The role of sphingomyelinase (SMase) activation and mitogen activated protein kinases (MAPKs) activation in cellular apoptosis was investigated during the hyperthermic treatment of HL-60 human leukemia cells. Treating the cells for 1 h at 43oC caused more than 50% of cellular apoptosis within several hours. The neutral-SMase activity in the cells treated for 1 h at 42degrees C was slightly increased but decreased in the cells treated at 43degrees C or 44degrees C for the same period whereas the acid SMase activity was slightly increased after heating the cells at 42degrees C and 43degrees C and markedly increased at 44degrees C for 1 h. Treatment of cells with inhibitors of SMase activation and ceramide formation significantly reduced the heat-induced apoptosis. Three major families of mitogen-activated protein kinases (MAPKs) i.e. ERK1/2, p38 and JNK, were activated by the hyperthermic treatment of cells. Inhibition of ERK1/2 with PD98059 exerted little effect on the heat-induced apoptosis and p38 inhibition with SB203580 slightly lessened apoptosis whereas, inhibition of JNK with SP600125 markedly suppressed the heat-induced apoptosis. These results indicate that heat-shock induced the activation of SMase, particularly acid-SMase, thereby causing apoptosis and that JNK played a pivotal role in heat-induced apoptosis in HL-60 leukemia cells.
Apoptosis/*physiology ; Enzyme Activation ; HL-60 Cells ; Heat ; Human ; Mitogen-Activated Protein Kinase Kinases/*metabolism ; Sphingomyelin Phosphodiesterase/*metabolism

PURPOSE: To evaluate the usefulness of electronic portal imaging device through objective compare of the images acquired using an EPID and a conventional port film. MATERIAL AND METHODS: From Apr. to Oct. 1997, a total of 150 sets of images from 20 patients who received radiation therapy in the pelvis area were evaluated in the Inha University Hospital and Severance Hospital. A dual image recording technique was devised to obtain both electronic portal images and port film images simultaneously with one treatment course. We did not perform double exposure. Five to ten images were acquired from each patient. All images were acquired from posteroanterior (PA) view except images from two patients. A dose rate of 100-300 MU/min and a 10- MV X-ray beam were used and 2-10 MUs were required to produce a verification image during treatment. Kodak diagnostic film with metal/film imaging cassette which was located on the top of the EPID detector was used for the port film. The source to detector distance was 140 cm. Eight anatomical landmarks (pelvic brim, sacrum, acetabulum, iliopectineal line, symphysis, ischium, obturator foramen, sacroiliac joint) were assessed. Four radiation oncologist joined to evaluate each image. The individual landmarks in the port film or in the EPID were rated - very clear (1), clear (2), visible (3), not clear (4), not visible (5). RESULTS: Using an video camera based EPID system, there was no difference of image quality between no enhanced EPID images and port film images. However, when we provided some change with window level for the portal image, the visibility of the sacrum and obturator foramen was improved in the portal images than in the port film images. All anatomical landmarks were more visible in the portal images than in the port film when we applied the CLAHE mode enhancement. The images acquired using an matrix ion chamber type EPID were also improved image quality after window level adjustment. CONCLUSION: The quality of image acquired using an electronic portal imaging device was comparable to that of the port film. When we used the enhance mode or window level adjustment, the image quality of the EPID was superior to that of the port film. EPID may replace the port film.
Acetabulum ; Animals ; Humans ; Ischium ; Mice ; Pelvis ; Sacrum

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

Tumor microenvironment is intrinsically hypoxic with abundant hypoxia-inducible factors-1α (HIF-1α), a primary regulator of the cellular response to hypoxia and various stresses imposed on the tumor cells. HIF-1α increases radioresistance and chemoresistance by reducing DNA damage, increasing repair of DNA damage, enhancing glycolysis that increases antioxidant capacity of tumors cells, and promoting angiogenesis. In addition, HIF-1α markedly enhances drug efflux, leading to multidrug resistance. Radiotherapy and certain chemotherapy drugs evoke profound anti-tumor immunity by inducing immunologic cell death that release tumor-associated antigens together with numerous pro-immunological factors, leading to priming of cytotoxic CD8+ T cells and enhancing the cytotoxicity of macrophages and natural killer cells. Radiotherapy and chemotherapy of tumors significantly increase HIF-1α activity in tumor cells. Unfortunately, HIF-1α effectively promotes various immune suppressive pathways including secretion of immune suppressive cytokines, activation of myeloid-derived suppressor cells, activation of regulatory T cells, inhibition of T cells priming and activity, and upregulation of immune checkpoints. Consequently, the anti-tumor immunity elevated by radiotherapy and chemotherapy is counterbalanced or masked by the potent immune suppression promoted by HIF-1α. Effective inhibition of HIF-1α may significantly increase the efficacy of radiotherapy and chemotherapy by increasing radiosensitivity and chemosensitivity of tumor cells and also by upregulating anti-tumor immunity.

BACKGROUND/AIMS: Sulglycotide is a non-systemic drug, used in the treatment of peptic ulcer and gastritis. The aim of this study was to assess the therapeutic effect and safety of Gliptide (sulglycotide 200 mg) in comparison with Mucosta (rebamipide 100 mg) for treatment of gastritis. MATERIALS AND METHODS: Two hundred and three symptomatic patients with erosive gastritis at endoscopy were randomized to receive sulglycotide or rebamipide for four weeks. Therapeutic effects of the drugs for gastritis were evaluated by follow up endoscopic scoring systems and clinical symptoms. We also sought possible adverse effects of the two drugs. RESULTS: Gliptide (sulglycotide) and Mucosta (rebamipide) treatment in symptomatic gastritis resulted in endoscopic improvement rates of gastritis by 52.0%, 60.6% in intention-to-treat (ITT) analysis, 53.4%, 61.1% in per protocol (PP) analysis, which means therapeutic effects was not different between the two groups. The symptom improvement rates in the sulglycotide and rebamipide treated group were 57.3%, 57.5% in ITT analysis, 54.7%, 58.8% in PP analysis, which mean statistically no significant difference between the two groups. Endoscopic findings such as cure rates of erosion, edema, improvement rates of redness, hemorrhage were not significantly different between the two groups. No statistical significant differences were observed for adverse events between the two groups. The results of 95% CIs for the difference in endoscopic improvement rate and symptom improvement rate met the criteria for the non-inferiority of sulglycotide to rebamipide. CONCLUSIONS: These results demonstrate that Gliptide (sulglycotide) was not inferior to Mucosta (rebamipide) for endoscopic and symptomatic improvements for symptomatic erosive gastritis.
Alanine ; Edema ; Endoscopy ; Follow-Up Studies ; Gastritis ; Hemorrhage ; Humans ; Peptic Ulcer ; Quinolones ; Sialoglycoproteins

BACKGROUND/AIMS: To investigate the effects of esomeprazole and rebamipide combination therapy on symptomatic improvement in patients with reflux esophagitis. METHODS: A total of 501 patients with reflux esophagitis were randomized into one of the following two treatment regimens: 40 mg esomeprazole plus 300 mg rebamipide daily (combination therapy group) or 40 mg esomeprazole daily (monotherapy group). We used a symptom questionnaire that evaluated heartburn, acid regurgitation, and four upper gastrointestinal symptoms. The primary efficacy end point was the mean decrease in the total symptom score. RESULTS: The mean decreases in the total symptom score at 4 weeks were estimated to be −18.1±13.8 in the combination therapy group and −15.1±11.9 in the monotherapy group (p=0.011). Changes in reflux symptoms from baseline after 4 weeks of treatment were −8.4±6.6 in the combination therapy group and −6.8±5.9 in the monotherapy group (p=0.009). CONCLUSIONS: Over a 4-week treatment course, esomeprazole and rebamipide combination therapy was more effective in decreasing the symptoms of reflux esophagitis than esomeprazole monotherapy.
Esomeprazole* ; Esophagitis, Peptic* ; Heartburn ; Humans

BACKGROUND/AIMS: To investigate the effects of esomeprazole and rebamipide combination therapy on symptomatic improvement in patients with reflux esophagitis. METHODS: A total of 501 patients with reflux esophagitis were randomized into one of the following two treatment regimens: 40 mg esomeprazole plus 300 mg rebamipide daily (combination therapy group) or 40 mg esomeprazole daily (monotherapy group). We used a symptom questionnaire that evaluated heartburn, acid regurgitation, and four upper gastrointestinal symptoms. The primary efficacy end point was the mean decrease in the total symptom score. RESULTS: The mean decreases in the total symptom score at 4 weeks were estimated to be −18.1±13.8 in the combination therapy group and −15.1±11.9 in the monotherapy group (p=0.011). Changes in reflux symptoms from baseline after 4 weeks of treatment were −8.4±6.6 in the combination therapy group and −6.8±5.9 in the monotherapy group (p=0.009). CONCLUSIONS: Over a 4-week treatment course, esomeprazole and rebamipide combination therapy was more effective in decreasing the symptoms of reflux esophagitis than esomeprazole monotherapy.
Esomeprazole* ; Esophagitis, Peptic* ; Heartburn ; Humans