The aryl hydrocarbon receptor nuclear translocator (Arnt) is required for tumor initiation by benzo[a]pyrene.

Benzo[a]pyrene (B[a]P) is a ligand for the aryl hydrocarbon receptor (Ahr). After binding ligand, Ahr dimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) protein, and the dimer upregulates the transcription of Cyp1a1, Cyp1b1 and other enzymes involved in the metabolic activation of B[a]P. Arnt null mice die in utero. Mice in which Arnt deletion occurs constitutively in the epidermis die perinatally. In the current study, mice were developed in which the Arnt gene could be deleted specifically in adult skin epidermis. This deletion had no overt pathological effect. Homozygosity for a null reduced nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase allele was introduced into the above mouse strain to render it more susceptible to tumor initiation by B[a]P. Deletion of Arnt in the epidermis of this strain completely prevented the induction of skin tumors in a tumor initiation-promotion protocol in which a single topical application of B[a]P acted as the tumor-initiating event, and tumor promotion was provided by repeated topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA). In contrast, deletion of Arnt did not prevent the induction of skin tumors in a protocol also using TPA as the promoter but using as the initiator N-methyl-N'-nitro-N-nitrosoguanidine, whose activity is unlikely to be affected by the activity of Ahr, Arnt or their target genes. These observations demonstrate that Arnt is required for tumor initiation by B[a]P in this system.

Human cytokine levels in nonperforated versus perforated appendicitis: molecular serum markers for extent of disease?

Appendicitis is a common surgical problem that is associated with a systemic inflammatory response. Previous studies have shown that cytokines are activated early in acute inflammation and sepsis and may serve as indicators of clinical severity. In this study we examined the role of cytokines as serum markers to distinguish nonperforated versus perforated appendicitis. Patients with the presumptive diagnosis of appendicitis had serum drawn preoperatively. Only patients (n = 59) with an intraoperative diagnosis of nonperforated (n = 34) and perforated (n = 25) appendicitis had serum drawn 12 hours postoperatively. Diagnosis was later confirmed by pathologic examination. The serum specimens were batch analyzed using enzyme-linked immunosorbent assays specific for interleukin (IL)-1beta, IL-2, IL-6, IL-8, and IL-10. Serum from normal healthy subjects served as control specimens (n = 9). Patients in the nonperforated and perforated groups were similar with regard to age, gender, race, white blood cell count, and fever. All cytokine levels including preoperative, postoperative, nonperforated, and perforated were higher in patients with appendicitis as compared with controls. IL-1beta, IL-2, and IL-10 levels were not different between groups with appendicitis. Preoperative serum levels of IL-6 (P = 0.036) and IL-8 (P = 0.047) were higher in patients with perforated versus nonperforated appendicitis. In addition postoperative serum levels of IL-6 (P = 0.0001) remained higher in the perforated group versus the nonperforated group. Serum levels of IL-6 and IL-8 may have a role in discerning the extent of disease in this condition. This initial step in systemically studying the role of cytokines in this disease may ultimately lead to the development of molecular indicators to aid in diagnosis and differentiate appendicitis from other conditions.

Improved survival following pancreaticoduodenectomy to treat adenocarcinoma of the pancreas: the influence of operative blood loss.

HYPOTHESIS: Although the safety of pancreaticoduodenectomy has notably improved over the past several decades, the reported survival of patients with pancreatic cancer remains poor. We hypothesized that, in recent years, the survival of patients with pancreatic adenocarcinoma following pancreaticoduodenectomy has substantially improved. DESIGN: Retrospective case series. SETTING: Major academic medical and pancreatic surgery center. PATIENTS: A total of 182 consecutive patients underwent pancreaticoduodenectomy for various diagnoses between 1987 and 2005. Patients from 1987-1995 were compared with patients from 1996-2005. INTERVENTIONS: Pancreaticoduodenectomy for patients with a diagnosis of pancreatic adenocarcinoma. MAIN OUTCOME MEASURES: Survival after pancreaticoduodenectomy and patient outcomes. RESULTS: During the time period analyzed, 182 patients underwent pancreaticoduodenectomy to treat ductal adenocarcinoma. There were no operative deaths, and 86.3% of patients had an R0 resection. The 5-year survival rate for the entire group was 27.4%. However, survival improved from 15.8% to 35.5% during the study period. Both groups had equivalent demographic and pathological characteristics, and the only predictors of poor survival in multivariate analysis were operative blood loss of more than 400 mL (hazard ratio, 2.17), poorly differentiated tumors (3.03), lymph node metastases (1.92), perineural invasion (2.66), and undergoing an operation before 1996 (1.42). CONCLUSIONS: The survival rate for patients undergoing pancreaticoduodenectomy to treat pancreatic cancer has substantially improved. This finding is partially owing to improved operative technique and limited operative blood loss.