Overview of Genetically Engineered Mouse Models of Papillary and Anaplastic Thyroid Cancers: Enabling Translational Biology for Patient Care Improvement.

The prognosis from thyroid cancer subtypes in humans covers a spectrum from "cured at almost 90%" to "100% lethal." Invasive and poorly differentiated forms of thyroid cancer are among the most aggressive human cancers, and there are few effective therapeutic options. Genetically engineered mice, based on mutations observed in patients, can accurately recapitulate the human disease and its progression, providing invaluable tools for the preclinical evaluation of novel therapeutic approaches. This overview details models developed to date as well as their uses for identifying novel anticancer agents. © 2015 by John Wiley & Sons, Inc.

The two -state model of receptor activation: The agonist and the efficacy

The Two State model describes how drugs activate receptors by inducing or supporting a conformational change in the receptor from “off” to “on”. The beta 2 adrenergic receptor system is the model system which was used to formalize the concept of two states, and the mechanism of hormone agonist stimulation of this receptor is similar to ligand activation of other seven transmembrane receptors. Hormone binding to beta 2 adrenergic receptors stimulates the intracellular production of cyclic adenosine monophosphate (cAMP), which is mediated through the stimulatory guanyl nucleotide binding protein (Gs) interacting with the membrane bound enzyme adenylylcyclase (AC). ^ The effects of cAMP include protein phosphorylation, metabolic regulation and transcriptional regulation. The beta 2 adrenergic receptor system is the most well known of its family of G protein coupled receptors. Ligands have been scrutinized extensively in search of more effective therapeutic agents at this receptor as well as for insight into the biochemical mechanism of receptor activation. Hormone binding to receptor is thought to induce a conformational change in the receptor that increases its affinity for inactive Gs, catalyzes the release of GDP and subsequent binding of GTP and activation of Gs. ^ However, some beta 2 ligands are more efficient at this transformation than others, and the underlying mechanism for this drug specificity is not fully understood. The central problem in pharmacology is the characterization of drugs in their effect on physiological systems, and consequently, the search for a rational scale of drug effectiveness has been the effort of many investigators, which continues to the present time as models are proposed, tested and modified. ^ The major results of this thesis show that for many b2 -adrenergic ligands, the Two State model is quite adequate to explain their activity, but dobutamine (+/−3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methylpropyl]- b -phenethylamine) fails to conform to the predictions of the Two State model. It is a weak partial agonist, but it forms a large amount of high affinity complexes, and these complexes are formed at low concentrations much better than at higher concentrations. Finally, dobutamine causes the beta 2 adrenergic receptor to form high affinity complexes at a much faster rate than can be accounted for by its low efficiency activating AC. Because the Two State model fails to predict the activity of dobutamine in three different ways, it has been disproven in its strictest form. ^

Heavy mineral content of ODP Leg 107 holes

Analyses of rock clasts and of heavy minerals in upper Miocene coarse detrital units drilled along the East Sardinia passive-type continental margin (Sites 654, 653, 652, and 656) reveal that the stretched basement contains quite complex rock suites. Taking also into account previous sampling data, in moving from west to east across the margin, the nature of the basement changes drastically. To the west there are mostly Hercynian basement rocks with their cover, referable to the alpine foreland of the Corsica-Sardinia block. To the east, along the lower margin, where crustal thinning is quite severe, the basement contains rock suites referable to a pre-upper Tortonian orogenized zone with units constituting parts of the Alpine and Apenninic chains (presumably with thickened continental crust prior to stretching). Largest thinning and ocean forming occurred then, in a rather short time, mostly at the expense of unstable crust just thickened by orogenetic/tectogenetic processes.

Magnetic properties and chemical composition at DSDP Hole 77-538A

Magnetic properties of doleritic and some metamorphic basement rocks underlying Catoche Knoll are studied. Doleritic rocks show a high saturation magnetic moment (2-5 emu/g) compared to metamorphic rocks (0.1-1 emu/g). Magnetic minerals of rocks from this hole show a high stability when heated in vacuo up to 600°C at a fixed rate of heating. Curie temperatures are distributed close to 550°C. These properties differ markedly from those of common submarine basalts observed before. X-ray microprobe analysis techniques were used to determine internal structures of ferromagnetic minerals; in most of ferromagnetic minerals there exist two different types of magnetic phases (i.e., products of high-temperature and low-temperature oxidations). Interpretations on the coexisting, seemingly contradictory, phases can be made based upon present analyses.

Sedimentology of cores from the continental rise west of the Antarctic Peninsula

The continental rise west of the Antarctic Peninsula includes a number of large sediment mounds interpreted as contourite drifts. Cores from six sediment drifts spanning some 650 km of the margin and 48 of latitude have been dated using chemical and isotopic tracers of palaeoproductivity and diatom biostratigraphy. Interglacial sedimentation rates range from 1.1 to 4.3 cm/ka. Glacial sedimentation rates range from 1.8 to 13.5 cm/ka, and decrease from proximal to distal sites on each drift. Late Quaternary sedimentation was cyclic, with brown, biogenic, burrowed mud containing ice-rafted debris (IRD) in interglacials and grey, barren, laminated mud in glacials. Foraminiferal intervals occur in interglacial stages 5 and 7 but not in the Holocene. Processes of terrigenous sediment supply during glacial stages differed; meltwater plumes were more important in stages 2-4, turbidity currents and ice-rafting in stage 6. The terrigenous component shows compositional changes along the margin, more marked in glacials. The major oxides Al2O3 and K2O are higher in the southwest, and CaO and TiO2 higher in the northeast. There is more smectite among the clay minerals in the northeast. Magnetic susceptibility varies along and between drifts. These changes reflect source variations along the margin. Interglacial sediments show less clear trends, and their IRD was derived from a wider area. Downslope processes were dominant in glacials, but alongslope processes may have attained equal importance in interglacials. The area contrasts with the East Antarctic continental slope in the SE Weddell Sea, where ice-rafting is the dominant process and where interglacial sedimentation rates are much higher than glacial. The differences in glacial setting and margin physiography can account for these contrasts.

(Table 1) Isotopes, calcite, aragonite and sample descriptions at DSDP Hole 55-433C

Calcite in the cavities and veins of igneous rocks has long been recognized as an alteration by-product (Dana, 1892). Elementary mineralogy textbooks report that the most common occurrence of aragonite is in the cavities of basalts and andesites (e.g., Kerr, 1977). Therefore, it is not surprising to find both carbonate minerals in association with the moderately to extensively altered basalt flows recovered during deep sea drilling on Suiko Seamount in the Emperor Seamount chain (DSDP Leg 55, Hole 433C). The thickness and vesicularity of the flows, along with the presence of oxidized flow tops, indicate that the basalt erupted subaerially (Site 433 Report, 1980). The stable isotopic contents of the carbonate phases filling and lining the veins and vesicles denote the environment of alteration. An isotopic study was undertaken to secure supportive evidence for a subaerial period in the development of the seamount. Also, the subsequent alteration history after submergence may be interpreted from this isotopic record.

Lithology, biostratigraphy, and geochemistry of the Black Sea sediments, DSDP Leg 42 (pt. 2) data

The monograph presents results of deep-sea drilling in the Black Sea carried out in 1975. Detailed lithological, biostratigraphic and geochemical studies of Miocene-Holocene sediments have been carried out by specialists from institutes of the USSR Academy of Sciences, Moscow State University and other organizations. Drilling results are compared with geophysical data. Geological history of the Black Sea basin is considered as well.

Mineralogy of sediments from the Exmouth Plateau and Argo Basin

Correlation of mineral associations from sediment recovered on the northwestern Australian continental margin document the juvenile-to-mature evolution of a segment of the Indian Ocean. Lower Cretaceous sediments contain sandy-to-silty radiolarian claystone that consists of highly smectitic mixed-layered illite/smectite (I/S) in addition to minor amounts of diagenetic pyrite, barite, and rhodochrosite. These immature, poorly sorted sediments were derived from nearby continental margin sources. Discrete bentonite layers and abundant smectite are the alteration products of volcanic material deposited during early basin formation. Abundant quartz-replaced radiolarian tests suggest high surface-water productivity, and calcareous fossils indicate water depths were above the calcite compensation depth (CCD) in the juvenile Indian Ocean. The increase in pelagic carbonate from the mid- to Late Cretaceous signals the transition to mature, open-ocean conditions. Similar to other slowly deposited contemporaneous deep-sea sediments, mid- to Upper Cretaceous sediments of the northwestern margin of Australia contain palygorskite. This palygorskite is associated with calcareous sediment across the ooze-to-chalk transition, detrital mixed-layered I/S, and zeolite minerals in places. This palygorskite occurs above the transformation from opal-A to opal-CT. The underlying opal-CT sediment contains abundant smectite and zeolite minerals. Calcareous sediment dominates the Cenozoic, except at abyssal sites that were not inundated by calcareous turbidites. Paleocene and Eocene sediments contain abundant smectite and zeolite minerals derived from the alteration of volcanic material. Palygorskite was found to be associated with sepiolite and dolomite in Miocene sediments from Site 765 in the Argo Basin. Pliocene and Quaternary sediments contain detrital kaolinite and mixed-layered I/S, abundant opal-A radiolarian tests, and minor amounts of pyrite

Insoluble residues of the fine-grained sediments from DSDP Leg 67 Holes

Insoluble residues of Late Cretaceous to Quaternary deep-sea samples from slope, trench, and oceanic plate sites south of Guatemala were examined, specifically for the distribution of clay minerals in the <2-µm fraction and of silt grains in the 20-63-µm fraction. Widespread "oceanic" particles (biogenic opal, rhyolitic glass) and their diagenetic products (smectite, clinoptilolite, heulandite) were distinguished from terrigenous material - illite, kaolinite, chlorite, plagioclase, quartz, and heavy minerals. The main results of this investigation are: (1) At Site 494 on the slope immediately adjacent to the trench, terrigenous supplies testify to a slope position of the whole sequence back to the Late Cretaceous. (2) At Site 495 on the Pacific Cocos Plate, "oceanic" and terrigenous sedimentation are clearly separated. Whereas the pelagic sedimentation prevailed in the early Miocene, terrigenous minerals appeared in the middle Miocene in the clay fraction, and in the early Pliocene in the coarse silt fraction. These terrigenous supplies are interpreted as having been transported by suspension clouds crossing the slope and even the trench. The alternative, however, an eolian transport, cannot be excluded.

Contenido de resveratrol en hojas de vides silvestres (Vitis spp.) mexicanas

El resveratrol es considerado una fitoalexina pues es sintetizado como respuesta a patógenos (factores bióticos) y en condiciones climáticas adversas (factores abióticos). Actualmente existe mucho interés en él por su potencial uso en farmacología como antioxidante. Mediante cromatografía de líquidos de alta resolución (HPLC) se determinó el contenido de resveratrol en hojas de 18 accesiones de vides nativas de Puebla, México, cuatro de ellas creciendo en cuatro condiciones ambientales diferentes. Las concentraciones fueron muy variables, estimándose 39,5 μg g−1 peso fresco como valor máximo, mientras que en algunas accesiones no fue posible detectar resveratrol. Se observaron diferencias en el contenido de resveratrol para accesiones creciendo en localidades diferentes, lo que sugiere alta influencia de los factores ambientales sobre la expresión del genotipo en la inducción o inhibición de la biosíntesis de dicho metabolito secundario.

Geochemistry of phosphatic crusts from the shelf off Peru

Authigenic phosphorite crusts from the shelf off Peru (9°40°S to 13°30°S) consist of a facies with phosphatic coated grains covered by younger phosphatic laminite. The crusts are composed of carbonate fluorapatite, which probably formed via an amorphous precursor close to the sediment water interface as indicated by low F/P2O5 ratios, Sr and Ca isotopes, as well as rare earth element patterns agreeing with seawater-dominated fluids. Small negative Ce anomalies and U enrichment in the laminite suggest suboxic conditions close to the sediment-water interface during its formation. Increased contents of chalcophilic elements and abundant sulfide minerals in the facies with phosphatic coated grains as well as in the laminite denote sulfate reduction and, consequently, point to episodical development of anoxic conditions during phosphogenesis. The Peruvian phosphorites formed episodically over an extended period of time lasting from Middle Miocene to Pleistocene. Individual phosphatic coated grains show a succession of phosphatic layers with varying contents of organic matter and sulfide-rich phosphatic layers. Coated grains supposedly formed as a result of episodic suspension caused by high turbulence and shifting redox conditions. Episodic anoxia in the pore water induced pyritization in the outermost carbonate fluorapatite layer. Phosphatic coated grains were later transported to the place of crust formation, where subsequent laminite formation was favored under lower energy conditions. A similar succession of phosphatic layers with varying contents of organic matter and sulfide-rich layers in the laminite suggests a formation mechanism analogous to that of individual coated grains.