K.-W. Jauch

Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice

Vascular endothelial growth factor (VEGF) is the major pro‐angiogenic factor for most tumors. VEGF expression has been shown to be associated with a poor prognosis in human pancreatic cancer. The purpose of our study was to determine the effect of blockade of VEGF receptor‐2 activity with or without gemcitabine on tumor growth and metastasis in an orthotopic model of human pancreatic cancer in nude mice. Therapy with gemcitabine or DC101, a VEGF receptor‐2 antibody, resulted in a significant reduction of primary pancreatic tumor growth compared to untreated controls. The combination of DC101 and gemcitabine inhibited primary pancreatic tumor growth and lymphatic metastasis to a greater degree than either agent alone. Treatment with DC101 decreased vessel counts and increased the area of hypoxic tumor tissue compared to controls. Immunofluorescent double staining for apoptotic endothelial cells demonstrated a significant increase in the number apoptotic endothelial cells 24 days after initiation of therapy with DC101 plus gemcitabine. DC101 plus gemcitabine also increased tumor cell death and decreased tumor cell proliferation in pancreatic tumors. These findings indicate that blockade of VEGF receptor activation interferes with the survival of tumor endothelial cells, resulting in a reduction of primary pancreatic tumor growth in nude mice. Furthermore, the data demonstrate that anti‐VEGF receptor‐2 therapy potentiates the tumoricidal effect of gemcitabine in this model. Anti‐VEGF receptor‐2 therapy in combination with gemcitabine may be a novel therapeutic approach for advanced pancreatic cancer.

Possibilities of Non-Viral Gene Transfer to Improve Cutaneous Wound Healing

Enhancement of dermal and epidermal regeneration represents a crucial goal for the treatment of acute, e.g. burn and trauma wounds, and chronic wounds, e.g. diabetic, autoimmune, arterial and venous wounds. Studies defining molecular mechanisms of the complex cascade of wound healing have shown that growth factors represent a new therapeutic strategy. The clinical application of growth factors in the form of proteins has been shown to be of little benefit. Therefore new delivery systems and therapeutic strategies needed to be developed to improve dermal and epidermal regeneration, one of which is gene therapy. For successful gene delivery the selection of an appropriate vector has been shown to be paramount. Because Retroviruses, Adenoviruses and Adeno-Associated Viruses can cause immunologic reactions and mutations, non-viral delivery systems for gene therapy, such as liposomal gene transfer appear advantageous over viral gene therapy. This review discusses the success, potential and limitations of non-viral gene transfer to improve regeneration of dermal and epidermal structures.

Hepatic O2 exchange and liver energy metabolism in hyperdynamic porcine endotoxemia: effects of iloprost.

Abstract Objective: To compare the effects of a 12xa0h continuous infusion of iloprost, a stable prostacyclin analogue, on hepatic blood flow (Qliv), O2 exchange, and energy metabolism during a 24xa0h hyperdynamic, porcine endotoxemia with volume resuscitation alone. Design: Prospective, randomized, experimental study with repeated measures. Setting: Investigational animal laboratory. Subjects: Twenty-eight domestic pigs: 16 animals during endotoxemia with volume resuscitation alone (ETX), 12 with endotoxemia, volume resuscitation, and treatment with iloprost (ILO). Interventions: Endotoxemia was initiated by continuous infusion of E. coli lipopolysaccharide. Animals were resuscitated with hetastarch, aimed at maintaining a MAP of >60xa0mmHg. After 12xa0h of endotoxemia, iloprost was administered for 12xa0h in the treatment group, titrated to avoid pharmacologically induced hypotension (MAP <60xa0mmHg). Measurements and results: Iloprost significantly increased Qliv, with no effect on hepatic O2 delivery. Mean capillary hemoglobin O2 saturation (HbScO2) on the liver surface, as well as HbScO2 frequency distributions –- a measure of microcirculatory O2 availability –- remained unchanged. Treatment with iloprost, however, significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased endogenous glucose production (EGP) rate, iloprost restored EGP to normal at the end of the experiment. Conclusions: Thus, in a clinically relevant model of human sepsis, iloprost did not produce potential adverse effects but rather ameliorated hepatic metabolic disturbances and, thereby, hepatic energy balance.

Effect of combining nicotinamide as a PARS-inhibitor with selective iNOS blockade during porcine endotoxemia

ObjectiveTo investigate the effects of combined selective inducible nitric oxide synthase (iNOS) inhibition using 1400xa0W with nicotinamide (NAD) as a PARS-inhibitor on hepato-splanchnic hemodynamics, O2 kinetics, and energy metabolism during hyperdynamic porcine endotoxemia.DesignProspective, randomized, controlled, interventional experiment.SettingAnimal research laboratory.SubjectsSeventeen domestic pigs.InterventionsAfter 12xa0h of continuous i.v. endotoxin (LPS) infusion 17 pigs received either no drug (CON, n=9) or 1400xa0W, titrated to maintain mean arterial pressure (MAP) at pre-endotoxin level, plus 10xa0mg·kg·h NAD (n=8;). Measurements were obtained before, 12xa0h, 18xa0h, and 24xa0h after starting LPS infusion.Measurements and resultsIn addition to systemic and pulmonary hemodynamics and gas exchange, we measured hepatic arterial and portal venous blood flow, liver and portal venous drained viscera O2 exchange, ileal mucosal-arterial PCO2 gap, and portal as well as hepatic venous lactate/pyruvate ratios. Expired NO and plasma nitrate levels were assessed as a parameter of NO production. Without affecting cardiac output, therapy maintained MAP and blunted the LPS-induced rise in expired NO levels, attenuated the progressive fall in liver lactate clearance, and blunted the impairment of hepato-splanchnic redox state. The rise of ileal mucosal-arterial PCO2 gap was not influenced.ConclusionsCombining selective iNOS inhibition with NAD as a PARS blocker may prevent circulatory failure and attenuate the detrimental consequences of LPS in intestinal and hepatocellular energy metabolism. Given the potential hepatotoxicity of high-dose NAD treatment, more potent PARS blockers with higher selectivity might further enhance the benefit of this therapeutic approach.

Synovial sarcoma - unusual presentation with cerebral hemorrhage

IntroductionSoft-tissue sarcomas account for 1% of all malignancies in adults. Typical symptoms comprise a growing and painless mass. Occasionally, the diagnosis is facilitated by secondaries.Materials and methodsHere we report the first case presented with intracranial hemorrhage caused by a metastasis of a previously unknown synovial sarcoma. The 74-year-old female patient was under anticoagulation for recurrent thrombosis of the right popliteal vein due to compression by the sarcoma, misdiagnosed as Baker`s cyst. The brain metastasis was resected, and after an incisional biopsy of the suspected tumor, which confirmed the diagnosis of a synovial sarcoma, an above knee amputation was performed because of the invasion of the neurovascular structures in the popliteal fossa.ResultsThe patient died 11xa0months after the initial event from pulmonary and further brain metastases.ConclusionBrain metastases are seldom the primary factor in the management of advanced synovial sarcoma. Initially, the primary tumor was thought to be a benign cyst; we therefore recommend a biopsy/excision of lesions greater than 5xa0cm in size and with growth tendency to allow appropriate treatment.

Hepatic oxygen exchange and energy metabolism in hyperdynamic porcine endotoxemia: effects of the combined thromboxane receptor antagonist and synthase inhibitor DTTX30

Abstract Objective: We compared the effects of thromboxane receptor antagonist and synthase inhibitor DTTX30 on systemic and liver blood flow, oxygen (O2) exchange and energy metabolism during 24xa0h of hyperdynamic endotoxemia with untreated endotoxemia. Design: Prospective, randomized, experimental study with repeated measures. Setting: Investigational animal laboratory. Subjects: Twenty-seven domestic pigs: 16 during endotoxemia with volume resuscitation alone; 11 with endotoxemia, volume resuscitation and treatment with DTTX30. Interventions: Continuous infusion of Escherichia coli lipopolysaccharide (LPS) for 24xa0h together with volume resuscitation. After 12xa0h of endotoxemia, DTTX30 was administered as a bolus of 0.12xa0mgxa0kg–1 followed by 12xa0h continuous infusion of 0.29xa0mgxa0kg–1 per h. Measurements and results: DTTX30 effectively counteracted the endotoxin-associated increase in TXB2 levels and increased 6-keto-PGF1α with a significant shift of the thromboxane/prostacyclin ratio towards predominance of prostacyclin. DTTX30 prevented the significant progressive endotoxin-induced decrease of mean arterial pressure (MAP) below baseline while maintaining cardiac output (CO), and increased the fractional contribution of liver blood flow to CO without an effect on either hepatic O2 delivery or O2 uptake. The mean capillary hemoglobin O2 saturation (HbO2) on the liver surface and HbO2 frequency distributions remained unchanged as well. Conclusions: DTTX30 significantly attenuated the endotoxin-induced derangements of cellular energy metabolism as reflected by the diminished progressive decrease in hepatic lactate uptake rate and a blunted increase in hepatic venous lactate/pyruvate ratios. While endotoxin significantly increased the endogenous glucose production (EGP) rate, EGP returned towards baseline levels in the DTTX30-treated group. Thus, in our model DTTX30 resulted in hemodynamic stabilization concomitant with improved hepatic metabolic performance.

Einfluss von Hitzeschockprotein 70 auf die biliäre Sekretion organischer Anionen bei experimenteller septischer Cholestase

Cholestasis and icterus are common problems in sepsis and endotoxemia. Both conditions indicate retention of bile acids and organic anions. These molecules may accumulate in the systemic circulation of within the cytoplasm. Both have been shown to be toxic and capable of inducing necrosis and apoptosis. In previous studies we have shown that heat stress preserves bile acid transport in endotoxemic rats. The aim of the present study was to investigate, if heat stress would also preserve the transport of organic anions. Sulfobromophthalein was used as marker Substrate in experiments determining the maximum transport rate in isolated perfused rat livers. Immunoblot analyses, Northern blot analyses and immunofluorescence microscopy determined the regulation and distribution of the basolateral and canalicular transport proteins. The experiments showed that heat stress is capable to prevent impairment of organic anion transport observed in endotoxemia. Preservation primarily affects the protein level rather than the RNA level. Distribution of transporters was not changed by heat stress. The protective effects of heat stress coincided with the induction of heat shock proteins 70 and 25, supporting a crucial role of these chaperones.

Hepatozellulärer Transport von Gallensäuren und organischen Anionen bei Sepsis und SIRS — Anhalt für unterschiedliche Regulationsmechanismen der Membrantransportproteine

Sepsis bezeichnet die systemische Reaktion auf das Eindringen von Mikroorganismen in sonst sterile Gewebe. Die charakteristische Symptomatik geht mit Veranderungen der Korpertemperatur, der Herz- und Atemfrequenz sowie mit einer Linksverschiebung bei gleichzeitig bestehender Leukozytose oder Leukopenie einher. Ein klinisch ahnliches Syndrom kann jedoch auch ohne eine manifeste Infektion im Verlauf anderer Erkrankungen wie Pankreatitis, Verbrennung oder Ischame beobachtet werden. Die Reaktion auf diese Noxen wurde als „systemic inflammatory response syndrome“ (SIRS) definiert [1].