Standard surgical treatment in pancreatic cancer

Pancreatic cancer is the third leading neoplasm of the gastrointestinal system and has a dismal prognosis. The majority of patients are no more suitable for resection at time of diagnosis due to early development of distant metastases or major infiltrations of adjacent structures. However, due to the resistance of pancreatic cancers against chemoradiation, curative resection represents the only therapy with a potential for cure. For the surgical treatment of pancreatic head cancer, the classical Whipple operation is still the standard procedure but during the last two decades, pylorus-preserving duodenopancreatectomy has been evolved as a more conservative procedure in order to omit the consequences of partial gastrectomy. For cancer of the pancreatic body and tail, distal pancreatectomy or total pancreatectomy represent the current standard treatment. More radical methods like regional pancreatectomy and resection with extended lymph node dissection have failed so far to demonstrate any improvements in long-term survival compared to the standard types of resection. To further improve the treatment of pancreatic cancer, prospectively randomised trials are needed to compare these extended surgical procedures with the standard types of resectio

Acellular Pertussis Booster in Adolescents Induces Th1 and Memory CD8+ T Cell Immune Response

In a number of countries, whole cell pertussis vaccines (wcP) were replaced by acellular vaccines (aP) due to an improved reactogenicity profile. Pertussis immunization leads to specific antibody production with the help of CD4+ T cells. In earlier studies in infants and young children, wcP vaccines selectively induced a Th1 dominated immune response, whereas aP vaccines led to a Th2 biased response. To obtain data on Th1 or Th2 dominance of the immune response in adolescents receiving an aP booster immunization after a wcP or aP primary immunization, we analyzed the concentration of Th1 (IL-2, TNF-α, INF-γ) and Th2 (IL-4, IL-5, IL-10) cytokines in supernatants of lymphocyte cultures specifically stimulated with pertussis antigens. We also investigated the presence of cytotoxic T cell responses against the facultative intracellular bacterium Bordetella pertussis by quantifying pertussis-specific CD8+ T cell activation following the aP booster immunization. Here we show that the adolescent aP booster vaccination predominantly leads to a Th1 immune response based on IFNgamma secretion upon stimulation with pertussis antigen, irrespective of a prior whole cell or acellular primary vaccination. The vaccination also induces an increase in peripheral CD8+CD69+ activated pertussis-specific memory T cells four weeks after vaccination. The Th1 bias of this immune response could play a role for the decreased local reactogenicity of this adolescent aP booster immunization when compared to the preceding childhood acellular pertussis booster. Pertussis-specific CD8+ memory T cells may contribute to protection against clinical pertussis

A Temporal Role Of Type I Interferon Signaling in CD8+ T Cell Maturation during Acute West Nile Virus Infection

A genetic absence of the common IFN- α/β signaling receptor (IFNAR) in mice is associated with enhanced viral replication and altered adaptive immune responses. However, analysis of IFNAR-/- mice is limited for studying the functions of type I IFN at discrete stages of viral infection. To define the temporal functions of type I IFN signaling in the context of infection by West Nile virus (WNV), we treated mice with MAR1-5A3, a neutralizing, non cell-depleting anti-IFNAR antibody. Inhibition of type I IFN signaling at or before day 2 after infection was associated with markedly enhanced viral burden, whereas treatment at day 4 had substantially less effect on WNV dissemination. While antibody treatment prior to infection resulted in massive expansion of virus-specific CD8+ T cells, blockade of type I IFN signaling starting at day 4 induced dysfunctional CD8+ T cells with depressed cytokine responses and expression of phenotypic markers suggesting exhaustion. Thus, only the later maturation phase of anti-WNV CD8+ T cell development requires type I IFN signaling. WNV infection experiments in BATF3-/- mice, which lack CD8-α dendritic cells and have impaired priming due to inefficient antigen cross-presentation, revealed a similar effect of blocking IFN signaling on CD8+ T cell maturation. Collectively, our results suggest that cell non-autonomous type I IFN signaling shapes maturation of antiviral CD8+ T cell response at a stage distinct from the initial priming event

Type I interferon: friend or foe?

Although the role of type I interferon (IFN) in the protection against viral infections has been known and studied for decades, its role in other immunologically relevant scenarios, including bacterial infections, shock, autoimmunity, and cancer, is less well defined and potentially much more complicated

Bile synthesis in rat models of inflammatory bowel diseases.

BACKGROUND: A broad spectrum of hepatobiliary disorders are found in patients with inflammatory bowel diseases. The aim of the present work was to study interactions between gut and liver in experimental rat models of colitis and small bowel inflammation. MATERIALS AND METHODS: Colitis was induced either by trinitrobenzene sulphonic acid or dextran sodium sulphate. Small-bowel inflammation was induced by indomethacin. Bile acid secretion, bile acid pool, and cholesterol 7-alpha hydroxylase were studied. Cholesterol 7-alpha hydroxylase protein expression was analysed in the microsomal liver fraction. As portal mediators released form the inflamed gut we measured lipopolysaccharide, tumour necrosis factor-alpha and interleukin-1beta in portal serum. The hepatic inflammatory response was evaluated by binding activity of nuclear factor-kappaB, activator protein-1 and alpha-2-macroglobulin. RESULTS: Increased bile acid secretion, total bile acid content in gut and liver (bile acid pool size), and hepatic cholesterol 7-alpha hydroxylase protein and mRNA levels were found in the two colitis models associated with only a minor hepatic acute phase and cytokine response. In contrast, during indomethacin-induced small-bowel inflammation bile acid secretion, pool size, and cholesterol 7-alpha hydroxylase decreased in parallel to a strong hepatic cytokine and acute phase response. CONCLUSIONS: Colitis without portal cytokine release and acute phase reaction shows an induction of bile acid secretion, pool size, and cholesterol 7-alpha hydroxylase. In contrast, intestinal inflammation after indomethacin treatment is associated with an acute phase response and a repression of bile acid synthesis

Lipopolysaccharide represses cholesterol 7-alpha hydroxylase and induces binding activity to the bile acid response element II.

BACKGROUND: Inflammatory states such as hepatitis and sepsis are frequently associated with alterations of bile acid synthesis. These conditions are mediated by bacterial wall products like lipopolysaccharide (LPS). Cholesterol 7-alpha hydroxylase is the rate-limiting enzyme of bile acid synthesis. Hydrophobic bile acids repress cholesterol 7-alpha hydroxylase transcription via binding to the farnesoid X receptor and interaction with the bile acid response element II in the cholesterol 7-alpha hydroxylase promoter. METHODS: We tested the effect of LPS on hepatic expression of cholesterol 7-alpha hydroxylase in C57BL/6 mice and Wistar rats. Further, we analyzed the binding activity of hepatic nuclear extracts to the bile acid response element II and the binding site for farnesoid X receptor heterodimers (ecdysone response element). RESULT: Lipopolysaccharide caused a 100-fold reduction of cholesterol 7-alpha hydroxylase mRNA levels in mice and a 10-fold reduction in rats. Protein levels of cholesterol 7-alpha hydroxylase also decreased in both species. These changes inversely correlated with the increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element. CONCLUSION: Lipopolysaccharide-induced repression of cholesterol 7-alpha hydroxylase occurs at the transcriptional level. The underlying mechanism involves an increased binding activity of nuclear proteins to the bile acid response element II and the ecdysone response element. In conclusion, the farnesoid and retinoid X receptors participate in LPS-induced cholesterol 7-alpha hydroxylase repression

The role of DNA-fragmentation in contrast-induced tubular cell damage

Background: Intravascular administration of iodinated contrast is a common cause of hospital-acquired acute kidney injury. Evidence suggests that radiocontrast agent induced nephrotoxicity is associated with increased oxidative stress, leading to renal tissue damage with DNA fragmentation. We tested whether an iso-osmolar contrast medium (Iodixanol) causes less oxidative DNA damage to renal tubular cells compared to a low-osmolar contrast medium (Iopromide). Method: Human kidney cells (HK-2 cells) were incubated in a predefined period of time (10 minutes - 2 hours) with increasing concentrations of Iodixanol and Iopromide (20 - 120mg/ml iodine) and the ammount of DNA damage induced on the cells was compared. DNA damage was analysed using the comet assay. Results: We found that the two different classes of contrast media induce DNA fragmentation in vitro in a time and concentration dependent manner. DNA fragmentation was maximal at 2 hours with 120 mg for iopromide and iodixanol; both were significantly different from the control value (Student’s t-test; p < 0.001). Furthermore, iodixanol produced significantly higher DNA fragmentation than iopromide . Conclusion: On the basis of the paradigm that DNA strand breaks or fragmentation are synonymous to oxidative stress, we effectively demonstrated that contrast media induced oxidative stress in HK-2 tubule cells. Renal cell damage was observed for both contrast media at high concentrations such as is presumed to occur in patients with impaired renal function; this effect is more evident in iodixanol than it is in iopromide. Collectively, we demonstrate that an iso-osmolar contrast medium induced greater oxidative stress and consecutive DNA damage than a low osmolar agent in HK-2 cells. This is contrary to the widespread notion that iso-osmolar contrast media may be less nephrotoxic than low-osmolar contrast media and could provide an explanation for the nephrotoxicity observed with iodixanol in clinical practice