pSpecifically, ?? SPECTRIN associates with Smad3, presenting it to the cytoplasmic domain of the TGF ??Type I receptor complex, followed by heteromeric complex associa tion with Smad4, nuclear translocation and target gene activation. Disruption of ?? SPECTRIN in mice leads to disruption of TGF ??signaling AZD7762 and re sults in a phenotype similar to Smad2 Smad3 mutant mice, mid gestational death due to gastroin testinal, liver, neural and heart defects, and loss of intrahepatic bile ducts. Interestingly, while the liver lineage is established, hepatocytes are poorly formed and liver architecture is lost with an absence of prim itive bile ducts as in the Smad2 Smad3 mutants. Moreover, bile duct formation can be induced in liver explants cultures treated with TGF ?? Many studies have reported a reduction of TGF ??receptors in up to 70 of HCC.
How ever, BMS 794833 Smad proteins shown to be impaired in other cancers appear to play a minor role in HCC. Yet, TGF ??levels in serum and urine are increased in HCC patients. In addition, up to 40 of HCC have increased TGF ??expression based on immuno histochemical analysis. High TGF ??levels have been correlated with advanced clinical stage of HCC. This dual role of TGF ??signaling in HCC was explained by its effect on the tumor tissue microenvironment and on selective loss of the TGF ??induced antiproliferative pathway. Tumor cells that have selectively lost their growth inhibitory responsiveness to TGF ??but retain an otherwise functional TGF ??signaling pathway may exhibit en hanced migration and invasive behavior in response to TGF ??stimulation.
TGF ??signaling also has been shown to induce an epithelial to mesenchymal transi tion process in tumor cells. EMT leads to en hanced migration and invasiveness. Recently, loss of ELF, a TGF ??adaptor and signaling molecule, in the liver leads to cancer formation by deregulated hepatocyte proliferation and stimulation of angio genesis. More recently, it was reported that STAT3 Oct4 positive HCC cells, which have dys functional TGF ??signaling, are likely cancer progen itor cells that have the potential to give rise to HCC. Notch pathway The Notch signaling pathway plays an im portant role in stem cell self renewal and differentia tion. However, other signaling pathways in fluence whether Notch functions as a tumor sup pressor or oncogene in a particular tissue.
Notch signaling is activated through four receptors that can interact in a redundant manner with five ligands of the Delta Jagged family. Ligand binding triggers a ??sevretase dependent proteolytic cleavage of Notch receptor and the release of Notch intracellular domain to the nucleus , which in turn displaces the co receptors associated with CSL transcription factors. Activating transcription factors are then re cruited and expression of target genes such as Hairy and Enhancer of Split and Deltex1 is induced. Notch signaling plays a well defined role in liver embryogenesis and bile duct formation. In addition, Notch fam

wiSelective. However, SB 431542 hits four kinases with IC50 much Similar between 100 to 300 nM, which foreclosure w Entered during these kinases Ing leads a very promiscuous Pmax 0.14. AZ 960 The distribution coefficient is therefore almost as selective as SB 431542 sunitinib. However, sunitinib inhibits kinases below 3 181 M and SB 431542 only 5 Therefore, we believe that Ka Gini and entropy selectivity t Are better, in general, a measure selectivity to t in this case. Another inhibitor is different MLN 518, which characterized in rows 26ST Pmax, but at 14 and 15 and Ka Gini entropy selectivity t. Again, these differences arise from the fact that this kinase inhibitor leads 4 hits with power almost equal between the two 10 nM, the Promiskuit t Pmax.
However, MLN 518 shots in only 10 kinases below 3 M, which is intuitively more selective as ZD 6474, beat 79-kinases below 3 M. The F Ll illustrate the above point Pmax indicates that only one kinase inhibitors have taken few Kr fte comparable. Gini score and entropy give gr Ere selectivity t selectivity t for this F Lle. After all, should a score selectivity t Consistent with the Deforolimus classification of a visual heatmap be. Other files 1 shows that rme generally compounds with gr Erer entropy in fact have a map busiest W. Lift a few exceptions, the eyes n the heart appear lighter than their classification entropy shows as SU 14 813, sunitinib and staurosporine. However, these compounds have low Kds extreme on Selected Selected targets. Therefore, they are relatively selective activity Th in the range of 1100 nm, whereas the activity of th Still within the outlines in S1 Uitdehaag.
Limit in a sense, the great e dynamic data visual assessment by a heatmap. Koh difference Between the methods of profiling in an n Next step, w We hlten 16 connections audience profile and measure the activity of t data through another service profiling. The 16 compounds represent a variety of molecular scaffolds, Promiskuit t and target classes. Even for these new data, we calculated the selectivity tsparameter. Ideally, the selectivity Tswerte Similar, independently Ngig of the profiling technology. Data from the two methods are shown in Figure 2. All parameters au He be the entropy Pmax and tend unevenness Distributed uniformly. For example, all Ka Gini values ranging between 0.93 and 1.00, where they vary theoretically between 0 and 1.
However, given the statistical correlation between the two S Protect calculate data indicate that R-squared is the linear regression and correlation, that the selectivity of t Entropy S and Ka Gini method more robust. Ideal w re There when the absolute value of the metric can be compared also appreciate between records being. This means that for example, a specificity t Of 1.2 in the first 1.2 seconds profile also highlight the profile. To get a glimpse of it, we calculated the best L Solution to a 1:1 correlation with standardized data. Gini score was reduced Ka

Examination of c fos expression in P16 18 mice demon strated activation of neurons throughout the brain. C fos reactivity was more widespread in the brains of GluA2L483Y/wt mice, which had been observed to have multiple seizures, than in WT animals that had undergone acute seizures induced by kainic acid injection. GluA2L483Y/wt mice were monitored from birth and it was found that the LT50 was 17. 5 days. Most mice died in the 3rd postnatal week, with quite number of surviving previous P30.

In Nissl stained sections we observed no obvious alterations in cell layers or density of GluA2L483Y/wt mice, and assessment of synaptic structure at the electron microscopic Pazopanib level did not reveal any alterations in the density or size of asymmetric excitatory synapses in area CA1 of the hippocampus. Glutamate Receptor Expression Is Altered in GluA2L483Y/wt Animals. Western blot examination of whole hippocampal homogenate demonstrated a distinct reduction in the quantity ofGluA1, and to a lesser degree GluA2 receptor subunit protein in GluA2L483Y/wt. Membrane receptors were also reduced in the isolated synaptoneurosome fraction. In this case, we observed a clear reduction in Ecdysone receptor protein and a smaller sized lower in GluA1 protein.

Because AMPA and NMDA receptors are colocalized at synapses and their relative contributions to synaptic signaling and expression are tightly linked, we also quantified the relative amount of GluN1 protein. Amazingly, we observed an up regulation of GluN1 expression in complete hippocampus, but again only a tiny alteration in the synaptoneurosome fraction. These information suggest that a number of compensatory alterations in glutamate receptor expression occur inGluA2L483Y/wt mice. To validate these alterations in receptor expression observed with Western blot assessment, we carried out immunohistochemical analysis on sections from GluA2L483Y/wt and GluA2wt/wt. Using quantitative measurements of labeling density in sections from WT andmutant animalswe compared expression of GluA1,GluA2, and GluN1 in the hippocampal regions stratum oriens, stratum pyramidale, and stratum radiatum.

Even though we did not see as clear alterations in antibody density in sections as we had in protein blots, there was a reduction in hippocampalGluA1 and FDA and a small boost in GluN1 dependable with our preliminary locating. Total these results demonstrate that introduction of the mutant Dovitinib allele triggers a drastic alteration in glutamate receptor expression in GluA2L483Y/wt mice. Glutamate Receptors Are Not Sequestered in the ER in GluA2L483Y/wt Mice. The expression of glutamate receptors is managed by mechanisms that regulate biogenesis and assembly of membrane proteins in the endoplasmic reticulum. Misfolded or improperly assembled receptors are not further trafficked into the secretory pathway, becoming trapped in theER.

Aprevious research demonstrated that when GluA2 was exogenously expressed in cultured neurons, receptor subunits assembled commonly in tetrameric complexes but ER Pazopanib exit of this mutant receptor was lowered. Using an EndoH assay to establish the glycosylation state of GluA2 receptor subunits, we located that AMPA receptors did not appear to be accumulating in intracellular compartments in GluA2L483Y/wt mice. There was no improve in the immature ER resident GluA2 protein, and in reality we observed much less immature protein, which is probably due to a reduce in the overall abundance of GluA2.

de VrieItinib sorafenib absorption and brain, and de Vries ENMD-2076 et al. ver ffentlichten similar results for topotecan. Thus, in pr Clinical trials erh Hte elacridar fa It significant brain penetration of drugs that are P gp dual BCRP substrates. Apart from these compounds, which have been developed for use as agents to reverse multiple drug resistance, several studies drugs that two P gp BCRP substrates were competitively inhibit both Tr hunter is. That’m Ren various anti-tyrosine kinase inhibitors has been shown to be substrates for both P gp and BCRP. In vitro studies have shown that tyrosine kinase inhibitors such as erlotinib, gefitinib, lapatinib and sunitinib ABC transporters, especially inhibits P gp and BCRP and beat the m Improve Possible use of these agents in combination therapy pharmacokinetics of drugs.
In 2006, Zhuang et al. showed that the co-administration of gefitinib leads to a significant Erh increase the brain penetration of topotecan. The same group showed that gefitinib and intracellular Re tumor exposure to topotecan in a mouse model of glioma increased Ht. In a recent clinical study using Furman and his colleagues inhibit Cilomilast intestinal P gp and BCRP and gefitinib has been shown to increased the oral bioavailability of irinotecan hen. An interesting study by Nakanishi et al. in 2006 showed that imatinib resistance reduced BCRP expression BCRP l mediates between. The mechanism behind these different reactions in downstream effects of imatinib, which went to the phosphorylation of Akt, then what expression to reduced BCRP.
Many tyrosine kinase inhibitors have an inhibitory effect on the k PI3K Pathway PTEN signaling These drugs act Can therefore reduce the functional activity of t and protein expression of ABC transporters, in particular by blocking the PI3K Akt signaling BCRP. Combination of tyrosine kinase inhibitors with other anticancer drugs may therefore have a bimodal effect of ABC transporters in which the transporter expression can be entered decreased function associated with competitive inhibition Dinner drug penetration increased fa it well above the BBB and drug concentrations potentially a significant increase in brain tumors. In conclusion, the simultaneous dual inhibitors BCRP P gp can therefore improve the delivery and efficacy of drugs that are substrates of the central nervous system.
Recent data indicate that to inhibit the use of tyrosine kinase inhibitors for the P gp BCRP k Nnten have many advantages, particularly when the anti-cancer agent improves the supply of its own. To the brain 5 The blood-brain barrier in brain tumors Recent studies show that the integrity of t The BBB in brain tumors found Hrdet is questioning their r Limitation in the delivery of chemotherapeutic agents to brain tumors. In fact, reports show that the concentrations of anticancer drugs in tumor tissue resected remarkably high. In this regard, Pitz et al. lt contains a summary of the concentrations of anticancer drugs to brain tumors, and showed that high concentrations of active ingredients in the field of tumor-enrichment. Hofer and colleagues

of Ransporters, the pharmacokinetics and efficacy of medicines. Thus m Possible drug compounds usually examined to determine whether it is substrates for ABC transporters. Therefore mediates the synthesis of drugs are medicinal chemists analogues multidrug resistance of ABC transporters deal. For example, camptothecin analogues were con ABCG2 substrate specificity and tested us t. Less polar WYE-354 compounds have to be used as substrates for ABCB1 or ABCG2. It also develops drugs for longer substrates for the transport of dissolved Most substances, proteins A superfamily of membrane transport shown recently, that play an r Can facilitate important in the pharmacokinetics of drugs to prevent the adoption of chemotherapy drugs and MDR. R Solute the Tr hunters in cancer chemotherapy has been recently discussed elsewhere.
However, Fasudil there is no conclusive evidence yet experimental overexpression of gel Most transporters in resistant tumor tissue. Develop compounds specifically target cancer cells multidrug Despite considerable efforts, inhibitors and modulators to discover natural products drug ABC transporters, there are no inhibitors currently used in clinical treatment. Verapamil, a first ABCB1 modulators present effectively reverse MDR mediated by ABCB1 was also one of the first compounds have a high toxicity t guarantees overexpress ABCB1 in Chinese hamster ovary cells. This sensitivity or hypersensitivity warranty provides researchers with an alternative approach to hedge against MDR induced by the overexpression of ABC transporters drugs k Can fight.
Many research groups are compounds whose toxicity t Substantial warranty MDR cell lines, can induce apoptosis specifically looking at MDR cell lines. These compounds have potential applications exist in the clinic, either alone or in combination with cancer chemotherapeutic agents already. Examples of compounds having a weight sensitivity Hrleistet are listed in Table 2. In 1987, Cano Gauci and Riordan found that overexpression of ABCB1 hypersensitive in the Chinese hamster were on calcium channel blockers such as verapamil, nifedipine and the calmodulin inhibitor trifluoperazine. This hypersensitivity is both independently Ngig and calcium-independent-Dependent intracellular Re accumulation of verapamil. Subsequent studies by Warr et al.
in 1988 showed that in addition to calcium channel blockers, vincristine-resistant CHO cells are also hypersensitive active on membrane agents quinidine, suggesting that calcium-channels the main objective of this hypersensitivity or toxicity t warranty. More recently Karwatsky et al. observed concentrated on mechanistic aspects of hypersensitivity MDR CHO cells verapamil. It was concluded that apoptosis is caused by the increase in the production of reactive oxygen species in the MDR cells. Furthermore, this toxicity T guarantee with increased FITTINGS ATPase activity T correlated independently Ngig of the activity t of p53 and

CNIH 2 co localize and co fractionate in hippocampus To determine whether or not CNIH 2 and TARPs interact in hippocampal neurons, we generated antibodies to CNIH 2. To distinguish in between these prospects, we transfected primary hippocampal cultures with 8. Untransfected neurons did not show glutamate evoked resensitization. Even so, resensitization was plainly evident in 8 transfected neurons. The kainate / glutamate ratios in 8 transfected neurons have been similar to the values detected in non neuronal cells containing GluA1o/2 and 8 subunits.

As in recombinant techniques, CNIH 2 transfection in 8 transfected hippocampal neurons blocked resensitization. These data indicate that resensitization can occur in neurons and suggests a balance exists in between 8 and CNIH 2 in hippocampal neuronal AMPA receptors to modulate channel function. We employed fast perfusion electrophysiology to evaluate Ecdysone if 8 and CNIH 2 synergistically modulate AMPA receptor kinetics. Comparable to preceding reports, GluA1 subunit expressed alone exhibits quickly kinetics, and co expression of 8 slowed deactivation and desensitization rates. CNIH 2 expression slowed deactivation / desensitization rates to a better degree than 8, which is analogous to a previous study evaluating 2 and CNIH 2/3.

Of note, co expression of HSP with 8 even more slowed deactivation / desensitization charges. Additionally, analyses of currents resulting from 1 ms and 200 ms glutamate applications uncovered that co expression of 8 and CNIH 2 provides GW786034 far more charge transfer than expression of both or 8 alone. To assess the role for endogenous CNIH 2 in hippocampal synaptic function, we sought to knockdown its expression employing shRNA and, then, measure pharmacologically isolated, AMPA receptormediated miniature excitatory submit synaptic responses. This shRNA approach diminished, but did not remove, CNIH 2 protein expression in transfected HEK 293T cells and cultured hippocampal neurons. Additionally, CNIH 2 knockdown considerably diminished hippocampal mEPSC charge transfer with no impact on rise time or frequency.

To much more directly measure small molecule library effects on extra synaptic and synaptic AMPA receptors, we utilized cultured stargazer cerebellar granule neurons, which lack functional AMPA receptors as well as TARP and CNIH 2/3 subunits. Equivalent to our heterologous cell findings, bath application of glutamate to 8 transfected stargazer granule cells produced a resensitizing present that was inhibited by co expression of CNIH 2. Transfection of CNIH 2 alone did not rescue synaptic AMPA receptors whereas transfection with 8 developed mEPSCs that decayed with a tau of 2. 5 ms. Importantly, co expression of CNIH 2 with 8 slowed mEPSCs and did not have important effects on amplitude relative to wild sort or 8 transfected stargazer granule cells.

Taken collectively, these outcomes display that CNIH 2 can modulate decay kinetics of synaptic AMPA receptors by means of synergic actions with 8 containing receptors. Both 8 and CNIH 2 regulate added synaptic hippocampal AMPA receptor function We next evaluated for CNIH 2 modulation of cyclothiazide actions on kainateevoked currents from AMPA receptors, for which Dovitinib the hippocampal neuronal phenotype has nevertheless to be recapitulated with co expression of fluorescent peptides and TARP subunits.

the US Four CR and 11 PR, signature approval by the U.S. Food and Drug Administration for the treatment of relapsed refractory CTCL. B cells and Hodgkin promising Brivanib BMS-540215 results were obtained with vorinostat study its effect on tumor B-cells, in particular obtained DLBCL. This study was made of how the Phase I trial expected since only one patient of 18 showed a completely’s Full response, w While 16 patients had progressive disease and stable disease. Vorinostat in HL showed a partial response in one patient and stable disease in nine of 25 patients tested f Rderf compatibility available. A phase I-II study in non-Hodgkin’s lymphoma, with a schedule of 200 mg twice t Possible administered for 14 days on a 21-day cycle, in four patients showed CR, two PR and SD in four of the 17 patients in the study.
Panobinostat was Hodgkin’s lymphomas in a multicenter Phase II study of CT IA partial response shows in 5 treated 13 patients for a metabolic response and F 2 fluoride positron emission tomography scan D-glucose deoxy investigated in 7 12 evaluable patients. Mocetinostat was also tested in the B-cell lymphomas and SRT1720 HL. In the first case, a clinical phase II study in patients with refractory showed Rer relapsed DLBCL and follicular Ren lymphoma treated with rituximab-based regimen one CR and three PR and 13 SD DLBCL group, one patient in ten FL achieved a PR. Interestingly, patients presented with DLBCL SD PFS 6 months to 1 year. Very encouraging results have been shown in a clinical study of the II phase relapse refractory HL at a dose of 85 or 110 mg three times per week.
In the 110-mg cohort had two CR and six PR, with a very long PFS, all patients in the 85 mg cohort, a reduction of the tumor with a PR and a standard deviation. After all, SD was in 7 of 13 evaluable patients in a Phase II trial with Givinostat in HL without severe toxicity Reported t. HDACIs in the treatment of acute leukemia Mie Myelo s Myelodysplastic syndromes and the activity of t Against Leuk Mie were in pr Clinical studies paved the way for a show is large number of clinical trials in leukemia Chemistry and myelodysplastic syndromes. Clinical trials of monotherapy proved to be interesting, but limited results, perhaps due to the fact that enrolled the Phase I and II clinical relapse refractory, heavily pretreated patients. The first in the treatment of AML HDACi and high risk MDS Valproins ure Used As a well-known drug used in the treatment of epilepsy.
The most groundbreaking studies reported the clinical efficacy of VPA alone, but always h More frequently in combination with S Retino acid Each trans. A pilot study of the combination of ATRA VPA in patients aged 11 de novo AML were performed, showed a complete remission marrow in three patients, including one complete response and two other h Hematological improvement. A German study, studying the combination of ATRA, VPA was also performed in 26 patients with poor risk AML, one patient with

Where Akt activation is suppressed and treated ht BAD activation is possible to change the K St insurance change other unknown destinations NDGA Nnte induce apoptosis neuroblastoma. However, 10 nM IGF-I is known to completely avoid the times when the activation of caspase-3 induced apoptosis stressor is not related to IGF-I signaling. In our experiments, caspase 3 activation remained strong after the LY2157299 administration of 10 nM IGF-I, suggesting that the rescue of the stimulated IGF not affected by NDGA treatment. IGF-I stimulates neuroblastoma cells with organized actin polymerization and lamellipodia extensions Verl, a Erh hung Erh the Zellmotilit Subir t produced. Erh Hte Zellmotilit t and FF Ability that makes digesting extracellular Re Matrix Re tumor cells, vessels of an era F gr Fassungsverm Tions penetrate tissue and blood s what.
For the spread of metastases and diffuse tissue This situation is particularly worrying in neuroblastoma, where tumor invasion of the bone production of IGF highly associated with poor response to treatment. We found that NDGA effectively inhibits IGF-I stimulates motility t t of neuroblastoma. AEE788 NDGA not show high selectivity t for a single receiver singer to AEW541 and NVP NVP ADW742 difference, and should not exclude Lich as an inhibitor of IGF IR Lich. NDGA probably works on a subset of receptor tyrosine kinases, including normal and normal IGF IR InsR new Her2 receptor. NDGA inhibits activation of the PDGF receptor and the DNA synthesis by PDGF-stimulated. Et al found no effect Seufferlein NDGA tion of the EGF receptor phosphorylation. Further efforts receptors by treatment NDGA are that IGF-I and insulin receptors are highly homologous t influenced Ben CONFIRMS k characterize Nnte, part of the effect of NDGA against tumorigenesis of neuroblastoma are mediated by inhibition of BIO. However, insulin is 200 times less potent than IGF-I in SH SY5Y not mediated proliferation and at least a third effect of insulin on the proliferation through activation of the IGF is InsR IR.
In addition, plasma concentrations of IGF-I 100 to 1000 times st Stronger focus than insulin. Thus the inhibition of InsR is unlikely to make a significant anti-tumor effects of NDGA in neuroblastoma. Interestingly, the efficacy against genotype NDGA InsR diabetic Ph forecasts cause. Paradoxically NDGA an effect on diabetic rats against the decrease in serum triglycerides and glucose without insulin. NDGA was previously considered for the treatment of diabetes by the inhibition of prostaglandin synthesis. Then k Nnte NDGA, inhibition of insulin receptor is not recorded diabetes td dinner toxicity due to their side effects on prostaglandin synthesis. NDGA analogs for more specificity T Era reached gr t be developed, and some have been tested for their efficacy against lung cancer. Further characterization of these analogs can lead to discovery of more specific agents tyr lead single receiver Lead singer

the nM range while no effect was seen in HBE135 E6E7 cells, even at concentrations as high as 1000 nM or twenty times the average IC50 observed in NSCLC cell lines. fgfr signaling These results suggest that NSCLC growth and survival mediated by a broad range of molecular factors are selectively sensitive to inhibition of PI3K by NVP BEZ235. Targets of NVP BEZ235 were determined by immunoblot analysis in cells with up to 24 hours drug exposure. Any drug exposure beyond 24 hours resulted in significant amount of dead cells and debris and would have limited the interpretability. pAKT, pP70S6K and pS6 decreased with exposure to the drug in a time dependent fashion, as shown by immunoblot analysis in Figure 4, panel A for H2170 and HCC2935 cell lines.
Relative to untreated cells, pAKT, pP70S6K, and pS6 were downregulated with NVP BKM120, LY294002, and NVP BEZ235. NVP BEZ235 was previously shown to cause PARP cleavage and induce apoptosis through activation of caspase 2, but not caspases 8, 9, and 10. We therefore studied the effect of NVP BEZ235 on PARP cleavage and caspase 2 activation in two most sensitive lung cancer cell Hesperidin lines, HCC2935 and H2170. As shown in Figure 4, panel B NVP BEZ235 treatment results in PARP cleavage and modest caspase 2 activation. Cleaved caspase 2 was not detected by western blotting in this assay. Synergism between the dual PI3K mTOR inhibitor NVPBEZ235 and the EGFR inhibitor erlotinib in NSCLC cell lines Our results so far show that mTOR blockade is necessary to enhance the inhibition of the PI3K pathway.
Given that inhibiting only one or two steps of the survival and proliferation pathways often proves to be therapeutically insufficient due to the various escape mechanisms, we studied the efficacy of multi level targeting by adding EGFR tyrosine kinase inhibition to dual PI3K mTOR inhibition in the same set of six NSCLC cell lines. Cells were treated with the PI3K inhibitor NVP BEZ235 alone or combined with erlotinib, at their respective single drug IC50, IC25 or IC10 concentrations, and viability was measured at 72 hours with the Cell Titer Glo assay. As shown in Table S6, synergism was seen in all six cell lines studied, including SW900 and SK MES 1 which are highly resistant to erlotinib alone. Notably, in all four erlotinib sensitive cell lines synergy was relatively more enhanced at higher concentrations of erlotinib.
A graphic example of the combined effect of these two drugs in H2170 and HCC2935 is shown in Figure 5 and Table S7. Of note, the majority of erlotinib concentrations used in these experiments are well below the reported steady state level of erlotinib achieved in actual patients which has been reported as 1200 2620 ng ml. This translates into 2797.2 21445.2 nM of erlotinib. Discussion Deregulation of the PI3K AKT mTOR signaling pathway has been demonstrated in NSCLC. In this study, we assessed the expression of PI3K subunits p85 and p110a in NSCLC tumor specimens. In the two