A rare low-grade myofibroblastic sarcoma in lower jaw with the resemblance to benign lesions.

BACKGROUND Low-grade myofibroblastic sarcoma (LGMS) is a rare solid infiltrative soft tissue tumor with a predilection for the head and neck region. CASE PRESENTATION We report the diagnostic steps of a fast-growing lesion of the lower left jaw in a 45-year-old otherwise healthy woman. A first biopsy and subsequent histopathological examination showed potential differentials of a benign myofibroma, benign nodular fasciitis or an LGMS. This diagnostic overlap was a challenge for the decision of the further treatment approach. The treatment consisted of a segmental en bloc resection of the mandible including the second premolar, first and second molar. Histopathological examination of the resected tumor confirmed an LGMS. CONCLUSION The histopathologic resemblance of LGMS to a range of benign and reactive tumors may lead to misdiagnosis and mistreatment. The rarity of LGMS explains the lack of established treatment protocols. This case shows the importance of adequate clinical decisions, expertise in the histopathology of rare tumors and interdisciplinary exchange to achieve state-of-the-art patient management

Hepatic teratoma and peritoneal gliomatosis: a case report

The hepatic teratoma is a very rare entity of which only 25 cases have been published so far. In our case the hepatic teratoma is associated with peritoneal gliomatosis, which is an indicator for an ongoing peritoneal spread of a teratoma. Wall calcifications and the homogeneity as well as the well defined border misled the radiologist to the diagnosis of an echinococcal cyst, which is the most common differential diagnosis, however the hepatic teratoma has to be taking into consideration when dealing with unclear hepatic cysts, although it is very rare

Lung tumour growth kinetics in SPC-c-Raf-1-BB transgenic mice assessed by longitudinal in-vivo micro-CT quantification

<p>Abstract</p> <p>Background</p> <p>SPC-c-Raf-1-BxB transgenic mice develop genetically induced disseminated lung adenocarcinoma allowing examination of carcinogenesis and evaluation of novel treatment strategies. We report on assessment of lung tumour growth kinetics using a semiautomated region growing segmentation algorithm.</p> <p>Methods</p> <p>156 non contrast-enhanced respiratory gated micro-CT of the lungs were obtained in 12 SPC-raf transgenic (n = 9) and normal (n = 3) mice at different time points. Region-growing segmentation of the aerated lung areas was obtained as an inverse surrogate for tumour burden. Time course of segmentation volumes was assessed to demonstrate the potential of the method for follow-up studies.</p> <p>Results</p> <p>Micro-CT allowed assessment of tumour growth kinetics and semiautomated region growing enabled quantitative analysis. Significant changes of the segmented lung volumes over time could be shown (<it>p </it>= 0.009). Significant group differences could be detected between transgenic and normal animals for time points 8 to 13 months (<it>p </it>= 0.043), when marked tumour progression occurred.</p> <p>Conclusion</p> <p>The presented region-growing segmentation algorithm allows in-vivo quantification of multifocal lung adenocarcinoma in SPC-raf transgenic mice. This enables the assessment of tumour load and progress for the study of carcinogenesis and the evaluation of novel treatment strategies.</p

Ferritin-Mediated Iron Sequestration Stabilizes Hypoxia-Inducible Factor-1α upon LPS Activation in the Presence of Ample Oxygen

SummaryBoth hypoxic and inflammatory conditions activate transcription factors such as hypoxia-inducible factor (HIF)-1α and nuclear factor (NF)-κB, which play a crucial role in adaptive responses to these challenges. In dendritic cells (DC), lipopolysaccharide (LPS)-induced HIF1α accumulation requires NF-κB signaling and promotes inflammatory DC function. The mechanisms that drive LPS-induced HIF1α accumulation under normoxia are unclear. Here, we demonstrate that LPS inhibits prolyl hydroxylase domain enzyme (PHD) activity and thereby blocks HIF1α degradation. Of note, LPS-induced PHD inhibition was neither due to cosubstrate depletion (oxygen or α-ketoglutarate) nor due to increased levels of reactive oxygen species, fumarate, and succinate. Instead, LPS inhibited PHD activity through NF-κB-mediated induction of the iron storage protein ferritin and subsequent decrease of intracellular available iron, a critical cofactor of PHD. Thus, hypoxia and LPS both induce HIF1α accumulation via PHD inhibition but deploy distinct molecular mechanisms (lack of cosubstrate oxygen versus deprivation of co-factor iron)

Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy

Tumor-derived lactic acid inhibits T and natural killer (NK) cell function and, thereby, tumor immunosurveillance. Here, we report that melanoma patients with high expression of glycolysis-related genes show a worse progression free survival upon anti-PD1 treatment. The non-steroidal anti-inflammatory drug (NSAID) diclofenac lowers lactate secretion of tumor cells and improves anti-PD1-induced T cell killing in vitro. Surprisingly, diclofenac, but not other NSAIDs, turns out to be a potent inhibitor of the lactate transporters monocarboxylate transporter 1 and 4 and diminishes lactate efflux. Notably, T cell activation, viability, and effector functions are preserved under diclofenac treatment and in a low glucose environment in vitro. Diclofenac, but not aspirin, delays tumor growth and improves the efficacy of checkpoint therapy in vivo. Moreover, genetic suppression of glycolysis in tumor cells strongly improves checkpoint therapy. These findings support the rationale for targeting glycolysis in patients with high glycolytic tumors together with checkpoint inhibitors in clinical trials

Correlations between milk and plasma levels of amino and carboxylic acids in dairy cows.

The objective of this study was to investigate the relationship between the concentrations of 19 amino acids, glucose, and seven carboxylic acids in the blood and milk of dairy cows and their correlations with established markers of ketosis. To that end, blood plasma and milk specimens were collected throughout lactation in two breeds of dairy cows of different milk yield. Plasma concentrations of glucose, pyruvate, lactate, α-aminobutyrate, β-hydroxybutyrate (BHBA), and most amino acids, except for glutamate and aspartate, were on average 9.9-fold higher than their respective milk levels. In contrast, glutamate, aspartate, and the Krebs cycle intermediates succinate, fumarate, malate, and citrate were on average 9.1-fold higher in milk than in plasma. For most metabolites, with the exception of BHBA and threonine, no significant correlations were observed between their levels in plasma and milk. Additionally, milk levels of acetone showed significant direct relationships with the glycine-to-alanine ratio and the BHBA concentration in plasma. The marked decline in plasma concentrations of glucose, pyruvate, lactate, and alanine in cows with plasma BHBA levels above the diagnostic cutoff point for subclinical ketosis suggests that these animals fail to meet their glucose demand and, as a consequence, rely increasingly on ketone bodies as a source of energy. The concomitant increase in plasma glycine may reflect not only the excessive depletion of protein reserves but also a potential deficiency of vitamin B6

Big-ET, ET und NO in experimental pig liver transplantation

Bei der orthotopen Lebertransplantation ist eine intakte Mikro- und Makrozirkulation in der frühen Reperfusion von grosser Bedeutung. Endothelin (ET), welches durch das Endothelin Converting Enzyme (ECE) aus seiner Vorstufe Big-Endothelin (Big-ET) gebildet wird, ist der derzeit stärkste bekannte Vasokonstriktor. Dem gegenüber führt NO (Stickstoffmonoxid) zu einer starken Gefässrelaxation. Ziel der Studie war die Untersuchung obiger Parameter im Rahmen der orthotopen Lebertransplantation. Bei 33 orthotopen Lebertransplantationen an Schweinen (Deutsche Landrasse) wurden bei verschiedenen Reperfusionsstrategien (Gabe von Hydroxyethylstärke (HAES), Hyperhydroxyethylstärke (HHES) oder Diaspirin Crosslinked Hemoglobin (DCLHb™) jeweils 5min vor Reperfusion) die Plasmaspiegel von Big-ET, ET und NO vor, bei und 5min nach Reperfusion, danach alle 15min während 1h, dann jeweils stündlich für weitere 5h bestimmt und mit Vitalparametern, Glutamat-Oxalacetat-Transaminase (GOT), Glutamat-Pyruvat-Transaminase (GPT), gamma-Glutamyl-Transpeptidase (g-GT) und der Glutamat-Dehydrogenase (GLDH) korreliert. In der Kontroll- und der HHES-Gruppe wurde eine systemisch tiefe Big-ET-Konzentration gemessen. Die Konzentration von ET war in allen drei Gruppen nach Reperfusion erhöht (3,8-5,2fmol/l). Der Median der Big-ET/ET/NO-Werte 5Min nach Reperfusion wurde benutzt um die Tiere in zwei Gruppen einzuteilen. Hohe ET-Werte korrelierten zum Zeitpunkt R1 mit einem höheren Herzzeitvolumen (4,5vs3,6l/min), einem höheren zentralen Venendruck (9vs8mmHg), höheren Wedge-Drücken (10,8vs8,9mmHg) sowie einer niedrigereren Herzfrequenz (98vs89min-1) als tiefe ET-Werte. Für Big-ET konnte diesbezüglich kein Zusammenhang gefunden werden. Bei tiefen Big-ET und ET-Spiegeln war eine höhere Aktivität der GOT (290vs150U/l), GPT (18vs11,8U/l) sowie der g-GT (16vs12U/l) meßbar. Generell sanken die NO-Plasmaspiegel nach Reperfusion kontinuierlich ab (38-84uM). Die Enzymaktivität der GOT (260vs140U/l), GPT (19vs9U/l), g-GT (17vs11U/l) und der GLDH (29vs10U/l) ist bei hohen NO-Werten erhöht. Diese Ergebnisse sprechen für eine lokale, schnelle und effektive Konvertierung des Big-ET zu ET, welche durch eine Sättigung der ECE limitiert wird. Die bessere Kreislaufgesamtsituation der Tiere bei hohen Big-ET und ET-Spiegeln erklärt den gemessenen verminderten Reperfusionsschaden. Umgekehrt reflektieren die hohen NO-Werte eine schlechte Kreislaufgesamtsituation mit entsprechend hohem Leberschaden.In orthotopic liver transplantation, a functioning micro- and macrocirculation in the early phase of reperfusion is of great importance. Endothelin Converting enzyme (ECE) converts Big Endothelin (Big ET) to Endothelin (ET) which is at present the strongest known vasoconstrictor. On the other hand, NO (nitrogen monoxide) leads to a strong vasodilatation. A goal of the study was the investigation of above parameters in the setting of an orthotopic liver transplantation. We performed 33 orthotopic pig liver transplantations (German land race). Different reperfusion strategies (application of Hydroxyethylstaerke (HAES), Hyperhydroxyethylstaerke (HHES) or Diaspirin Crosslinked Hemoglobin (DCLHb) 5min before reperfusion) were performed to determine the plasma levels of Big ET, ET and NO before, during and 5min after reperfusion, thereafter every 15min during 1h, then for further 5h once per hour. We correlated these results with vital parameters, glutamat oxalacetat-transaminase (GOT), glutamat pyruvat transaminase (GPT), gamma glutamyl transpeptidase (g-GT) and glutamat dehydrogenase (GLDH). In the control and the HHES-group a systemically low Big ET concentration was measured. The ET concentration was increased in all three groups after reperfusion (3,8-5,2fmol/l). The median of the Big ET/ET/NO values 5min after reperfusion was used to generate two groups. High ET levels correlated at the time R1 with a higher cardiac output (4,5vs3,6l/min), a higher central vein pressure (9vs8mmHg), higher wedge pressures (10,8vs8,9mmHg) as well as a lower heart rate (98vs89min-1) as did low ET levels. There was no correlation found for Big ET. Low Big ET and ET levels showed a higher activity of the GOT (290vs150U/l), GPT (18vs11,8U/l) and the g-GT(16vs12U/l) as did high levels. The NO plasma concentration decreased continuously after reperfusion (38-84uM). The enzyme activity of the GOT (260vs140U/l), GPT (19vs9U/l), g-GT (17vs11U/l) and the GLDH (29vs10U/l) is increased at high NO concentrations. These results support a local, fast and effective conversion of Big ET to ET, which is limited by a saturation of the ECE. The better hemodynamic state of the animals with high Big ET and ET levels explains the low reperfusion injury. On the other hand, high NO values reflect a bad hemodynamic situation with a higher liver damage