Thomas Adrian - Academia.edu (original) (raw)
Papers by Thomas Adrian
American Journal of Pathology, 2002
The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from ... more The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from apoptosis. Inhibition of 5-LOX blocks proliferation and induces apoptosis in human pancreatic cancer cells. However , the expression of 5-LOX and its downstream signaling pathway have not been investigated in human pancreatic adenocarcinoma. Reverse transcriptase-polymerase chain reaction revealed expression of 5-LOX mRNA in all pancreatic cancer cell lines tested including , PANC-1 , AsPC-1 , and MiaPaCa2 cells, but not in normal pancreatic ductal cells. The expression of 5-LOX protein in pancreatic cancer cell lines was demonstrated by Western blotting. Finally , 5-LOX up-regulation in human pancreatic cancer tissues was verified by intense positive staining in cancer cells by immunohistochemistry. Staining for the 5-LOX protein was particularly evident in the ductal components of the more differentiated tumors but not in ductal cells in normal pancreatic tissues from cadaver donors. Immunohistochemistry also revealed strong staining of cancer tissues with an antibody to the receptor of the downstream 5-LOX metabolite , leukotriene B 4 . The current study demonstrated marked expression of 5-LOX and the leukotriene B 4 receptor in human pancreatic cancer tissues. These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease. Pancreatic adenocarcinoma is characterized by a poor prognosis and lack of response to conventional therapy. This dreadful disease is now the fourth leading cause of cancer death in both men and women in the United States. The incidence has shown no significant sign of
American Journal of Surgery, 1993
Diabetes in patients with pancreatic cancer occurs in 70% to 80% of the patients and is character... more Diabetes in patients with pancreatic cancer occurs in 70% to 80% of the patients and is characterized by high plasma levels of insulin. In type II diabetes that is not associated with pancreatic cancer, peripheral insulin resistance and impaired muscle glycogen synthesis are major pathogenic factors. We investigated peripheral insulin sensitivity in patients with pancreatic cancer before and after tumor removed. The effects of pancreatic tumor extracts on glycogen synthesis in skeletal muscle in vitro and the tumor content of pancreatic islet hormones were also investigated.
Islet amyloid polypeptide in patients with pancreatic cancer and diabetes
New England Journal of Medicine, 1994
The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked i... more The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked insulin resistance that declines after tumor resection. Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro. In this study, we examined the relation between IAPP and diabetes in patients with pancreatic cancer. We measured IAPP in plasma from 30 patients with pancreatic cancer, 46 patients with other cancers, 23 patients with diabetes, and 25 normal subjects. IAPP immunoreactivity and IAPP messenger RNA were studied in pancreatic cancers, pancreatic tissue adjacent to cancers, and normal pancreatic tissue. Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P &amp;amp;amp;lt; 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes. Among the patients with pancreatic cancer, the concentrations were 25.0 +/- 8.7 pmol per liter in the 7 patients with diabetes who required insulin, 31.4 +/- 12.6 pmol per liter in the 11 patients with diabetes who did not require insulin, and 12.2 +/- 2.4 pmol per liter in the 9 patients with normal glucose tolerance (3 patients had impaired glucose tolerance; their mean plasma IAPP concentration was 11.7 +/- 5.5 pmol per liter). Plasma IAPP concentrations decreased after surgery in the seven patients with pancreatic cancer who were studied before and after subtotal pancreatectomy (28.9 +/- 16.4 vs. 5.6 +/- 3.4 pmol per liter, P = 0.01). Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P &amp;amp;amp;lt; 0.001). In samples from the patients with both pancreatic cancer and diabetes, immunostaining for IAPP was reduced in islets of pancreatic tissue surrounding the tumor; in situ hybridization studies suggested that transcription occurred normally in these islets. Plasma IAPP concentrations are elevated in patients with pancreatic cancer who have diabetes. Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients.
Free radical scavengers prevent reflux esophagitis in rats
Digestive Diseases and Sciences, 1995
Free radical damage in reflux esophagitis of rats induced by 24-hr duodenojejunal ligation was st... more Free radical damage in reflux esophagitis of rats induced by 24-hr duodenojejunal ligation was studied. Oxygen free radicals were selectively blocked. Groups were: sham operation, reflux, reflux+superoxide dismutase (SOD), catalse, dimethylthiourea, allopurinol, and inactivated SOD or inactivated catalase alone or in the combination SOD+catalase or SOD+catalase+dimethylthiourea+allopurinol. Macroscopic esophagitis was inhibited only by SOD, alone or in combination with other agents. Esophageal mucosal lipid peroxidation was 10-fold increased in the reflux group compared to the sham group (P<0.05). This response was damped by SOD>catalase (P<0.05) but not by the inactivated enzymes, dimethylthiourea or allopurinol. SOD+catalase showed no significant improvement on SOD alone. Total inhibition of lipid peroxidation was achieved by combining all scavengers. Total glutathione (GSH) in the esophageal mucosa was stimulated by reflux. This response was inhibited by scavengers equivalent to their efficacy in preventing lipid peroxidation. It is concluded that reflux esophagitis is associated with free radical release with O2− being the main source. Free radicals appear to stimulate GSH production in this prolonged oxidative stress.
Esophagitis in sprague-dawley rats is mediated by free radicals
Digestive Diseases and Sciences, 1995
Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux... more Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux) or acid reflux in rats. The influence of reflux on esophageal glutathione levels was also examined. Mixed reflux caused more gross mucosal injury than acid reflux. Gross mucosal injury occurred in the mid-esophagus. Total glutathione (GSH) in the esophageal mucosa of control rats was highest in the distal esophagus. The time course of esophageal GSH in rats treated by mixed reflux showed a significant decrease 4 hr after initiation of reflux, followed by a significant increase from the 12th hour on. Mucosal GSH was increased in both reflux groups after 24 hr but significantly more so in the mixed than in the acid reflux group. The free radical scavenger superoxide dismutase (SOD) prevented esophagitis and was associated with decreased GSH levels. GSH depletion by buthionine sulfoximine (BSO) prevented esophagitis and stimulated SOD production in the esophageal mucosa. It is concluded that gastroesophageal reflux is associated with oxidative stress in the esophageal mucosa. The lower GSH levels in the mid-esophagus may predispose to damage in this area. Duodenogastroesophageal reflux causes more damage than pure acid reflux. Oxidative stress leads to GSH depletion of the esophageal mucosa in the first few hours following damage but then stimulates GSH production. GSH depletion by BSO does not worsen esophagitis since it increases the esophageal SOD concentration.
American Journal of Pathology, 2002
The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from ... more The 5-lipoxygenase (5-LOX) pathway is critical for pancreatic cancer cell growth and escape from apoptosis. Inhibition of 5-LOX blocks proliferation and induces apoptosis in human pancreatic cancer cells. However , the expression of 5-LOX and its downstream signaling pathway have not been investigated in human pancreatic adenocarcinoma. Reverse transcriptase-polymerase chain reaction revealed expression of 5-LOX mRNA in all pancreatic cancer cell lines tested including , PANC-1 , AsPC-1 , and MiaPaCa2 cells, but not in normal pancreatic ductal cells. The expression of 5-LOX protein in pancreatic cancer cell lines was demonstrated by Western blotting. Finally , 5-LOX up-regulation in human pancreatic cancer tissues was verified by intense positive staining in cancer cells by immunohistochemistry. Staining for the 5-LOX protein was particularly evident in the ductal components of the more differentiated tumors but not in ductal cells in normal pancreatic tissues from cadaver donors. Immunohistochemistry also revealed strong staining of cancer tissues with an antibody to the receptor of the downstream 5-LOX metabolite , leukotriene B 4 . The current study demonstrated marked expression of 5-LOX and the leukotriene B 4 receptor in human pancreatic cancer tissues. These findings provide further evidence of up-regulation of this pathway in pancreatic cancer and that LOX inhibitors are likely to be valuable in the treatment of this dreadful disease. Pancreatic adenocarcinoma is characterized by a poor prognosis and lack of response to conventional therapy. This dreadful disease is now the fourth leading cause of cancer death in both men and women in the United States. The incidence has shown no significant sign of
American Journal of Surgery, 1993
Diabetes in patients with pancreatic cancer occurs in 70% to 80% of the patients and is character... more Diabetes in patients with pancreatic cancer occurs in 70% to 80% of the patients and is characterized by high plasma levels of insulin. In type II diabetes that is not associated with pancreatic cancer, peripheral insulin resistance and impaired muscle glycogen synthesis are major pathogenic factors. We investigated peripheral insulin sensitivity in patients with pancreatic cancer before and after tumor removed. The effects of pancreatic tumor extracts on glycogen synthesis in skeletal muscle in vitro and the tumor content of pancreatic islet hormones were also investigated.
Islet amyloid polypeptide in patients with pancreatic cancer and diabetes
New England Journal of Medicine, 1994
The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked i... more The diabetes mellitus that occurs in patients with pancreatic cancer is characterized by marked insulin resistance that declines after tumor resection. Islet amyloid polypeptide (IAPP), a hormonal factor secreted from the pancreatic beta cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro. In this study, we examined the relation between IAPP and diabetes in patients with pancreatic cancer. We measured IAPP in plasma from 30 patients with pancreatic cancer, 46 patients with other cancers, 23 patients with diabetes, and 25 normal subjects. IAPP immunoreactivity and IAPP messenger RNA were studied in pancreatic cancers, pancreatic tissue adjacent to cancers, and normal pancreatic tissue. Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P &amp;amp;amp;lt; 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes. Among the patients with pancreatic cancer, the concentrations were 25.0 +/- 8.7 pmol per liter in the 7 patients with diabetes who required insulin, 31.4 +/- 12.6 pmol per liter in the 11 patients with diabetes who did not require insulin, and 12.2 +/- 2.4 pmol per liter in the 9 patients with normal glucose tolerance (3 patients had impaired glucose tolerance; their mean plasma IAPP concentration was 11.7 +/- 5.5 pmol per liter). Plasma IAPP concentrations decreased after surgery in the seven patients with pancreatic cancer who were studied before and after subtotal pancreatectomy (28.9 +/- 16.4 vs. 5.6 +/- 3.4 pmol per liter, P = 0.01). Pancreatic cancers contained IAPP, but the concentrations were lower than in normal pancreatic tissue (17 +/- 16 vs. 183 +/- 129 pmol per gram, P &amp;amp;amp;lt; 0.001). In samples from the patients with both pancreatic cancer and diabetes, immunostaining for IAPP was reduced in islets of pancreatic tissue surrounding the tumor; in situ hybridization studies suggested that transcription occurred normally in these islets. Plasma IAPP concentrations are elevated in patients with pancreatic cancer who have diabetes. Since IAPP may cause insulin resistance, its overproduction may contribute to the diabetes that occurs in these patients.
Free radical scavengers prevent reflux esophagitis in rats
Digestive Diseases and Sciences, 1995
Free radical damage in reflux esophagitis of rats induced by 24-hr duodenojejunal ligation was st... more Free radical damage in reflux esophagitis of rats induced by 24-hr duodenojejunal ligation was studied. Oxygen free radicals were selectively blocked. Groups were: sham operation, reflux, reflux+superoxide dismutase (SOD), catalse, dimethylthiourea, allopurinol, and inactivated SOD or inactivated catalase alone or in the combination SOD+catalase or SOD+catalase+dimethylthiourea+allopurinol. Macroscopic esophagitis was inhibited only by SOD, alone or in combination with other agents. Esophageal mucosal lipid peroxidation was 10-fold increased in the reflux group compared to the sham group (P<0.05). This response was damped by SOD>catalase (P<0.05) but not by the inactivated enzymes, dimethylthiourea or allopurinol. SOD+catalase showed no significant improvement on SOD alone. Total inhibition of lipid peroxidation was achieved by combining all scavengers. Total glutathione (GSH) in the esophageal mucosa was stimulated by reflux. This response was inhibited by scavengers equivalent to their efficacy in preventing lipid peroxidation. It is concluded that reflux esophagitis is associated with free radical release with O2− being the main source. Free radicals appear to stimulate GSH production in this prolonged oxidative stress.
Esophagitis in sprague-dawley rats is mediated by free radicals
Digestive Diseases and Sciences, 1995
Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux... more Free radical-mediated esophagitis was studied during duodenogastroesophageal reflux (mixed reflux) or acid reflux in rats. The influence of reflux on esophageal glutathione levels was also examined. Mixed reflux caused more gross mucosal injury than acid reflux. Gross mucosal injury occurred in the mid-esophagus. Total glutathione (GSH) in the esophageal mucosa of control rats was highest in the distal esophagus. The time course of esophageal GSH in rats treated by mixed reflux showed a significant decrease 4 hr after initiation of reflux, followed by a significant increase from the 12th hour on. Mucosal GSH was increased in both reflux groups after 24 hr but significantly more so in the mixed than in the acid reflux group. The free radical scavenger superoxide dismutase (SOD) prevented esophagitis and was associated with decreased GSH levels. GSH depletion by buthionine sulfoximine (BSO) prevented esophagitis and stimulated SOD production in the esophageal mucosa. It is concluded that gastroesophageal reflux is associated with oxidative stress in the esophageal mucosa. The lower GSH levels in the mid-esophagus may predispose to damage in this area. Duodenogastroesophageal reflux causes more damage than pure acid reflux. Oxidative stress leads to GSH depletion of the esophageal mucosa in the first few hours following damage but then stimulates GSH production. GSH depletion by BSO does not worsen esophagitis since it increases the esophageal SOD concentration.