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In modern warship, coordinated combat strategies require missiles hit targets simultaneously, sometimes even require angle constraints, which is difficult to replicate in three-dimensional (3-D) models. This paper proposes a novel 3-D sliding mode guidance law with multiple constraints. First, the 3-D no-thrust guidance model is derived in the coordinate system with Y -axis upward. Second, a novel guidance strategy is proposed. In pitch direction, a fast nonsingular sliding mode surface algorithm is proposed to satisfy the desired line-of-sight elevation angle. In yaw direction, based on the guidance conditions, a special sliding mode surface is proposed, which can achieve desired line-of-sight azimuth angle and desired impact time when reaching the sliding surface. Finally, simulations and comparisons verify the good performance. [ABSTRACT FROM AUTHOR]

Cultivated land intensive utilization (CLIU) exhibits spatial heterogeneity that is influenced by both natural and anthropogenic factors, with land dissected into different scale systems; however, CLIU has not yet been systematically explored. This study takes the Beibu Gulf urban agglomeration, a national-level model area for integrated land and sea development in China, as an example to investigate the spatial heterogeneity of CLIU and explore its driving factors through multiple econometrical and geographical methods, including identifying its underlying mechanisms. The results indicate that (1) the CLIU index is 0.334, its Gini coefficient is 0.183, and its comprehensive level has a low intensity and obvious spatial nonequilibrium characteristics. Hypervariable density (50.33%) and the intraprovincial gap (45.6%) are the main sources. (2) Among the independent effects of single factors, the multiple cropping index (0.57), labor force index (0.489), and intensification of construction land (0.375) exert the most influence on CLIU spatial variation. The interaction effects of two factors primarily manifested as nonlinear enhancements, with the interaction between the labor force index and multiple cropping index being particularly noteworthy (0.859). (3) The geographically weighted regression coefficients reveal that temperature (0.332), multiple cropping index (0.211), and labor force index (0.209) have relatively large and positive impacts on CLIU, while slope (−0.1), precipitation (−0.087), and population urbanization (−0.039) have relatively small and negative impacts; all factors exhibit spatial nonstationarity. The spatial heterogeneity of CLIU in the Beibu Gulf urban agglomeration is characterized by patterns' nonequilibrium and factors' nonstationarity. The driving mode of multiple factors on CLIU is manifested as follows: natural factors of cropland utilization provide basic guarantees, internal factors of CLIU provide positive enhancement, and external factors of land intensive utilization provide auxiliary promotion. [ABSTRACT FROM AUTHOR]

The Internet of Vehicles (IoV) autonomous driving technology based on deep learning has achieved great success. However, under the tunnel environment, the computer vision‐based IoV may fail due to low illumination. In order to handle this issue, this paper deploys an image enhancement module at the terminal of the IoV to alleviate the low illumination influence. The enhanced images can be submitted through IoT to the cloud server for further processing. The core algorithm of image enhancement is implemented by a dynamic graph embedded transformer network based on federated learning which can fully utilize the data resources of multiple devices in IoV and improve the generalization. Extensive comparative experiments are conducted on the publicly available dataset and the self‐built dataset which is collected under the tunnel environment. Compared with other deep models, all results confirm that the proposed graph embedded Transformer model can effectively enhance the detail information of the low‐light image, which can greatly improve the following tasks in IoV. [ABSTRACT FROM AUTHOR]

Background: MicroRNA-155 has been discussed as a biomarker in cancer diagnosis and prognosis. Although relevant studies have been published, the role of microRNA-155 remains uncertain because of insufficient data. Methods: We conducted a literature search in PubMed, Embase, and Web of Science databases to obtain relevant articles and extract data to evaluate the role of microRNA-155 in cancer diagnosis and prognosis. Results: The pooled results showed that microRNA-155 presented a remarkable diagnostic value in cancers (area under the curve = 0.90, 95% confidence interval (CI 0.87–0.92; sensitivity = 0.83, 95% CI 0.79–0.87; specificity = 0.83, 95% CI 0.80–0.86), which was maintained in the subgroups stratified by ethnicity (Asian and Caucasian), cancer types (breast cancer, lung cancer, hepatocellular carcinoma, leukemia, and pancreatic ductal adenocarcinoma), sample types (plasma, serum, tissue), and sample size (n >100 and n <100). In prognosis, a combined hazard ratio (HR) showed that microRNA-155 was significantly associated with poor overall survival (HR = 1.38, 95% CI 1.25–1.54) and recurrence-free survival (HR = 2.13, 95% CI 1.65–2.76), and was boundary significant with poor progression-free survival (HR = 1.20, 95% CI 1.00–1.44), but not significant with disease-free survival (HR = 1.14, 95% CI 0.70–1.85). Subgroup analyses in overall survival showed that microRNA-155 was associated with poor overall survival in the subgroups stratified by ethnicity and sample size. However, the significant association was maintained in cancer types subgroups of leukemia, lung cancer, and oral squamous cell carcinoma, but not in colorectal cancer, hepatocellular carcinoma, and breast cancer, and was maintained in sample types subgroups of bone marrow and tissue, but not in plasma and serum. Conclusions: Results from this meta-analysis demonstrated that microRNA-155 was a valuable biomarker in cancer diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

Background: Mainland China has the most smartphone users worldwide, especially among college students, while mindfulness intervention can significantly alleviate the level of problematic smartphone use. We examined the effects of a brief mindfulness intervention on problematic smartphone use and investigated if this effect is mediated by self-control. Methods: Participants were recruited randomly from a university in Beijing of China. Forty-four college students were assigned to a mindfulness group or a control group. The mindfulness group took part in a brief (30 min) single-session mindfulness intervention. The control group was instructed to listen to a neutral news audio recording for the same duration (30 min). The Freiburg Mindfulness Inventory, Mobile Phone Addiction Tendency Scale, and Self-control Scale were used to measure state mindfulness, problematic smartphone use, and self-control of college students at pre-intervention and post-intervention, respectively. Results: Two-way repeated-measures ANOVA revealed that the mindfulness group had significant improvements in state mindfulness (p =.049) and self-control (p =.012), and had significant alleviation in problematic smartphone use (p <.001) at post-intervention. In the regression model, self-control had a mediating effect between mindfulness intervention and problematic smartphone use (95% CI [0.490, 7.216]). Conclusions: A brief single-session mindfulness intervention can alleviate the level of problematic smartphone use and increase the level of state mindfulness and self-control compared to the control group. Self-control can completely mediate the efficacy of the mindfulness intervention in reducing problematic smartphone use. [ABSTRACT FROM AUTHOR]

Background: Inflammation proteins play an important role in stroke occurrence. IL1A, IL1B, PTGS2, MMP2, and MMP9 were the mediators involved in the immune response, and the association of these genetic variations with ischemic stroke (IS) risk was still unclear. Methods: To investigate the susceptibility of genetic variations of IL1A, IL1B, PTGS2, MMP2, and MMP9 to IS risk, we performed a case–control study involving 299 patients and 300 controls in a Chinese population. Thirteen genetic variations of investigated genes of all participants were genotyped using an improved multiplex ligase detection–reaction technique. Results: No SNP in all genes showed an association with overall IS. However, in subgroup analysis, PTGS2 rs689466 (dominant model: CT vs TT – ORadjusted= 2.51, 95% CI: 1.22– 5.16, p = 0.012; co-dominant model: CT/CC vs TT – ORadjusted= 2.53, 95% CI: 1.26– 5.07, p = 0.009; additive model – ORadjusted= 2.26, 95% CI: 1.19– 4.28, p = 0.013) and rs5275 (dominant model: GG vs AA – ORadjusted= 0.31, 95% CI: 0.12– 0.80, p = 0.016; co-dominant model: GA/GG vs AA – ORadjusted= 0.45, 95% CI: 0.21– 0.95, p = 0.036; additive model – ORadjusted= 0.60, 95% CI: 0.39– 0.92, p = 0.020) were associated with IS type of small-vessel occlusion. Conclusion: Our study suggested that PTGS2 rs689466 C and rs5275 A were potentially associated with IS subtype of small-vessel occlusion. Our result should be confirmed with further large sample sized studies. [ABSTRACT FROM AUTHOR]

Background. Flow is characterized by the strong concentration in competitions, eliminating irrelevant thoughts and emotions, integrating all tasks, and continuing the competition smoothly even in challenging situations. The present study was into whether or not brief mindfulness training can improve athletes' flow and further explore the mediating effect of resilience in the intervention. Methods. The 2 (experimental conditions) × 2 (time) mixed design was used in this study. Fifty-seven student-athletes were recruited and randomly assigned into either a brief mindfulness group (n = 29) or a control group (n = 28). Before and after the intervention, every participant completed a self-report measure including mindfulness, flow, and resilience. Results. Participants in the brief mindfulness group showed increased mindfulness, flow, and resilience (p < 0.001) after brief mindfulness training; when putting resilience change (B = 0.30, 95% CI [0.031, 0.564]) into the equation, the direct (95% CI [3.156, 13.583]) and indirect (95% CI [0.470, 5.048]) effects of mindfulness training were both significant. Conclusion. It was concluded that brief mindfulness training could significantly improve athletes' flow and resilience, and resilience partly mediated the effects of brief mindfulness training on flow. [ABSTRACT FROM AUTHOR]

Aim: To investigate the behavioral deficits, cognitive impairment and possible mechanisms induced by chronic unpredictable stress (CUS) in mice of different ages. Methods: The behaviors and cognition were tested using the open field test, tail suspension test and the Morris water maze. The changes in the insulin-like growth factor II (IGF-II) and the extracellular signal-regulated kinase (ERK) and phosphorylation (p-ERK) in the hippocampus (HP) and prefrontal cortex (PFC) were evaluated by immunohistochemistry. Results: The 15-month-old mice revealed a significant decline in spontaneous behavior and the learning–memory function and showed a decrease in IGF-II and p-ERK expression levels in HP and PFC. Four weeks of CUS exposure induced significant anxiety- and depression-like behavior and learning–memory function impairment in 3- to 15-month-old mice, and reduced IGF-II and p-ERK expression levels in HP and PFC, compared with control group mice, respectively. Conclusions: The behavioral deficits and cognitive impairment induced by CUS and aging in mice could be associated with the down-regulated expression of IGF-II and p-ERK in HP and PFC. This role seems to be dependent on the intracellular ERK pathway. [ABSTRACT FROM AUTHOR]

Manual annotation of sentiment lexicons costs too much labor and time, and it is also difficult to get accurate quantification of emotional intensity. Besides, the excessive emphasis on one specific field has greatly limited the applicability of domain sentiment lexicons (Wang et al., 2010). This paper implements statistical training for large-scale Chinese corpus through neural network language model and proposes an automatic method of constructing a multidimensional sentiment lexicon based on constraints of coordinate offset. In order to distinguish the sentiment polarities of those words which may express either positive or negative meanings in different contexts, we further present a sentiment disambiguation algorithm to increase the flexibility of our lexicon. Lastly, we present a global optimization framework that provides a unified way to combine several human-annotated resources for learning our 10-dimensional sentiment lexicon SentiRuc. Experiments show the superior performance of SentiRuc lexicon in category labeling test, intensity labeling test, and sentiment classification tasks. It is worth mentioning that, in intensity label test, SentiRuc outperforms the second place by 21 percent. [ABSTRACT FROM AUTHOR]

The rapid industrial development has led to the intermittent outbreak of pm2.5 or haze in developing countries, which has brought about great environmental issues, especially in big cities such as Beijing and New Delhi. We investigated the factors and mechanisms of haze change and present a long-term prediction model of Beijing haze episodes using time series analysis. We construct a dynamic structural measurement model of daily haze increment and reduce the model to a vector autoregressive model. Typical case studies on 886 continuous days indicate that our model performs very well on next day’s Air Quality Index (AQI) prediction, and in severely polluted cases (AQI ≥ 300) the accuracy rate of AQI prediction even reaches up to 87.8%. The experiment of one-week prediction shows that our model has excellent sensitivity when a sudden haze burst or dissipation happens, which results in good long-term stability on the accuracy of the next 3–7 days’ AQI prediction. [ABSTRACT FROM AUTHOR]

Mycobacterium bovis is the causative agent of tuberculosis in a wide range of mammals, including humans. Macrophages are the first line of host defense. They secrete proinflammatory cytokines, such as interleukin-1 beta (IL-1β), in response to mycobacterial infection, but the underlying mechanisms by which human macrophages are activated and release IL-1β following M. bovis infection are poorly understood. Here we show that the ‘nucleotide binding and oligomerization of domain-like receptor (NLR) family pyrin domain containing 7 protein’ (NLRP7) inflammasome is involved in IL-1β secretion and caspase-1 activation induced by M. bovis infection in THP-1 macrophages. NLRP7 inflammasome activation promotes the induction of pyroptosis as well as the expression of tumor necrosis factor alpha (TNF-α), Chemokine (C-C motif) ligand 3 (CCL3) and IL-1β mRNAs. Thus, the NLRP7 inflammasome contributes to IL-1β secretion and induction of pyroptosis in response to M. bovis infection in THP-1 macrophages. [ABSTRACT FROM AUTHOR]

Mycobacterium bovis is the causative agent of tuberculosis in cattle. Infection of macrophages with M. bovis leads to the activation of the 'nucleotide binding and oligomerization, leucine-rich repeat and pyrin domains-containing protein 3' (NLRP3) and 'absent in melanoma 2' (AIM2) inflammasomes, which in turn triggers release of the proinflammatory cytokine interleukin-1β (IL-1β) that contributes to bacterial clearance and plays a crucial role in the host defense. However, NLRP3 and AIM2 inflammasome activation is influenced by several factors and how IL-1β secretion by M. bovis-infected macrophages is regulated via the inflammasome pathway remains unclear. Here we found that IL-1β secretion and pro-IL-1β protein accumulation were inhibited in THP-1 macrophages upon exposure to the virulent M. bovis Beijing strain in the presence of high K concentrations, cycloheximide (a protein synthesis inhibitor) and PR-619 (a deubiquitinating enzyme inhibitor). Scavenging reactive oxygen species (ROS) induced by N-acetylcysteine reduced IL-1β release independent of the mitochondrial permeability transition. Collectively, our results suggest that IL-1β secretion by M. bovis-infected THP-1 macrophages is reduced by high extracellular K concentration, inhibition of new protein synthesis, deubiquitination, and ROS generation. [ABSTRACT FROM AUTHOR]

Prion diseases are known as neurodegenerative diseases of the central nervous system with a long incubation period. Alzheimer's disease (AD) and prion diseases share the hallmark of severe neuronal loss, although their pathogenic mechanisms are similarly incomplete. It appears that these two neurodegenerative diseases share a complex deterioration of function involved in the onset of neuronal loss. To investigate presymptomatic biochemical changes indicative of the initial stage of prion diseases and decipher the pathophysiological mechanisms of these two neurodegenerative diseases, we performed a differential proteomic analysis on brain tissues of 263K-infected hamsters during the presymptomatic period and transgenic APPSWE, PSEN1dE9 mice (a mouse model of AD). We identified 7 differentially expressed proteins including the β-soluble N-ethylmaleimide-sensitive factor attachment protein (β-SNAP) by 2-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The β-SNAP expression patterns in the brains of cases and controls were further quantified by Western blotting. β-SNAP showed an early decrease followed by a progressive depletion. The expression of β-SNAP was also significantly downregulated in the mouse model of AD. β-SNAP is brain-specific and known to bind to the SNAP receptors and is therefore involved in the control of neurotransmitter release as well as in constitutive vesicular transport. Our results suggest that presynaptic failure and abnormalities in neurotransmission may be early events in the development of neuronal dysfunction. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Streptococcus suis serotype 2 is an important zoonotic pathogen. Antimicrobial resistance phenotypes and genotypic characterizations of S. suis 2 from carrier sows and diseased pigs remain largely unknown. In this study, 96 swine S. suis type 2, 62 from healthy sows and 34 from diseased pigs, were analyzed. High frequency of tetracycline resistance was observed, followed by sulfonamides. The lowest resistance of S. suis 2 for β-lactams supports their use as the primary antibiotics to treat the infection of serotype 2. In contrast, 35 of 37 S. suis 2 with MLSB phenotypes were isolated from healthy sows, mostly encoded by the ermB and/or the mefA genes. Significantly lower frequency of mrp+/epf+/sly+ was observed among serotype 2 from healthy sows compared to those from diseased pigs. Furthermore, isolates from diseased pigs showed more homogeneously genetic patterns, with most of them clustered in pulsotypes A and E. The data indicate the genetic complexity of S. suis 2 between herds and a close linkage among isolates from healthy sows and diseased pigs. Moreover, many factors, such as extensive use of tetracycline or diffusion of Tn916 with tetM, might have favored for the pathogenicity and widespread dissemination of S. suis serotype 2. [ABSTRACT FROM AUTHOR]

Prion diseases are neurodegenerative disorders characterized by the accumulation of a disease-associated prion protein and apoptotic neuronal death. Previous studies indicated that the ubiquitous expression of c-Abl tyrosine kinase transduces a variety of extrinsic and intrinsic cellular signals. In this study, we demonstrated that a synthetic neurotoxic prion fragment (PrP106-126) activated c-Abl tyrosine kinase, which in turn triggered the upregulation of MST1 and BIM, suggesting the activation of the c-Abl-BIM signaling pathway. The peptide fragment was found to result in cell death via mitochondrial dysfunction in neuron cultures. Knockdown of c-Abl using small interfering RNA protected neuronal cells from PrP106-126-induced mitochondrial dysfunction, production of reactive oxygen species, and apoptotic events inducing translocation of Bax to the mitochondria, cytochrome c release into the cytosol, and activation of caspase-9 and caspase-3. Blocking the c-Abl tyrosine kinase also prevented neuronal cells from PrP106-126-induced apoptotic morphological changes. This is the first study reporting that c-Abl tyrosine kinase as a novel upstream activator of MST1 and BIM plays an important role in prion-induced neuron apoptosis via mitochondrial dysfunction. Our findings suggest that c-Abl tyrosine kinase is a potential therapeutic target for prion disease. [ABSTRACT FROM AUTHOR]

This review is primarily a follow up to an initial review on this subject that the authors published 4 years ago [Lubet et al., Exp Lung Res. 2000; 581-593]. The present review gives a brief discussion of certain background points and rationale for development of these specific models, which had been presented in greater detail in the earlier article. In that initial article the authors identified the potential use of mutant mice in screening for carcinogens as well as preventive or therapeutic agents, discussed the relevance of the dominant-negative P53 mutation, as contrasted with knockout P53 mice, and briefly discussed the pros and cons of mice with a germline mutation in tumor suppressor genes in developing mouse models. The primary objective of the present review is to describe more recent studies using mice the dominant-negative P53 mutation as well as to introduce studies with mice with a heterozygous knockout of the P16/Ink4A ARF locus. [ABSTRACT FROM AUTHOR]

To determine if: (1) 5' CpG island methylation is related to Fhit inactivation; (2) there are tumor or carcinogen-specific methylation patterns, we examined 35 CpG sites in the promoter, exon and intron 1 of the mouse Fhit gene. In primary tumors of lung, urinary bladder and tongue, induced by different carcinogens, 15-35% of sites were methylated, with specific methylation patterns associated with each cancer type, suggesting cancer- or tissue-specific methylation patterns. The methylation patterns were associated with reduced Fhit expression, as determined by immunohistochemical analyses. Methylation of rat Fhit 5' CpGs in mammary adenocarcinomas, detected by methylation specific PCR amplification, also correlated with reduced gene expression. Thus, there was an overall association between promoter/exon 1 methylation and decreased Fhit expression. In contrast, in cancer-derived cell lines 70-95% of the CpG sites were methylated. This is the first detailed study of the relationship between Fhit 5' CpG island methylation and Fhit expression in murine tumors, our main models for preclinical cancer studies, and provides evidence that loss of Fhit expression and methylation are correlated in these mouse models and these models will be useful to examine the complex relationships among gene expression, methylation patterns and organ specificity. [ABSTRACT FROM AUTHOR]

Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants. Previously, clinical studies have shown a significant chemo-preventive efficacy of ATB against human esophageal and lung cancers. In the present study, A/J mice harboring a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf and treated with benzo[a]pyrene were used to investigate the chemopreventive effects of ATB on chemically induced lung tumorigenesis. Mice with various genotypes treated with ATB displayed a significant reduction in lung tumor multiplicity and tumor load. Treatment with ATB resulted in an approximately 40% decrease in tumor multiplicity and a 70% decrease in tumor load in both wild-type mice and in mice with a loss of the Ink4a/Arf tumor suppressor genes. Interestingly, ATB decreased tumor multiplicity and volume by 50 and 90%, respectively, in mice with a dominant-negative p53 and in mice with both a p53 mutation and deletion of Ink4a/Arf. Kras2 mutation analysis of the lung tumors revealed that tumors harbored mutations in the 12th codon of Kras2. There were no differences in either the incidence or types of mutations between tumors treated with or without ATB. Oligonucleotide array analysis revealed 284 genes that were differentially expressed in mouse lung tumors as compared to the normal lung, and it was found that 114 out of these 284 genes changed their expression toward the normal levels in tumors treated with ATB. Most of the genes modulated by ATB belong to several cellular signaling pathways, including Notch (Notch homolog 2, manic fringe homolog), growth factor (FGF intracellular-binding protein, PDGFoc), G protein-Ras-MAPK (MAPK3, MAP3K4, rab3A, Rapi, RSGS, PKCO), ubiquitin-proteasome (CDC34, Cullinl, 26S proteasome), and apoptosis (BAD promoter, caspase 3). These results suggest that ATB is an effective chemopreventive against mouse lung tumorigenesis. Furthermore, ATB exhibited an enhanced inhibitory effect in animals harboring genetic alterations (Kras2, p53, and Ink4a/Arf), which are often seen in human ling adenocarcinomas. [ABSTRACT FROM AUTHOR]

Demonstrates chemoprevention of lung adenocarcinoma in transgenic mice. Classes of chemopreventive agents; Chemotherapeutic agents; Tumor suppressor genes; Drug efficacy rate; Glucocorticoids; Role of p53 in lung tumorigenesis; Tumor volume; Effects of budenoside on farnesyltransferase inhibitors; Tumor multiplicity.

Pulmonary adenoma susceptibility 1 (Pas1), located on chromosome 6, is the major locus affecting inherited predisposition to lung tumor development in mice. We have fine mapped the Pas1 locus to a region of ≃0.5 megabases by using congenic strains of mice, constructed by placing the Pas1 region of chromosome 6 from A/J mice onto the genetic background of C57BL/6J mice. Systematic characterization of Pas1 candidates establishes the Las1 (lung adenoma susceptibility 1) and Kras2 (Kirsten rat sarcoma oncogene 2) genes as primary candidates for the Pas1 locus. Clearly, Kras2 affects lung tumor progression only, and Las1 is likely to affect lung tumor multiplicity. [ABSTRACT FROM AUTHOR]

Previous observation has shown that the wild-type Kras2 allele is a suppressor of lung cancer in mice. Here we report that loss of heterozygosity (LOH) of chromosome 12p was detected in ~50% of human lung adenocarcinomas and large cell carcinomas, and Kras2 mutations were detected at codon 12 in ~40% of adenocarcinomas and large cell carcinomas. Interestingly, all of the lung adenocarcinomas and large cell carcinomas containing a Kras2 mutation exhibited allelic loss of the wild-type Kras2 allele when a correlation between LOH of the region on chromosome 12p and Kras2 mutation was made. These results from human lung cancer tissues provide a strong evidence in support of our previous observation in mouse models that the wild-type Kras2 is a tumor suppressor of lung cancer.Oncogene (2003) 22, 1243-1246. doi:10.1038/sj.onc.1206192 [ABSTRACT FROM AUTHOR]

Although the ras genes have long been established as proto-oncogenes, the dominant role of activated ras in cell transformation has been questioned. Previous studies have shown frequent loss of the wildtype Kras2 allele in both mouse and human lung adenocarcinomas. To address the possible tumor suppressor role of wildtype Kras2 in lung tumorigenesis, we have carried out a lung tumor bioassay in heterozygous Kras2-deficient mice. Mice with a heterozygous Kras2 deficiency were highly susceptible to the chemical induction of lung tumors when compared to wildtype mice. Activating Kras2 mutations were detected in all chemically induced lung tumors obtained from both wildtype and heterozygous Kras2-deficient mice. Furthermore, wildtype Kras2 inhibited colony formation and tumor development by transformed NIH/3T3 cells and a mouse lung tumor cell line containing an activated Kras2 allele. Allelic loss of wildtype Kras2 was found in 67% to 100% of chemically induced mouse lung adenocarcinomas that harbor a mutant Kras2 allele. Finally, an inverse correlation between the level of wildtype Kras2 expression and extracellular signal-regulated kinase (ERK) activity was observed in these cells. These data strongly suggest that wildtype Kras2 has tumor suppressor activity and is frequently lost during lung tumor progression. [ABSTRACT FROM AUTHOR]

The studies presented were designed to test the efficacy of farnesyltransferase inhibitors (FTIs) as potential chemopreventive compounds in the mouse lung tumor model, and in tumor cell lines. The compounds included manumycin, gliotoxin, dihydroepiandrosterone (DHEA), perillyl alcohol (POH), and FTI-276. Each of these compounds had the potential, based on in vitro and limited in vivo evidence, to inhibit mouse lung tumorigenesis. In vitro studies were conducted with both K-ras-transformed NIH-3T3 cells and mouse lung tumor epithelial cell lines. Weutilized 2 primary mouse lung tumor models that reliably produce lung tumors with an oncogenic K-ras mutation when induced by 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK). Manumycin, gliotoxin, DHEA, and POH were administered 3 times per week peritoneally (IP), starting 1 week prior to carcinogen treatment, and throughout the test period (4.5 months). FTI-276 was delivered daily for 4 months by a time-release pellet method. Both the manumycin and gliotoxin treatment groups demonstrated 100% incidence and an increase in tumor multiplicity over control, of 66% and 58% increase respectively (P<.05). Although DHEA showed no significant chemopreventive effect, POH treatment demonstrated a 22% reduction in tumor incidence (P<.05) and a 58% reduction in tumor multiplicity (P<.05). Finally, FTI-276 reduced both the tumor multiplicity by 41.7% (P <.005), and the total tumor volume/burden per mouse by 79.4% (P<.0001). The apoptotic index in FTI-276-treated tumors showed an increase of 77% over control tumors (P<.05). In vitro, all compounds demonstrated growth inhibition at a dose-response manner; however, manumycin, gliotoxin, and DHEA demonstrated an initial increase in growth rate at lower doses. In summary, we have shown that POH and FTI-276 are chemopreventive in a primary mouse lung tumor model. In contrast, DHEA was not significantly chemopreventive at the dosage utilized, and treatment of an immunocompetent host with manumycin or gliotoxin demonstrated a significant increase in tumorigenicity over carcinogen control. [ABSTRACT FROM AUTHOR]

The tumor suppressor gene p53 is perhaps the most commonly mutated gene in human cancer, being mutated in a high percentage of colon, breast, skin, bladder, and many cancers of the aerodigestive tract. Individuals with Li-Fraumeni syndrome, who routinely have a germline mutation in the p53 tumor suppressor gene, are at high risk for lung cancer, confirming its intimate role in lung tumorigenesis in humans. In contrast, the majority of chemically induced or spontaneous cancers in rodents do not contain mutations in p53. Therefore, we examined a transgenic mouse that contains a dominant negative mutation (Arg135Val) in the p53 gene placed under the control of its own endogenous promoter. The resulting mice have 3 copies of the mutated transgene as well as 2 normal p53 alleles. In the chemical carcinogenesis studies, we employed mice containing the mutated p53 gene to examine for carcinogen susceptibility. We found that mice with the p53 mutation, on an A/JF1 background, were more susceptible to a number of potential lung carcinogens, including N-methyl-N-nitrosourea (MNU) and the known tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK) and benzo(a)pyrene (BP). Mice with a mutant p53 developed larger tumors and roughly 3 times as many tumors, emphasizing the potential effects of a p53 mutation both on tumor initiation and progression. In addition, we examined 2 nonlung carcinogens, 1,2-dimethylhydrazine (DMH), a colon carcinogen, and Nbutyl-N-(4-hydroxybutyl)-nitrosamine(OHBBN),a bladder carcinogen. Interestinglya germlinep53 mutation increased the incidence of DMH-induced colon, lung, hepatic, and uterine tumors, while having limited effects on OHBBN-induced bladder tumors. Because of its heightened susceptibility we are examining the use of this model in smoke-induced tumorigenesis in A/Jmice as well. Employing the lung adenomas induced by NNK, we found that mice with or without a p53 mutation were equally susceptible to the chemopreventive effects of dexamethasone plus myo-inisitol and green tea. These tumors, which arise in a highly reproducible manner in p53 transgenic mice following carcinogen treatment, have mutations in both p53 and the K-ras oncogene. Thus, this model appears useful for examining for potential chemotherapeutic agents. p53-mutated or wild-type mice were equally susceptible to the therapeutic effects of Taxol or Adriamycin. Interestingly, piroxicam was similarly effective in inhibiting colon tumor formation by DMH in mice with or without a mutation in the p53 tumor suppressor gene. In contrast, lung and uterine tumors developing in these mice were not susceptible to the chemopreventive effects of piroxicam. In summary, mice with mutations in the p53 tumor suppressor gene appear to be particularly applicable for basic mechanistic studies, for screening for potential carcinogens, and for screening for chemopreventive or chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

The Ras protein undergoes a series of post-translational modifications at the C-terminal CAAX motif, which culminates with the anchoring of p21 Ras to the plasma membrane where it relays growth regulatory signals from receptor tyrosine kinases to various pathways of cell signal transduction. FTI-276 is a CAAX peptidomimetic of the carboxyl terminal of Ras proteins. Pharmacokinetic analysis of FTI-276 in A/J mice with a time-release pellet system showed a dose of 50 mg/kg body wt achieved an average serum level of 1.68 μg/ml for up to 30 days following implantation. In the present study, 4 week old A/J mice were initiated with a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (100 mg/kg), and monitored for 18 weeks. Mice were grouped for daily delivery (time-release pellet) of 50 mg/kg of FTI-276 for 30 days (n = 12) and the control group (n = 12). Analysis of tumors from time-release pellet treated animals showed a 60% reduction in tumor multiplicity and a 42% reduction in tumor incidence. Moreover, FTI-276 treatment resulted in a significant reduction in tumor volume (~58%). Mutation analysis of the lung tumors from both treatment groups revealed that most of the tumors harbored mutations in the codon 12 of K-ras and there is no significant difference in the incidence and types of mutations between tumors from the treated and control animals. This is the first demonstration of chemotherapeutic efficacy of a synthetic CAAX peptidomimetic farnesyltransferase inhibitor in a primary lung tumor model. [ABSTRACT FROM PUBLISHER]

In a number of recent studies, a lung tumor resistance locus designated either Par2 or Pas7 was mapped to distal chromosome 18 in crosses between susceptible A/Jand more resistant BALB/c mice. This locus is important in that it accounts for as much as 60&percnt; of the difference in lung tumor susceptibility between the A/J and BALB/c mice, both of which contain the susceptible allele of Kras2, a marker and strong candidate for the major lung tumor susceptibility gene on mouse chromosome 6. We have now fine-mapped the Par2 locus by using congenic mice that were constructed by placing part of chromosome 18 from the susceptible A/Jonto the genetic background of lung tumor–resistant BALB/c mice. After 7 generations of backcrossing, N7 mice that carried 28 cM of the A/Jquantitative trait locus (QTL) region were crossed to the BALB/c to generate the N8 generation. Congenic strains (N8) that contain various QTL regions were generated. N9 mice, generated from N8 males 3 BALB/c females, were genotyped in the region of the Par2 locus and treated with an initiating dose of urethane and allowed to form lung tumors over 6 months. The mice were killed and the lung tumors counted. With this cross the Par2 locus was narrowed to a 6-cM region. Potential candidate genes in this region include Smad4, Smad2, and Dcc. Previously, we excluded Smad4 and Smad2 as candidates for Par2 based on the lack of functional polymorphism(s) and differential expression in lungs from A/Jand BALB/c mice. In this study, no polymorphism of the coding sequence of Dcc was observed between A/Jand BALB/c mice. Further fine mapping and positional cloning are required for the identification of the Par2 gene. [ABSTRACT FROM AUTHOR]