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)

The pathogenesis of polycystic liver disease is not well understood. The putative function of the associated proteins, hepatocystin and Sec63p, do not give insight in their role in cystogenesis and their tissue-wide expression does not fit with the liver-specific phenotype of the disease. We designed this study with the specific aim to dissect whether pathways involved in polycystic kidney diseases are also implicated in polycystic liver disease. Therefore, we immunohistochemically stained cyst tissue specimen with antibodies directed against markers for apoptosis, proliferation, growth receptors, signaling and adhesion. We analyzed genotyped polycystic liver disease cyst tissue (n=21) compared with normal liver tissue (n=13). None of the cysts showed proliferation of epithelial cells. In addition, anti-apoptosis marker Bcl-2 revealed slight increase in expression, with variable increase of apoptosis marker active caspase 3. Growth factor receptors, EGFR and c-erbB-2, were overexpressed and mislocalized. We found EGFR staining in the nuclei of cyst epithelial cells regardless of mutational state of the patient. Further, in hepatocystin-mutant polycystic liver disease patients, apical membranous staining of c-erbB-2 and adhesion markers, MUC1 and CEA, was lost and the proteins appeared to be retained in cytoplasm of cyst epithelia. Finally, we found loss of adhesion molecules E-cadherin and Ep-CAM in cyst epithelium of all patients. Nevertheless, we observed normal beta-catenin expression. Our results show that polycystic liver disease cystogenesis is different from renal cystogenesis. Polycystic liver disease involves overexpression of growth factor receptors and loss of adhesion. In contrast, proliferation or deregulated apoptosis do not seem to be implicated. Moreover differential findings for PRKCSH- and SEC63-associated polycystic liver disease suggest a divergent mechanism for cystogenesis in these two groups.
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PMID:Disrupted cell adhesion but not proliferation mediates cyst formation in polycystic liver disease. 1858 25

The early detection of recurrences after surgical or radiation treatment of squamous cancers of the head and neck is often difficult. A rise in circulating tumor marker levels such as SCCA and CEA often precedes the clinical appearance of recurrences by about several months. The combined analysis of SCCA and CEA can facilitate the early detection of local relapse or distant recurrence and can therefore accelerate specific diagnostic and/or therapeutic procedures. Therefore, after primary therapy of locally advanced head and neck cancers, the combined analysis of SCCA and CEA normally every 3-6 months can be recommended. Molecular markers give increasing insight into tumor biology, prognosis and response to chemotherapy, radiation and molecular targeted therapies. Biomarkers require a careful validation before being implemented into clinical decision making, but promising markers such as EGFR, p53 and HPV oncogene may become important stratification factors for individualized tumor treatment algorithms.
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PMID:[Tumor markers and biomarkers in squamous cell cancer of the head and neck]. 1869 18

The author reports a rare case of primary large cystic extragastrointestinal stromal tumor (eGIST) of the transverse mesocolon with genetic analyses of the c-kit and platelet-derived growth factor receptor-alpha (PDGFRA) genes. A 78-year-old man was found to have a large cystic tumor in the abdomen, and the tumor was resected. Grossly, the tumor was located in the transverse mesocolon, and cystic. Microscopically, the tumor consisted of epithelioid cells with atypia. Mitotic figures were noted in five of 50 high power fields. Immunohistochemically, the tumor cells were positive for KIT, CD34, PDGFRA, and vimentin, but negative for cytokeratins, neuron specific enolase, desmin, S100 protein, alpha-smooth muscle actin, p53 protein, HMB45, CD68, CEA, factor VIII-related antigen, chromogranin, and synaptophysin. Ki67 labeling was 5%. Genetically, the tumor showed a point mutation (GAC --> GTC) at codon 842 of exon 18 of the PDGFRA gene. Exon 12 of the PDGFRA gene and exons 9, 11, 13, and 17 of the c-kit gene showed no mutations. No recurrence is noted 3 years after the operation. This case shows that eGIST may occur in the transverse mesocolon.
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PMID:Primary extragastrointestinal stromal tumor of the transverse mesocolon without c-kit mutations but with PDGFRA mutations. 1877 14

Natural killer (NK) cells are at the crossroad between innate and adaptive immunity and play a major role in cancer immunosurveillance. NK cell stimulation depends on a balance between inhibitory and activating receptors, such as the stimulatory lectin-like receptor NKG2D. To redirect NK cells against tumor cells, we designed bifunctional proteins able to specifically bind tumor cells and to induce their lysis by NK cells, after NKG2D engagement. To this aim, we used the 'knob into hole' heterodimerization strategy, in which 'knob' and 'hole' variants were generated by directed mutagenesis within the CH3 domain of human IgG1 Fc fragments fused to an anti-CEA or anti-HER2 scFv or to the H60 murine ligand of NKG2D, respectively. We demonstrated the capacity of the bifunctional proteins produced to specifically coat tumor cells surface with H60 ligand. Most importantly, we demonstrated that these bifunctional proteins were able to induce an NKG2D-dependent and antibody-specific tumor cell lysis by murine NK cells. Overall, the results show the possibility to redirect NK cytotoxicity to tumor cells by a new format of recombinant bispecific antibody, opening the way of potential NK cell-based cancer immunotherapies by specific activation of the NKG2D receptor at the tumor site.
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PMID:Redirecting NK cells mediated tumor cell lysis by a new recombinant bifunctional protein. 1879 Jul 93

In vivo electroporation of plasmid DNA (DNA-EP) is an efficient and safe method for vaccines resulting in increased DNA uptake, enhanced protein expression and increased immune responses to the target antigen in a variety of species. To further enhance the efficacy of DNA-EP, we have evaluated the toll-like receptor7 (TLR7) agonist-2, 9, substituted 8-hydroxyadenosine derivative or SM360320--as an adjuvant to vaccines against HER2/neu and CEA in BALB-neuT and CEA transgenic mice (CEA.Tg), respectively. SM360320 induced in vivo secretion of interferon alpha (IFNalpha) and exerted a significant antitumor effect in CEA.Tg mice challenged with a syngenic tumor cell line expressing CEA and an additive effect with a CEA vaccine. Additionally, combination of SM360320 with plasmid encoding the extracellular and transmembrane domain of ratHER2/neu affected the spontaneous tumor progression in BALB-neuT mice treated in an advanced disease setting. The antitumor effect in mice treated with DNA-EP and SM360320 was associated with an anti-CEA and anti-p185(neu) antibody isotype switch from IgG1 to IgG2a. These data demonstrate that SM360320 exerts significant antitumor effects and can act in association with DNA-EP for CEA-positive colon cancer and HER2-positive mammary carcinoma. These observations therefore emphasize the potential of SM360320 as immunological adjuvant for therapeutic DNA vaccines.
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PMID:An oral TLR7 agonist is a potent adjuvant of DNA vaccination in transgenic mouse tumor models. 1898 54

The author reports herein an extremely rare case of primary small cell carcinoma of the mediastinum with an emphasis on KIT and PDGFRA genes. A 66-year-old man was found to have a mediastinal tumor on a routine chest X-ray examination, and was admitted to our hospital. Imaging modalities revealed a 5 x 4 cm tumor in the middle mediastinum near the bronchial carina. No other tumors were detected in the body including the lungs. Video-assisted thoracoscopy confirmed the mediastinal tumor, and a large incisional biopsy was performed. The tumor was histologically small cell carcinoma. An immunohistochemical study revealed positive reactions for cytokeratins (AE1/3, polyclonal), synaptophysin, neuron-specific enolase, CD56, KIT, and PDGFRA, and negative reactions for chromogranin, CEA, CD45, CD20, and CD3. Ki-67 labeling showed a value of 80%. A molecular genetic analysis using PCR-direct sequencing identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The patient received radiation and chemotherapy, and the tumor was fully resolved. The patient has remained free of recurrence for 6 years after the first presentation. The present case is the first reported case of primary small cell carcinoma of the mediastinum with an examination of KIT and PDGFRA expressions and KIT and PDFGRA gene mutations.
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PMID:Primary small cell carcinoma of the mediastinum: a case report with immunohistochemical and molecular genetic analyses of KIT and PDGFRA genes. 1898 97

Small, engineered antibody fragments such as diabodies (50 kDa noncovalent dimers of single-chain Fv fragments) are useful alternatives to their larger antibody counterparts. However, due to their size, they are more susceptible to disruption of their antigen binding sites when modified using random conjugation techniques. Previous work has demonstrated the utility of a C-terminal cysteine modification for site-specific radiolabeling of an anti-CEA diabody, resulting in the creation of a cys-diabody (CysDb). In the present work, the adaptability of the CysDb system was explored by creating two additional CysDbs: one specific for CD20 and one for HER2. Purified CysDbs of both specificities demonstrated behavior consistent with stable, covalent dimers harboring a readily reducible disulfide bond. Each CysDb was site-specifically conjugated to three different fluorophores for optical detection: the large fluorescent proteins phycoerythrin (PE) and allophycocyanin (APC), and the small fluorescent molecule Alexa Fluor488. Fluorophore-conjugated CysDbs bound specifically to their targets in both antigen systems and with each different fluorescent tag as determined by flow cytometry. In vitro specific antigen binding was observed in the presence of a mixture of specific and nonspecifically conjugated CysDbs. Conjugates retained both specificity and fluorescence, demonstrating the successful expansion of the CysDb repertoire to new targets and to new site-specific conjugation possibilities.
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PMID:Site-specific, thiol-mediated conjugation of fluorescent probes to cysteine-modified diabodies targeting CD20 or HER2. 1905 10

The author reports herein two cases of ductal adenoma of the breast with an emphasis on immunohistochemistry. Both cases (patient 1, 58-year-old woman; patient 2, 78-year-old woman) were clinically suspected as carcinoma, and core biopsies were 'indeterminate' or 'suspicious for malignancy'. Excisional biopsy and wide excision were performed. Histologically, both cases were ductal adenomas composed of ductal epithelial cells and myoepithelial cells. Patient 1 had extensive apocrine metaplasia. Immunohistochemically, myoepithelial cells were noted in both cases; cytokeratin (CK) 14 and p63 were the most reliable myoepithelial markers, followed by CD10, alpha-smooth muscle actin and S100 protein. CK profile was as follows: positive expression of CK5/6, CK18, CK19, and high-molecular-weight CK, and negative expression of CK20. This CK profile was the same as that of non-tumorous ducts, suggesting that the CK profile does not alter in tumorigenesis. The tumor cells expressed p53 protein (case 1, positive cell percentage 5%; case 2, 7%), c-erbB2 (HER2/neu, 76%, 64%), CEA (5%, 0%), estrogen receptor (33%, 84%), but were negative for progesterone receptor. Ki-67 labeling was 5% and 3%, respectively. MUC apomucin expression was as follows: MUC1, 92%, 100%; MUC2, 0%, 0%; MUC5AC, 0%, 0%; and MUC6, 5%, 0%. Non-tumorous ducts expressed MUC1, but were negative for MUC2, MUC5AC and MUC6.
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PMID:Ductal adenoma of the breast: immunohistochemistry of two cases. 1906 57

Recent molecular studies support the hypothesis that clear cell carcinoma and mucinous adenocarcinoma are refractory cancers that are biologically distinct from serous adenocarcinoma. Treatment of these cancers has not yet been adequately tested, so separate clinical trials are needed for each type. Paclitaxel(175 mg/m2/3hr)combined with carboplatin AUC 6(TC regimen)is the current gold standard for treating ovarian cancer. Clear cell carcinoma and mucinous adenocarcinoma are less sensitive to a TC regimen than serous adenocarcinoma, and an international randomized trial for clear cell carcinoma is now underway(GCIG/JGOG3017). Targeted therapy is attractive for chemoresistant clear cell carcinoma, thus VEGFR inhibitor(sunitinib), PDGFR inhibitor(sorafenib), m-TOR inhibitor (temsirolimus), and monoclonal antibody(bevacizumab)are being evaluated. Mucinous adenocarcinoma often shows CK20- and CEA-positive patterns in immunohistochemistry, and furthermore, p53-negative and K-ras-positive in molecular markers, which suggests that mucinous adenocarcinoma resembles colorectal, stomach, and pancreas cancers more than serous ovarian adenocarcinoma. Trials are needed to test the agents effective for gastrointestinal cancer. The GOG will start a randomized phase III trial comparing TC regimen with capecitabine plus oxaliplatin(GOG241). We are starting a phase II study of S-1 plus oxaliplatin in Japan. For refractory cancers, molecular biology-based, cross- organ treatment with cytotoxic/cytostatic agents is needed.
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PMID:[Treatments of epithelial ovarian cancer by histologic subtype]. 1922 34

Appendiceal mucinous neoplasms have been the focus of considerable debate in recent years. We histologically classified 70 appendiceal mucinous neoplasms into three categories: 32 mucinous adenoma, 23 mucinous neoplasm of uncertain malignant potential, and 15 mucinous adenocarcinomas. Immunohistochemistry was performed for 24 proteins in different functional categories, specifically, oncogenic proteins (bcl-2, beta-catenin, CEA, C-erbB2, c-kit, Cox-2, Cyclin D1, EGFR, Ki-67, NF-kappaB, VEGF), tumor suppressors (E-cadherin, FHIT, hMLH1, p53, p63, smad4), cell-cycle regulators (p21, p27, p16), and mucin proteins (MUC1, MUC2, MUC5AC, MUC6). Our data showed that 9 out of the 24 proteins were more frequently altered in the mucinous adenocarcinoma group than in the mucinous adenoma group (P<0.05), including beta-catenin (13% in mucinous adenoma vs 60% in mucinous adenocarcinoma), CyclinD1 (44 vs 87%), Ki-67 (high labeling index: 31 vs 67%), NF-kappaB (19 vs 60%), VEGF (16 vs 87%), E-cadherin (0 vs 47%), p53 (6 vs 40%), MUC2 (9 vs 67%), and MUC5AC (3 vs 40%). The distinct immunoexpression profile of mucinous neoplasm of uncertain malignant potential was placed between those of mucinous adenoma and mucinous adenocarcinoma (P<0.05). Moreover, the mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma categories displayed differences in terms of the number of altered markers among the nine proteins (P<0.05; mean 1.4 vs 2.6 vs 5.5, respectively). In mucinous adenocarcinoma, the p53 status was related to disease-free survival and overall survival of patients (P<0.05, both). NF-kappaB status and the number of altered protein markers made statistically marginal impacts on disease-free survival; also beta-catenin loss, on overall survival of patients. In conclusion, protein immunoexpression profiles may facilitate the classification of appendiceal mucinous neoplasms. In our study, the three tumor categories of mucinous adenoma, mucinous neoplasm of uncertain malignant potential, and mucinous adenocarcinoma exhibited distinct immunoexpression profiles. Five and more altered protein markers, p53 overexpression, NF-kappaB positivity, and beta-catenin loss were predictive factors of adverse clinical outcomes in appendiceal mucinous adenocarcinomas.
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PMID:Differential protein immunoexpression profiles in appendiceal mucinous neoplasms: a special reference to classification and predictive factors. 1944 92


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