathways in rat urinary bladder cancers treated with Iressa. Eleven bladder tumors from control rats, seven tumors from rats treated with Iressa, and seven normal bladder epithelia were profiled by the Affymetrix Rat Exon 1.0 ST Arrays. We identified 713 downregulated and 641 upregulated genes in comparing bladder tumors versus normal bladder epithelia. In addition, 178 genes were downregulated and 96 genes were upregulated when comparing control tumors versus Iressa-treated tumors. Two coexpression modules that were significantly correlated with tumor status and treatment status were identified [r = 0.70, P = 2.80 × 10(-15) (bladder tumor vs. normal bladder epithelium) and r = 0.63, P = 2.00 × 10(-42) (Iressa-treated tumor vs. control tumor), respectively]. Both tumor module and treatment module were enriched for genes involved in cell-cycle processes. Twenty-four and twenty-one highly connected hub genes likely to be key drivers in cell cycle were identified in the tumor module and treatment module, respectively. Analysis of microRNA genes on the array chips showed that tumor module and treatment module were significantly associated with expression levels of let-7c (r = 0.54, P = 3.70 × 10(-8) and r = 0.73, P = 1.50 × 10(-65), respectively). These results suggest that let-7c downregulation and its regulated cell-cycle pathway may play an integral role in governing bladder tumor suppression or collaborative oncogenesis and that Iressa exhibits its preventive efficacy on bladder tumorigenesis by upregulating let-7 and inhibiting the cell cycle. Cell culture study confirmed that the increased expression of let-7c decreases Iressa-treated bladder tumor cell growth. The identified hub genes may also serve as pharmacodynamic or efficacy biomarkers in clinical trials of chemoprevention in human bladder cancer.

Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice.

To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm(3) (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10(-6)). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies.

Chemoprevention of lung carcinogenesis by the combination of aerosolized budesonide and oral pioglitazone in A/J mice.

Budesonide, a synthetic glucocorticoid used for treating asthma, and pioglitazone, a synthetic peroxisome proliferator-activated receptors γ ligand used for the treatment of diabetes, were evaluated for their combinational chemopreventive efficacy on mouse lung cancer using female A/J mice with benzo(a)pyrene used as the carcinogen. All chemopreventive treatments began 2-wk post-carcinogen treatment and continued daily for 20 wk. Budesonide was administered by the aerosol route using an improved aerosol delivery system. Pioglitazone was introduced by oral gavage. The characterization of drug distribution showed that budesonide introduced by aerosol delivery accumulated only in the lung. Budesonide alone reduced tumor load by 78% and pioglitazone alone reduced tumor load by 63%. By combining aerosolized budesonide with pioglitazone, the inhibition on tumor load was 90%. In vitro experiments using human cancer cells showed that budesonide and pioglitazone exhibited independent, additive inhibitory effects on cell growth. Our results provide evidence that aerosolized budesonide and oral pioglitazone could be a promising drug combination for lung cancer chemoprevention.

Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models.

Genes differentially expressed by tumor cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models. This study examined the suitability of rodent models of bladder cancer in B6D2F1 mice and Fischer-344 rats to model clinical bladder cancer specimens in humans. Using a global gene expression approach cross-species analysis showed that 13-34% of total genes in the genome were differentially expressed between tumor and normal tissues in each of five datasets from humans, rats, and mice. About 20% of these differentially expressed genes overlapped among species, corresponding to 2.6 to 4.8% of total genes in the genome. Several genes were consistently dysregulated in bladder tumors in both humans and rodents. Notably, CNN1, MYL9, PDLIM3, ITIH5, MYH11, PCP4 and FM05 were found to commonly down-regulated; while T0P2A, CCNB2, KIF20A and RRM2 were up-regulated. These genes are likely to have conserved functions contributing to bladder carcinogenesis. Gene set enrichment analysis detected a number of molecular pathways commonly activated in both humans and rodent bladder cancer. These pathways affect the cell cycle, HIF-1 and MYC expression, and regulation of apoptosis. We also compared expression changes at mRNA and protein levels in the rat model and identified several genes/proteins exhibiting concordant changes in bladder tumors, including ANXA1, ANXA2, CA2, KRT14, LDHA, LGALS4, SERPINA1, KRT18 and LDHB. In general, rodent models of bladder cancer represent the clinical disease to an extent that will allow successful mining of target genes and permit studies on the molecular mechanisms of bladder carcinogenesis.

Chemopreventive effects of pioglitazone on chemically induced lung carcinogenesis in mice.

Pioglitazone [(RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione] is a ligand of nuclear receptor peroxisome proliferator-activated receptor γ that is approved for the treatment of type II diabetes mellitus. Activation of peroxisome proliferator-activated receptor γ has been associated with anticancer activities in a variety of cancer cell lines through inhibition of proliferation and promotion of apoptosis. We examined the effect of pioglitazone on lung cancer development in carcinogen-induced lung adenocarcinoma and squamous cell carcinoma (SCC). When pioglitazone was administered beginning 8 weeks after the first carcinogen treatment when microscopic adenomas already existed, pioglitazone significantly inhibited tumor load (sum of tumor volume per lung in average) by 64% (P < 0.05) in p53(wt/wt) mice and 50% (P < 0.05) in p53(wt/Ala135Val) mice in the lung adenocarcinoma model. Delayed administration of pioglitazone caused a limited (35%, P < 0.05) decrease in lung SCC. Induction of apoptosis occurred in both model systems. These data show that pioglitazone significantly inhibited progression of both adenocarcinoma and SCC in the two mouse model systems.

Preventive effects of bexarotene and budesonide in a genetically engineered mouse model of small cell lung cancer.

In the present study, we examined the effect of bexarotene (Targretin) and budesonide in the chemoprevention of small cell lung carcinoma using a lung-specific knockout model of Rb1 and p53. Upon treatment with bexarotene, tumor incidence, number, and load were significantly reduced (P < 0.05). Budesonide treatment trended to inhibition, but the effect was not statistically significant (P > 0.05). Immunohistochemical staining indicated that bexarotene treatment decreased cell proliferation and increased apoptosis in tumors. The Rb1/p53 gene-targeted mouse seems to be a valuable model for chemopreventive studies on human small cell lung cancer. Our results indicate that the retinoid X receptor agonist bexarotene may be a potent chemopreventive agent in this cancer type.

Haplotype and cell proliferation analyses of candidate lung cancer susceptibility genes on chromosome 15q24-25.1.

Recent genome-wide association studies have linked the chromosome 15q24-25.1 locus to nicotine addiction and lung cancer susceptibility. To refine the 15q24-25.1 locus, we performed a haplotype-based association analysis of 194 familial lung cases and 219 cancer-free controls from the Genetic Epidemiology of Lung Cancer Consortium (GELCC) collection, and used proliferation and apoptosis analyses to determine which gene(s) in the 15q24-25.1 locus mediates effects on lung cancer cell growth in vitro. We identified two distinct subregions, hapL (P = 3.20 x 10(-6)) and hapN (P = 1.51 x 10(-6)), which were significantly associated with familial lung cancer. hapL encompasses IREB2, LOC123688, and PSMA4, and hapN encompasses the three nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3, and CHRNB4. Examination of the genes around hapL revealed that PSMA4 plays a role in promoting cancer cell proliferation. PSMA4 mRNA levels were increased in lung tumors compared with normal lung tissues. Down-regulation of PSMA4 expression decreased proteasome activity and induced apoptosis. Proteasome dysfunction leads to many diseases including cancer, and drugs that inhibit proteasome activity show promise as a form of cancer treatment. Genes around hapN were also investigated, but did not show any direct effect on lung cancer cell proliferation. We concluded that PSMA4 is a strong candidate mediator of lung cancer cell growth, and may directly affect lung cancer susceptibility through its modulation of cell proliferation and apoptosis.

Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus.

Lung cancer is the leading cause of cancer death worldwide. Here, we describe a genome-wide association study of chemically induced lung tumorigenesis on 593 mice from 21 inbred strains using 115,904 genotyped and 1,952,918 imputed single nucleotide polymorphisms (SNPs). Using a genetic background-controlled genome search, we identified a novel lung tumor susceptibility gene Las2 (Lung adenoma susceptibility 2) on distal chromosome 18. Las2 showed strong association with resistance to tumor induction (rs30245983; P = 1.87 x 10(-9)) as well as epistatic interactions (P = 1.71 x 10(-3)) with the pulmonary adenoma susceptibility 1 locus, a major locus affecting mouse lung tumor development (rs13459098, P = 5.64 x 10(-27)). Sequencing analysis revealed four nonsynonymous SNPs and two insertions/deletions in the susceptible allele of Las2, resulting in the loss of tumor suppressor activities in both cell colony formation and nude mouse tumorigenicity assays. Deletion of LAS2 was observed in approximately 40% of human lung adenocarcinomas, implying that loss of function of LAS2 may be a key step for lung tumorigenesis.

[The mechanism of inhibitory effect on parotid gland secretion with local injection of botulinum toxin type A in the rat].

OBJECTIVE: To determine the mechanism of inhibitory effect of botulinum toxin type A (BTX-A) on parotid gland secretion. METHODS: Female Wistar rats (n = 18) were randomly divided into saline injection group (n = 6) and BTX-A injection group ( n = 12), respectively. 0.1 ml of saline was injected into left parotid gland and 2.5 U of BTX-A injected into right parotid gland. Rats were sacrificed at day 7, 12 and 35 post-injections respectively for morphology and vasoactive intestinal polypeptide (VIP) immunoreactivity of parotid gland. RESULTS: Following BTX-A injection, some atrophic cells and reduction of number of VIP-immunoreactive (VIP-IR) fibers were found in gland and tube at day 7 (P < 0.05); at day 12, there was more obvious reduction of VIP-IR fibers around tube and vessels and atrophy of cells in BTX-A injection gland than saline injection gland (P < 0.001); at day 35, the glandular cells and VIP-IR fibers were similar to saline injection group. CONCLUSIONS: BTX-A is effective for temporary elimination of hyperfunctioning sialorrhea via inhibition of VIP release which plays a key role in modulation of parotid glands secretion.

Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.

PURPOSE: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP). EXPERIMENTAL DESIGN: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. RESULTS: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels. CONCLUSION: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.