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)

A phase II trial was designed to evaluate the effectiveness of docetaxel/cisplatin as primary or neoadjuvant chemotherapy of locally advanced breast carcinoma (LABC). Patients with newly diagnosed breast cancers > or = 5 cm in size by palpation were treated with docetaxel/cisplatin, both at 70 mg/m2 intravenously every 21 days for 4 courses. Upon completion of chemotherapy, all patients underwent modified radical mastectomy with axillary nodal dissection. Pathologic complete response (pCR) was defined as absence of any invasive carcinoma in the breast. Standard AC (doxorubicin/cyclophosphamide) at 60 mg/m2 and 600 mg/m2, respectively, for 4 cycles was given as adjuvant therapy to maximally eradicate occult distant disease. Between March 1998 and October 2001, 57 women were entered onto this trial, 28 (49%) with inoperable T4 and inflammatory cancers. Pretreatment median tumor size was 9 cm. Thirty-six patients (63%) had estrogen receptor-positive tumors and 10 patients (18%) had tumors with HER2 overexpression. All tumors became operable after neoadjuvant chemotherapy. Pathologic complete response in the breast was achieved in 15 patients (26%) and pCR in the breast and the axilla was achieved in 11 patients (20%). All neoadjuvant chemotherapy courses were administered at full doses without treatment delays caused by toxicity. The most common side effects were hyperglycemia, anemia, and mild neuropathy. The results of this study suggest that the docetaxel/cisplatin combination can be an effective and well-tolerated induction treatment of LABC, even in very large mostly HER2-nonoverexpressing tumors.
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PMID:Docetaxel and cisplatin as primary chemotherapy for treatment of locally advanced breast cancers. 1558 76

The clinical spectrum of mast cell disease ranges from relatively innocuous and histologically subtle urticarial skin lesions to an aggressive and fatal leukemic form of mast cell proliferation. Not surprisingly, mast cell infiltrates may show significant microscopic heterogeneity, particularly in the bone marrow, the most common site of involvement in systemic mastocytosis (SM). Herein, 3 cases are presented to illustrate the clinical and morphologic heterogeneity of mast cell disease: the first patient, with long standing urticaria pigmentosa, developed anemia and thrombocytopenia; the second patient presented with a pathologic fracture; and the third patient was suspected to have refractory anemia. Upon bone marrow examination, all 3 patients showed mast cell infiltration with distinct morphologic features and all met the WHO criteria for aggressive systemic mastocytosis. Histochemical methods continue to play a role in the identification of mast cells, with some limitations depending on the degree of differentiation of the mast cells and tissue processing methods. Immunohistochemistry has contributed to the identification of mast cells. Coexpression of CD117 and CD25, as well as expression of the more specific immunohistochemical marker tryptase, is seen in systemic SM. The latter may also be employed as a serum marker in the diagnosis and follow-up of patients with SM. The mast cells, in the majority adults with SM, have somatic point mutations of KIT.
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PMID:The faces of mast cell disease: bone marrow infiltrates in 3 patients with systemic mastocytosis. 1580 14

Imatinib targets KIT and platelet-derived growth factor receptors (PDGFR) and is highly effective in the treatment of CML and GIST patients. Pancreatic cancers express KIT and PDGFRs. Therefore, 26 patients with unresectable pancreatic cancer were randomized to either gemcitabine (1000 mg/m2 weekly) or imatinib (2x400 mg po) treatment daily. Pancreatic adenocarcinoma was confirmed histologically and expression of KIT and PDGFRbeta was determined immunohistochemically in the biopsy specimens. Quality of life was assessed with two standard questionnaires. No objective responses were seen in either group. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 140 and 60 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment responses were independent of KIT and PDGFRbeta expression in patients treated with imatinib. Grade 3/4 toxicities of imatinib treatment were anemia, elevated liver enzymes, vomiting, and dyspnea. Patients treated with imatinib reported diarrhoea and/or altered bowel function more frequently, which were treatable symptomatically. Quality of life was similar in both groups. In this small series of pancreatic cancer patients, treatment with imatinib was not associated with a significant control of cancer progression.
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PMID:The tyrosine kinase inhibitor imatinib fails to inhibit pancreatic cancer progression. 1589 16

Our aim was to establish the reference values of the new parameter reticulocyte hemoglobin equivalent (RET-He) and to investigate its role in differentiating between iron deficiency anemia and anemia of chronic diseases. We found that RET-He was useful for diagnosing iron deficiency anemia. A cut-off point of 25 pg provided a specificity of 0.81 and a sensitivity of 0.76.
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PMID:Clinical utility of the new Sysmex XE 2100 parameter - reticulocyte hemoglobin equivalent - in the diagnosis of anemia. 1607 14

A cohort of patients with intraductal growth-type intrahepatic cholangiocarcinoma (IG-ICC) and its precursor lesions, collectively termed intraductal papillary neoplasm of the liver (IPNL), was characterized with respect to demographics, clinical manifestations, perioperative management, long-term survival, and molecular features associated with carcinogenesis. A total of 122 patients with IPNL types 1 through 4, 108 patients with non-IG-ICC and 210 patients with hepatolithiasis alone were studied. Expression of CDX2, TFF1, MUC1, MUC2, MUC5AC, EGFR, and p53 was determined by using immunohistochemistry. Females predominated in those with hepatolithiasis alone and IPNL. The mean age of patients with hepatolithiasis alone was 6 to 8 years younger than that of those with IPNL. The association with hepatolithiasis in patients with IPNL types 1 and 2, IPNL types 3 and 4, and non-IG-ICC was 100%, 79%, and 64%, respectively. Mucobilia, anemia, and elevated serum carcinoembryonic antigen levels were helpful in distinguishing IG-ICC and its precursor lesions. The mean survival of patients with IPNL type 3, IPNL type 4, and non-IG-ICC was 55.5 months, 36.9 months, and 15.8 months, respectively. The incidence of expression of CDX2 and TFF1 was maximal in IPNL type 3. Expression and cellular distribution of MUC2 and CDX2 were similar. MUC5AC was strongly expressed in all patients with IPNL; EGFR and p53 were rarely expressed in patients with IPNL. In conclusion, hepatolithiasis appears to be a precipitating factor in the development of IPNL. Signs of mucobilia were specific for the diagnosis of IPNL. Expression of CDX2 and MUC2 are helpful in differentiating IPNL and non-IG-ICC. Significant differences in survival associated with the various lesions studied warrants a more aggressive surgical strategy in their management.
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PMID:Characterization of intrahepatic cholangiocarcinoma of the intraductal growth-type and its precursor lesions. 1611 40

Gastrointestinal stromal tumors (GISTs), specific KIT- or PDFGRA-signaling driven mesenchymal tumors, are rare in children and young adults, and their clinicopathologic and molecular genetic profile is incompletely understood. In this study, we analyzed 44 gastric GISTs occurring by the age of 21 years. There were 32 females and 12 males, youngest of whom were a 5-year-old boy and an 8-year-old girl. All but 1 of 25 patients under the age of 16 were girls. The patients most commonly received medical attention because of chronic, insidious gastrointestinal bleeding with anemia, less commonly with acute GI bleeding. Only 1 patient had Carney triad with pulmonary chondroma. None of the patients had family members with GIST. The tumors measured from 1.5 to 24 cm (median, 5.6 cm). A total of 21 tumors with specified location were in the antrum and 8 were in the gastric body. Histologically, 26 tumors were composed of epithelioid cells, 12 of spindle cells, and 6 of combination thereof. Mitotic activity varied form 0 to 65/50 HPF (median, 5/50). All but one of the 24 tumors tested were KIT-positive, and 20 were CD34-positive. Eleven patients developed liver or abdominal metastases, and 6 of them died of tumor surviving 5.5 to 35.5 years (median, 16 years) after the first surgery; three of these tumors had a low mitotic activity and size <10 cm. Twenty-one patients were alive with no evidence for disease 7 to 41 years (median, 17 years) after the first surgery. None of the 13 tumors examined (7 of them 8- to 16-year-old females) had KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as typically seen in adult GISTs. Gastric GISTs in children have mainly epithelioid morphology, often occur in antrum, and have a somewhat unpredictable but slow course of disease. Their pathogenesis may differ from that of adult GISTs because no KIT or PDGFRA mutations were found; connection with Carney triad seems infrequent despite demographic and histologic similarities.
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PMID:Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature. 1616 Apr 81

The aims of this study were to diagnose iron-restricted erythropoiesis (functional iron deficiency) in patients with classic iron deficiency (ID), anemia of chronic disease (ACD) and the combined state of ID/ACD with the use of two hematological methods for the measurement of reticulocyte hemoglobinization. In comparison, the biochemical markers of iron status were determined. We studied 474 anemic patients admitted to hospital with a broad spectrum of diseases. We measured indicators of reticulocyte hemoglobinization. CHr was determined on an Advia 120 hematology analyzer. A Sysmex XE-2100 hematology analyzer was used to determine RET-Y, the forward scatter of fluorescence-labeled reticulocytes, which can also be expressed as the reticulocyte hemoglobin equivalent (RET-H(e)), as well as RBC-Y, the forward scatter of fluorescence-labeled erythrocytes, which can be expressed as the erythrocyte hemoglobin equivalent. Ferritin, soluble transferrin receptor (sTfR) and the sTfR/log ferritin ratio (sTfR-F index) were used as biochemical markers. The comparison of RET-Y with CHr demonstrated an excellent curvilinear relationship between the two parameters. The normal reference range for Ret-Y was 1630-1860 arbitrary units (AU); mathematical transformation to RET-H(e) gave a range of 28.2-35.7 pg. Correlations of biochemical iron markers with RET-H(e) were as weak as with CHr in patients with ACD and acute phase response. In a diagnostic plot to identify iron status, RET-H(e) could replace CHr without any loss of sensitivity or specificity. Patient mismatch analysis between RET-H(e) and CHr in the diagnostic plot demonstrated agreement for 449 of 474 patients (94.4%). Patient specific anemia mismatches were 2.9-6.2%. According to our results, the indicators of reticulocyte hemoglobinization, RET-H(e) and CHr, measure the same phenomenon. RET-H(e) is as valuable as CHr for the diagnosis of iron-restricted erythropoiesis. The combination of RET-H(e) and the sTfR-F index in a diagnostic plot offers an attractive tool for the evaluation of iron status and identification of the progression of ID.
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PMID:Reticulocyte hemoglobin measurement--comparison of two methods in the diagnosis of iron-restricted erythropoiesis. 1623 85

We present the fourth case of a primary pancreatic anaplastic large cell lymphoma (ALCL), ALK-. An 80-year-old man was admitted to our clinic for further investigation of a fever of unknown origin. He noted anorexia, weight loss and fatigue. His laboratory tests showed anemia and a great elevation of ESR, LDH, and beta (2) microglobulin. In CT and MRI scan, a soft tissue mass in the pancreas was observed. A repeated endoscopy after his admission revealed an ulcerated mass-like deformity of the duodenal bulb. Explorative laparotomy confirmed a diffuse spread of an unresectable malignant pancreatic mass extending to the adjacent organs. Duodenal and surgical biopsies identified an ALCL of T-cell lineage, ALK-. The patient died in the Intensive Care Unit due to hemodynamic instability. Our case is the first one indicating that primary pancreatic lymphoma should be suspected in a patient with pancreatic mass and elevated serum LDH and beta(2) microglobulin.
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PMID:Primary pancreatic anaplastic large cell lymphoma, ALK negative: a case report. 1627 56

Gastrointestinal stromal tumors (GISTs), the specific KIT- or PDFGRA-signaling driven mesenchymal tumors, most commonly occur sporadically, but there seems to be some increased tendency for these tumors to develop in patients with neurofibromatosis 1 (NF1). The clinicopathologic profile, KIT, and PDGFRA mutation status and long-term prognosis of patients with GIST in NF1 are incompletely characterized. In this study, we analyzed 45 patients who had NF1 and GIST. There were 26 females and 19 males with a median age of 49 years (10 years lower than the median age of GIST patients in general). A great majority of tumors occurred in the jejunum or ileum, with multiple tumors occurring in 28 cases. Ten patients had a duodenal and one had a gastric GIST. The most common presentations were gastrointestinal bleeding and anemia, and many patients had intermittent bleeding over several years. The majority of the tumors were small and mitotically inactive; only 7 had mitotic activity >5/50 HPFs and 15 tumors were >5 cm. Associated Cajal cell hyperplasia was common. One patient had an intraabdominal peri-intestinal neurofibroma. Five of 35 patients with follow-up died of metastatic disease; all of these had a tumor >5 cm, mitotic rate >5/50 HPFs, or both; three of these tumors were located in the duodenum. The presence of multiple small tumors was not associated with progressive disease. Most patients with long-term follow-up enjoyed a good prognosis; 2 died of other NF1-associated tumors (malignant peripheral nerve sheath tumors, brain tumor). None of the 16 tumors from 15 patients had a KIT exon 9, 11, 13, or 17 or PDGFRA exon 12 or 18 mutation as is typically seen in sporadic GISTs, indicating that GISTs in NF1 patients have a different pathogenesis than sporadic GISTs.
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PMID:Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. 1633 Sep 47

Normal erythropoiesis critically depends on the balance between the renewal of precursor cells and their differentiation. If the renewal phase is shortened, the decrease in the precursor pool results in anemia; conversely, impaired differentiation increases the number of proliferating progenitors and the potential risk of leukemic transformation. Using gene ablation, we have discovered 2 self-sustaining signal transduction loops that antagonize each other and regulate erythroid progenitor proliferation and differentiation, respectively. We identify Raf-1 as the main activator of the MEK/ERK cascade and as the key molecule in maintaining progenitor proliferation. Differentiation, in contrast, is mediated by Fas via the activation of both the ASK1/JNK/p38 module and the caspase cascade. The point of convergence between the 2 cascades is activated ERK, which positively feeds back on the proliferation pathway by maintaining the expression of Raf-1, while inhibiting the expression of Fas and therefore differentiation. In turn, Fas, once expressed, antagonizes proliferation by exerting a negative feedback on ERK activation and Raf-1 expression. Simultaneously, Fas-mediated caspase activation precipitates differentiation. These results identify Raf-1 and Fas as the key molecules whose expression finely tunes erythropoiesis and the extent of ERK activation as the switch that tips the balance between them.
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PMID:A balance between Raf-1 and Fas expression sets the pace of erythroid differentiation. 1652 94


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