Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

EGFR mutations are a major determinant of lung tumor response to gefitinib, an EGFR-specific tyrosine kinase inhibitor. Obtaining a response from lung tumors expressing wild-type EGFR is a major obstacle. The combination of gefitinib and cytotoxic drugs is one strategy against lung cancers expressing wild-type EGFR. The DNA topoisomerase inhibitor irinotecan sulfate (CPT-11) is active against lung cancer. We examined the sensitivity of lung cancers expressing wild- or mutant-type EGFR to the combination of gefitinib and CPT-11. The in vitro effect of gefitinib and SN-38 (the active metabolite of CPT-11) was examined in seven lung cancer cell lines using the dye formation assay with a combination index. When administered concurrently, gefitinib and SN-38 had a synergistic effect in five of the seven cell lines expressing wild-type EGFR, whereas the combination was antagonistic in PC-9 cells and a PC-9 subline resistant to gefitinib and expressing deletional mutant EGFR (PC-9/ZD). When administered sequentially, treatment with SN-38 followed by gefitinib had remarkable synergistic effects in the PC-9 and PC-9/ZD cells. In an in vivo tumor-bearing model, this combination had a schedule-dependent synergistic effect in the PC-9 and PC-9/ZD cells. An immunohistochemical analysis of the tumors in mice treated with CPT-11 and gefitinib demonstrated that the number of Ki-67 positive tumor cells induced by CPT-11 treatment was decreased when CPT-11 was administered in combination with gefitinib. In conclusion, the sequential combination of CPT-11 and gefitinib is considered to be active against lung cancer.
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PMID:Effects of different combinations of gefitinib and irinotecan in lung cancer cell lines expressing wild or deletional EGFR. 1671 12

Adenoid cystic carcinoma (ACC) accounts for about 1% of all head and neck malignancies. It has a tendency for a prolonged clinical course, with local recurrences and distant metastases sometimes occurring many years after presentation. Standard treatment for salivary gland ACC is surgery and post-operative radiotherapy. The aim of this review was to examine the reported efficacy of various chemotherapy regimens and molecular therapies on recurrent/metastatic salivary gland ACC. One hundred and fourteen publications were reviewed on chemotherapy as well as possible molecular targets of therapy, including KIT, epidermal growth factor receptor (EGFR), human epidermal growth receptor-2 (HER-2), oestrogen and progesterone receptors, proliferating cell nuclear antigen (PCNA), Ki-67 and the p53, bcl-2 and SOX-4 genes. Reported response rates to combination chemotherapy are low and response duration generally short lived. The response to molecular therapies is low also. More research into novel molecular targets is needed.
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PMID:Salivary gland adenoid cystic carcinoma: a review of chemotherapy and molecular therapies. 1675 3

Angiogenesis is important for tumor growth, and is regulated by angiogenetic factors such as vascular endothelial growth factor (VEGF). In the present study, we investigated whether or not expression of VEGF receptors (VEGFRs) is related to the proliferation of tumor cells in hepatocellular carcinoma (HCC). We simultaneously stained proliferation marker Ki-67 antigen and either VEGFR1 (Flt-1) or VEGFR2 (Flk-1) on paraffin-embedded tissue sections from 50 cases of surgically resected human HCC. Based on the staining pattern of VEGFRs, we classified the cases into 4 categories; receptor double-negative, Flt-1 single-positive, Flk-1 single-positive, receptor double-positive. Interestingly, the Ki-67 index was significantly lower in receptor double-negative cases in comparison to that in either Flt-1 single-positive or Flk-1 single-positive cases (P = 0.0491, P = 0.0196, respectively). Moreover, the index was also significantly lower in receptor double-positive cases in comparison to either Flt-1 single-positive or Flk-1 single-positive cases (P = 0.0026, P < 0.0001, respectively). We further investigated 35 cases showing a Ki67 index > 10% to determine the expression of VEGFRs on Ki-67 antigen-positive proliferating cells. Surprisingly, the histological grade of HCC and the expression pattern of VEGFRs showed a characteristic relation; the well-differentiated HCC cases were all distributed in the Flk-1-positive group (7/7), moderately differentiated HCC cases were distributed in either the Flt-1 or Flk-1 single-positive group (20/21), and poorly differentiated HCC cases were predominantly distributed in either the receptor double-negative or double-positive group (6/7). These findings suggest that the expression pattern of VEGFRs influences the histological differentiation of HCC.
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PMID:Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma. 1678 16

Fine needle aspiration is an established diagnostic tool in breast carcinoma. Although the potential of using the same diagnostic aspirate material to provide additional cytomorphologic prognostic or predictive information has been investigated, no well-recognized, practical grading system has been established. Such system is necessary in guiding treatment, monitoring neoadjuvant chemotherapy effect and predicting outcome. We herein propose a new grading system, combining nuclear grade, cellular dyscohesion, and bare atypical nuclei to arrive at one cytoprognostic score. Cytoprognostic scores were compared with other known prognostic factors. Fine needle aspirations of breast diagnosed as adenocarcinoma from 55 patients were reviewed. The cytoprognostic score combined three features including nuclear grade (score 1-3), cellular dyscohesion (score 1-3), and bare atypical nuclei (score 0, 1). A cytoprognostic score of 3 and below was considered a low score, and a score of 4-7 was considered a high score. The cytoprognostic score was then compared to histologic grade, lymph node status, and expressions of estrogen receptor, progesterone receptor, Her2-Neu, Ki-67, and p53 in the subsequently excised tumor. A low cytoprognostic score predicted a low to intermediate grade carcinoma and a high score predicted an intermediate to high-grade carcinoma. A high cytoprognostic score also correlated with more positive lymph node metastasis, and poor expression of prognostic markers. In conclusion, cytoprognostic score is performed with ease and shows a great promise as a cost-effective way to predict biological behavior of breast carcinoma and guide clinical management.
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PMID:Proposed prognostic score for breast carcinoma on fine needle aspiration based on nuclear grade, cellular dyscohesion and bare atypical nuclei. 1685 Apr 93

Secretory carcinomas (SBC) are characterized by their characteristic histomorphology and more favorable prognosis compared to invasive ductal carcinoma of usual type (IDC). On this basis, 13 SBCs are evaluated by molecular and immunohistochemical (IH) methods. 13 SBCs and 4 IDCs were analyzed for ETV6-NTRK3 gene fusion by reverse transcriptase-polymerase chain reaction (RT-PCR) and by Fluorescence in situ Hybridization (FISH). 8 of 13 microdissected SBCs with evaluable DNA were evaluated for genetic alterations (GA) by comparative genomic hybridization (CGH). IH included estrogen-receptor (ER), progesterone-receptor (PR), Her-2/neu and Ki-67 (MIB-1) in all 13 cases. Molecular and immunohistochemical results in SBCs were compared with previous data regarding immunohistochemical and molecular characteristics of IDCs. 12 of 13 (92 %) SBC cases, but not IDCs expressed the ETV6-NTRK3 fusion gene which encodes a chimeric tyrosine kinase. Retroviral transfer of ETV6-NTRK3 (EN) into murine mammary epithelial cells resulted in transformed cells that readily formed epithelial tumors in nude mice. CGH revealed an average of 2.0 GAs (range 0-6), including recurrent gains of chromosome 8q and 1q and losses of 22q. Four SBCs were positive for ER and 2 were positive for PR. The mean MIB-1-labeling index was 11.4% (range: <1-34%). Her-2/ neu protein overexpression was detected in 1 case (score 3+). Compared to previous findings in IDCs, SBCs are characterized by the recurrent expression of ETV6-NTRK3 fusion gene, a relatively low number of GAs, low proliferative rate, infrequent Her-2/ neu protein overexpression and a lower rate of steroid hormone receptor expression. These results support the hypothesis that SBCs have immunohistochemical and genetic features that specifically distinguish them from IDCs.
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PMID:Secretory carcinoma of the breast: a genetically defined carcinoma entity. 1688 13

Previous studies have demonstrated HER2 protein overexpression and/or gene amplification in a subset of patients with clinically significant prostate cancer (PCa), especially in the androgen-independent phase of the disease. There are no studies on incidentally detected PCa. The aim of the study was to analyze HER2 expression and gene amplification in PCa incidentally detected in cystoprostatectomies. High-grade prostatic intraepithelial neoplasia (HGPIN) was also investigated. Comparison was made with clinically detected PCa, both untreated and hormonally treated, and with androgen-independent PCa. Nineteen cystoprostatectomy (CyP) and 44 radical prostatectomy specimens (25 untreated and 19 hormonally treated) with pT2a Gleason score 6 cancer and HGPIN were used in this study. It also included 9 specimens of transurethral resection of the prostate with hormone-independent cancer and 8 cases of normal prostate tissue from CyP specimens without PCa and prostatic intraepithelial neoplasia. HER2 protein and Ki-67 were investigated immunohistochemically. Patients with immunohistochemical scores of 2+ and 3+ were considered to have HER2 overexpression (HercepTest method). Dual-color fluorescence in situ hybridization analysis was performed using the CEP-17/HER dual probe combination. High-grade prostatic intraepithelial neoplasia showed HER2 overexpression in 26% of the CyP cases and in 40% and 83% of the untreated and treated cases, respectively. Prostate cancer showed HER2 overexpression in 16% of cases in the CyP group and in 36% and 47.5% in the untreated and treated groups, respectively. HER2 overexpression was present in 78% of androgen-independent cancers. HER2 gene amplification was seen in a small proportion of nuclei and some of the cases. In HGPIN, it ranged from 1.1% (in 5 cases) in the CyP group to 2.1% (in 10 cases) and 1.9% (in 6 cases) in the untreated and treated groups, respectively. In PCa, the proportion of nuclei with gene amplification was 0.7% (in 3 cases) in the CyP group, 2.6% (in 10 cases) and 2.5% (in 12 cases) in the untreated and treated groups, respectively, and 9% (in 6 cases) in the androgen-independent PCa. Ki-67 expression in HGPIN and PCa in CyP specimens was lower than in the radical prostatectomies and cases of transurethral resection of the prostate. Our findings in the current HER2-related study indicate that incidentally detected cancer has features of less aggressiveness than clinically detected cancer. This may contribute to a better understanding of the results obtained in screening programs where insignificant cancers are detected along with clinically significant cancers.
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PMID:HER2 expression and gene amplification in pT2a Gleason score 6 prostate cancer incidentally detected in cystoprostatectomies: comparison with clinically detected androgen-dependent and androgen-independent cancer. 1693 18

Signaling pathways regulating cell proliferation and survival have become attractive targets for anticancer strategies. In the present study, we analyzed by immunohistochemistry, a panel of benign nevi, superficial spreading and nodular primary melanomas and metastases for expression of activated p38/mitogen-activated protein kinase (p-p38) and c-jun N-terminal kinase (JNK) (p-JNK) and correlated the findings with known prognostic variables. Twenty-five and 35% of the primaries and 9 and 25% of the metastases expressed variable levels of p-p38 and p-JNK, respectively. In benign nevi, 73.5% expressed p-JNK and 7% expressed p-p38. For patients with superficial spreading melanomas, high level of cytoplasmic p-JNK was associated with thicker tumors (P=0.017) and shorter disease-free survival (P=0.003) as well as with markers of cell proliferation (cyclin A (P=0.017) and p21 (P=0.021)). In nodular melanomas, nuclear p-p38 was associated with Ki-67 (P=0.012), but neither cytoplasmic nor nuclear localized p-p38 was associated with disease outcome. Of note, in superficial spreading melanomas, a positive correlation between cytoplasmic p-JNK and cytoplasmic p-extracellular signal-regulated kinase ERK(1/2) (P=0.005) and p-p38 (P=0.003) was observed. Likewise, p-p38 in cytoplasm was positively associated with cytoplasmic p-ERK1/2 (P<0.0005) and p-Akt (P=0.047). In contrast, except for a positive correlation between nuclear p-p38 and membranous p-TrkA (P=0.02), no correlation between the activation status of the different signaling pathways was observed in nodular melanomas. In conclusion, our results suggest that in benign nevi activated JNK may have a role in restricting uncontrolled cell proliferation or survival. However, during tumor progression, activation of JNK is associated with cell proliferation and shorter relapse-free period for patients with superficial spreading melanomas, suggesting that the JNK activation status could be a marker for clinical outcome in at least a subgroup of malignant melanoma. In contrast, activation of p38 seems to play a less important role in development and progression of malignant melanomas.
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PMID:Activation of c-jun N-terminal kinase is associated with cell proliferation and shorter relapse-free period in superficial spreading malignant melanoma. 1695 73

Heterotopic intrathymic thyroid tissue is an extremely rare condition, but it is important to distinguish it from metastases of clinically undetected thyroid carcinoma because metastatic papillary thyroid carcinoma is often so well differentiated, simulating normal thyroid tissue. Described herein are histological findings of heterotopic intrathymic thyroid tissue that was incidentally identified in a woman with papillary thyroid carcinoma during histological examination of a radical neck dissection specimen. These findings emphasize that this rare incidence may occur and should be differentiated from metastatic papillary carcinoma. Histologically, the patient's intrathymic thyroid follicles were identical to the normal thyroid follicles, having flat cuboidal cells with uniformly small nuclei without nuclear grooves or inclusions. The follicular cells had a low Ki-67 labeling index close to zero, and immunonegativity for galectin-3, HBME-1, and RET oncoprotein, in contrast to the tumor cells in primary papillary thyroid carcinoma of the patient. To the authors' knowledge this is the first case report of intrathymic heterotopic thyroid tissue posing a diagnostic difficulty in a patient with papillary thyroid carcinoma.
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PMID:Heterotopic intrathymic thyroid tissue. 1698 21

Urothelial neoplasms in patients 19 years of age or younger are rare, and the data regarding clinical outcome are conflicting. Molecular data are not available. Urothelial tumours from 14 patients aged 4 to 19 years were analysed, including FGFR3 and TP53 mutation screening, comparative genomic hybridization (CGH), UroVysion FISH analysis, polymerase chain reaction for human papillomavirus (HPV), microsatellite analysis using the NIH consensus panel for detection of microsatellite instability (MSI) and six markers for loss of heterozygosity on chromosome arms 9p, 9q, and 17p and immunohistochemistry for TP53, Ki-67, CK20 and the mismatch repair proteins (MRPs) hMSH2, hMLH1, and hMSH6. Based on the 2004 WHO classification, one urothelial papilloma, seven papillary urothelial neoplasms of low malignant potential (PUNLMPs), five low-grade, and one high-grade papillary urothelial carcinoma were included. No multifocal tumours were found and recurrence was seen in only one patient with a urothelial papilloma. All patients were alive with no evidence of disease at a median follow-up of 3.0 years. We found no mutations in FGFR3, deletions of chromosome arms 9p, 9q or 17p, MSI or MRP loss, or HPV positivity in any of the patients. Three cases showed chromosome alterations in CGH analyses, urothelial dedifferentiation with CK20 overexpression, or aneuploidy, and one TP53 mutation with TP53 overexpression was found. Urothelial neoplasms in people younger than 20 years are predominantly low grade and are associated with a favourable clinical outcome. Genetic alterations frequently seen in older adults are extremely rare in young patients. Urothelial neoplasms in children and young adults appear to be biologically distinct and lack genetic instability in most cases.
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PMID:Genomic aberrations are rare in urothelial neoplasms of patients 19 years or younger. 1707 25

The goal of this study was to investigate differences in the clinicopathologic and genetic characteristics of gastric and extragastric gastrointestinal stromal tumors (GISTs). We evaluated 13 extragastric GISTs and compared them with 56 gastric GISTs, which were described previously. DNA was extracted from paraffin-embedded tumor specimens, and exons 9, 11, 13, and 17 of the KIT gene and exons 12 and 18 of the platelet-derived growth factor receptor alpha (PDGFRA) gene were amplified by polymerase chain reaction and sequenced. Immunohistochemistry was performed for KIT, CD34, Ki-67 (as a marker of cell proliferation), and CD31 (as a marker of microvessel density), and apoptosis was assessed by in situ DNA nick end-labeling. Of the 13 extragastric GISTs 7 (54%) had a mutation in exon 11 of KIT, and 2 (15%) had a mutation in exon 13 of KIT. Deletions in exon 11 of KIT were the most common mutation encountered in the extragastric GISTs. The extragastric GISTs, especially small intestinal GISTs, showed larger deletions, leading to deletions of amino acid residues in the KIT protein, and higher vascularity than did the gastric GISTs. These data suggest that extragastric GISTs differ from gastric GISTs with respect to associated mutations and angiogenic activity.
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PMID:Genetic and pathologic characteristics of gastrointestinal stromal tumors in extragastric lesions. 1708 9


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