Publications by authors named "Kevin T Nguyen"

18 Publications

  • Page 1 of 1

Patients with Non-invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features are Unlikely to have Malignant Preoperative Cytology.

Ann Surg Oncol 2017 Oct 11;24(11):3300-3305. Epub 2017 Aug 11.

Department of Surgery, University of California, Davis Medical Center, Sacramento, CA, USA.

Background: The newly termed tumor 'noninvasive follicular thyroid neoplasm with papillary-like nuclear features' (NIFTP) acts in an indolent manner and can likely be safely managed with a thyroid lobectomy. Preoperative fine-needle aspiration (FNA) is the cornerstone of surgical planning, but the ability of FNA to distinguish NIFTP from other variants of papillary thyroid carcinoma (PTC) has not been well-evaluated.

Methods: A 9-year retrospective review of the preoperative cytology and surgical pathology of PTC patients who underwent a thyroidectomy at our tertiary referral center.

Results: Overall, 174 patients with 177 PTCs had a preoperative FNA followed by a thyroidectomy, and met our inclusion criteria. Of the 21 patients with NIFTP, the preoperative cytology was read as malignant in three (14%), suspicious for malignancy in three (14%), follicular neoplasm in ten (48%), atypia of undetermined significance in four (19%), and benign in one (5%) nodule. When comparing patients with NIFTP with other variants of PTC, patients with NIFTP were younger (p = 0.023) and less likely to have malignant cytology (p < 0.001). On multivariable regression modeling, malignant cytology was independently associated with a decreased risk of a final diagnosis of NIFTP (odds ratio 0.064, 95% confidence interval 0.018-0.233, p < 0.001).

Conclusions: Patients with a final diagnosis of NIFTP are less likely to have preoperative FNA diagnosis of malignancy than those with final pathology of classical or other variants of PTC. Surgeons should take this into consideration when considering between a lobectomy and total thyroidectomy for patients with suspected PTC.
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http://dx.doi.org/10.1245/s10434-017-6038-5DOI Listing
October 2017

P2-quinazolinones and bis-macrocycles as new templates for next-generation hepatitis C virus NS3/4a protease inhibitors: discovery of MK-2748 and MK-6325.

ChemMedChem 2015 Apr 10;10(4):727-35. Epub 2015 Mar 10.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA (USA).

With the goal of identifying inhibitors of hepatitis C virus (HCV) NS3/4a protease that are potent against a wide range of genotypes and clinically relevant mutant viruses, several subseries of macrocycles were investigated based on observations made during the discovery of MK-5172. Quinazolinone-containing macrocycles were identified as promising leads, and optimization for superior cross-genotype and mutant enzyme potency as well as rat liver and plasma concentrations following oral dosing, led to the development of MK-2748. Additional investigation of a series of bis-macrocycles containing a fused 18- and 15-membered ring system were also optimized for the same properties, leading to the discovery of MK-6325. Both compounds display the broad genotype and mutant potency necessary for clinical development as next-generation HCV NS3/4a protease inhibitors.
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http://dx.doi.org/10.1002/cmdc.201402558DOI Listing
April 2015

Tumor size predicts vascular invasion and histologic grade among patients undergoing resection of intrahepatic cholangiocarcinoma.

J Gastrointest Surg 2014 Jul 20;18(7):1284-91. Epub 2014 May 20.

Department of Surgery at Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The association between tumor size and survival in patients with intrahepatic cholangiocarcinoma (ICC) undergoing surgical resection is controversial. We sought to define the incidence of major and microscopic vascular invasion relative to ICC tumor size, and identify predictors of microscopic vascular invasion in patients with ICC ≥5 cm. A total of 443 patients undergoing surgical resection for ICC between 1973 and 2011 at one of 11 participating institutions were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses. As tumor sized increased, the incidence of microscopic vascular invasion increased: <3 cm, 3.6 %; 3-5 cm, 24.7 %; 5-7 cm, 38.3 %; 7-15 cm, 32.9 %, ≥15 cm, 55.6 %; (p < 0.001). Increasing tumor size was also found to be associated with worsening tumor grade. The incidence of poorly differentiated tumors increased with increasing ICC tumor size: <3 cm, 9.7 %; 3-5 cm, 19.8 %; 5-7 cm, 24.2 %; 7-15 cm, 21.1 %; >15 cm, 31.6 % (p = 0.04). The presence of perineural invasion (odds ratio [OR] = 2.98) and regional lymph node metastasis (OR = 4.43) were independently associated with an increased risk of microscopic vascular invasion in tumors ≥5 cm (both p < 0.05). Risk of microscopic vascular invasion and worse tumor grade increased with tumor size. Large tumors likely harbor worse pathologic features; this information should be considered when determining therapy and prognosis of patients with large ICC.
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http://dx.doi.org/10.1007/s11605-014-2533-1DOI Listing
July 2014

Quantitative phosphoproteomic analysis identifies activation of the RET and IGF-1R/IR signaling pathways in neuroblastoma.

PLoS One 2013 11;8(12):e82513. Epub 2013 Dec 11.

Division of Pediatric Hematology-Oncology, Department of Pediatrics, The Warren Albert School of Medicine at Brown University, Providence, Rhode Island, United States of America.

Neuroblastoma is an embryonal tumor of childhood with a heterogenous clinical presentation that reflects differences in activation of complex biological signaling pathways. Protein phosphorylation is a key component of cellular signal transduction and plays a critical role in processes that control cancer cell growth and survival. We used shotgun LC/MS to compare phosphorylation between a human MYCN amplified neuroblastoma cell line (NB10), modeling a resistant tumor, and a human neural precursor cell line (NPC), modeling a normal baseline neural crest cell. 2181 unique phosphorylation sites representing 1171 proteins and 2598 phosphopeptides were found. Protein kinases accounted for 6% of the proteome, with a predominance of tyrosine kinases, supporting their prominent role in oncogenic signaling pathways. Highly abundant receptor tyrosine kinase (RTK) phosphopeptides in the NB10 cell line relative to the NPC cell line included RET, insulin-like growth factor 1 receptor/insulin receptor (IGF-1R/IR), and fibroblast growth factor receptor 1 (FGFR1). Multiple phosphorylated peptides from downstream mediators of the PI3K/AKT/mTOR and RAS pathways were also highly abundant in NB10 relative to NPC. Our analysis highlights the importance of RET, IGF-1R/IR and FGFR1 as RTKs in neuroblastoma and suggests a methodology that can be used to identify potential novel biological therapeutic targets. Furthermore, application of this previously unexploited technology in the clinic opens the possibility of providing a new wide-scale molecular signature to assess disease progression and prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859635PMC
October 2014

Recurrence after operative management of intrahepatic cholangiocarcinoma.

Surgery 2013 Jun 15;153(6):811-8. Epub 2013 Mar 15.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Introduction: Data on recurrence after operation for intrahepatic cholangiocarcinoma (ICC) are limited. We sought to investigate rates and patterns of recurrence in patients after operative intervention for ICC.

Methods: We identified 301 patients who underwent operation for ICC between 1990 and 2011 from an international, multi-institutional database. Clinicopathologic data, recurrence patterns, and recurrence-free survival (RFS) were analyzed.

Results: During the median follow up duration of 31 months (range 1-208), 53.5% developed a recurrence. Median RFS was 20.2 months and 5-year actuarial disease-free survival, 32.1%. The most common site for initial recurrence after operation of ICC was intrahepatic (n = 98; 60.9%), followed by simultaneous intra- and extrahepatic disease (n = 30; 18.6%); 33 (21.0%) patients developed extrahepatic recurrence only as the first site of recurrence. Macrovascular invasion (hazard ratio [HR], 2.08; 95% confidence interval [CI], 1.34-3.21; P < .001), nodal metastasis (HR, 1.55; 95% CI, 1.01-2.45; P = .04), unknown nodal status (HR, 1.57; 95% CI, 1.10-2.25; P = .04), and tumor size ≥ 5 cm (HR, 1.84; 95% CI, 1.28-2.65; P < .001) were independently associated with increased risk of recurrence. Patients were assigned a clinical score from 0 to 3 according to the presence of these risk factors. The 5-year RFS for patients with scores of 0, 1, 2, and 3 was 61.8%, 36.2%, 19.5%, and 9.6%, respectively.

Conclusion: Recurrence after operative intervention for ICC was common. Disease recurred both at intra- and extrahepatic sites with roughly the same frequency. Factors such as lymph node metastasis, tumor size, and vascular invasion predict highest risk of recurrence.
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http://dx.doi.org/10.1016/j.surg.2012.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3980567PMC
June 2013

Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers.

Bioorg Med Chem Lett 2012 Dec 2;22(23):7207-13. Epub 2012 Oct 2.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.
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http://dx.doi.org/10.1016/j.bmcl.2012.09.061DOI Listing
December 2012

Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease.

Bioorg Med Chem Lett 2012 Dec 7;22(23):7201-6. Epub 2012 Sep 7.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.
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http://dx.doi.org/10.1016/j.bmcl.2012.08.106DOI Listing
December 2012

The CRM1 nuclear export protein in normal development and disease.

Int J Biochem Mol Biol 2012 18;3(2):137-51. Epub 2012 May 18.

Department of Pediatrics, Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital and The Warren Alpert Medical School at Brown University Providence, Rhode Island, USA.

CRM1 (Chromosomal Maintenance 1, also known as Exportin 1) is the major mammalian export protein that facilitates the transport of large macromolecules including RNA and protein across the nuclear membrane to the cytoplasm. The gene encoding CRM1 was originally identified in yeast as required to maintain higher order chromosome structure. In mammalian cells, CRM1 was found to bind several nuclear pore proteins hence its role in nuclear-cytosolic transport was discovered. In addition to nuclear-cytosolic transport, CRM1 also plays a role in centrosome duplication and spindle assembly, especially in response to DNA damage. The crystal structure of CRM1 suggests a complex protein that binds the Ran protein bound to GTP, allowing for a conformational change that facilitates binding to different cargo proteins through a nuclear export signal (NES). Included in the cadre of cargo are multiple tumor suppressor and oncoproteins as p53, BRCA1, Survivin, NPM, and APC, which function in the nucleus to regulate transcription or aid in chromosomal assembly and movement. An imbalance in the cytosolic level of these proteins has been observed in cancer cells, resulting in either inactivation (tumor suppressor) or an excess of anti-apoptotic activity (oncoprotein). Thus, the concept of inhibiting CRM1 has been explored as a potential therapeutic intervention. Indeed, inhibition of CRM1 by a variety of small molecules that interfere with cargo-NES binding results in cancer cell death. Whether all of these proteins together are responsible for this phenotype or whether specific proteins are required for this effect is unclear at this time.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3388738PMC
October 2012

Discovery of MK-5172, a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor.

ACS Med Chem Lett 2012 Apr 2;3(4):332-6. Epub 2012 Mar 2.

Departments of Medicinal Chemistry, Antiviral Research, Drug Metabolism, and Chemistry, Modeling and Informatics, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.
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http://dx.doi.org/10.1021/ml300017pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025840PMC
April 2012

Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment.

J Clin Oncol 2011 Aug 5;29(23):3140-5. Epub 2011 Jul 5.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Purpose: To identify factors associated with outcome after surgical management of intrahepatic cholangiocarcinoma (ICC) and examine the impact of lymph node (LN) assessment on survival.

Patients And Methods: From an international multi-institutional database, 449 patients who underwent surgery for ICC between 1973 and 2010 were identified. Clinical and pathologic data were evaluated using uni- and multivariate analyses.

Results: Median tumor size was 6.5 cm. Most patients had a solitary tumor (73%) and no vascular invasion (69%). Median survival was 27 months, and 5-year survival was 31%. Factors associated with adverse prognosis included positive margin status (hazard ratio [HR], 2.20; P < .001), multiple lesions (HR, 1.80; P = .001), and vascular invasion (HR, 1.59; P = .015). Tumor size was not a prognostic factor (HR, 1.03; P = .23). Patients were stratified using the American Joint Committee on Cancer/International Union Against Cancer T1, T2a, and T2b categories (seventh edition) in a discrete step-wise fashion (P < .001). Lymphadenectomy was performed in 248 patients (55%); 74 of these (30%) had LN metastasis. LN metastasis was associated with worse outcome (median survival: N0, 30 months v N1, 24 months; P = .03). Although patients with no LN metastasis were able to be stratified by tumor number and vascular invasion (N0; P < .001), among patients with N1 disease, multiple tumors and vascular invasion, either alone or together, failed to discriminate patients into discrete prognostic groups (P = .34).

Conclusion: Although tumor size provides no prognostic information, tumor number, vascular invasion, and LN metastasis were associated with survival. N1 status adversely affected overall survival and also influenced the relative effect of tumor number and vascular invasion on prognosis. Lymphadenectomy should be strongly considered for ICC, because up to 30% of patients will have LN metastasis.
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http://dx.doi.org/10.1200/JCO.2011.35.6519DOI Listing
August 2011

Discovery of MK-1220: A Macrocyclic Inhibitor of Hepatitis C Virus NS3/4A Protease with Improved Preclinical Plasma Exposure.

ACS Med Chem Lett 2011 Mar 12;2(3):207-12. Epub 2011 Jan 12.

Departments of Medicinal Chemistry, Molecular Systems, Antiviral Research, and Drug Metabolism, Merck Research Laboratories , West Point, Pennsylvania 19486, United States.

The discovery of MK-1220 is reported along with the development of a series of HCV NS3/4A protease inhibitors containing a P2 to P4 macrocyclic constraint with improved preclinical pharmacokinetics. Optimization of the P2 heterocycle substitution pattern as well as the P3 amino acid led to compounds with greatly improved plasma exposure following oral dosing in both rats and dogs while maintaining excellent enzyme potency and cellular activity. These studies led to the identification of MK-1220.
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http://dx.doi.org/10.1021/ml1002426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017977PMC
March 2011

Robotic-assisted major pancreatic resection and reconstruction.

Arch Surg 2011 Mar 15;146(3):256-61. Epub 2010 Nov 15.

Division of Surgical Oncology, University of Pittsburgh Medical Center Pancreatic Cancer Center, 3550 Terrace St., Pittsburgh, PA 15261, USA.

Hypothesis: Robotic-assisted pancreatic resection and reconstruction are safe and can reproduce perioperative results seen in open surgery.

Design: Single-institution retrospective review.

Setting: Tertiary care center.

Patients: Patients undergoing completed robotic-assisted pancreatic resection and reconstruction at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, between October 3, 2008, and February 26, 2010.

Main Outcome Measures: Primary pathology, operative time, operative blood loss, perioperative blood transfusions, pancreatic fistula, 90-day morbidity and mortality, and readmission rate.

Results: Thirty patients with a median age of 70 years (range, 32-85 years) underwent completed robotic-assisted pancreatic resection and reconstruction. Procedures were robotic-assisted non-pylorus-preserving pancreaticoduodenectomy (n = 24), robotic-assisted central pancreatectomy (n = 4), and the robotic-assisted Frey procedure (n = 2). The median operative time was 512 minutes (range, 327-848 minutes). The median blood loss was 320 mL (range, 50-1000 mL), with a median length of hospital stay of 9 days (range, 4-87 days). The final diagnoses included periampullary adenocarcinoma (n = 7), pancreatic ductal adenocarcinoma (n = 6), pancreatic neuroendocrine tumor (n = 5), intraductal papillary mucinous neoplasm (n = 4), mucinous cystic neoplasm (n = 3), serous cystic adenoma (n = 2), chronic pancreatitis (n = 2), and solid pseudopapillary neoplasm (n = 1). There was 1 postoperative death. The overall pancreatic fistula rate was 27% (n = 8). The clinically significant pancreatic fistula rate (International Study Group on Pancreatic Fistula grades B and C) was 10% (n = 3). Clavien grade III and IV complications occurred in 7 patients (23%), while Clavien grade I and II complications occurred in 8 patients (27%).

Conclusions: Robotic-assisted complex pancreatic surgery can be performed safely in a high-volume pancreatic tertiary care center with perioperative outcomes comparable to those of open surgery. Advances in robotic technology and increasing experience may improve long operative times.
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http://dx.doi.org/10.1001/archsurg.2010.246DOI Listing
March 2011

Discovery of vaniprevir (MK-7009), a macrocyclic hepatitis C virus NS3/4a protease inhibitor.

J Med Chem 2010 Mar;53(6):2443-63

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.
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http://dx.doi.org/10.1021/jm9015526DOI Listing
March 2010

Molecular modeling based approach to potent P2-P4 macrocyclic inhibitors of hepatitis C NS3/4A protease.

J Am Chem Soc 2008 Apr 14;130(14):4607-9. Epub 2008 Mar 14.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

Molecular modeling of inhibitor bound full length HCV NS3/4A protease structures proved to be a valuable tool in the design of a new series of potent NS3 protease inhibitors. Optimization of initial compounds provided 25a. The in vitro activity and selectivity as well as the rat pharmacokinetic profile of 25a compare favorably with the data for other NS3/4A protease inhibitors currently in clinical development for the treatment of HCV.
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http://dx.doi.org/10.1021/ja711120rDOI Listing
April 2008

Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists.

Bioorg Med Chem Lett 2007 Jul 29;17(14):3997-4000. Epub 2007 Apr 29.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.

A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.
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http://dx.doi.org/10.1016/j.bmcl.2007.04.084DOI Listing
July 2007

Identification and characterization of 4-methylbenzyl 4-[(pyrimidin-2-ylamino)methyl]piperidine-1-carboxylate, an orally bioavailable, brain penetrant NR2B selective N-methyl-D-aspartate receptor antagonist.

J Med Chem 2007 Feb 24;50(4):807-19. Epub 2007 Jan 24.

Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
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http://dx.doi.org/10.1021/jm060983wDOI Listing
February 2007

The role of phosphatidylinositol 3-kinase, rho family GTPases, and STAT3 in Ros-induced cell transformation.

J Biol Chem 2002 Mar 17;277(13):11107-15. Epub 2002 Jan 17.

Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029, USA.

Using loss-of-function mutants of Ros and inducible epidermal growth factor receptor-Ros chimeras we investigated the role of various signaling pathways in Ros-induced cell transformation. Inhibition of the mitogen-activated protein kinase (MAPK) pathway with the MEK (MAP/extracellular signal-regulated kinase kinase) inhibitor PD98059 had little effect on the Ros-induced monolayer and anchorage-independent growth of chicken embryo fibroblasts and NIH3T3 cells even though more than 70% of the MAPK was inhibited. In contrast, inhibiting the phosphatidylinositol 3-kinase (PI3K) pathway with the drug LY294002, a dominant negative mutant of PI3K, Deltap85, or the phosphatidylinositol phosphatase PTEN (phosphatase and tensin homologue deleted in chromosome ten) resulted in a dramatic reduction of v-Ros- and epidermal growth factor receptor-Ros-promoted anchorage-independent growth of chicken embryo fibroblasts and NIH3T3 cells, respectively. Parallel and downstream components of PI3K signaling such as the Rho family GTPases (Rac, Rho, Cdc42) and the survival factor Akt were all shown to contribute to Ros-induced anchorage-independent growth, although Rac appeared to be less important for Ros-induced colony formation in NIH3T3 cells. Furthermore, the transformation-attenuated v-Ros mutants F419 and DI could be complemented by constitutively active mutants of PI3K and Akt. Finally, we found that overexpressing a constitutively active mutant of STAT3 (STAT3C) conferred a resistance to the inhibition of Ros-induced anchorage-independent growth by LY294002, suggesting a possible overlap of functions between PI3K and STAT3 signaling in mediating Ros-induced anchorage-independent growth.
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http://dx.doi.org/10.1074/jbc.M108166200DOI Listing
March 2002