Algebraic construction of a Nambu bracket for the two-dimensional vorticity equation

So far fluid mechanical Nambu brackets have mainly been given on an intuitive basis. Alternatively an algorithmic construction of such a bracket for the two-dimensional vorticity equation is presented here. Starting from the Lie--Poisson form and its algebraic properties it is shown how the Nambu representation can be explicitly constructed as the continuum limit from the structure preserving Zeitlin discretization

Mitotane Targets Lipid Droplets to Induce Lipolysis in Adrenocortical Carcinoma

INTRODUCTION Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and resistance. Mitotane's efficacy is attributed to the accumulation of toxic free cholesterol, predominantly through cholesterol storage inhibition. However, targeting this pathway has proven unsuccessful. We hypothesize that mitotane-induced free-cholesterol accumulation is also mediated through enhanced breakdown of lipid droplets. METHODOLOGY ATCC-H295R (mitotane-sensitive) and MUC-1 (mitotane-resistant) ACC cells were evaluated for lipid content using specific BODIPY dyes. Protein expression was evaluated by immunoblotting and flow cytometry. Cell viability was measured by quantifying propidium iodide-positive cells following mitotane treatment and pharmacological inhibitors of lipolysis. RESULTS H295R and MUC-1 cells demonstrated similar neutral lipid droplet numbers at baseline. However, evaluation of lipid machinery demonstrated distinct profiles in each model. Analysis of intracellular lipid droplet content showed H295R cells preferentially store cholesteryl esters, whereas MUC-1 cells store triacylglycerol. Decreased lipid droplets were associated with increased lipolysis in H295R and in MUC-1 at toxic mitotane concentrations. Pharmacological inhibition of lipolysis attenuated mitotane-induced toxicity in both models. CONCLUSION We highlight that lipid droplet breakdown and activation of lipolysis represent a putative additional mechanism for mitotane-induced cytotoxicity in ACC. Further understanding of cholesterol and lipids in ACC offers potential novel therapeutic exploitation, especially in mitotane-resistant disease

Liver X receptor inhibition potentiates mitotane induced adrenotoxicity in ACC

Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with a poor outcome largely due to limited treatment options. Here, we propose a novel therapeutic approach through modulating intracellular free cholesterol via the liver X receptor alpha (LXRα) in combination with current first line pharmacotherapy, mitotane. H295R and MUC-1 ACC cell lines were pretreated with LXRα inhibitors in combination with mitotane. In H295R, mitotane (20, 40, 50µM) induced dose-dependent cell death, however, in MUC-1 this only occurred at a supratherapeutic concentration (200µM). LXRα inhibition potentiated mitotane-induced cytotoxicity in both cell lines. This was confirmed through use of the CompuSyn model which showed moderate pharmacological synergism and was indicative of apoptotic cell death via an increase in annexinV and cleaved-caspase 3 expression. Inhibition of LXRα was confirmed through downregulation of cholesterol efflux pumps ABCA1 and ABCG1, however, combination treatment with mitotane attenuated this effect. Intracellular free cholesterol levels were associated with increased cytotoxicity in H295R (r2=0.5210) and MUC-1 (r2=0.9299) cells. While both cell lines exhibited similar levels of free cholesterol at baseline, H295R were cholesterol ester rich whereas MUC-1 were cholesterol ester poor. We highlight the importance of LXRα mediated cholesterol metabolism in the management of ACC, drawing attention to its role in the therapeutics of mitotane sensitive tumours. We also demonstrate significant differences in cholesterol storage between mitotane sensitive and resistant disease.</jats:p

Sugar-Sweetened Beverage Intake and Cancer Recurrence and Survival in CALGB 89803 (Alliance)

Background: In colon cancer patients, obesity, sedentary lifestyle, and high dietary glycemic load have been associated with increased risk of cancer recurrence. High sugar-sweetened beverage intake has been associated with obesity, diabetes, and cardio-metabolic diseases, but the influence on colon cancer survival is unknown. Methods: We assessed the association between sugar-sweetened beverage consumption on cancer recurrence and mortality in 1,011 stage III colon cancer patients who completed food frequency questionnaires as part of a U.S. National Cancer Institute-sponsored adjuvant chemotherapy trial. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazard models. Results: Patients consuming ≥2 servings of sugar-sweetened beverages per day experienced an adjusted HR for disease recurrence or mortality of 1.67 (95% CI, 1.04–2.68), compared with those consuming <2 servings per month (Ptrend = 0.02). The association of sugar-sweetened beverages on cancer recurrence or mortality appeared greater among patients who were both overweight (body mass index ≥25 kg/m2) and less physically active (metabolic equivalent task-hours per week <18) (HR = 2.22; 95% CI, 1.29–3.81, Ptrend = 0.0025). Conclusion: Higher sugar-sweetened beverage intake was associated with a significantly increased risk of cancer recurrence and mortality in stage III colon cancer patients

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Ein vertikal-integriertes Modell der Passatschicht : A vertically integrated model of the trade layer

In der vorliegenden Arbeit wird ein getriebenes Modell der untersten tropisch-subtropischen Atmosphäre für den Bereich vom Äquator bis etwa 30° Breite entworfen. Modellgleichungen sind die von der Meeresoberfläche bis zu einem horizontal und zeitlich variablen Niveau ("Passatinversion") vertikal-integrierten Erhaltungssätze für Horizontalimpuls, Masse und Enthalpie. Antriebsfunktionen sind (a) die Nettoenergiezufuhr in die Schicht (im wesentlichen Summe der Vertikalflüsse fühlbarer und latenter Wärme von der Meeresoberfläche), (b) die sogenannte Entrainmentfunktion, welche die Massenzufuhr durch großräumiges Absinken parametrisiert sowie (c) die sogenannte Hot-Tower-Funktion, die den RIEHL-MALKUS'schen Mechanismus der nadelähnlichen Ejektion von Masse und anderen transportierbaren Eigenschaften innerhalb hochreichender Konvektionszellen aus der planetarischen Grenzschicht in die mittlere und hohe Troposphäre beschreibt. Wesentliche Fragestellung ist die nach den großskaligen Auswirkungen, welche die Antriebsfunktionen, vor allem (b) und (c), auf die Zirkulationsstruktur der Passatschicht haben. Während die Entrainmentfunktion im gesamten Modellbereich maßvoll positive Werte haben sollte (höhere Werte im Passat, geringere in den inneren Tropen), erwartet man von der Hot-Tower-Funktion sehr hohe Werte in der ITCZ, dagegen praktisches Verschwinden im Passat. Die stationären Modellgleichungen werden einer Skalenanalyse unterworfen. Die dimensionsfreien Gleichungen werden in zonal symmetrischer Formulierung auf die Messungen des deutschen Forschungsschiffes „METEOR" 1965 im Atlantik angewandt; die Ergebnisse stützen die entwickelten Vorstellungen über das Breitenprofil von Entrainment- und Hot-Tower-Funktion. Für denselben Gleichungssatz werden anschließend bei vorgegebenen Antriebsfunktionen die nichtlinearen, jedoch durch Quadraturen lösbaren Modellgleichungen integriert. Die Reaktion des Modells besteht in (1) der Ausbildung einer breiten Zone tropischer Ostströmung, die jedoch am Äquator verschwindet und damit eine Tendenz zur Bildung einer äquatorialen Westwindzone zeigt; (2) einem Breitenprofil der Dicke der Passatschicht, die in den Subtropen niedrig liegt und zum Äquator hin kräftig ansteigt und (3) in einem Breitenprofil des Energieinhalts der Passatschicht, das weitgehend parallel zu (2) verläuft, jedoch charakteristische Abweichungen zeigt. Variationen der Modellparameter und Antriebsfunktionen gestatten Rückschlüsse auf das Auftreten charakteristischer Instabilitäten, die sich im Imaginärwerden der Passatschichtdicke innerhalb gewisser Zonen äußern. Der Standort dieses Modells im Rahmen einer Klassifikation von Modellen der theoretischen Klimatologie wird diskutiert.In the present paper a driven model is designed of the lowest tropical-subtropical atmosphere for the region from the equator to 30° latitude. Model equations are the conservation relations for horizantal momentum, mass, and enthalpy, integrated vertically from the sea surface up to a level ("trade inversion") which varies both horizontally and with time - the "trade layer". Forcing functions are (a) the net energy input into the layer (mainly the sum of the vertical fluxes of sensible and latent heat from the sea surface), (b) the so-called entrainment function which parameterizes the mass input due to largescale subsidence, and (c) the so-called hot-tower-function which describes the RIEHLMALKUS mechanism of needle-like ejection of mass and other transportable properties whithin deep convection cells out of the planetary boundary layer into the middle and higher troposphere. The main question is: What is the large-scale impact of the forcing functions, specifically (b) and ( c ), on the circulation pattern of the trade layer? While the entrainment function should have moderately positive values throughout the model area (higher values in the trades, lower values in the deep tropics), the hot-tower-function is expected to have very high values in the ITCZ and to practically vanish in the trades. A scale analysis is performed with the model equations. The nondimensionalized equations, in zonally symmetric form, are applied to the measurements of the German research vessel "METEOR" 1965 in the Atlantic; the results corroborate the previously discussed ideas concerning the latitudinal profile of the entrainment- and hot-tower-function. Subsequently the nonlinear model equations are integrated for this case with specified forcing functions. The principal response of the model is: (1) Development of a broad zone of a tropical easterly current which, however, vanishes at the equator; this points at the tendency of the model to create a zone of equatorial westerlies; (2) a latitudinal pattern of the thickness of the trade layer which is low in the subtropics and rises considerably towards the equator; and (3) a latitudinal pattern of the energy content of the layer that runs, on the whole, parallel to (2), but shows characteristic deviations. Variations of the model parameters and forcing functions lead to conclusions concerning characteristic instabilities that show up in form of imaginary values of the layer thickness in certain zones. The significance of this model within the frameworjc of a classification of models of theoretical climatology is discussed

Die Zweischichtung der tropischen Atmosphäre anhand der "Meteor"-Daten 1965

The tropical circulation exhibits a prominent two-layer structure in the vertical: a moist-unstable lower layer (the "trade layer") with an ITCZ-ward directed mass transport, and a stable upper layer. The aerolo�gical measurements of the German research vessel "Meteor" in Nov.-Dec. 1965 over the Eastern Atlantic (19° W) show that this mean structure is valid even in actual meridional sections, if disturbances are absent. It follows that vertical averages over each of the two layers are appropriate to characterize the tropical atmosphere. In this paper only the trade layer is studied. Its upper boundary is defined by (a) the vertical minimum of static energy; (b) the vertical extreme value of various physical quantities such as temperature and humidity gradients; ( c) constant surfaces of a quantity c which proved useful for the data evaluations. All these definitions are more or less equivalent. The boundary surface is permeable for vertical property transports which are parameterized in terms of the hot tower- and subsidence-process (RIEHL & MALKUS). It is not possible, however, to calculate these fluxes, since meridional profiles of the horizontal mass and energy transport divergence cannot be inferred from the "Meteor" data. The main results are: (1) the static energy surface (a) is always parallel to, but systematically several 100 meters above, the surfaces (b ). (2) The sea surface pressure is practically independent of the trade layer thickness. (3) The components of the horizontal transport of momentum and energy are practically uncorrelated in the vertical; this demonstrates the Hadley-like character of the trade layer. (5) Water vapour plays with > 50% contribution the dominant role in the horizontal energy transport. ( 6) In the diabatic forcing function the flux of latent heat across the sea surface contributes the biggest part.These results show that vertically integrated two-layer models represent the gross features of the tropical circulation. Such formulations are thus a good approach towards simple and straightforward models for numerical experiments