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)

The proto-oncogene HER2 presents a novel therapeutic target. We report results in 25 patients with HER2+ advanced prostate cancer treated with the bispecific antibody MDX-H210 15 microg m(-2)by intravenous infusion plus GM-CSF 5 microg kg(-1)day(-1)by subcutaneous injection for 4 days repeated weekly for 6 weeks. Patients with stable disease or better received further cycles of treatment until disease progression or study withdrawal. 1 patient received no treatment and 4 received less than 1 cycle and are included in the toxicity analysis only. Median duration of follow up was 105+ (range 21-188) days. Toxicity was generally NCI-CTG 0-2. There were 2 grade 4 adverse events (heart failure and dyspnoea) and 1 grade 3 event (allergic reaction) resulting in discontinuation of the study medication. There were 9 further grade 3 events not resulting in trial withdrawal. There were no treatment-related deaths. 7/20 (35%) evaluable patients had a >50% PSA response of median duration 128 (range 71-184+) days. 7/12 (58%) patients with evaluable pain had improvements in pain scores. The PSA relative velocity on therapy decreased in 15/18 (83%) assessable patients compared to pre-study. GM-CSF and MDX-H210 is active in hormone refractory prostate carcinoma with acceptable toxicity; further studies are warranted.
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PMID:A phase II study of the bispecific antibody MDX-H210 (anti-HER2 x CD64) with GM-CSF in HER2+ advanced prostate cancer. 1146 Oct 69

Hypertrophy is an adaptive response of the heart to myocardial injury or hemodynamic overload that may progress and contribute to cardiac decompensation and eventually to heart failure. The signaling pathways controlling this response in the cardiac myocyte are poorly understood. A data mining effort of a human failed heart cDNA library was undertaken in an effort to identify novel signaling molecules involved in cardiac hypertrophy. This effort identified a novel kinase (MLK7) homologous to the mixed lineage kinase family of proteins. The mixed lineage kinases are mitogen-activated protein kinase kinase kinases (MAPKKKs) which activate stress activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase pathways. They contain a catalytic domain with homology to both serine/threonine and tyrosine-specific kinases and a dual leucine zipper. MLK7 is identical to leucine zipper and sterile-alpha motif protein kinase (ZAK) through the leucine zipper domain but has a completely divergent COOH-terminus and shares approximately 40% homology with the other MLKs overall. Expression of MLK7 mRNA is most abundant in skeletal muscle and heart, with expression restricted to the cardiac myocyte. The recombinant histidine tagged MLK7 expressed and purified from insect cells exhibited serine/threonine kinase activity in vitro with myelin basic protein as substrate. When expressed in cardiac myocytes, MLK7 activated SAPK/JNK1, and ERK and p38 to a lesser extent. Additionally, MLK7 altered fetal gene expression and increased protein synthesis in cardiac myocytes. These data suggest that MLK7 is a new member of the mixed lineage kinase family that modulates cardiac SAPK/JNK pathway and may play a role in cardiac hypertrophy and progression to heart failure.
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PMID:Tissue distribution and functional expression of a cDNA encoding a novel mixed lineage kinase. 1154 52

Approximately 25,000 patients have been treated to date with the humanized anti-HER2 monoclonal antibody, Herceptin. This therapy has proved effective and well tolerated in patients with HER2-positive metastatic breast cancer; adverse events were generally infusion-related fever and chills of mild-to-moderate severity. Cardiotoxicity and infusion-related reactions emerged as the two main safety concerns with the use of Herceptin. Retrospective analysis revealed a higher incidence of heart failure when Herceptin was combined with anthracyclines than that expected with anthracyclines alone. Age, anthracycline exposure and cardiac risk factors were found to be predictors of cardiac adverse events. Patients experiencing cardiac dysfunction responded well to standard cardiac medication and the majority improved. Cardiac function should be monitored regularly and Herceptin should be discontinued if significant heart failure develops unless the benefits for an individual patient outweigh the risks. Of 25,000 patients, 74 (0.3%) were reported to have experienced a serious infusion-related reaction. The majority occurred during or shortly after the first infusion and were characterized by respiratory symptoms. Most patients were successfully treated; a total of 33 patients continued Herceptin therapy with no recurrence of infusion reactions. Although the benefit to risk ratio of Herceptin remains favorable, physicians must be vigilant and aggressive in managing cardiotoxicity and infusion-related reactions.
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PMID:Retrospective analysis of the safety of Herceptin immunotherapy in metastatic breast cancer. 1169 89

In HER2-positive breast cancer patients, the humanized anti-HER-2 monoclonal antibody trastuzumab (Herceptin) may improve overall survival. No reports exist regarding the application of trastuzumab in patients with cytotoxically induced cardiac failure and decreased left ventricular ejection fraction or about locally recurrent and advanced disease. In this case report, trastuzumab resulted in a complete and long-lasting response of recurrent and locally advanced breast cancer and was well tolerated in a severely cytotoxically pretreated patient with cardiac failure. We encourage other oncologists to offer trastuzumab also to severely cytotoxically pretreated patients with conditions after cardiac insufficiency or with locally advanced breast cancer.
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PMID:Effectiveness of Trastuzumab (Herceptin) in a patient with locally recurrent breast cancer after cardiac failure caused by severe cytotoxic pretreatment. 1172 Nov 73

Blockade of the renin-angiotensin-aldosterone cascade is now recognised as a very effective approach to treat hypertensive, heart failure and high cardiovascular risk patients and to retard the development of renal failure. The purpose of this review is to discuss the state of development of currently available drugs blocking the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors, renin inhibitors and angiotensin II receptor antagonists, with a special emphasis on the results of the most recent trials conducted with AT(2) receptor antagonists in heart failure and Type 2 diabetes. In addition, the future perspectives of drugs with dual mechanisms of action, such as NEP/ACE inhibitors, also named vasopeptidase inhibitors, are presented.
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PMID:Novel angiotensin II inhibitors in cardiovascular medicine. 1177 99

Cardiac insufficiency represents a major risk factor in patients about to undergo non-cardiac surgery. The post-operative mortality is linked to the severity of the pre-operative functional impairment: rising from 4% in NYHA class 1 to 67% in class IV. The operative risk is greater when the cardiac insufficiency is more disabling, the patient is older (> 70 years) and if there is a history of acute pulmonary oedema and a gallop bruit on auscultation. The use of metabolic equivalents (Duke Activity Status Index) is recommended: the functional capacity is defined as excellent if > 7 MET, moderate between 4 and 7, or poor if < 4. A non-invasive evaluation of left ventricular function is necessary in each patient with obvious congestive cardiac insufficiency or poor control under the American consensus, but it is rare that the patient has not already been seen by a cardiologist. The degree of per-operative haemodynamic constraint is linked to the surgical technique and is stratified according to the type of surgical intervention and whether or not it is performed as an emergency. An intervention duration > 5 hours is associated with an increased peri-operative risk of congestive cardiac insufficiency and non-cardiac death. Deaths from a cardiac cause are thus twice as frequent after intra-abdominal, non-cardiac thoracic or aortic surgery and the post-operative cardiac complications are six times more frequent. Numerous studies have attempted to document the impact of different anaesthetic techniques on the prognosis for the population at increased risk of post-operative cardiovascular complications. It is advisable to opt for peripheral nerve blocks. The cardiovascular morbidity and overall mortality do not differ between general anaesthetic, epidural anaesthetic or spinal nerve block. The ASA (American Society of Anesthesiologists) classification is widely used to determine the overall risk. The ASA class and the age are however too coarse as methods of evaluation for the individual risk and for giving judicious pre-operative advice. Multifactorial cardiac risk indexes such as that of Goldman allow overall evaluation (taking the patient and the intervention into account) of the peri-operative cardiovascular risk in non-cardiac surgery as a function of predictive clinical elements. Nine variables concerning the patient's history, the physical examination and several simple supplementary examinations are identified for which the relative weight is recorded under a points system. The average risk score for a given procedure is converted into an average risk for a given patient using a nomogram such as Detsky's. Surgical acts which do not impose major constraints on the cardiocirculatory apparatus (ophthalmic surgery for example) do not require supplementary examinations. The risk of post-operative cardiac complications is low in the absence of the 9 risk factors defined by Goldman, as is an ischaemic syndrome (angina on light physical activity, unstable angina, myocardial infarction). Certain risk factors (jugular congestion, gallop bruit, recent myocardial infarction, non-sinus rhythm, extrasystoles, aortic stenosis) obviously require appropriate treatment beforehand. The sometimes difficult process demands a dialogue between the cardiologist and the surgeon, the recognition of the risk of surgery in a given centre, and the opinion of the patient duly informed of the terms of the discussion about him.
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PMID:[Evaluation of the cardiac risks in non-cardiac surgery in patients with heart failure]. 1193 51

Cardiac hypertrophy often leads to heart failure and is associated with abnormal myocardial adrenergic signaling. This enlargement of myocardial mass can involve not only an increase in cardiomyocyte size, but increased proliferation of cardiac fibroblasts. A potential key player in the cardiac hypertrophic response is the ERK family of MAPKs. To gain mechanistic insight into adrenergic regulation of myocardial mitogenic signaling, we examined beta-adrenergic receptor (beta-AR) stimulation of ERK activation and DNA synthesis in cultured adult rat cardiac fibroblasts, including the involvement of tyrosine kinases in this signaling pathway. Addition of the beta-AR agonist isoproterenol (ISO) to serum-starved cells induced DNA synthesis in a dose-dependent manner, and this was inhibited by selective inhibitors of the epidermal growth factor receptor (EGFR). Importantly and in agreement with the involvement of MAPKs and the EGFR in this response in cardiac fibroblasts, the EGFR inhibitor AG1478 attenuated ISO-induced ERK phosphorylation. Moreover, pretreatment with PP2, a selective inhibitor of the Src tyrosine kinase, attenuated both ISO-mediated EGFR phosphorylation and ERK activation. Furthermore, studies in these cardiac fibroblasts showed that phosphatidylinositol 3-kinase contributed to beta-AR-mediated ERK activation, but not to EGFR activation. Finally, studies using selective inhibitors of matrix metalloproteases indicated that they and heparin-bound EGF shedding were involved in beta-AR-induced ERK activation and subsequent DNA synthesis in cardiac fibroblasts. Because these cells primarily express the beta(2)-AR subtype, our findings indicate that beta(2)-AR-mediated EGFR transactivation of intracellular tyrosine kinase signaling pathways is the major signaling pathway responsible for the adrenergic stimulation of mitogenesis of cardiac fibroblasts.
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PMID:Beta-adrenergic receptor-mediated DNA synthesis in cardiac fibroblasts is dependent on transactivation of the epidermal growth factor receptor and subsequent activation of extracellular signal-regulated kinases. 1204 15

Trastuzumab, a monoclonal antibody that is selective for cells that overexpress the erbB2 receptor protein tyrosine kinase, is a promising targeted therapy for the treatment of breast cancer. Surprisingly, toxic cardiovascular side effects were discovered in late-phase clinical trials, and these effects were most prominent when trastuzumab was combined with anthracycline chemotherapy. We review recent data focusing on how erbB2 monoclonal antibodies could exert a cardiotoxic effect through unique cardiomyocyte cell surface and intracellular structural features, and how an individual's cardiac susceptibility to erbB2 monoclonal antibodies may be dictated by the ability of erbB2 monoclonal antibodies to bind cardiomyocytes. In addition, we discuss ways that anthracyclines may also affect erbB2/erbB4/neuregulin receptor signaling, explaining the apparent synergistic effect. Further investigation of the role of normal and aberrant erbB2 signaling in the development of cardiac dysfunction could lead to an improved understanding of the pathophysiology of cardiac dysfunction and may lead to novel therapies for the treatment of heart failure, regardless of etiology. Understanding the nature and specificity of trastuzumab's cardiotoxic effects is important in better defining clinical criteria for inclusion and exclusion of patients who can safely receive trastuzumab for the treatment of breast cancer, or possibly other malignancies.
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PMID:Trastuzumab cardiotoxicity: Speculations regarding pathophysiology and targets for further study. 1213 94

The enzyme neutral endopeptidase (NEP; EC 3.4.24.11) cleaves several vasoactive peptides such as the atrial natriuretic peptide (ANP). ANP is a hormone of cardiac origin with diuretic and natriuretic actions. Despite elevated circulating levels of ANP, congestive heart failure (CHF) is characterized by progressive sodium and water retention. In order to elucidate the loss of natriuretic and diuretic properties of ANP in CHF we analyzed activity, protein concentrations, mRNA and immunostaining of NEP in kidneys of different models of severe CHF in the rat.CHF was induced by either aortocaval shunt, aortic banding or myocardial infarction in the rat. All models were defined by increased left ventricular end-diastolic pressure and decreased contractility. The diminished effectiveness of ANP was reflected by reduced cGMP/ANP ratio in animals with shunt or infarction. Renal NEP activity was increased in rats with aortocaval shunt (203 +/- 7%, p < 0.001), aortic banding (184 +/- 11%, p < 0.001) and infarction (149 +/- 10%, p < 0.005). Western blot analysis revealed a significant increase in renal NEP protein content in two models of CHF (shunt: 214 +/- 57%, p < 0.05; infarction: 310 +/- 53 %, p < 0.01). The elevated protein expression was paralleled by a threefold increase in renal NEP-mRNA level in the infarction model. The increased renal NEP protein expression and activity may lead to enhanced degradation of ANP and may contribute to the decreased renal response to ANP in heart failure. Thus, the capacity to counteract sodium and water retention, would be diminished. The increased renal NEP activity may therefore be a hitherto unknown factor in the progression of CHF.
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PMID:Increased expression of renal neutral endopeptidase in severe heart failure. 1238 78

We have isolated a cardiomyogenic cell line (CMG cell) from murine bone marrow mesenchymal stem cells. The cells showed a fibroblast-like morphology, but the morphology changed after 5-azacytidine exposure. They began spontaneous beating after 2 weeks, and expressed ANP and BNP. Electron microscopy revealed a cardiomyocyte-like ultrastructure. These cells had several types of action potentials: sinus-node-like and ventricular-cell-like action potentials. The isoform of contractile protein genes indicated that their muscle phenotype was similar to fetal ventricular cardiomyocytes. They expressed alpha 1A, alpha 1B, alpha 1D, beta 1, and beta 2 adrenergic and M1 and M2 muscarinic receptors. Stimulation with phenylephrine, isoproterenol and carbachol increased ERK phosphorylation and second messengers. Isoproterenol increased the beating rate, which was blocked with CGP20712A (beta 1-selective blocker). These findings indicated that cell transplantation therapy for the patients with heart failure might possibly be achieved using the regenerated cardiomyocytes from autologous bone marrow cells in the near future.
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PMID:Reprogramming of bone marrow mesenchymal stem cells into cardiomyocytes. 1249


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