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Effective Therapeutic Strategies (effective + therapeutic_strategy)
Selected AbstractsRemodeling of extracellular matrix and epileptogenesisEPILEPSIA, Issue 2010Alexander Dityatev Summary Extracellular matrix (ECM) in the brain is composed of molecules synthesized and secreted by neurons and glial cells, which form stable aggregates of diverse composition in the extracellular space. In the mature brain, ECM undergoes a slow turnover and restrains structural plasticity while supporting multiple physiologic processes, including perisomatic ,-aminobutyric acid (GABA)ergic inhibition, synaptic plasticity, and homeostatic regulations. Seizures lead to striking remodeling of ECM, which may be essentially engaged in different aspects of epileptogenesis. This view is supported by human genetic studies linking ECM molecules and epilepsy, by data showing altered epileptogenesis in mice deficient in ECM molecules, and by evidence that ECM may shape seizure-induced sprouting of mossy fibers, granule cell dispersion, and astrogliosis. Therefore, restraining seizure-induced remodeling of ECM or suppressing the signaling triggered by the remodeled ECM might provide effective therapeutic strategies to antagonize the progression of epileptogenesis. [source] The North American Immune Tolerance Registry: contributions to the thirty-year experience with immune tolerance therapyHAEMOPHILIA, Issue 1 2009D. DIMICHELE Summary., The North American Immune Tolerance Registry (NAITR) began in 1992 as a project of the ISTH Factor VIII/IX Subcommittee with the goal of further determining immune tolerance induction (ITI) practices in Canada and the United States. This retrospective registry study, published in 2002, was limited in its capacity to provide definitive answers to many unresolved ITI practice issues. Nonetheless, it played a role in developing guidelines for current ITI practice and in generating hypotheses that must now be examined through rigorous prospective data collection efforts. For haemophilia A, the logical next step has been the initiation of international prospective randomized studies of ITI outcome relative to factor VIII (FVIII) dose and purity for subjects with high titre inhibitors. Both trials will additionally provide platforms for translational study of the immunology of tolerance, a prelude to the next generation of safe and effective tolerizing strategies. For the less common problem of FIX inhibitor eradication, prospective randomized studies will not be a feasible way to confirm the NAITR observations. Coordinated international efforts will still be required to prospectively collect data on ITI outcome to document new potentially effective therapeutic strategies for inhibitor eradication. These registries will hopefully also serve to identify potential subjects for scientific studies of immunology of haemophilia B-related allergic phenomena, a devastating complication of FIX antibody development. [source] Akt is frequently activated in HER2/neu-positive breast cancers and associated with poor prognosis among hormone-treated patientsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Eriko Tokunaga Abstract Akt/PKB is a serine/threonine kinase that plays an important role in survival when cells are exposed to different apoptotic stimuli. Aberrant activation of Akt/PKB in breast carcinoma is associated with poor prognosis and resistance to endocrine therapy and chemotherapy. The Akt signaling pathway currently attracts considerable attention as a new target for effective therapeutic strategies. We therefore investigated the relationship between activation of Akt and clinicopathologic variables including hormone receptor and HER2/neu status. Breast cancer tissues obtained from 252 patients were utilized for this study. We evaluated Akt activation by immunohistochemical assessment of the expression of phosphorylated Akt (pAkt) at Ser-473. Eighty-four cases (33.3%) were diagnosed as positive for pAkt expression. pAkt was significantly associated with HER2/neu overexpression (p < 0.0001). There was an inverse correlation between pAkt and PR expression (p = 0.0321); however, there was no association between pAkt and ER expression. Survival analysis showed that pAkt positivity was associated with poor disease-free survival in cases with postoperative hormone therapy; however, there was no association in cases without hormone therapy. Our results indicate that Akt activation induced poor prognosis in patients who received adjuvant hormone therapy. This finding suggests that inhibition of the Akt signaling pathway may increase the efficacy of hormone therapy and improve the prognosis of patients who receive adjuvant hormone therapy. © 2005 Wiley-Liss, Inc. [source] Urinary catecholamine excretion in tetanusANAESTHESIA, Issue 4 2006C. L. Thwaites Summary Imperfect understanding of the pathophysiology of tetanus has limited therapeutic advances. Autonomic disturbance is a major cause of mortality and is believed to be associated with catecholamine release, predominantly norepinephrine. We measured epinephrine and norepinephrine concentrations in 24-h urine collections from tetanus and critically ill patients suffering from other severe diseases. In patients with severe tetanus, mean (SD) epinephrine was 164.18 (129.37) nmol.day,1 compared with 45.18 (37.74) nmol.day,1 in mild-moderate disease (p = 0.008). In the severe group, mean (SD) norepinephrine was 411.64 (208.5), and 121.00 (81.81) nmol.day,1 in moderately ill patients (p < 0.001). Compared with critically ill control patients, median epinephrine was 331.77 in tetanus patients and 89.70 nmol.day,1 in controls (p < 0.001). Median norepinephrine concentration was 788.02 nmol.day,1 in tetanus and 300.05 nmol.day,1 in control patients, p = 0.006. The study finds a novel result of increased epinephrine excretion in tetanus and confirms that catecholamine excretion in tetanus exceeds that in other critically ill patients. These results should be considered in designing more effective therapeutic strategies. [source] Either interleukin-12 or interferon-, can correct the dendritic cell defect induced by transforming growth factor ,1 in patients with myelomaBRITISH JOURNAL OF HAEMATOLOGY, Issue 6 2004Ross Brown Summary The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor ,1 (TGF,1) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGF,1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon- , neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123,) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon- , to future immunotherapy trials involving these patients should be considered. [source] Intracerebral transplantation of neural stem cells combined with trehalose ingestion alleviates pathology in a mouse model of Huntington's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2009Chia-Ron Yang Abstract The present investigation examined the neuroprotective benefits for combined trehalose administration with C17.2 neural stem cell transplantation in a transgenic mouse model of Huntington's disease (HD), R6/2. C17.2 neural stem cells have the potential of differentiating into a neuronal phenotype in vitro and have been shown to be effective in the treatment of a variety of lysosomal lipid storage disorders in the nervous system. In this study, we transplanted these cells into the lateral ventricle of R6/2 transgenic mice in order to examine the efficacy of using these cells for correcting the accumulated polyglutamine storage materials in HD. To improve efficacy, animals were fed with a diet rich in trehalose, which has been shown to be beneficial to retard aggregate formation. The combined treatment strategy not only decreased ubiquitin-positive aggregation in striatum, alleviated polyglutamine aggregation formation, and reduced striatal volume, but also extended life span in the R6/2 animal model. Behavioral evaluation showed that the combination treatment improved motor function. Statistical analysis revealed that the combination treatment was more effective than treatment with trehalose alone on the basis of the above biochemical and behavioral criteria. This study provides a strong a basis for further developing an effective therapeutic strategy for HD. © 2008 Wiley-Liss, Inc. [source] Strategy to prevent recurrent portal vein stenosis following interventional radiology in pediatric liver transplantationLIVER TRANSPLANTATION, Issue 3 2010Yukihiro Sanada Portal vein complications after liver transplantation (LT) are serious complications that can lead to graft liver failure. Although the treatment of interventional radiology (IVR) by means of balloon dilatation for portal vein stenosis (PVS) after LT is an effective method, the high rate of recurrent PVS is an agonizing problem. Anticoagulant therapy for PVS is an important factor for preventing short-term recurrence following IVR, but no established regimen has been reported for the prevention of recurrent PVS following IVR. In our population of 197 pediatric patients who underwent living donor liver transplantation (LDLT), 22 patients (22/197, 11.2%) suffered PVS. In the 9 earliest patients, unfractionated heparin was the only anticoagulant therapy given following IVR. In the 13 more recent patients, 3-agent anticoagulant therapy using low-molecular-weight heparin, warfarin, and aspirin was employed. In the initial group of 9 patients, 5 patients (55.6%) suffered recurrent PVS and required repeat balloon dilatation. Among the 13 more recent patients, none experienced recurrent PVS (P = 0.002). In conclusion, our 3-agent anticoagulant therapy following IVR for PVS in pediatric LDLT can be an effective therapeutic strategy for preventing recurrent PVS. Liver Transpl 16:332,339, 2010. © 2010 AASLD. [source] Day 15 bone marrow driven double induction in young adult patients with acute myeloid leukemia: Feasibility, toxicity, and therapeutic results,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2010Felicetto Ferrara The strategy named double induction (DI) in acute myeloid leukemia (AML) consists of two courses of chemotherapy irrespective of the degree of cytoreduction in the bone marrow (BM) after the first course, unless severe complications prohibit its application. We describe treatment results from a series of 33 patients in whom DI was adopted only after demonstration of persistence of more than 10% blast cells at day 15 (D15) examination of BM. All patients received as induction idarubicin, cytarabine, and etoposide. As second induction, we administered the combination of fludarabine, intermediate dose cytarabine, and Granulocyte colony stimulating factor (G-CSF). The median blast count at D15 was 30 (15,90). Overall, 30 of 33 patients were judged as eligible to receive DI, reasons for exclusion being in all cases active infection in the context of severe pancytopenia. Nineteen patients (63%) had unfavorable karyotype and 11 (37%) normal karyotype; seven of these had Fms-like tyrosine kinase gene internal tandem duplication (FLT3/ITD) mutation. Overall, complete remission (CR) was achieved in 20/30 patients (67%), while eight patients (27%) were refractory and two died of infectious complications. All refractory patients had unfavorable cytogenetics. All patients achieving CR were programmed to receive allogeneic stem cell transplantation (allo-SCT), which was actually performed in 11 patients. Our study suggest that D15 driven DI represents a feasible and effective therapeutic strategy in young adult AML patients, improving therapeutic results and not compromising feasibility of allo-SCT. When compared with conventional DI, it offers the potential to avoid unnecessary toxicity in a consistent proportion of patients. Am. J. Hematol., 2010. © 2010 Wiley-Liss, Inc. [source] Successful carboplatin desensitization in patients with proven carboplatin allergyCANCER, Issue 3 2005Ronit Confino-Cohen M.D. Abstract BACKGROUND Carboplatin is one of the most useful and well tolerated cytotoxic drugs for gynecologic malignancies. Hypersensitivity to carboplatin is not rare among patients receiving multiple recurrent treatments with this drug. The aim of the current study was to offer a safe and convenient carboplatin desensitization strategy to patients with a proven allergic reaction to this drug. METHODS Patients with an immediate objective allergic reaction to carboplatin were skin tested with the drug. A 6-hour carboplatin desensitization protocol was administered to the patients with a carboplatin-positive skin test on each of the following treatment courses. RESULTS Twenty-three patients with an allergic reaction to carboplatin and a positive skin test were included in the current study. Twenty patients (86.9%) were desensitized. One patient developed a mild urticarial rash. Nineteen patients tolerated 80 desensitization courses uneventfully. CONCLUSIONS The data presented a successful desensitization protocol for individuals with a proven allergic reaction to carboplatin. The protocol was safe and convenient and offered an effective therapeutic strategy to patients who required this drug. Cancer 2005. © 2005 American Cancer Society. [source] | ||||||||||||||||||||||