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Effective Target (effective + target)
Selected AbstractsCD20-mediated apoptosis: signalling through lipid raftsIMMUNOLOGY, Issue 2 2002Julie P. Deans Summary CD20 is an effective target for therapeutic B-cell depletion with monoclonal antibodies. One proposed mechanism of action is direct cytotoxicity mediated via tyrosine kinase-dependent signalling pathways activated upon CD20 cross-linking. The association of CD20 with membrane microdomains known as lipid rafts, enriched in src-family tyrosine kinases and other signalling effectors, suggests an indirect mechanism of anti-CD20-induced apoptosis in which activation of src-family kinases occurs as a consequence of lipid raft clustering. [source] Paradoxical aspects of parkinsonian tremorMOVEMENT DISORDERS, Issue 2 2008Paul S. Fishman MD Abstract Although resting tremor is the most identifiable sign of Parkinson's disease, its underlying basis appears to be the most complex of the cardinal signs. The variable relationship of resting tremor to other symptoms of PD has implications for diagnosis, prognosis, medical and surgical treatment. Structural lesions very rarely cause classic resting tremor, with likely contributions to tremor by a network of neurons both within and outside the basal ganglia. Patients with only resting tremor show dopaminergic deficits with radioligand imaging, but severity of tremor correlates poorly in such dopamine imaging studies. Correlation of tremor severity to changes in radioligand studies is also limited by the use of mostly qualitative measures of tremor severity. A complex pharmacologic basis of parkinsonian resting tremor is supported by treatment studies. Although levodopa is clearly effective for resting tremor, several agents have shown efficacy that appears to be superior or additive to that of levodopa including anticholinergics, clozapine, pramipexole, and budipine. Although the thalamus has the greatest body of evidence supporting its role as an effective target for surgical treatment of tremor, recent studies suggest that the subthalamic nucleus may be a reasonable alternative target for patients with Parkinson's disease and severe tremor as the predominant symptom. © 2007 Movement Disorder Society [source] Gene Transduction of an Active Mutant of Akt Exerts Cytoprotection and Reduces Graft Injury After Liver TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2007M. Morales-Ruiz Akt is expected to be an effective target for the treatment of ischemia-reperfusion injury (I/R) due to its anti-apoptotic properties and its ability to activate the endothelial nitric oxide synthase (eNOS) enzyme. Therefore, this study was aimed to determine the efficacy of an active mutant of Akt (myr-Akt) to decrease I/R injury in a model of orthotopic liver transplantation in pigs. In addition, we analyzed the contribution of nitric oxide in the Akt-mediated effects by using an eNOS mutant (S1179DeNOS) that mimics the phosphorylation promoted by Akt in the eNOS sequence. Donors were treated with adenoviruses codifying for myr-Akt, S1179DeNOS or ,-galactosidase 24 h before liver harvesting. Then, liver grafts were orthotopically transplanted into their corresponding recipients. Levels of transaminases and lactate dehydrogenase (LDH) increased in all recipients after 24 h of transplant. However, transaminases and LDH levels were significantly lower in the myr-Akt group compared with vehicle. The percentage of apoptotic cells and the amount of activated-caspase 3 protein were also markedly reduced in myr-Akt-treated grafts after 4 days of liver transplant compared with vehicle and S1179DeNOS groups. In conclusion, myr-Akt gene therapy effectively exerts cytoprotection against hepatic I/R injury regardless of the Akt-dependent eNOS activation. [source] Crystallization and preliminary X-ray crystallographic study of 1-deoxy- d -xylulose 5-phosphate reductoisomerase from Plasmodium falciparumACTA CRYSTALLOGRAPHICA SECTION F (ELECTRONIC), Issue 3 2010Tomonobu Umeda The nonmevalonate pathway of isoprenoid biosynthesis present in Plasmodium falciparum is known to be an effective target for antimalarial drugs. The second enzyme of the nonmevalonate pathway, 1-deoxy- d -xylulose 5-phosphate reductoisomerase (DXR), catalyzes the transformation of 1-deoxy- d -xylulose 5-phosphate (DXP) to 2- C -methyl- d -erythritol 4-phosphate (MEP). For crystallographic studies, DXR from the human malaria parasite P. falciparum (PfDXR) was overproduced in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method in the presence of NADPH. X-ray diffraction data to 1.85,Å resolution were collected from a monoclinic crystal form belonging to space group C2 with unit-cell parameters a = 168.89, b = 59.65, c = 86.58,Å, , = 117.8°. Structural analysis by molecular replacement is in progress. [source] Recent advances in the molecular pathology of soft tissue sarcoma: Implications for diagnosis, patient prognosis, and molecular target therapy in the futureCANCER SCIENCE, Issue 2 2009Yoshinao Oda In the present paper, recent advances in the molecular pathology of soft tissue sarcomas (STS) and the implications for their prognostic value are reviewed, and the potential targets of molecular therapy are discussed. According to the molecular genetic aspect, STS are divided into two groups: chromosome translocation-associated sarcomas and sarcomas without specific translocation. In the former group, specific fusion transcripts, such as SS18,SSX, EWS,FLI1, and PAX3,FKHR, could be detected in synovial sarcoma, Ewing's sarcoma and primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma, respectively. The direct or indirect interactions between these fusion transcripts and cell cycle regulators have been elucidated by several investigators. Therefore, these fusion transcripts are promising candidates as molecular targets. As evaluated in carcinomas, alterations of several tumor-suppressor genes and adhesion molecules and overexpression of growth factors and their receptors have been extensively assessed in STS. In mixed-type STS, epidermal growth factor receptor overexpression was associated with decreased overall survival, suggesting the beneficial role of epidermal growth factor receptor inhibitors in STS. In malignant rhabdoid tumor and epithelioid sarcoma, frequent alteration of the SMARCB1/INI1tumor-suppressor gene and the loss of its protein have been demonstrated, indicating that this molecule could be an effective target of these sarcomas. In sarcomas with epithelioid differentiation, such as synovial sarcoma and epithelioid sarcoma, overexpression of dysadherin, which downregulates E-cadherin expression, was a poor prognostic factor. In conclusion, further studies are necessary to search for effective and specific molecules for the inhibition of tumor growth in each type of STS, especially in sarcomas without specific translocation. (Cancer Sci 2009; 100: 200,208) [source] What are the reasons for negative phase III trials of molecular-target-based drugs?CANCER SCIENCE, Issue 10 2004Nagahiro Saijo The results of molecular-biological studies of cancer are changing the way we diagnose and treat cancer. Target-based drug discovery selects agents for development based on their mechanisms of action. The interaction between target-based drugs and their targets can be described by classical drug-receptor theory. Clinical trials have demonstrated that some effective target-based drugs induce apoptosis, even though they are considered to be cyto-static. Numerous phase III trials of target-based drugs have been conducted. Although some have yielded strongly positive results, the majority of the results have been negative. This article seeks to clarify the value of molecular-target-based therapy and to discuss the reasons for negative results in phase III trials. The importance of proof-of-principle studies is stressed throughout preclinical and clinical trials of molecular-target-based drugs. [source] | ||||||||||