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Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model

World Journal of Gastroenterology 2011年第44期17卷 4858-4866页

作者： Beatriz Pagán angel a isidro Myrella L Cruz Domenico Coppola Caroline B Appleyard Department of Physiology and Pharmacology Ponce School of Medicine Department of Anatomic Pathology H.Lee Moffitt Cancer Center and Research Institute

AIM:To investigate the role of epidermal growth factor receptor(EGFR) in colitis-associated dysplasia using the EGFR tyrosine kinase inhibitor ***:Sprague-Dawley rats received trinitrobenzene sulfonic acid(TNBS;30 mg in 50% ethanol,ic),followed 6 wk later by reactivation with TNBS(5 mg/kg,iv) for 3 *** induce colitis-associated dysplasia,rats then received TNBS(iv) twice a week for 10 *** group received erlotinib(10 mg/kg,ip) for 1 wk before the start of the reactivation of the colitis and 2 wk after(21 d);the rest received the *** rats were euthanized,the colons were removed and analyzed for damage and expression of the EGFR downstream effectors Erk1/2 and ***:Ninety percent of the vehicle-treated animals had dysplasia in any region of the ***-treated animals had a significant decrease in the incidence of dysplasia compared to vehicle-treated animals in all regions of the colon(50.00% ± 11.47% vs 90.00% ± 10.00% in proximal,P < 0.05;15.00% ± 8.19% vs 50.00% ± 16.67% in mid,P < 0.05;and 20.00% ± 9.17% vs 70.00% ± 15.28% in distal,P < 0.01).Erlotinib-treated animals also had reduced cell proliferation,reduced active Erk1/2,and reduced c-Myc in colon epithelium compared with the vehicle-treated *** vitro,erlotinib treatment was shown to markedly decrease c-Myc and pErk1/2 levels in rat epithelial *** of rat epithelial cells was stimulated by epidermal growth factor and inhibited by erlotinib(P < 0.05).CONCLUSION:Erlotinib can decrease the development of colitis-associated dysplasia,suggesting a potential therapeutic use for erlotinib in patients with long-standing colitis.

关键词： Animal model Epidermal growth factor receptor Colitis Dysplasia Erlotinib

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Serum vitamin D and colonic vitamin D receptor in inflammatory bowel disease

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World Journal of Gastroenterology 2016年第13期22卷 3581-3591页

作者： Yamilka Abreu-Delgado Raymond A isidro Esther A Torres Alexandra González Myrella L Cruz angel a isidro Carmen I González-Keelan Priscilla Medero Caroline B Appleyard Division of Gastroenterology Department of Medicine University of Puerto Rico Medical Sciences Campus-School of Medicine Department of Basic Sciences Physiology Division Ponce Health Sciences University-Medical School and Ponce Research Institute Department of Pathology and Laboratory Medicine University of Puerto Rico-Medical Sciences Campus

AIM: To determine serum vitamin D levels and colonic vitamin D receptor(VDR) expression in inflammatory bowel disease(IBD) and non-IBD patients and correlate these with ***: Puerto Rican IBD(n = 10) and non-IBD(n = 10) patients ≥ 21 years old scheduled for colonoscopy were recruited. Each patient completed a questionnaire and provided a serum sample and a colonic biopsy of normal-appearing mucosa. For IBD patients, an additional biopsy was collected from visually diseased mucosa. Serum vitamin D levels were measured by ultra-performance liquid chromatography and mass spectrometry. Hematoxylin and eosin stained tissue sections from colonic biopsies were classified histologically as normal or colitis(active/inactive), and scored for the degree of inflammation present(0-3, inactive/absent to severe). Tissue sections from colonic biopsies were also stained by immunohistochemistry for VDR, for which representative diagnostic areas were photographed and scored for staining intensity using a 4-point ***: The IBD cohort was significantly younger(40.40 ± 5.27, P < 0.05) than the non-IBD cohort(56.70 ± 1.64) with a higher prevalence of vitamin D deficiency(40% vs 20%, respectively) and insufficiency(70% vs 50%, respectively). Histologic inflammation was significantly higher in visually diseased mucosa from IBD patients(1.95 ± 0.25) than in normalappearing mucosa from control patients(0.25 ± 0.08, P < 0.01) and from IBD patients(0.65 ± 0.36, P < 0.05) and correlated inversely with VDR expression in visually diseased colonic tissue from IBD patients(r =-0.44, P < 0.05) and from IBD patients with Crohn's disease(r =-0.69, P < 0.05), but not in normal-appearing colonic tissue from control patients or IBD patients. Control and IBD patient serum vitamin D levels correlated positively with VDR expression in normal colon from control and IBD patients(r = 0.38, P < 0.05) and with patient age(r = 0.54, P < 0.01). CONCLUSION: Levels of serum vitamin D correl

关键词： Colitis Inflammation Vitamin D Vitamin D receptor Inflammatory bowel disease

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Immunohistochemical expression of SP-NK-1R-EGFR pathway and VDR in colonic inflammation and neoplasia

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World Journal of Gastroenterology 2015年第6期21卷 1749-1758页

作者： Raymond A isidro Myrella L Cruz angel a isidro Axel Baez Axel Arroyo William A González-Marqués Carmen González-Keelan Esther A Torres Caroline B Appleyard Department of Physiology and Pharmacology Ponce School of Medicine and Health Sciences Ponce Department of Pathology Ponce School of Medicine and Health Sciences Ponce Department of Anatomy Ponce School of Medicine and Health Sciences Ponce Departments of Pathology and Laboratory Medicine University of Puerto Rico School of Medicine Department of Medicine University of Puerto Rico School of Medicine

AIM:To determine the expression of neurokinin-1receptor(NK-1R),phosphorylated epidermal growth factor receptor(p EGFR),cyclooxygenase-2(Cox-2),and vitamin D receptor(VDR)in normal,inflammatory bowel disease(IBD),and colorectal neoplasia tissues from Puerto ***:Tissues from patients with IBD,colitisassociated colorectal cancer(CAC),sporadic dysplasia,and sporadic colorectal cancer(CRC),as well as normal controls,were identified at several centers in Puerto *** formalin-fixed,paraffin-embedded tissues were de-identified and processed by immunohistochemistry for NK-1R,p EGFR,Cox-2,and *** of representative areas of each tissues diagnosis were taken and scored by three observers using a4-point scale that assessed intensity of *** with CAC were further analyzed by photographing representative areas of IBD and the different grades of dysplasia,in addition to the areas of cancer,within each *** in the average age between the five patient groups were assessed with one-way analysis of variance and Tukey-Kramer multiple comparisons *** mean scores for normal tissues and tissues with IBD,dysplasia,CRC,and CAC were calculatedand statistically compared using one-way analysis of variance and Dunnett’s multiple comparisons *** between protein expression patterns were analyzed with the Pearson’s product-moment correlation *** are presented as mean±***:On average,patients with IBD were younger(34.60±5.81)than normal(63.20±6.13,P<0.01),sporadic dysplasia(68.80±4.42,P<0.01),sporadic cancer(74.80±4.91,P<0.001),and CAC(57.50±5.11,P<0.05)***-1R in cancer tissue(sporadic CRC,1.73±0.34;CAC,1.57±0.53)and sporadic dysplasia(2.00±0.45)were higher than in normal tissues(0.73±0.19).p EGFR was significantly increased in sporadic CRC(1.53±0.43)and CAC(2.25±0.47)when compared to normal tissue(0.07±0.25,P<0.05,P<0.001,respectively).Cox-2 was significantly increased in sporadic colorectal cancer(

关键词： Colitis Colon cancer Dysplasia Neurokinin Vitamin

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Effect of paricalcitol and enalapril on renal inflammation/oxidative stress in atherosclerosis

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World Journal of Biological Chemistry 2015年第3期6卷 240-248页

作者： Kazim Husain Edu Suarez angel isidro Wilfredo Hernandez Leon Ferder Department of Physiology Pharmacology and Toxicology Ponce School of Medicine and Health Sciences Department of Biochemistry Ponce School of Medicine and Health Sciences

AIM: To investigate the protective effect of paricalcitol and enalapril on renal inflammation and oxidative stress in Apo E-knock out mice. METHODS: Animals treated for 4 mo as group(1) Apo E-knock out plus vehicle, group(2) Apo E-knock out plus paricalcitol(200 ng thrice a week),(3) Apo Eknock out plus enalapril(30 mg/L),(4) Apo E-knock out plus paricalcitol plus enalapril and(5) normal. Blood pressure(BP) was recorded using tail cuff method. The kidneys were isolated for biochemical assays using spectrophotometer and Western blot analyses. RESULTS: Apo E-deficient mice developed high BP(127 ± 3 mm Hg) and it was ameliorated by enalapril and enalapril plus paricalcitol treatments but not with paricalcitol alone. Renal malondialdehyde concentrations, p22 phox, manganese-superoxide dismutase, inducible nitric oxide synthase(NOS), monocyte chemoattractant protein-1, tumor necrosis factor-alpha and transforming growth factor-β1 levels significantly elevated but reduced glutathione, Cu Zn-SOD and e NOS levels significantly depleted in Apo E-knock out animals compared to normal. Administration of paricalcitol, enalapril and combined together ameliorated the renal inflammation and oxidative stress in Apo E-knock out animals. CONCLUSION: Paricalcitol and enalapril combo treatment ameliorates renal inflammation as well as oxidative stress in atherosclerotic animals.

关键词： Atherosclerosis Enalapril Paricalcitol Renal inflammation Oxidative stress

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Clinical and prognostic implications of atrial fibrillation in patients undergoing transcatheter aortic valve implantation

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World Journal of Cardiology 2012年第1期4卷 8-14页

作者： Pablo Salinas Raúl Moreno Luis Calvo Santiago Jiménez-Valero Guillermo Galeote angel Sánchez-Recalde Teresa López-Fernández Sergio Garcia-Blas Diego Iglesias Luis Riera isidro Moreno-Gómez Jose María Mesa Ignacio Plaza Rocio Ayala Rosa Gonzalez José-Luis López-Sendón Division of Interventional Cardiology University Hospital La Paz Unit of Echocardiography University Hospital La Paz Department of Cardiology University Hospital La Paz Vascular Surgery University Hospital La Paz Department of Cardiac Anaesthesia University Hospital La Paz Cardiac Surgery University Hospital La Paz Department of Cardiology Hospital Infanta Sofia Department of Cardiology Hospital de la Cruz Roja

AIM: To study a cohort of consecutive patients under-going transcatheter aortic valve implantation (TAVI) and compare the outcomes of atrial fibrillation (AF) patients vs patients in sinus rhythm (SR). METHODS: All consecutive patients undergoing TAVI in our hospital were included. The AF group comprised patients in AF at the time of TAVI or with history of AF, and were compared with the SR group. Procedural, echocardiographic and follow-up variables were compared. Likewise, the CHA 2 DS 2-VASC stroke risk score and HAS-BLED bleeding risk score and antithrombotic treatment at discharge in AF patients were compared with that in SR patients. RESULTS: From a total of 34 patients undergoing TAVI, 17 (50%) were allocated to the AF group, of whom 15 (88%) were under chronic oral anticoagulation. Patients in the AF group were similar to those in the SR group except for a trend (P = 0.07) for a higher logistic EuroSCORE (28% vs 19%), and a higher prevalence of hypertension (82% vs 53%) and chronic renal failure (17% vs 0%). Risk of both stroke and bleeding was high in the AF group (mean CHA 2 DS 2-VASC 4.3, mean HAS-BLED 2.9). In the AF group, treatment at discharge included chronic oral anticoagulation in all except one case, and in association with an antiplatelet drug in 57% of patients. During a mean follow-up of 11 mo (maximum 32), there were only two strokes, none of them during the peri-procedural period: one in the AF group at 30 mo and one in the SR group at 3 mo. There were no statistical differences in procedural success, and clinical outcome (survival at 1 year 81% vs 74% in AF and SR groups, respectively, P = NS). CONCLUSION: Patients in AF undergoing TAVI show a trend to a higher surgical risk. However, in our cohort, patients in AF did not have a higher stroke rate compared to the SR group, and the prognosis was similar in both groups.

关键词： Aortic stenosis Transcatheter aortic valve implantation Stroke Atrial fibrillation

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