This study sought to examine the effect of nonlethal moderate whole body hypoxic challenge (10% 02/90% N2) on rat myocardial angiogenesis. Sprague Dawley rats were subjected to 4 h of systemic ...normobaric hypoxemic hypoxia (10 +/- 0.4% O2) in an anesthesia chamber or to 4 h of normoxia (ambient 20.9 +/- 0.4% O2) to time-match the duration of hypoxia. All rats were then kept under normoxic conditions. Rats were sacrificed and hearts harvested either after 2 h for subsequent electrophoretic mobility gel shift assay for NF kappa B, or after 24 h for subsequent Western blot analysis for vascular endothelial growth factor (VEGF) and after 7 days for immunohistochemistry for capillary density measurement. We also used pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF kappa B, before 1 h of hypoxia to establish the possible role of NF kappa B in modulating myocardial angiogenesis. The results showed significant induction of VEGF protein expression after 4 h of hypoxia followed by 24 h of reoxygenation in the rat myocardium. The DNA binding activity of NF kappa B was increased compared with the hypoxic group. However inhibition of NF kappa B by PDTC decreased capillary density significantly when compared with the hypoxic group. These findings demonstrate the role of NF kappa B and VEGF in myocardial angiogenesis for the first time.
Background:
Every TKI has it's unique adverse events (AEs) and AEs drive therapeutic outcome down in patient with CML‐CP. Treatment completion rate(TCR), complete molecular response(MR4.5), and ...treatment free remission(TFR) were examined.
Aims:
We conducted this study aiming at improving TCR, MR4.5, and TFR by stepwise dose escalation method of nilotinib.
Methods:
TCR, MR4.5, and TFR (6, 12, and 18 months) were examined by stepwise dose escalation method of nilotinib (4‐Stepwise method, i.e., 150mg‐14day, 300mg‐14day, 450mg‐14day, 600mg‐2years) in imatinib experienced or newly diagnosed patient with CML‐CP.
Results:
25 cases were enrolled in this study and all patient were received this method. Consequently, all patients achieved 600 mg, TCR was 100% by the method. 22 cases (88%) achieved MR4.5, and all of them transferred to treatment discontinuation phase. 7 cases out of 22 lost MMR in non‐treatment period, and all of them remained in the CP phase and were administered nilotinib again. TFR at 6, 12, 18 months were 86%(19/22), 75%(15/20), 79%(15/19), respectively. NK cell activity at before treatment, one of important biomarker, showed a significant difference between not achieved MR4.5 group and achieved MR4.5 group(P = 0.04).
Summary/Conclusion:
In this study, our stepwise dose escalation method of nilotinib (4‐Stepwise method, i.e., 150mg‐14day, 300mg‐14day, 450mg‐14day, 600mg‐2years) will make good use of improving therapeutic outcome. TCR was 100%. 22 out of 25 cases (88%) achieved MR4.5, and all of them were transferred to treatment discontinuation phase. 7 out of 22 cases lost MMR, TFR at 6, 12, 18 months were 86%(19/22), 75%(15/20), 79%(15/19), respectively. NK cell activity at before treatment, showed a significant difference between not achieved MR4.5 group and achieved MR4.5 group(P = 0.04).
The novel cytokine interferon-gamma-inducing factor (IGIF) augments natural killer (NK) cell activity in cultures of human peripheral blood mononuclear cells (PBMC), similarly to the structurally ...unrelated cytokine interleukin (IL)-12. IGIF has been found to enhance the production of interferon-gamma (IFN-gamma) and granulocyte/macrophage colony-stimulating factor (GM-CSF) while inhibiting the production of IL-10 in concanavalin A (Con A)-stimulated PBMC. In this study, when anti-CD3 monoclonal antibody (mAb)-stimulated human enriched T cells were exposed to IGIF, the cytokine dose-dependently enhanced the proliferation of the cells and this could be completely inhibited by a neutralizing antibody against IL-2 at lower concentrations of IGIF. Neutralizing antibody against IFN-gamma had only insignificant inhibitory effects on T cell proliferation at higher concentrations of IGIF. Enzyme-linked immunosorbent assays (ELISA) revealed that, like PBMC, T cells exposed to IGIF produced large amounts of IFN-gamma; however, changes in the production of IL-4 and IL-10 were minimal. IGIF, but not IL-12, significantly enhanced IL-2 and GM-CSF production in T cell cultures, as determined by CTLL-2 bioassay and ELISA, respectively; however, both IGIF and IL-12 enhanced IFN-gamma production by the T cells. When T cells were exposed to a combination of IGIF and IL-12, a synergistic effect was observed on the production of IFN-gamma, but not on production of IL-2 and GM-CSF. In conclusion, IGIF enhances T cell proliferation apparently through an IL-2-dependent pathway and enhances Th1 cytokine production in vitro and exhibits synergism when combined with IL-12 in terms of enhanced IFN-gamma production but not IL-2 and GM-CSF production. Based on structural and functional differences from any known cytokines, it was recently proposed that this cytokine be designated interleukin-18.
The efficacy of encephalo-duro-arterio-synangiosis (EDAS) using superficial temporal artery was evaluated for the treatment of the occlusive/stenotic cerebrovascular disease. Nine patients with the ...occlusive/stenotic cerebrovascular disease underwent EDAS in our hospital. The mean follow-up period was 6.6 months. Postoperative angiography showed no collateral formation via EDAS in any of the nine patients. We analyzed the following points: 1) operative procedure, 2) follow up period after surgery, 3) preoperative cerebral blood flow, and 4) age of the patients. Results showed that EDAS as a treatment of occlusive/stenotic cerebrovascular disease was not effective. This study failed to reinforce the suggestion that indirect extracranial/intracranial bypass surgery is effective as the treatment of occlusive/stenotic cerebrovascular disease.
To investigate the treatment results of intracranial meningiomas treated with hypofractionated stereotactic radiation therapy in three to five fractions.
Thirty-one patients (32 lesions) with ...intracranial meningioma were treated with hypofractionated stereotactic radiation therapy in three to five fractions using CyberKnife. Fifteen lesions were diagnosed as Grade I (World Health Organization classification) by surgical resection and 17 lesions were diagnosed as meningioma based on radiological findings. The median follow-up time was 48 months. The median planning target volume was 6.3 cm(3) (range, 1.4-27.1), and the prescribed dose (D90≤) ranged from 21 to 36 Gy (median, 27.8) administrated in three to five fractions.
Five-year overall and progression-free survival rate of all 31 patients with intracranial meningioma was 86 and 83%, respectively. Five-year progression-free rate of all 32 lesions was 87%. Six of the 31 patients (19%) developed marked peritumoral edema, three of whom were asymptomatic and three symptomatic, the latter with late adverse effects of more than or equal to Grade 3. The mean planning target volume of the six lesions with marked peritumoral edema was 15.6 cm(3), and for the remaining 26 lesions without marked peritumoral edema was 7.1 cm(3) (P = 0.004). The threshold diameter of 2.56 cm for meningioma was calculated from the planning target volume (11 cm(3)) and was used as marker of developing peritumoral edema (P = 0.003).
Tumor volume is a significant indicative factor for peritumoral edema in intracranial meningioma treated with hypofractionated stereotactic radiation therapy in three to five factions.
Objective: This study was designed to determine whether biological markers related to apoptosis or proliferative activity are associated with the clinical outcome in patients with squamous cell ...carcinoma (SCC) of the larynx treated with concurrent chemoradiotherapy.
Methods: Immunostaining with antibodies specific to p53, bcl-2, bax, and MIB-1 was performed to evaluate expression of these proteins in formalin-fixed, paraffin-embedded specimens of 59 patients treated with concurrent chemoradiotherapy (carboplatin, 100 mg/m
2, four to six times every week; total radiation dose of 40–65 Gy over 4–6.5 weeks).
Results: Multivariate analysis indicated that nodal status was a significant indicator of overall survival (OS;
P=0.001). Patients with bcl-2 positive tumors had better OS than those with bcl-2 negative tumors in both univariate (
P=0.002) and multivariate analyses (
P<0.001). In the univariate analysis, a considerable difference in OS was observed among the expressions of bax (
P=0.077), MIB-1 proteins (
P=0.071), and OS, but the difference was not statistically significant.
Conclusion: This study indicates that nodal status is the major prognostic factor in patients with SCC of the larynx treated with concurrent chemoradiotherapy. These results provide useful information for predicting prognosis. Further analysis of biological factors is needed to evaluate the value as predictive markers.
Sodium 5,6-benzylideneascorbate (SBA), which is known to be an antitumor substance, was found to induce apoptotic cell death of L929 tumor cells directly in a concentration- and time-dependent ...manner. The dying cells exhibited cell shrinkage, disappearance of cell surface microvilli, chromatin condensation and DNA fragmentation into nucleosomal oligomers characteristic of apoptosis. These results indicate a possible mechanism by which SBA induces tumor regression in vivo.
The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic stem and progenitor cells. Although some post-receptor signaling events of Flt3 have been ...characterized, the involvement of the Janus kinase/signal transducer and activator of transcription (Jak/Stat) pathway in Flt3 signaling has not been thoroughly evaluated. To this aim, we examined whether Flt3 activates the Jak/Stat pathway in Baf3/Flt3 cells, a line stably expressing human Flt3 receptor. Stat5a, but not Stats 1-4, 5b, or 6, was potently activated by Flt3 ligand (FL) stimulation. Interestingly, FL did not activate any Jaks. Activation of Stat5a required the kinase activity of Flt3. A selective role for Stat5a in the proliferative response of primary hematopoietic progenitor cells to FL was documented, as FL did not act on progenitors from marrows of Stat5a(-/-) mice, but did stimulate/costimulate proliferation of these cells from Stat5a(+/+), Stat5b(-/-), and Stat5b(+/+) mice. Thus, Stat5a is essential for at least certain effects of FL. Moreover, our data confirm that Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.
The effect of dibutyryl cyclic AMP (dbcAMP) on interaction of human cytomegalovirus (HCMV) with human central nervous system cell lines was examined. Activation of the major immediate-early (IE) ...promoter (MIEP) of HCMV by dbcAMP was observed in human neuroblastoma IMR-32 cells, but not in glioma 118MGC and astrocytoma U373-MG cells. The 19 bp repeat element in the enhancer of the MIEP was most likely to be the cis-element that responded to dbcAMP in IMR-32 cells as we expected. In IMR-32 cells activation of the MIEP led to enhanced synthesis of the major IE proteins and infectious HCMV.
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