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Biomedical subjects

J Gugenheim

Publications and source records attributed to J Gugenheim.

At least 19 recordsLinked to original sources
PubMed2006

Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126.

Current experimental and clinical knowledge supports the optimisation of endothelial cell targeting using a strategy combining anti-EGFR drugs with antivascular agents. The purpose of the present study was to examine the effects of the association of ZD6126, an antivascular microtubule-destabilising agent, with gefitinib and irradiation on the growth of six head and neck human cancer cell lines xenografted in nude mice and to study predictive and molecular factors responsible for antitumour effects. CAL33- and Hep-2-grafted cell lines were the most sensitive to ZD6126 treatment, with VEGF levels significantly higher (P=0.0336) in these tumour xenografts compared to Detroit 562- and CAL27-grafted cell lines with relatively low VEGF levels that were not sensitive to ZD6126. In contrast, neither IL8 levels nor EGFR expression was linked to the antitumour effects of ZD6126. ZD6126 in combination with gefitinib resulted in a synergistic cytotoxic interaction with greater antitumour effects than gefitinib alone. The synergistic interaction between ZD6126 and gefitinib was corroborated by a significant decrease in CD31 labelling. The present study may serve for future innovative clinical applications, as it suggests that VEGF tumour levels are possible predictors for ZD6126 antitumour efficacy. It also supports the notion of antitumour supra-additivity when combining gefitinib and ZD6126, and identifies neoangiogenesis as the main determinant of this synergistic combination.

Angiogenesis Inhibitors↗
PubMed2006

Involvement of protein kinase B and mitogen-activated protein kinases in experimental normothermic liver ischaemia-reperfusion injury.

BACKGROUND: This study evaluated the role of protein kinase B (PKB), phosphatidylinositol 3-kinase (PI3-K), Bcl-2-associated death protein (BAD) and mitogen-activated protein kinases (MAPKs) in normothermic ischaemia-reperfusion (IR)-induced apoptosis in rat liver. METHODS: Rats were divided into two groups that received either phosphate-buffered saline (control) or the caspase inhibitor Z-Asp-2,6-dichorobenzoyloxymethylketone (Z-Asp-cmk), injected intravenously 2 min before the induction of 120 min of normothermic liver ischaemia. Liver apoptosis was assessed by the terminal deoxyribonucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) method. PI3-K, PKB, BAD and MAPK activities were measured in ischaemic and non-ischaemic lobes at various times after reperfusion. RESULTS: The number of TUNEL-positive cells was significantly decreased after pretreatment with Z-Asp-cmk. In controls, PI3-K and PKB activities and BAD phosphorylation were inhibited in ischaemic liver lobes. The MAPKs (extracellular signal-regulated kinases, c-Jun N-terminal kinase and p38) showed different patterns of activation during IR. PKB activity was not modified by pretreatment with Z-Asp-cmk. CONCLUSION: Induction of apoptosis during IR liver injury might be triggered by inactivation of the antiapoptotic PI3-K-PKB pathway and activation of the proapoptotic MAPKs.

Analysis of Variance↗
PubMed2006

Alterations in protein tyrosine kinase pathways in rat liver following normothermic ischemia-reperfusion.

The phosphoregulation of signal transduction pathways is a complex series of reactions that modulate the cellular response to ischemia-reperfusion (I-R). The aim of this study was to evaluate the effect of normothermic liver I-R on protein tyrosine phosphorylation, production of angiogenic growth factors, and activation of signal proteins in tyrosine kinase pathways. A segmental normothermic ischemia of the liver was induced in rats by occluding the blood vessels (including the bile duct) to the median and left lateral lobes for 120 minutes. Liver extracts from either ischemic or nonischemic lobes were prepared at 0, 1, 3, and 6 hours after reperfusion. Liver tyrosine phosphorylation of proteins was examined by Western blot analysis, whereas vascular endothelial growth factor (VEGF) mRNA was analyzed by Northern blot. In ischemic liver lobes, VEGF mRNA and total protein levels increased at 1 and 3 hours after reperfusion. Tyrosine phosphorylation of the VEGF receptor Flk-1 and the platelet-derived growth factor receptor (PDGF-R) was increased only at 1 hour after reperfusion, while c-Src tyrosine phosphorylation remained increased at 3 hours and remained up to 6 hours after reperfusion. In conclusion, 1-R led to alterations in protein tyrosine phosphorylation and increased expression of VEGF in rat liver.

Animals↗
PubMed2005

Laparoscopic subtotal colectomy with cecorectal anastomosis for slow-transit constipation.

Subtotal colectomy with cecorectal anastomosis represents an interesting alternative to total colectomy with ileorectal anastomosis. Several technical variants to the methods for performing the anastomosis between the cecum and the rectal stump after subtotal colectomy have been reported. The mechanical, antiperistaltic, end-to-end cecorectal anastomosis is safe and easy to perform. The authors aimed to assess the safety and feasibility of this technique performed laparoscopically in a series of four patients. All the procedures were completed laparoscopically. The mean time for surgery was 200 min (range, 180-220 min). There was no mortality and no postoperative complications. The mean hospital stay was 4 days (range, 3-5 days). This technique can be performed laparoscopically with all the advantages inherent to the minimally invasive approach.

Adult↗
PubMed2005

Epidermal growth factor receptor (EGFR) status in primary colorectal tumors correlates with EGFR expression in related metastatic sites: biological and clinical implications.

BACKGROUND: Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of colorectal cancer (CRC). There are several potential strategies to target EGFR. However, monoclonal antibodies and low molecular weight tyrosine kinase inhibitors are the most advanced in clinical development. The majority of studies so far have merely required EGFRs to be expressed by CRC cells. The detection of EGFR expression is usually performed by immunohistochemistry (IHC) in the primary tumor. There are few data regarding the EGFR status in the corresponding distant metastases. PATIENTS AND METHODS: EGFR status was analyzed by IHC in 80 patients (31 male, 49 female) with CRC (70 colon, 10 rectum) and at least one distant metastatic lesion. Metastatic sites analyzed (n=80) were liver (79 patients) and lung (one patient). RESULTS: EGFR reactivity was similar in the primary tumor and the related metastases. Among the 80 paired primary/metastatic tumors, only five (6.3%) showed discordance in EGFR status: two cases with EGFR expression in the primary tumor but not in the metastasis, and three samples with EGFR expression in the metastasis but not in the primary tumor. CONCLUSIONS: Between the paired primary tumors and distant metastatic lesions, 94% of samples had concordant EGFR status when analyzed by IHC.

Adult↗
PubMed2005

[Vaginal evisceration. Report of a new case].

Vaginal evisceration is rare and most commonly found in postmenopausal women. We report the case of a postmenopausal woman due to ruptured enterocele. Surgical treatment was done through a midline laparotomy and consisted of bowel resection with primary anastomosis and vaginal vault suture repair. Risk factors for this rare clinical entity are discussed along with the different therapeutic options.

Anastomosis, Surgical↗
PubMed2005

[Bowel perforation as late complication of tension-free vaginal tape].

Tension-free vaginal tape (TVT) is considered as the treatment of choice for female stress urinary incontinence. Bowel erosion is a rare complication of TVT that generally occurs a few days after surgery with a clinical picture of peritonitis and/or intestinal obstruction. Herein is reported a case of a bowel erosion with a late clinical manifestation 3 months after hysterectomy and TVT placement for genital prolapse and urinary incontinence. Bowel erosion may complicate TVT operation several months after surgery and should be considered as differential diagnosis in patients presenting with a clinical picture of peritonitis and/or intestinal obstruction.

Aged↗
PubMed2003

Diagnostic and therapeutic laparoscopy for stab wounds of the anterior abdomen.

BACKGROUND: At present, laparoscopy is used mainly as a diagnostic tool in patients with abdominal stab wounds. PATIENTS AND METHODS: Thirty-two hemodynamically stable patients with isolated stab wounds of the anterior abdomen, thought to be penetrating, were prospectively selected to undergo treatment via a laparoscopic approach. When possible, parenchymal wounds were coagulated or sealed, and wounds to the intestines were sutured or stapled. RESULTS: The results of laparoscopy were negative in 6 (18.8%) of the cases: nonpenetrating wounds in 4 cases and nonsignificant organ injury in 2 cases. A hemoperitoneum was identified in 13 (40.6%) of the cases, and significant organ injuries in 26 (81.3%) of the cases: stomach, 2; small bowel, 5; colon, 2; pancreas, 1; vascular injuries, 4; liver, 5; mesentery, 9. Laparoscopy was therapeutic in 20 (62.3%) of the cases. Conversion to open surgery was required in 6 (18.8%) of the cases. No injuries were missed, and no mortality occurred. Postoperative complications developed in 2 (6.2%) of the cases. The mean hospital stay was 4 days, with no late complications. CONCLUSIONS: Laparoscopy can avoid a number of unnecessary laparotomies and can treat most of the lesions found in hemodynamically stable patients with anterior abdominal stab wounds.

Abdominal Injuries↗
PubMed2003

Gallbladder torsion. A case report.

Gallbladder torsion is a rare condition causing acalculus cholecystitis. Its preoperative identification is difficult with current radiological means and it is generally diagnosed at surgery. A case of gallbladder torsion due to an extremely rare anomaly consisting of partial fixation of the fundus to a fore-shortened liver bed is reported. The etiology, diagnosis and treatment of this condition are discussed.

Aged↗
PubMed2002

Small bowel volvulus resulting from a congenital band treated laparoscopically.

In recent years, laparoscopy has dramatically changed the approach to the patient with acute abdominal pain. We report the case of a patient with small bowel volvulus caused by a congenital band binding the greater omentum to the mesentery, which was promptly diagnosed and treated using laparoscopy. Early intervention averted irreversible ischemic lesions of the intestine and the need for bowel resection. With the routine use of laparoscopy in the setting of acute abdominal pain, rare affections can be easily diagnosed and effectively treated.

Abdominal Pain↗
PubMed2002

[Idiopathic infarction of the left segment of the greater omentum].

Idiopathic infarction of the greater omentum is a rare cause of acute abdominal pain whose diagnosis remains difficult. Most of the cases reported in the literature concern the right segment of the greater omentum, simulating appendicitis or cholecystitis. We report a case of an idiopathic leftsided segmental infarction of the greater omentum, in a previously healthy 59 years old woman. Laparoscopy permitted to confirm the diagnosis and to remove the infarcted omentum.

Diagnosis, Differential↗
PubMed2002

Spontaneous apoptosis in primary cultures of human and rat hepatocytes: molecular mechanisms and regulation by dexamethasone.

To elucidate the biochemical pathways leading to spontaneous apoptosis in primary cultures of human and rat hepatocytes, we examined the activation of the caspase cascade, the expression of Bcl-2-related-proteins and heat shock proteins. Comparisons were made before and after dexamethasone (DEX) treatment. We show that DEX inhibited spontaneous apoptosis in a dose-dependent manner. DEX increases the expression of anti-apoptotic Bcl-2 and Bcl-x(L) proteins, decreases the expression of pro-apoptotic Bax and inhibits Bad translocation thereby preventing the release of cytochrome c, the activation of caspases, and cell death. Although, the expression of Hsp27 and Hsp70 proteins remained unchanged, the oncogenic protein c-Myc is upregulated upon DEX-treatment. These results indicate that DEX mediates its survival effect against spontaneous apoptosis by acting upstream of the mitochondrial changes. Thus, the mitochondrial apoptotic pathway plays a major role in regulating spontaneous apoptosis in these cells. Blocking this pathway therefore may assist with organ preservation for transplant, drug screening, and other purposes.

Animals↗
PubMed2001

Low rejection rates with tacrolimus-based dual and triple regimens following liver transplantation.

We studied the outcome of 345 liver transplant patients who received tacrolimus-based immunosuppressive therapy either as a dual regimen (with corticosteroids, n=172) or as a triple regimen (with corticosteroids and azathioprine, n=173) for 3 months after transplantation (3-month cohort). A further analysis was conducted for the first 195 patients randomised (dual n=100, triple n=95) who were followed up for 12 months after transplantation (12-month cohort). For the 3-month cohort, patient survival was 90.7% (dual) and 91.9% (triple), graft survival after 3 months was 88.4% (dual therapy) and 89.6% (triple therapy). Acute rejections were experienced by 67/172, 39.0% of patients on dual therapy and by 60/173, 34.7% of patients on triple therapy; corticosteroid-resistant rejections were reported in 9 patients (5.2%) in either treatment group. The overall safety profile was similar for the two treatment groups. Significant differences, however, were found for thrombocytopenia (dual 13/172, 7.6%, triple 37/173, 21.4%, p<0.001) and leukopenia (dual 4/172, 2.3%, triple 24/173, 13.9%, p<0.001). For the 12-month cohort, patient survival was 85.6% (dual) and 88.4% (triple) after 1 year. Graft survival was 81.7% (dual) and 85.2% (triple) 12 months after transplantation. Acute rejections were reported for 38/100, 38.0% of patients on dual therapy and 36/95, 37.9% of patients on triple therapy, corticosteroid-resistant rejections were 7/100, 7.0% (dual) and 7/95, 7.4% (triple) of patients. In the 12-month cohort, no significant differences in the safety profiles of the treatment groups were found. We conclude that both tacrolimus-based dual and triple drug regimens provide effective and safe immunosuppression following orthotopic liver transplantation.

Azathioprine↗
PubMed2001

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction.

We examined the effects of dexamethasone (DEX) on the apoptotic process in primary cultures of human and rat hepatocytes. DEX prolonged cell viability, inhibited the development of an apoptotic morphology, and stabilised the expression of procaspase-3 in both human and rat hepatocytes. In addition, the inhibition of apoptosis by DEX was strongly correlated with a decrease of caspase-3-like protease activity. Moreover, DEX treatment increased the expression of anti-apoptotic Bcl-2 and Bcl-xL proteins in human and rat hepatocytes, respectively, whereas the expression of pro-apoptotic proteins Bcl-xS or Bad was not detected or remained unchanged. The bcl-xL transcript is regulated at the transcriptional level and its expression paralleled that of Bcl-xL protein in DEX-treated rat hepatocytes. Taken together, these results indicate that this glucocorticoid exerts a protective role on cell survival and it delays apoptosis of human and rat hepatocytes by modulating caspase-3-like protease activity and bcl-2 and bcl-x gene expression.

Animals↗