Eutropics Pharmaceuticals (United States)

Recent developments of carbon capture and storage and geothermal subsurface prospects in the Middle Jurassic limestone of the central part of the Paris Basin have rejuvenated interest in the world class outcrops of the Bathonian Oolithe Blanche Formation on the southeastern edge of the Basin. Here, ooid-bioclast grainstones occur as large-scale (10–15 m high) clinoforms in the upper part of the Oolithe Blanche, which remain enigmatic and variously interpreted. High-resolution sequence stratigraphic correlations, constrained by biostratigraphic markers and integrated with regional palaeogeography, indicate that the clinoforms are giant dunes developed during the early part of the regressive phase of a third-order transgressive–regressive sequence (Bt3), in the northern part of the Burgundy Bathonian carbonate ramp. Carbonate sand bodies up to 15 m high with intervening troughs, formed subaqueous giant dune field(s) with calculated wavelengths of about 500–800 m. Using dune height as a proxy for calculating the palaeobathymetry of deposition, it is concluded that the dunes formed under a minimum water depth of about 60 m. A detailed facies analysis of the sediments underlying the dunes, which include beds rich in brachiopods in living position corresponding to the MFS of the third-order transgressive–regressive sequence (Bt3), supports such a water depth. The constitutive facies of the dunes themselves also reflect a significant water depth, despite the presence of ooids that are definitely transported away from their main production zone. This new interpretation of the large-scale clinoforms in the upper Oolithe Blanche and the associated revised palaeobathymetry have implications for the interpretations of Bathonian carbonates across the Paris Basin, which are relevant to ongoing projects of reservoir characterization of subsurface prospects.

7087 Background: Chronic lymphocytic leukemia (CLL) patient outcomes may benefit from targeting therapies alone or in combination to individuals with favorable molecular profiles. Whether such pers...

Insensitivity to standard clinical interventions, including chemotherapy, radiotherapy, and tyrosine kinase inhibitor (TKI) treatment, remains a substantial hindrance towards improving the prognosis of patients with non-small cell lung cancer (NSCLC). The molecular mechanism of therapeutic resistance remains poorly understood. The TNF-like weak inducer of apoptosis (TWEAK)-FGF-inducible 14 (TNFRSF12A/Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and the upregulation of prosurvival Bcl-2 family members. Here, a role was determined for TWEAK-Fn14 prosurvival signaling in NSCLC through the upregulation of myeloid cell leukemia sequence 1 (MCL1/Mcl-1). Mcl-1 expression significantly correlated with Fn14 expression, advanced NSCLC tumor stage, and poor patient prognosis in human primary NSCLC tumors. TWEAK stimulation of NSCLC cells induced NF-κB-dependent Mcl-1 protein expression and conferred Mcl-1-dependent chemo- and radioresistance. Depletion of Mcl-1 via siRNA or pharmacologic inhibition of Mcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatin- or radiation-mediated inhibition of cell survival. Moreover, EU-5148 inhibited cell survival across a panel of NSCLC cell lines. In contrast, inhibition of Bcl-2/Bcl-xL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK-Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival and open new therapeutic avenues to abrogate the high mortality rate seen in NSCLC. The TWEAK-Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK-Fn14 and Mcl-1 as therapeutic opportunities in lung cancer.

The Cenomanian/Turonian shallow water deposits of the Sarvak Formation constitute one of the main reservoirs in SW Iran. Heterogeneities in these reservoirs are controlled by lateral facies changes, caused by intrashelf basin to platform transitions, and by diagenetic overprint related to three (regional) exposure surfaces that subdivide the succession in third order depositional sequences. This diagenetic imprint has been studied in superb exposures of this formation in the outcrops of coastal Fars, which are considered as good outcrop analogues for the nearby oilfields.

The molecular chaperone heat shock protein (hsp)-90 maintains estrogen receptor (ER)-alpha in an active conformation, allowing it to bind 17beta-estradiol (E2) and transactivate genes, including progesterone receptor (PR)-beta and the class IIB histone deacetylase HDAC6. By inhibiting HDAC6, the hydroxamic acid analogue pan-HDAC inhibitors (HA-HDI; e.g., LAQ824, LBH589, and vorinostat) induce hyperacetylation of the HDAC6 substrates alpha-tubulin and hsp90. Hyperacetylation of hsp90 inhibits its chaperone function, thereby depleting hsp90 client proteins. Here, we determined the effect of HA-HDIs on the levels and activity of ERalpha, as well as on the survival of ERalpha-expressing, estrogen-responsive human breast cancer MCF-7 and BT-474 cells. Following exposure to HA-HDIs, hsp90 binding, polyubiquitylation levels, and transcriptional activity of ERalpha, as well as apoptosis and loss of survival, were determined in MCF-7 and BT-474 cells. Treatment with HA-HDI induced hsp90 hyperacetylation, decreased its binding to ERalpha, and increased polyubiquitylation and depletion of ERalpha levels. HA-HDI treatment abrogated E2-induced estrogen response element-luciferase expression and attenuated PRbeta and HDAC6 levels. Exposure to HA-HDI also depleted p-Akt, Akt, c-Raf, and phospho-extracellular signal-regulated kinase-1/2 levels, inhibited growth, and sensitized ERalpha-positive breast cancer cells to tamoxifen. These findings show that treatment with HA-HDI abrogates ERalpha levels and activity and could sensitize ERalpha-positive breast cancers to E2 depletion or ERalpha antagonists.

Smokeless tobacco has been proposed as a reduced risk substitute for smoking, but no large studies have investigated exposure to the powerful carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in smokeless tobacco users versus smokers. The purpose of this study was to carry out such a comparison. Levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronides (total NNAL), a biomarker of NNK exposure, and cotinine, a biomarker of nicotine exposure, were quantified in the urine of 420 smokers and 182 smokeless tobacco users who were participants in studies designed to reduce their use of these products. The measurements were taken at baseline, before intervention. Levels of total NNAL per milliliter of urine were significantly higher in smokeless tobacco users than in smokers (P < 0.0001). When adjusted for age and gender, levels of total NNAL per milligram of creatinine were also significantly higher in smokeless tobacco users than in smokers (P < 0.001). Levels of cotinine per milliliter of urine and per milligram of creatinine were significantly higher in smokeless tobacco users than in smokers (P < 0.001). These results show similar exposures to the potent tobacco-specific carcinogen NNK in smokeless tobacco users and smokers. These findings do not support the use of smokeless tobacco as a safe substitute for smoking.

Abstract Nuclear Magnetic Resonance (NMR) Logging has gained widespread acceptance over the past decade. Those using NMR data need assurance regarding the quality of the data and the interpreted product. This is particularly true as NMR replaces other logging devices and is of paramount importance when NMR is run as a standalone service. NMR applications require proper job planning and acquisition for successful data processing, interpretation and integration with conventional logs. Quality control procedures are particularly important during data acquisition and during the creation of integrated computed products. This paper seeks to provide a reference for quality control of NMR data at acquisition and during subsequent interpretation. Examples are shown that demonstrate the importance of quality control related to data acquisition and processing. Quality assessment is divided into three areas; 1) Adherence to service company standards for calibration, tuning, and raw data quality. 2) Repeatability of NMR results. 3) Coherence of data with other available data. Respective of these three areas, some simple guidelines for quality assurance of NMR data and products are presented.

SUMMARY The Station Quarry Beds were deposited during a transgressive episode at the beginning of the Brigantian in a structurally controlled basin on the Derbyshire carbonate platform. The initial flooding of this basin was marked by the deposition of sediment reworked from subtidal, shoreface and back barrier intertidal sediments on the karstified and calcretised surface of the Bee Low Limestones. As sea level continued to rise, low energy, sub-wave-base conditions, interrupted by occasional storms, were established within the intrashelf basin. The generally low-energy environment is attributed to the sheltered setting of the intra-shelf basin rather than water depth. The near normal to fully marine salinity, together with the well-oxygenated conditions of deposition, suggest that the intra-shelf basin was probably connected to a larger body of fully marine water.