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Lung cancer is a heterogeneous and complex disease. Genomic and transcriptomic profiling of lung cancer not only further our knowledge about cancer initiation and progression, but could also provide guidance on treatment decisions. The fact that targeted treatment is most successful in a subset of tumors indicates the need for better classification of clinically related molecular tumor phenotypes based on better understanding of the mutations in relevant genes, especially in those oncogenic driver mutations. EGFR gene mutations, KRAS gene mutations, EML4-ALK rearrangements and altered MET signaling are widely recognized alterations that play important roles in both the biological mechanisms and the clinical sensitivity to treatment in lung cancer. In this article, we reviewed the discovery of the clinical values of these oncogenic driver mutations and the clinical studies revealing the prognostic and predictive values of these biomarkers for clinical sensitivity and resistance to anti-EGFR therapy or other targeted therapies. These form the basis of personalized treatment in lung cancer based on biomarker profiles of individual tumor, leading to therapeutic advancement and betterment.
Keywords:Lung cancer; Driver mutations; EGFR; ALK
Lung cancer is the leading cause of cancer-related death worldwide. In the past, therapeutic decisions have been based on histological classifications, which distinguish small cell lung cancers (SCLC) and non-small cell lung cancer (NSCLC). The latter comprises three major subtypes: squamous cell carcinoma, large cell carcinoma, and adenocarcinoma [1]. Although the histological features have been proven to play an important role in the selection of chemotherapy [1], the overall survival remains very poor as a result of presentation of disease at advanced stage.
A diversity of genomic and epigenetic abnormalities has been reported in NSCLC. Oncogenic driver mutations refer to mutations that are responsible for both the initiation and maintenance of the cancer. These mutations are often found in genes that encode for signaling proteins that are critical for maintaining normal cellular proliferation and survival. The presence of mutations on these genes will confer growth advantage on cancer cells, favoring their being selected during tumor progression [2]. NSCLC, especially lung adenocarcinomas, can be further sub-classified by their genetic mutation profiles, making personalized treatment strategies based on the identification of oncogenic driver mutations feasible.
Epidermal Growth Factor Receptor (EGFR) gene mutations were the first targets for targeted treatment in NSCLC. Clinical efficacy and outcomes of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been reviewed thoroughly [3-7]. Deletions in exon 19 and the missense mutation L858R or L861Q in exon 21 exhibit an association with favorable response to reversible EGFR-TKIs whereas the secondary mutation T790M in exon 20 and insertions in exon 20 will confer resistance to gefitinib and erlotinib, while the nature and clinical sensitivity of other less common mutations like those mutations in exon 18 in the tyrosine kinase (TK) domain of EGFR are not well defined [8].
Apart from EGFR targeted therapy, more molecular targeted agents have developed to improve therapeutic outcomes, for example, bevacizumab which is an angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) [9], pemetrexed inhibiting thymidylate synthase and other folate dependent enzymes [10], as well as a mammalian target of rapamycin (mTOR) inhibitor everolimas [11]. Meanwhile, other oncogenic mutations that can define clinically relevant molecular subsets of NSCLC have been identified. The presence of individual driver gene is usually found to be mutually exclusive to each other. In this article, we review the four commonly known oncogenic driver mutations in lung cancer – EGFR mutations at exons 18 – 21, KRAS gene mutation at codons 12 and 13, EML4-ALK fusion genes and deregulation of MET signaling.
EGFR mutations
The epidermal growth factor receptor family of tyrosine kinases consists of four forms: EGFR (ErbB1, HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4) [6]. The binding of specific ligands leads to homo- and hetero-dimerization, with subsequent autophosphorylation of the intracellular receptor TK domain. The activated TK activity subsequently recruits appropriate downstream components of the TK signaling pathway which are involved in multiple cellular processes, including cell proliferation, cell survival, cell motility and cell invasion [12].
EGFR mutations have been extensively studies in NSCLC with about 27% overall incidence (according to COSMIC database, http://www.sanger.ac.uk webcite). EGFR-mutant NSCLC, which often exhibits adenocarcinoma histology, has been found to be associated with a better prognosis compared to EGFR wild-typed NSCLC in most populations [13-18], except for a study in Chinese patients [19]. The activating EGFR mutations have been identified in exons 18 to 21 of the TK domain, about 90% of which are deletions in exon 19 (Figure 1) and the point mutation L858R in exon 21 (Figure 2) [6]. The mutant EGFR shows a preferential binding of gefitinib or erlotinib to ATP, thus correlating with higher sensitivity to these two anti-EGFR TKIs [20,21]. Several trials have revealed the clinical role of activating EGFR mutations in EGFR-TKI therapy. A randomized prospective Phase III study (NEJ002) with 230 Japanese advanced, untreated and EGFR-mutant NSCLC patients sustained improved progression-free survival in the first-line gefitinib versus standard chemotherapy [22]. According to a study in Spain, erlotinib also showed similar effectiveness in EGFR-mutant patients [23].
Figure 1. Analysis of EGFR exon 19 mutation by direct sequencing. (A) Wild-type EGFR exon 19; (B) An example of inframe deletion in EGFR exon 19 (2481_2495del). The arrows indicate the span of deletion in each amplified sequence of exon 19.
Figure 2. EGFR exon 21 mutation analysis via direct sequencing. (A) Wild-type EGFR exon 21; (B) One missense mutation (L858R) in EGFR exon 21. The arrow indicates the position of the mutant nucleotide. Only forward sequences are shown.
Some EGFR mutations, although they occur in exons 18 to 21, are related to primary resistance to EGFR-TKIs, for example, small insertions or duplications in exon 20. Additionally, the presence of other types of mutations can induce acquired resistance to EGFR inhibitors, such as T790M (exon 20), L747S (exon 19), D761Y (exon 19) and T854A (exon 21) [24]. Other genetic alterations contribute to primary or acquired resistance to EGFR-TKIs, including KARS mutations, PIK3CA mutations, loss of PTEN function, MET amplification and altered EGFR-related signaling [25]. Therefore, strategies to overcome resistance to EGFR-TKIs have been under investigation, including development of second- and third-generation of EGFR-TKIs, combinational therapy targeting compensatory pathways, alternative TKI dosing to delay drug resistance, or continuation therapy with EGFR-TKIs [13,25].
Apart from erlotinib and gefitinib, second-generation irreversible EGFR-TKIs have been under extensive investigation, for example, afatinib and dacomitinib. Afatinib (BIBW 2992; Boehringer Ingelheim; Ingelheim, Germany) is a highly selective and irreversible inhibitor of both EGFR and HER2[26]. It has been found to be effective in NSCLC with EGFR mutations, especially with de novo T790M mutations [27]. Several phase III trials of afatinib are undergoing, including LUX-Lung 3), in which afatinib is compared to cisplatin/pemetrexed in the first-line treatment of advanced NSCLC patients with activating EGFR mutations, as well as LUX-Lung 6 comparing afatinib with cisplatin/gemcitabine in the same population as LUX-Lung 3 with more recruitment in China, India and South Korea. Dacomitinib (PF-00299804, Pfizer; New London, CT, USA) is an irreversible pan-HER inhibitor, which showed remarkable activity to gefitinib-resistant EGFR T790M mutations or HER2 mutations [28]. A phase I/II study of this inhibitor in Asian populations who were refractory to chemotherapy and erlotinib or gefitinib, 15% response rate and 32% 6-month overall survival achieved [29]. Therefore, a randomized phase III trial (JBR-26) comparing dacomitinib to placebo in the third-line treatment in patients have failed chemotherapy and EGFR TKIs is ongoing.
KRAS mutations
A milestone study in 1984 identified a KRAS mutation in a squamous cell lung carcinoma with the absence of this point mutation in the corresponding normal bronchial or parenchymal tissue [30]. Since then KRAS mutations have been found frequently in NSCLC, and according to clinical trials, the incidence of KRAS mutations in NSCLC ranges from 8% to 24% [31]. Most activating KRAS mutations in NSCLC are located in codons 12 or 13, and are also reported in lung adenocarcinomas [32]. The study in which KRAS mutations were analyzed in nearly 500 lung adenocarcinomas showed that KRAS mutations were found in 15%, 22% and 25% of tumors from never smokers, former smokers and current smokers respectively [33]. Whereas EGFR mutations tend to occur more frequently in never-smokers with lung cancer, the presence of KRAS mutations cannot be easily predicted based on smoking status alone [34]. Another novel finding of this study was that KRAS transition mutations were more common in never smokers, whereas former/current smokers were more likely to harbor KRAS transversion mutations. This implies that transversions may be smoking related.
The mutated KRAS proteins exhibit impaired GTPase activity, resulting in constitutive activation of RAS signaling. Since KRAS is downstream of EGFR, constitutive activation of KRAS renders resistance to anti-EGFR therapy. Many studies have observed lower efficacy of EGFR-TKI therapy in KRAS mutated NSCLC patients [35,36]. The presence of EGFR mutations and KRAS mutations are mutually exclusive in the same tumor. However, there was a report on a case series of three patients with both activating EGFR mutations and KRAS mutations demonstrated that all EGFR+/KRAS+ patients showed a positive response to gefitinib or erlotinib [37]. Several large clinical observational studies failed to identify KRAS mutation to be a significant response predictor to EGFR-TKIs [38-40]. As a result, KRAS positivity cannot be established as a criterion to exclude NSCLC patients from EGFR-TKI therapy.
The development of therapeutic agents targeting mutated KRAS signaling is under intensive investigation. An obstacle is that mutant KRAS proteins entail loss-of-function. It is more difficult to inhibit loss-of-function proteins than gain-of-function ones like mutant EGFR. Current approaches try either to inhibit protein synthesis of mutated KRAS or to impede downstream effectors of mutant KRAS.
EML4-ALK rearrangement
The anaplastic lymphoma kinase (ALK) protein is a receptor tyrosine kinase in the insulin receptor superfamily. In 2007, Soda et al. identified a small inversion within the short arm of chromosome 2, resulting in the fusion of the N-terminal of the echinoderm microtubule-associated protein-like 4 (EML4) gene with the ALK gene [41]. Up to now, at least 11 different EML4-ALK variants have been reported, all of which involve the coiled-coil domain of EML4 and the intracellular tyrosine kinase domain of ALK[42]. Furthermore, all EML4-ALK variants exhibit dimerization and constitutive activation of the fusion proteins [42,43].
There is no "gold standard" method to screen the ALK gene rearrangements. Three detection technologies have been evaluated, including fluorescence in situ hybridization (FISH), reverse transcriptase PCR, and immunohistochemistry (IHC). The frequency of EML4-ALK fusions in unselected NSCLC patients, according to previous studies mostly with East Asians, ranges from 1.6% to 11.6% [42,44-46]. Although other histological sub-types rarely contain EML4-ALK rearrangements, lung adenocarcinoma has been reported to be the major type showing EML4-ALK translocations. The majority of Caucasian lung adenocarcinoma harboring EML4-ALK show the signet-ring cell histology, whereas the acinar pattern is pre-dominant in ALK-positive Asian adenocarcinomas [47]. ALK-positivity tends to be found in younger NSCLC patients [44]. Similar to EGFR mutations, EML4-ALK fusions are associated with never or light smokers [48]. EML4-ALK translocations and EGFR mutations are mutually exclusive except for rare cases [45].
In Shaw et al. study, wild-type NSCLC patients and ALK-positive NSCLC patients displayed a similar response to chemotherapy and no significant differences in overall survival, however, EML4-ALK translocations have been found to be associated with resistance to EGFR-TKIs [44]. Similarly, EML4-ALK fusion gene was not a significant prognostic factor based on the analysis of 720 resected lung adenocarcinomas [49]. Consistent with these findings, EML4-ALK status did not affect the sensitivity of advanced NSCLC patients to platinum-based combination chemotherapy in terms of response rate and progression-free survival although overall survival of EML4-ALK positive patients tended to be shorter than that of the EGFR mutated cohort nut resembled that in the wild-type cohort [50]. In contrast, according to a study including EGFR wild-type and advanced-stage lung adenocarcinoma patients who received either monotherapy or platinum-doublet chemotherapy, ALK positivity conferred superior overall survival [51]. Compared with aforementioned studies, this study enrolled more EML4-ALK translocated patients (39 out of 116, 34%), which may partially explain better outcome. Additionally, in Chinese patients with advanced NSCLC, response rate to EGFR-TKI was similar between ALK rearranged and EGFR mutated patients although median progression-free survival was significantly shorter in those with EML4-ALK gene [52]. The apparent discrepancy between findings of this study and that of the study by Shaw et al. may be explained by predominantly Asian population in this study and the limited sample sizes in both studies. The clinicopathological features of EML4-ALK rearrangement in NSCLC patients needs further investigation.
In order to treat ALK-positive patients, selective tyrosine kinase inhibitors of ALK are currently under clinical trials, including an ALK/MET inhibitor PF-02341066 (crizotinib) [53]. Unfortunately, acquired resistance will emerge in EML4-ALK-positive tumors. Several secondary mutations in the ALK gene, such as L1196M and C1156Y, have been revealed to contribute to resistance to crizotinib [54,55]. In order to overcome resistance, new molecules continue to be developed. CH5424802, a selective, potent, and orally available ALK inhibitor, have exhibited remarkable activity against C1156Y- and L1196M-resistant EML4-ALK mutants [56]. Clinical trials have been conducted to confirm safety and efficacy of this agent in ALK-positive NSCLC [46].
MET signaling
The MET gene, which is located on chromosome 7, encodes a receptor tyrosine kinase composed of an extracellular α-chain and a transmembrane β-chain. The natural ligand for MET receptor is hepatocyte growth factor (HGF), also called scatter factor (SF). Since MET interacts with numerous downstream effectors, the activation of MET signaling affects many pathways and regulates various cellular processes, including cell proliferation, cell motility, cell scattering, cell invasion, metastasis, angiogenesis and epithelial to mesenchymal transition (EMT) [57-59]. Therefore, it is not surprising that deregulation of this signaling pathway can be considered as a driving force in tumor initiation and tumor maintenance.
In transformed cells, MET can be altered via overexpression, genomic amplification, mutations, or alternative splicing [57,60,61]. These alterations result in aberrant MET activation which can be mediated through HGF-dependent or HGF-independent mechanisms.
MET overexpression has been observed in NSCLC. In a study using 32 lung cancer tissues, all tumor samples expressed MET with no significant MET staining in corresponding normal lung tissues, and 61% (14 of 23) of NSCLC showed strong MET expression examined by IHC. Furthermore, an increase in MET activity identified by higher levels of phosphorylated MET (p-MET) at sites Y1003 and Y1230/1234/1235 came along with MET overexpression in this study. It was also mentionable that the activated p-MET was preferentially expressed in tumor cells located at the invasive front of NSCLC tissues [62]. In another study with 183 lung adenocarcinomas, MET amplification was observed in 8 (4%) patients with wild-typed EGFR and wild-typed KRAS, indicating that the presence of MET gene amplification might be mutually exclusive with EGFR and KRAS mutations. Phosphorylation of MET at sites Y1234/1235 has been found to be associated with poor survival in patients who have complete resection of lung tumors [63].
MET gene copy number variations have also been reported in NSCLC. MET status was analyzed with FISH in 447 NSCLC patients and high MET gene copy number (≥5 copies/cell) was observed in 48 cases (11.1%), and patients with high MET gene copy number (MET-positive) exhibited shorter survival than MET-negative patients [64].
Mutations provide another mechanism for MET dysregulation. Mutated MET allows the kinase to overcome inhibitory mechanisms, thus becoming constructively activated or hyperresponsive to stimuli. Mutations could also prolong the duration of stimulating signals by increasing the level of activation or by preventing the degradation of the kinase. One study examined individual exons of semaphorin, juxtamembrane, and tyrosine kinase domains of MET in 141 East Asians, 76 Caucasians and 66 African Americans [65]. The results showed that MET mutations varied with ethnicity. N375S, occurred within the semaphorin domain, was the most frequent non-synonymous mutation, and the frequency of this mutation was higher in East Asians compared to Caucasians. In both East Asians and Caucasians, the frequency of N375S was higher in squamous cell carcinoma than in other non-small cell lung cancer. Among East Asians, the frequency of N375S in males was much higher compared with females [65]. Since there is a relationship between ethnic differences and MET mutations, greater knowledge of this correlation can help us understand incidence, prognosis and treatment of lung cancer.
Several agents targeting MET signaling are under investigation. Among them, a non-ATP competitive MET inhibitor, tivatinib (ARQ197), has been used in combination with erlotinib (EGFR-TKI) as second-line treatment for previously-treated non-small cell lung cancer [66]. The dual MET-EGFR combinatorial inhibition is well-tolerated in advanced stage lung cancer patients. Although no significant change in progression-free survival (PFS) or overall survival (OS) has been reported in the intent-to-treat population, improvement in PFS and/or OS can be seen when including key prognostic factors and/or biomarkers, for example, presence of KRAS mutations. More MET-targeted agents are under preclinical and clinical studies, making MET the next major biomarkers in lung cancer.
Other oncogenic driver mutations
The identification of oncogenic driver mutations reveals the complexity and heterogeneity of NSCLC. A collaborative study investigated 623 candidate cancer genes in 188 lung adenocarcinomas. 26 genes were discovered to be somatically mutated at high frequencies and thus may be related to tumorigenesis, including ERBB3, ERBB4, VEGFR, multiple ephrin receptors genes and NTRK genes [67].
Significance of oncogenic driver mutations in lung cancer severity and therapy
Table 1 lists these four molecular targets with their respective detection methods and inhibitors. The presence of oncogenic driver mutations leads to a phenomenon called 'oncogene addiction' wherein tumor cells tend to be dependent on the specific mutant oncogene for their own survival and growth. Blocking the relevant oncogenic pathway by specific inhibitors may induce 'oncogenic shock' which ultimately results in cancer cell apoptosis [68]. This hypothesis suggests that the promising future of lung cancer treatment is indeed personalized therapy with drugs targeting specific driver oncogenes that "drive" tumorigenesis. The selection of proper therapeutic approach should be based on both histological features and the tumor mutation profiles of individual patient (Figure 3). This combination can contribute to better prediction of the malignant behavior and to improved clinical management. EGFR mutations could be present in early stage NSCLC [69,70], suggesting that it may be possible to detect of lung cancer at more early stages via the molecular testing of mentioned driver mutations in susceptible individuals.
As we further our understanding into the biological mechanisms underlying these oncogenic driver mutations, the clinical relevance of these driver mutations will allow for further advancement into targeted therapeutics in lung cancer.
Authors' contributions
Susan Y Luo (SYL) carried out the molecular tests and drafted the manuscript. David CL Lam (DCL) planned, wrote and reviewed the manuscript. All authors read and approved the final manuscript.
Declaration of competing interests
The authors declare that they have no competing interests.
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Sasaki T, Rodig SJ, Chirieac LR, Jänne PA: The biology and treatment of EML4-ALK non-small cell lung cancer.
Eur J Cancer 2010, 46(10):1773-1780. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Fukui T, Yatabe Y, Kobayashi Y, Tomizawa K, Ito S, Hatooka S, Matsuo K, Mitsudomi T: Clinicoradiologic characteristics of patients with lung adenocarcinoma harboring EML4-ALK fusion oncogene.
Lung Cancer 2012, 77(2):319-325. PubMed Abstract | Publisher Full Text
Takeda M, Okamoto I, Sakai K, Kawakami H, Nishio K, Nakagawa K: Clinical outcome for EML4-ALK-positive patients with advanced non-small-cell lung cancer treated with first-line platinum-based chemotherapy.
Ann Oncol 2012, 23(11):2931-2936. PubMed Abstract | Publisher Full Text
Wu SG, Kuo YW, Chang YL, Shih JY, Chen YH, Tsai MF, Yu CJ, Yang CH, Yang PC: EML4-ALK translocation predicts better outcome in lung adenocarcinoma patients with wild-type EGFR.
J Thorac Oncol 2012, 7(1):98-104. PubMed Abstract | Publisher Full Text
Wang Z, Zhang X, Bai H, Zhao J, Zhuo M, An T, Duan J, Yang L, Wu M, Wang S: EML4-ALK rearrangement and its clinical significance in Chinese patients with advanced non-small cell lung cancer.
Oncology 2012, 83(5):248-256. PubMed Abstract | Publisher Full Text
Ou SH, Bazhenova L, Camidge DR, Solomon BJ, Herman J, Kain T, Bang YJ, Kwak EL, Shaw AT, Salgia R: Rapid and dramatic radiographic and clinical response to an ALK inhibitor (crizotinib, PF02341066) in an ALK translocation-positive patient with non-small cell lung cancer.
J Thorac Oncol 2010, 5(12):2044-2046. PubMed Abstract | Publisher Full Text
Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H: EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
New Engl J Med 2010, 363(18):1734-1739. PubMed Abstract | Publisher Full Text
Heuckmann JM, Holzel M, Sos ML, Heynck S, Balke-Want H, Koker M, Peifer M, Weiss J, Lovly CM, Grutter C: ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.
Clin Cancer Res 2011, 17(23):7394-7401. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y: CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
Cancer Cell 2011, 19(5):679-690. PubMed Abstract | Publisher Full Text
Feng Y, Thiagarajan PS, Ma PC: MET signaling: novel targeted inhibition and its clinical development in lung cancer.
J Thorac Oncol 2012, 7(2):459-467. PubMed Abstract | Publisher Full Text
Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K, Possemato A, Nardone J, Innocenti G, Wetzel R: Signaling networks assembled by oncogenic EGFR and c-Met.
Proc Natl Acad Sci 2008, 105(2):692-697. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Organ SL, Tsao MS: An overview of the c-MET signaling pathway.
Ther Adv Med Oncol 2011, 3(1 Suppl):S7-S19. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Lawrence RE, Salgia R: MET molecular mechanisms and therapies in lung cancer.
Sattler M, Reddy MM, Hasina R, Gangadhar T, Salgia R: The role of the c-Met pathway in lung cancer and the potential for targeted therapy.
Ther Adv Med Oncol 2011, 3(4):171-184. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Ma PC: Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in Non-small cell lung cancer.
Cancer Res 2005, 65(4):1479-1488. PubMed Abstract | Publisher Full Text
Onitsuka T, Uramoto H, Ono K, Takenoyama M, Hanagiri T, Oyama T, Izumi H, Kohno K, Yasumoto K: Comprehensive molecular analyses of lung adenocarcinoma with regard to the epidermal growth factor receptor, K-ras, MET, and hepatocyte growth factor status.
J Thorac Oncol 2010, 5(5):591-596. PubMed Abstract | Publisher Full Text
Cappuzzo F, Marchetti A, Skokan M, Rossi E, Gajapathy S, Felicioni L, del Grammastro M, Sciarrotta MG, Buttitta F, Incarbone M: Increased MET gene copy number negatively affects survival of surgically resected Non-small-cell lung cancer patients.
J Clin Oncol 2009, 27(10):1667-1674. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Krishnaswamy S, Kanteti R, Duke-Cohan JS, Loganathan S, Liu W, Ma PC, Sattler M, Singleton PA, Ramnath N, Innocenti F: Ethnic differences and functional analysis of MET mutations in lung cancer.
Clin Cancer Res 2009, 15(18):5714-5723. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Sequist LV, von Pawel J, Garmey EG, Akerley WL, Brugger W, Ferrari D, Chen Y, Costa DB, Gerber DE, Orlov S: Randomized phase II study of erlotinib plus tivantinib versus erlotinib plus placebo in previously treated non-small-cell lung cancer.
J Clin Oncol 2011, 29(24):3307-3315. PubMed Abstract | Publisher Full Text
Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB: Somatic mutations affect key pathways in lung adenocarcinoma.
Nature 2008, 455(7216):1069-1075. PubMed Abstract | Publisher Full Text | PubMed Central Full Text
Sharma SV, Settleman J: Oncogenic shock: turning an activated kinase against the tumor cell.
Cell Cycle 2006, 5(24):2878-2880. PubMed Abstract | Publisher Full Text
Ji H, Li D, Chen L, Shimamura T, Kobayashi S, McNamara K, Mahmood U, Mitchell A, Sun Y, Al-Hashem R: The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies.
Cancer Cell 2006, 9(6):485-495. PubMed Abstract | Publisher Full Text
Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, Gazdar AF, Wistuba II: EGFR tyrosine kinase domain mutations are detected in histologically normal respiratory epithelium in lung cancer patients.
Cancer Res 2005, 65(17):7568-7572. PubMed Abstract | Publisher Full Text


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PC Pandora 7.0
PC Pandora 7.0 : Access Schedules New in this edition, PC Pandora can set a schedule for when the kids can use the Internet and separately schedule when they're allowed on the computer.
12 / 18
Bottom Line
PC Pandora 7.0 monitors tons of specific actions on your child's computer, including keystroke logging and periodic screenshots and webcam shots. It's changed very little since the last version, though, and the remote configuration and log viewing option remains unduly expensive.

subset: commoncrawl


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doug's blog
FaceFX 2013 Released - $899
FaceFX 2013 Beta Release
We need your help!
We are putting the final touches on FaceFX 2013, but before we release, we need feedback on the new FBX workflow.
Just create an FBX file with your bones and morph targets keyed on the correct frames (specify the target names and frame numbers in a batch export text file like the one in the Samples/Src directory), then drag it onto FaceFX Studio 2013.
FaceFX outsourcing by NarraSoft
Need help with rigging, character setup, or FaceFX animation work? NarraSoft has a large staff of professional animators that can help!
FaceFX at GDC 2012 - Booth 716
Come check out what's new with FaceFX in San Francisco next week at the Game Developers Conference!
December Unity Sale
(Update! FaceFX is now $899 all the time, so the 50% discount off of the $1995 price mentioned below is old news!)
Not ready for the holidays? Well this should get you in the mood! In honor of Christmas, Festivus, Hanukkah, Kwanzaa, and New Years Eve (alphabetically ordered), for the entire month of December, OC3 Entertainment is offering 50% off FaceFX Studio Professional purchases to all Unity Pro users.
Just send us your Unity Pro license invoice number to info (at) oc3ent.com and put "December Unity Sale" in the subject line and we'll send you instructions on how to proceed.
FaceFX 2012.1 is released
An update to FaceFX 2012 has been released. FaceFX 2012 plugin users can install the latest Tools and Evaluation installer to get access to the new plugins. FaceFX Studio Professional users will be notified of the free update from inside of FaceFX Studio Professional 2012 application.
New Features
- Plugins can now save and open XML files
- The full path to the audio file is accessible from the plugin script function: fxgetaudiopath
FaceFX 2012 is released!
See you in Vancouver!
OC3 Entertainment will be at Siggraph 2011 in Vancouver. Booth #869. Please swing by and check out the latest developments on FaceFX 2012!
TSJ Online & Develop press
FaceFX picked up some press in the April issue of Develop magazine and the Training & Simulation Journal.
The April issue of Develop focuses on facial animation, and mentions FaceFX on page 26:
Training & Simulation Journal reporter Kristin Quinn covers the importance of facial animation technology in the military simulation space, and how OC3 Entertainment & Darwin Dimensions are addressing the need.
FaceFX at Unite and I/ITSEC
OC3 Entertainment will be attending the following trade-shows.
If you plan on attending either, please contact us to set up a meeting!
- Unite in Montreal from November 10 - 12
- I/ITSEC in Orlando from November 29th - December 2nd. Booth 2976


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Wath Brow chomping at bit to start new rugby season
Last updated at 12:57, Friday, 12 August 2011
Wath Brow Hornets coach Ian Rooney says his players cannot wait to get stuck into summer rugby – but added that they will not be taking this truncated season lightly.
The short National Conference League season, played in mini localised groups, begins this weekend with a mouth-watering tie against local rivals Egremont at Wath Brow, ko 2.30pm.
The season will run from Saturday through to the end of November before the league takes a break and comes back in its normal format for a full summer term, beginning in March.
"Summer rugby is eagerly anticipated," admitted Rooney, "I was always a fan of moving to summer. Your player pool needs to come from the youth structures and they are already playing in summer and are accustomed to it.
"They would probably question why winter, it is just because we are used to it.
"But this shortened season is also a great opportunity for the club, we are going to treat it as a normal season, even though there are just 12 games.
"On the travelling side, it will be shorter as we play Egremont, Millom and Askam which is great.
"We will certainly treat it with respect and I don't think it is any lower in value just because it is shorter. Every game we play, we will play to win."
And Rooney says beginning against Egremont is a great start.
"Any game against Egremont creates a lot of local interest and both clubs will be looking forward to this," he added.
"I think there will be some good opportunities for youngsters coming through to play at this kind of level, against Egremont, Leigh Miners and Thatto Heath.
"Then they will know what to expect when we hit the summer season."
Brow will be without Mark Troughton, who is recovering after a shoulder operation while Craig Johnstone and Dave Currie have took a back seat from the first team.
Ryan Campbell has returned to his amateur roots to ply his trade while Rooney is hoping that some of the under-16s from last year will come through, along with the likes of Scott Pink, Karl Dixon and the Huby brothers.
Rooney will once again coach the first team with Ian Rudd but Paul Taylor has left the club and physio Tom Graffin has also decided to call it a day.
Rooney added: "These two will be sorely missed at the club and will be very hard to replace."
Egremont Rangers are hoping that this season will allow some of their younger players to shine through.
They will have a new assistant coach on board in the form of Mally Caton, who will be second in command to John Brocklebank.
Caton will also continue to play and Mark Cottam has switched codes from rugby union to try his hand at league.
Brocklebank says this is a real chance for the youngsters, saying: "I expect Lewis Beckwith to play a bigger part this season, he was one of our under-18s last year.
"And Leon Crellin is another. He is a second rower/centre but he had a learning years on the wing last season but he will have a bigger part to play this year."
Brocklebank, who thanked Wath Brow for allowing them to switch the game to their newly improved pitch, is looking forward to Saturday's match and says that being able to play against their fellow NCL Cumbrian sides is a great opportunity.
First published at 11:27, Friday, 12 August 2011
Published by http://www.newsandstar.co.uk
More sports


text: Nor'easter Weakening But Atlantic coast can still expect strong winds By Newser Editors and Wire Services Posted Nov 7, 2012 5:02 AM CST STORY COMMENTS (1) (Newser) – Weather experts have good news for beleaguered northeast coastal residents: A new storm that threatened to complicate Hurricane Sandy cleanup efforts now looks like it will be weaker than expected. As the nor'easter moves up the Atlantic coast from Florida it now is expected to veer farther offshore than earlier projections had indicated. Experts say that means less wind and rain on land, though winds could still gust to 50mph in New York and New Jersey this afternoon and evening. New Jersey Gov. Chris Christie warned yesterday that high winds may mean some residents who regained power will lose it again, and the wind could also slow efforts to restore power. There is "nothing we can do to stop the storms," he said. Along the Jersey shore, which was devastated by last week's superstorm, there was some relief that damage projections from the nor'easter have been scaled back. But there was still concern about the ocean barreling past beaches and dunes that were largely washed away and saturated, causing fresh flooding. A sign warning against looting is posted in, Brick, NJ, where residents in low-lying waterfront sections have been told to leave their homes. (AP Photo/Mel Evans) A sign outside a flood-wrecked home in Point Pleasant Beach, New Jersey. (AP Photo/Wayne Parry) ADVERTISEMENT(Click Prev or Next to continue viewing images.) « Prev« Prev | Next »Next » Slideshow Associated Press (Source Grid ») US New York City • New Jersey • severe weather • Hurricane Sandy • nor'easter CLICK BELOW TO VOTE 4% 11% 4% 17% 38% 26% RETURN TO THE STORY To report an error on this story, notify our editors.


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A day after he was caught driving around LA in a 13mpg Dodge Challenger, Governor Arnold Schwarzenegger was back at the podium highlighting California's environmental initiatives and the future of clean tech. The former actor paid a surprise visit to the 2008 Solar Power International conference in San Diego acknowledging the tough economic times but saying that they're one of the reasons we need to focus on solar and the environment. "We should not listen to those who say [that] should take a back seat," he said "That's just plain wrong."
"You know something's going on when Congress gets involved," he continued. "I was so happy that they finally got their act together in Washington. … It's about time and it will be great for the industry and great for the nation. When you look on the map, we're [California] a small place, but when it comes to the influence that we have, we're more like a continent. We're going full speed ahead and showing the country how it's done."
Schwarzenegger championed the solar industry, proclaiming that it cannot be stopped and that one day, he hopes ever warehouse roof has photovoltaic panels. His enthusiasm was so great, that he said it won't be long before he returns driving a "solar-powered Hummer." Ugh.
Arnold — before we talk about that Hummer, can you please do something about the extensive private jet travel and choice in road transportation?
via GreenTechMedia
About Michael dEstriesMichael has been blogging since 2005 on issues such as sustainability, renewable energy, philanthropy, and healthy living. He regularly contributes to a slew of publications, as well as consulting with companies looking to make an impact using the web and social media. He lives in Ithaca, NY with his family on an apple farm.
View all posts by Michael dEstries →
Pingback: Gov. Schwarzenegger Commemorates New Staples Center Solar Rooftop // Archives // ecorazzi.com :: the latest in green gossip()


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Thanks Curiosity, after my last post, got curious myelf and did a bit of research and decided Q2 should have been a PNP transistor as per your revised diagram. I'll se if I can findone today.
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Thanks Curiosity, after my last post, got curious myelf and did a bit of research and decided Q2 should have been a PNP transistor as per your revised diagram. I'll se if I can findone today.
I gave up on the two transistor circuit and redid it all from scratch using just one transistor on the 12 volt line to reduce the voltage and fed it into the 4069 NOT gate.
To make sure signal voltages input into the bilateral switch were the same, I fed the inverted output back into another NOT gate rather than use the enable line directly.
Anyway, I finished soldering the board. With the 4069 in place, the switching logic feeds into the bilateral are correct. All I have to do now is to solder the RCA's on and try it out, but as it's 11:00 pm here, I thought I'd better call it a day.
I will post some pics and an updated circuit diagram when I get a chance.
Well, as long as it works. That's the point. :)
I'm always using an NPN as a pull-down so I still don't know why that first one didn't work. I used pretty high resistance values, so it may not have been enough current to energize both transistors. PNP is just opposite. Grounding the gate enables it. As far as the bilateral switch, you just need the control voltage to go to 0 and as high as the supply and it should be fine.
Great work on this so far Rodweb,just have a question,i am planning on going back to a headunit for music so then i can use the comp.mostly for GPS, i am planning on using tallisman to redisign the gui and run ozi and igo and wmp for that matter straight from a tallisman shell there by solving the focus issues etc,etc of embedding in a front end,now to the question,do you think this unit will be fairly quick and reasonalbly quite to be able to switch h/u output off when computer speaks directions,i wonder if it would be possible to fade in and out?
You don't need hardware to switch volume when the GPS speaks. I use Navimon http://www.mp3car.com/vbulletin/road...tenuation.html and it works a treat. It does not fully mute the music but attenuates the volume back to a level you set. I don't think it is specific to any front end, so it should work for you. Set the WAve volume to 100%, set IGO to volume of 80% or lower in that software and tell Navimon to cut in at 80% volume or less.
To fade the volume in and out on the line level input would require a digital potentiometer added to the output and some logic to turn it up and down. As curiosity has said There are some neat chips that include multi channel mixing with audio controls inbuilt but they are very small form factors and thus probably beyond my soldering skills. You'd probably need to add a microprocessor or use the FB to control it all and write some on chip software to tie it all together and knowing your love of programming, you probably wouldn't want to stuff around with this...
Sounds like a USB soundcard to me... why program it all yourself.
If I can get this going, all I need is to turn the head unit on and I can listen to the radio. Turn the head unit off and I will be back listening to the PC if it is turned on.
Having said that, I have got a good sound card picked out if I can't get this going. This will cost $20 and the sound card $200 :)


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Working like a charm! Ziggo (drm't) live tv app on a rooted note 10.1 working great with multi-window and note 10.1! It took me 1 1/2 day to work it out but now i can view live dutch tv: full screen/split screen or in a window on my precious! :s...
There's a free app called "phone info" my friend. That will show you everything ;) On the rom download page if you scroll down you will see a bootloader link.. thats the one you need but you dont even need to upgrade your bl.. you only need a ...
Strange, I use it on Echoe 21 an use same on 18 and no problem. Sorry if didn't worked. Maybe don't work on 22. Sent from my GT-I9505 using XDA Premium 4 mobile app No worries bro, i am patient. thanks for trying! i am on v21 and ael v2 a...
Thank U very much for this geat firmware. My note feels like new again. No more lagging that stock kk gave me and I`m enjoying the floating stuff to the fullest.. Thanks!
Updated trough Kies (stock NL), Cwm and root are gone now, so rooted supersu V2.0 and installed latest CWM again. supersu was blocked by knox after the first use of it (update su didn.t work), deleted (manual) and froze knox files (titanium) and...


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The Hamilton Area YMCA offers a variety of convenient and affordable membership options. You do not have to be a resident of Hamilton to join the Y family.
Our Facility Plus Membership includes the following:*
*Note: All members must follow facility policies at all times
Members have the option to pay for their membership on a monthly or annual basis with no contract! And now, members have the ability to pay for the Joiner's Fee at one-time or over a 12-month span.
**Family membership consists of two adults and all children under 18 (24 if full-time college student), living at the same address
***Max down payment – Down payment will be prorated according to date of sign-up.
****Monthly Bank Draft – Bank Draft option is perpetual. Draft is automatic and can be from either a credit card or checking account. You must complete form to terminate monthly draft. Monthly bank draft occurs on the 15th of each month following the period covered by the down payment. If terminating, you must cancel in writing before the 10th of the month to avoid bank draft for that month. If terminating, you must provide 30-day notice.
Our Facility Membership includes the following:*
*Note: All members must follow facility policies at all times.
****Monthly Bank Draft – Bank Draft option is perpetual. Draft is automatic and can be from either a credit card or checking account. You must complete form to terminate monthly draft. Monthly bank draft occurs on the 15th of each month following the period covered by the down payment. If terminating, you must cancel in writing before the 10th of the month to avoid bank draft for that month. If terminating, you must provide 30-day notice.
Our Program Membership lets you pre-register for classes and programs at the JKR Branch, Sawmill Branch and Cranbrook. Excludes facility usage such as pools, gym, and/or wellness center track.
A current Horizon participant or employee? Try our YMCA free for 30 days! Simply present your Horizon card with photo ID at our Member Services Desk and we'll be glad to get you started.
A current member of AAA Motor Club and age 18 or older? Show us your card and you will receive our AAA membership rate — a 5% discount on our current Facility Membership rates. Applies to Facility Membership ages 18+.
Some insurance companies and HMOs will reimburse participants for partial or all membership fees. We will be happy to verify your membership but will not bill the insurance company for fees due. If you need verification, we will gladly write a letter indicating your current membership status. Check with your insurance carrier for details.
The whole family can beat the heat this summer at our Sawmill Family Pool. Become a member at our beautiful outdoor oasis and ride down the 100-foot waterslide all summer long! With your membership, you can also enjoy scenic picnic areas with BBQ grills under the pavilions and access to the playground, sports fields and air-conditioned recreation center. The Sawmill Pool opens Saturday of Memorial Day weekend each year. Please call the Sawmill Branch at 609.581.9622 ext. 21000 for more information.
Healthy, happy and productive employees are the key to every successful business. Corporate Memberships at the Y are an opportunity for local companies to provide discounted Facility Memberships to their employees. Let's work together to encourage a healthy lifestyle for your employees! For more information, contact Joe Fuhrman, Director of Member Initiatives, at 609.581.9622 ext. 132 or email@example.com
We currently offer corporate memberships for the following companies:
The Hamilton Area YMCA offers a Military membership to those who qualify. This is a six-month Family Facility membership. Contact Military OneSource at 1.800.342.9647 to see if you qualify.
It is the policy of the Hamilton Area YMCA to provide services for any person who desires to participate and understands the benefits of the YMCA, regardless of their ability to pay standard membership or program fees. Those not able to pay the full fee may be awarded partial assistance based on demonstrated need. Assistance is granted on the basis of financial need, when funds are available. Household income guidelines are used as initial eligibility criteria. The YMCA believes a strong sense of ownership and pride is developed if the financial assistance recipient contributes to the cost of their YMCA involvement; therefore, applicants may be asked to pay a portion of the membership or program fees.
Click for an application. Please allow a minimum of 21 business days for a response. Processing period begins upon submission of completed application. For more information, contact Joe Fuhrman, Director Member Initiatives, at 609.581.9622 ext. 132 or firstname.lastname@example.com.
A.W.A.Y means "Always Welcome at YMCAs." Our members are part of a nationwide association of people helping to build strong kids, strong families, and strong communities. The A.W.A.Y. program provides access to participating YMCAs in the United States when you travel away from home on business or vacation. A YMCA's participation in this program is voluntary. Some restrictions apply.
Because each local YMCA sets its own policies, each participating YMCA in the A.W.A.Y. program has its own local restrictions. If you are planning to be out of town and would like to visit another YMCA, please call that YMCA for its visitor policies before you go. To find information on any YMCA in the United States, go to www.ymca.net and conduct a "Find Your YMCA" search. YMCAs participating in the A.W.A.Y. program are noted.
The state of NJ has a reciprocal membership agreement which allows you to visit participating YMCAs in NJ at no cost following their policies. You must use your Home YMCA (the YMCA you are paying dues to) the most. Please call the YMCA you are planning to visit in advance to find out their specific policies and types of facilities available to you.
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2009-2010 Catalog
The 2009-2010 Catalog is available in PDF which requires Adobe Acrobat Reader.
- General Information
- Administration
- Accreditation
- University Calendars
- Tarleton State University - An Overview
- Admissions
- Expenses
- Financial Aid
- Student Life
- Academic Information
- Division of General Studies
- Department of Military Science
- Undergraduate Programs
- Campus Outreach Programs
- Southwest Metroplex and Outreach Program
- Waco Outreach Program
- Academic Colleges and Departments
- College of Agriculture and Human Sciences
- College of Business Administration
- College of Education
- College of Liberal and Fine Arts
- College of Science and Technology
- College of Graduate Studies : Graduate Degrees in Colleges
- Graduate and Undergraduate Course Listings
- Faculty and Staff
This catalog is printed to provide information about the academic programs of Tarleton State University to students, prospective students, faculty, and staff of the University. While every effort has been made to make this catalog as complete and accurate as possible, changes may occur at any time in requirements, deadlines, fees, curricula, and courses listed in this catalog.
This catalog was prepared in advance of its effective date; therefore, academic programs and course descriptions may vary from actual program requirements and course content. Thus, the contents of the catalog cannot be considered an agreement or contract between individual students and the University.
The Tarleton State University Schedule of Classes is published for each semester and summer term and is available upon request from the Office of School Relations. Students should refer to the Schedule of Classes for the offerings in any given semester. For administrative reasons, because of insufficient enrollment or limited resources, a given course may not be offered in the announced semester.


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Archive for Thursday, November 18, 2004
Community worship for Thanksgiving Sunday at UMC
The Eudora Ministerial Alliance will have its annual community Thanksgiving service at 7 p.m. Sunday at Eudora United Methodist Church, 703 Church St. The community is invited to attend.
Those planning to attend are asked to bring non-perishable food items or monetary donations, which will be given to the ministerial alliance's food pantry, housed at St. Paul United Church of Christ.
Commenting has been disabled for this item.


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You must try Cashmere Luminance.
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By popular demand, experience the service for only $150 (normally a $250 service) through the end of August.
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text: I'll try to post a pic when the battery charges, but my bike met a DWP cover when I dropped it trying to make a roadside adjustment today. It got a dent about 1 inch long vertically about half way along the top tube. I knew scandium tubes were thin, but was still surprised at how easily it dented. Where the dent is, I can squeeze the tube and it bends a little, almost like a soda can. Anyway, I was hoping people could tell me if that's of major concern or if it's in a non crucial area. Will post pics asap.


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St. James member, St. Mary office manager to receive Manifesting the Kingdom Awards
Their friends and colleagues say they both will do anything for anyone, and that's why John Nard, a member of St. James Church in Sewickley, and Barbara Cox, office manager for St. Mary Church in Aleppo, will be honored with the Manifesting the Kingdom Award.
They will be among more than 200 recognized by the Catholic Diocese of Pittsburgh for their service to church and community at the 2:30 p.m. Sunday Mass at St. Paul Cathedral in Oakland, where Bishop David Zubik will be celebrant.
Nard, of Bell Acres, said he was a bit taken aback when he received a letter announcing the award.
"I never got a letter from the bishop before, and I thought, 'uh oh,'" he said with a laugh.
The Rev. Thomas Burke of St. James Church said he nominated Nard because "in just the five months as the new pastor here at St. James I saw him always around the parish helping out.
"Not only is he involved with the St. Vincent de Paul Society, he lectors at the 6:45 a.m. daily Mass and recently help set up and clean up the Christmas decorations in church."
Nard and seven others help with the church's food bank, collect clothing, give donations to other organizations through St. Vincent de Paul.
Nard said one incident that has stuck with him is seeing grown men in tears as he and others helped local victims of Hurricane Ivan in 2004.
St. Vincent de Paul member Bill Battisti of Bell Acres said Nard is a teacher and friend.
"John is humble, kind and smart. He has the ability to put people at ease, which in the St. Vincent de Paul arena is important," he said.
"He is a good listener and doesn't pass judgment on people. He will listen to people in need and follow his thoughts with action. He helps people out through difficult times, and he's never out to say, 'Look what I did.' "
Nard said his late mother and father, Kathleen and John Sr., instilled in him his faith and his love of helping others.
His mother volunteered at Heritage Valley Sewickley hospital, and his father was always the one to stop and help someone who broke down on the side of the road. He made sure his children always went to church.
Nard said the best thing about helping others is "seeing Jesus in the people you serve. Hopefully, we bring Him to them. God said, 'When you wait on the least, you wait on me.'"
Cox, who has worked at St. Mary for seven years, said she was humbled when the Rev. David Jastrab, church pastor, told her about the award.
"I always tell her she is one of those people who can't say no. Every time I ask her to do something, she is always capable of doing it. She is very loyal to the people of the church," said Geraldine Donahue, head of the church's women's guild.
Cox also helps with the guild's fundraisers.
In addition, Cox coordinates weddings and funerals at the church, puts out the church bulletin, is a member of the altar society and is the safe-environment coordinator ensuring those who work with children in the church have proper clearances.
Jastrab said Cox received the award because she "shows the light of the love of the Lord in her work at the parish.
"Barbara always shows the people consideration and respect," Jastrab said. "She is always pleasant and spends quality time with everyone."
But, Cox, of Ohio Township, said it's second nature for her to give back. She said she also learned about caring from the nuns as she was educated for 12 years in Catholic school in Brooklyn, N.Y.
The church's parishioners, who also never hesitate to help, make caring easy, she added.
Their caring, loving attitude is what brought Cox, her husband, Mark Muto, and their daughter, Emily Muto, to the church 15 years ago, she said.
Donahue said she is glad Cox will receive the award.
"She is multi-talented. She is the type of person who should receive it."
Joanne Barron is a staff writer for Trib Total Media. She can be reached at 412-324-1406 or firstname.lastname@example.com.
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No Favre Mania In The Falls … Wednesday Cup O'Chiefs
From River Falls, Wisconsin
Some 45 miles away, a football drama was playing out in the Twin Cities.
After so many reports, rumors, exclusives and false starts, Brett Favre landed in Minnesota on Tuesday. He signed a two-year contract, took a physical and then went out to practice for the Vikings at their facility in Eden Prairie.
That's Favre signing the paperwork on the right, with Vikings owner Zygi Wilf standing to Favre's left, while other team officials check out the contract. (Photo from the Vikings)
And get this, he is expected to start on Friday night when the Chiefs travel to the Metrodome to face the Vikings in pre-season game No. 2.
So what was the reaction just a few miles away, here in woods of Wisconsin? How about a yawn, a shrug, and a "who gives a bleep" look.
Vikings fans were storming the team's offices and dialing incessantly for tickets and the Chiefs were just trying to get through another day of training camp work.
"Really? That's nice," said OLB Tamba Hali when told Favre was joining the Vikings and had practiced with them on Tuesday. When he was told Favre was likely to start against the Chiefs, Hali said "Really? Huh." Then he shrugged and walked away.
Others had more to say, but the general attitude was not that of a group of guys wrapped up in the Favre moment. One Minneapolis TV station was broadcasting live the arrival of Favre in a private jet, his pickup by head coach Brad Childress in an SUV and then the drive from the airport in St. Paul to the Vikings offices. The only thing missing was the white Bronco.
The Chiefs were in meetings and missed the whole drama.
"Even though he is almost 40, he wants to play, so let him play," said SS Bernard Pollard.
Veteran OLB Mike Vrabel said Favre's routine of missing training camp and then showing up and automatically becoming the team's starting quarterback wouldn't fly in the current Chiefs situation.
"It would be a distraction here for someone to show up in the middle of camp," Vrabel said. "That's not what we're looking for here."
When asked if he agreed with Vrabel's assessment, Todd Haley put things into a Chiefs perspective.
"I'm just worried about this house; it's on fire and I'm just trying to keep it from burning down," the Chiefs head coach said with a smile.
"He's one of the great players of all time," Haley added. "We (Arizona) went up there to the Meadowlands last year and he probably had one of his better games in a long time against us. So I don't have fond memories of Brett Favre."
Favre threw for six touchdown passes last year against the Arizona Cardinals in a victory for the Jets. He threw three interceptions against the Chiefs last year at the Meadowlands, but then hit the winning TD p ass l ate in the game. Brandon Flowers got his first two NFL interceptions off Favre, including one he ran back 91 yards for a score. He looks forward to another one Friday night.
"Everybody wants to play against a quarterback like Brett Favre," Flowers said. "Those are games you never forget, when you play against a great quarterback. I hope he plays."
Vrabel saw Favre twice last season, including a came where the veteran QB hit 26 of 33 passes for 258 yards and two TDs in a Jets victory.
"He always puts his team in a position to win," Vrabel said. "He's a competitor and I'm sure that's what is driving him now. I hope for his sake his body can still match his competitiveness."
Whether Favre's body can hold up or not, the Chiefs will get the first chance to see.
Former Chiefs, Vikings, Raiders and Redskins QB Rich Gannon lives in the Twin Cities and he is well versed on the situation with the Vikings and with Favre. Speaking on Sirius NFL Radio on Tuesday, Gannon predicted some trouble ahead for Favre and the Vikings head coach.
Here's a transcript of what Gannon had to say on the subject:
"Here's the other thing that no one's talked about which I know is going to happen; Brett Favre and Brad Childress are going to butt heads. Brad Childress is a stickler for doing it his way. He's a very detailed guy, doesn't really want to think outside the box.
"Brett's going to come in there, he's going to be hand signaling the receivers, he's going to be trying to change plays at the line of scrimmage, he's going to do stuff that they don't do in that system and he's going to drive Brad Childress crazy.
"He's got a history in this system. He knows it as well if not better than Brad and they've done a lot more – a lot of different things that have been added on over the years – in Green Bay and it's part of his repertoire. He's going to do it because that's what he knows and that's what he's comfortable doing. When push comes to shove and he's out there in a critical situation in a game he's going to revert to what he knows and what he's done in the past and it may not be what Brad Childress had thought about or even installed in the game plan."
This makes it sound like this whole season could be fun!
BILLS – CB Drayton Florence has a sprained knee and will be out two to four weeks.
BROWNS – claimed WR Paul Raymond on waivers; released LB Bo Ruud.
BUCCANEERS – S Tanard Jackson suspended four games by the NFL for violations of the substance-abuse policy.
JETS – waived S Keith Fitzhugh.
LIONS – released WR Bobby Sippio and T Kirk Barton; signed G Terrence Metcalf and WR Dane Looker.
RAIDERS – WR Chaz Schilens broke a bone in his left foot and will miss the next three weeks; signed CB Ricky Manning, Jr.
On August 19, 1967 the Chiefs beat the Oakland Raiders 48-0 in Portland, Oregon's Civic Stadium. Noland Smith had a 72-yard punt return TD. QB Pete Beathard threw three touchdown passes, going to WR Otis Taylor for 25 yards, RB Gene Thomas for 47 yards and then 20 yards to WR Gloster Richardson. DB Fletcher Smith returned an interception 36 yards for a TD. Overall the Chiefs had three INTs as DL Buck Buchanan and Gene Trosch also grabbed picks. All three were thrown by QB George Blanda.
On August 19, 1988 the Chiefs and Green Bay Packers played to a 21-21 tie in a pre-season game at County Stadium in Milwaukee. The Packers sent the game into an extra period with a pair of fourth-quarter TDs, including a 78-yard scoring catch by WR Sterling Sharpe. The Chiefs got their scores on a 6-yard TD pass from QB Bill Kenney to TE Jonathan Hayes, a 5-yard pass from QB Steve DeBerg to TE Alfredo Roberts and a 4-yard run by Paul Palmer. WR Stephone Paige had six catches for 76 yards in the game.
Born on August 19, 1951 in Pascagoula, Mississippi was S Clyde Powers. He joined the Chiefs in 1978, after playing four seasons with the New York Giants. Powers appeared in just one game with the Chiefs.
Born on August 19, 1960 in Copenhagen, Denmark was K Morten Anderson. He joined the Chiefs in 2002 for two seasons (2002-03), appearing in 30 games. It was one stop on what was a 25-year career in pro football. Andersen also kicked for the Saints, Falcons, Giants, Vikings and Chiefs. In two seasons, he hit 38 of 46 FG attempts, the longest being a 50-yarder.
Born on August 19, 1961 in Garland, Texas was LB Jeff Paine. He was a fifth-round selection in the 1984 NFL Draft out of Texans A&M. Paine spent two seasons with the Chiefs (1984-85), appearing in 12 games.
37 Responses to "No Favre Mania In The Falls … Wednesday Cup O'Chiefs"
August 19, 2009 - Harold C. says:
Must be a slow news day….we're talking about Favre again.
August 19, 2009 - Josh says:
Dear Bernard "Bone Crusher" Pollard,
Remember what you did to Tom Brady in the opening game of last season? You can become KC's favorite son if you do it to Favre on Friday.
August 19, 2009 - Josh says:
Josh, not only KC's favorite son, Greenbay's as well. LOL
August 19, 2009 - Harold C. says:
You're joshing me again.
August 19, 2009 - ED says:
Vikings will have a losing season despite them now according to the media being a quarterback away from being a Super Bowl oontender. Childress will get fired and Farve will retire again. Hey didn't we see this movie last year.
August 19, 2009 - Scott says:
"I'm just worried about this house; it's on fire and I'm just trying to keep it from burning down," the Chiefs head coach said with a smile.
That has to be my favorite Haley quote so far. He may have said it "with a smile"…but it's true. He knows it…and we know it, too.
Pioli and Haley have to put out the fire, clear the debris, lay the foundation, and start building from the ground up. It won't be an easy process…and it won't be as fast as some of us might like. How far they are along in the process already is up for debate. But, I think they'll get the job done in due time.
August 19, 2009 - gorillafan says:
I agree scott. I had a long drawn out comment and it wouldnt post it. so now im tired of typing!
August 19, 2009 - Anonymous says:
I agree Scott Doesn't sound like rose colored glasses Haley is wearing.Some people just like sour grapes on their cereal it makes them bitter just like they are. I like the way Haley is going about changing this team attitude . To those that question the change we only have too look at the failure rate of our chiefs to see we need change.If you are lost its time……. for a Garman ( Parcell) system…….. to stop going down the same road.
August 19, 2009 - gorillafan says:
oh sure, not it works
August 19, 2009 - arrowhead1978 says:
another 5 year plan??? Wow, imagine that… The Lions release Sippio, I guess he isn't going to stick in the NFL…
August 19, 2009 - True Red and Gold says:
Day two: arrowhead1978, Please refrain from being a douchebag.
August 19, 2009 - Scott says:
Building a New England/Pittsburg/Indy type team, that's "in the hunt" year in and year out will take a little time. Patience, Grasshopper.
August 19, 2009 - Scott says:
Listen guys…
Chiefs fans, TRUE Chiefs fans…are the best NFL fans there are. Period. We've seen some good times…and God knows we've seen MORE than our fair share of bad times. The last two years being probably the worst ever. We're at rock bottom. Nowhere to go but up…and that is exactly where we are going. I truly believe that in the next few years we are going to be rewarded for all of our pain and suffering. Someday, we will look back at the 2009 season as the turning point. The point at which our pride began to be restored. The point where we started to become a feared and dominating franchise. The time has come. We've waited long enough. The wait is over.
August 19, 2009 - Jim Lloyd+ says:
Ed , I didn't see the movie—Read the book—Farve will set a record that will never be touched .
August 19, 2009 - Rin Tin Tin says:
The big news of the day: a QB of course – but not a Favre.
A Mutt & the fact that he has not thrown an INT – yet – as practice has yet to conclude there River Falls … details on the 2-3 he will later Rin's sportscast (back at 10, see you then.)
- – - – - – - –
That exhibition game in 1967 KC vs OAK – Rin was there in Portland, still have the game program & ticket stub. More so, still can see "Supergnat" Noland Smith putting on darn near the greatest kick return performance in one game ever seen.
Not only did he return a punt for a 72 yard TD, he had another 72 yarder that didn't go all the way, plus another TD return was called back.
On the night Smith totaled 225 yards officially, but in fact had over 300 yards sans penalties – on just 5 returns.
He was and remains without question the greatest return man in Texans/Chiefs franchise history.
August 19, 2009 - Rin Tin Tin says:
arrowhead1978 said
"another 5 year plan???"
- don't be ridiculous arrowhead1978- were talking about & roll: here: the greatest football men in all of creation – the guys who placed the 'sliced' in bread.
5 years? Why they'll hang themselves in effigy if it takes them longer than…oh, 22 days, any (and Rin will do it for/to them if they don't – daily, via this blog.)
Yup; they're all that alright… right. 'check'
August 19, 2009 - Scott says:
Cassel throws an INT in practice. So? What's the big deal? I don't know why so many seem to think it is. I truly don't.
I would certainly HOPE our DB's are good enough to pick a few from a QB they see EVERY day. Because if not…I'd say there's something wrong there. Seriously.
August 19, 2009 - truthfull T says:
bob were here for cheif news not vikings/ packer news you gotta be more creative with your writing
August 19, 2009 - Rin Tin Tin says:
Scottie – Rin's faithful Shadow nee Lap Dog – how have you been? Oh? I'm sorry to hear that… well keep your chin up – it's easier for you to see it coming that way…
August 19, 2009 - arrowhead1978 says:
TR&G dont be such an antagonist, lol… How do you feel about the Dwayne Bowe trade rumors him going to the Jets? Wow, the chiefs could maybe get stuckey in return or a 3rd and a 7th round pick… That would be another block buster trade, wouldn't it??
August 19, 2009 - ILChiefsFan says:
"How do you feel about the Dwayne Bowe trade rumors him going to the Jets?"
What trade rumors? The rumor is that the Jets are interested in him. There's no indication that they've even talked to the Chiefs.
August 19, 2009 - Scott says:
I've been fine, BitterRin. Thanks for your concern.
Your "poison pen" does nothing to dampen my enthusiasm for my team. And never will. Your're welcome to keep trying, though. Whatever makes your bitter little world spin.
August 19, 2009 - burnsomatic says:
what is this rumor with bowe and the jets?
August 19, 2009 - get real says:
The Jets need a WR badly (don't we all) and say Marshal from Den or Bowe. Doubt it has any weight. Haley has spent to much time motivating Bowe to let him go. What could you get for him? A 2nd like Tony, what a waste. NY will not give up a 1st. Besides without a "threat" at WR, defenses will load up against the run and make the QB throw to win games (we really, really do not want that).
August 19, 2009 - True Red and Gold says:
How about we trade you and Rin for a piece of Brett Favre's used toilet paper?
August 19, 2009 - Rin Tin Tin says:
Scott said
"I've been fine, Bitter"
- no, I meant anything new beyond the status quo yours…
"Rin. Thanks for your concern."
- oh, I wasn't – it just seemed heroic on His part to seem so…
"Your "poison pen" does nothing to dampen my enthusiasm for my team. And never will. Your're welcome to keep trying, though. Whatever makes your bitter little world spin."
- you'll have to let go of Rin's ankle, quit tugging on my cape & stop following me to be taken seriously; if Rin has to make a sudden stop or a sharp turn, you're gonna break your neck…
August 19, 2009 - SG says:
"…say Marshal from Den or Bowe."
Spe-cu-la-tion…speculation…it's speculation. The Hallelujah Chorus for sportswriters who want to write about something other than Favre.
August 19, 2009 - Rin Tin Tin says:
"a piece of Brett Favre's used toilet paper? "
- stop picking on Scottie – his feelings be as soft as Brett's preferred choice, Charmin…
August 19, 2009 - burnsomatic says:
thanks guys, I found some stuff on it. There is no way we get rid of bowe. I read his salary for the next 3 years, that alone is worth keeping him.
August 19, 2009 - burnsomatic says:
And he is our best wideout
August 19, 2009 - Chris_Texas says:
I too enjoyed the Haley comment and have liked his approach to training camp and personel. Who cares if someone is making more its who is playing the best and works the most and as he says "Gets it" or your gone. Really like this Coach more and more as the days go by.
August 19, 2009 - Todd's The Man says:
Keep up the great work Coach Haley. ALL of KC is behind you and we know that you will lead us back to glory very soon now.
AND NOW, Clark Hunt has affirmed Todd's The Man!
August 19, 2009 - Anonymous says:
Welcome to the dialog …….Dog .Its not hard to be civil state your case …….then step a side. As you are surely aware ever one has a Charmin need . I maybe the only one that likes your blog ……… most of the time . Well some of the time anyway .PnS
August 19, 2009 - Rin Tin Tin says:
Anonymous said (to himself, as he addressed self in a formal way)
"Self? Welcome to the dialog …….Dog .Its not hard to be civil state your case …….then step a side. As you are surely aware ever one has a Charmin need . I maybe the only one that likes your blog ……… most of the time . Well some of the time anyway .PnS"
- then he tried saying it with the lights on…
August 19, 2009 - Mark says:
If the Jets are SERIOUS about wanting Bowe, they can START the conversation with C Nick Mangold and a #1. That's just for starters. Bowe's going nowhere but the Pro bowl as one of Haley's soldiers.
August 19, 2009 - DoorMatCastle says:
I wish I could play for the Jets because I'm not good enough to start in Kansas City. Both Brodie and Tyler are so much better than me and show it everyday and in the games. I'm a loser.


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November 26, 2015
The summer is a great time to be outdoors, but if you're not careful you could run into a spider.
"Spiders are particularly active in warmer weather, in the winter, they are still around of course, but they are really secluded and try to stay warm." Urban Regional Extension Agent Phillip Carter said.
Carter says most spiders in the wiregrass are harmless, but two spiders known for their unique marks, could be deadly.
"The only spiders I would be particularly concerned with are the black widow, or a brown recluse spider also known as the violin spider." Carter said.
If you're bitten by a black widow spider, you'll start to feel the effects almost immediately.
You'll feel a sting, and then may even feel tightness in your chest.
A brown recluse bite can dissolve the flesh.
"It can get really nasty and the tissue kind of just melts away and looks ulcerous so it can be life threatening." Carter said.
Paramedics say if you are bitten, you need to tend to the bite immediately.
"The first thing you want to do if you've been bit by any spider is wash it with soap and water." Paramedic Gary Wells said.
Then go see a doctor as soon as possible.
Spiders tend to hide in wood piles or leaf piles in yards, so carter recommends not leaving too much debris on your lawn.
Carter says brown recluse spiders also like to be in dark places like a closet.
So if you haven't worn a pair of shoes in awhile, check them before you put them on.
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