Prospective Study of the Iliac Branch Device E-liac in Patients with Common Iliac Artery Aneurysms: 12 Month Results.

OBJECTIVES: At 12 months follow up of the PLIANT study, clinical success and efficacy of the E-liac Stent Graft System (JOTEC GmbH, Hechingen, Germany) were evaluated. Clinical success was defined as aneurysm exclusion (no type I, III, IV endoleak) with primary patency of the internal iliac artery (IIA) and external iliac artery (EIA) on the E-liac implantation side. METHODS: In this prospective multicentre European observational study, clinical and morphological data of 45 patients (93% male, mean age 72 y) were prospectively collected in 11 European centres between July 2014 and June 2016. Forty patients underwent an aorto-iliac (three patients bilaterally) treatment and five an isolated iliac treatment. RESULTS: At 12 months follow up, data were available for 42 patients. Overall clinical success at 12 months was 90%, with a survival rate of 100%. Four patients (10%) did not achieve clinical success, one with an internal iliac artery (IIA) occlusion on the E-liac implantation side, one with an infrarenal type Ia endoleak, and two with type Ib endoleaks in IIA. At 12 months the primary patency rate in the internal iliac artery on the iliac side branch implantation side was 98%. Two patients (5%) received E-liac related re-interventions: one caused by an edge stenosis at the distal end of the graft limb in the external iliac artery (EIA) and one caused by thrombo-embolism in the external iliac artery. Thus, for the EIA, primary and secondary patency rates were 98% and 100%, respectively. CONCLUSIONS: The low device related re-intervention rate of 5%, the high survival rate of 100%, and the high primary patency rates of 98% for the IIA and EIA at 12 month follow up demonstrate the safety and efficacy of the E-liac Stent Graft System. Long term 36 month results are awaited to confirm the efficacy and durability.

Anthropogenic control over wintertime oxidation of atmospheric pollutants.

During winter in the mid-latitudes, photochemical oxidation is significantly slower than in summer and the main radical oxidants driving formation of secondary pollutants, such as fine particulate matter and ozone, remain uncertain, owing to a lack of observations in this season. Using airborne observations, we quantify the contribution of various oxidants on a regional basis during winter, enabling improved chemical descriptions of wintertime air pollution transformations. We show that 25-60% of NOx is converted to N2O5 via multiphase reactions between gas-phase nitrogen oxide reservoirs and aerosol particles, with ~93% reacting in the marine boundary layer to form >2.5 ppbv ClNO2. This results in >70% of the oxidizing capacity of polluted air during winter being controlled, not by typical photochemical reactions, but from these multiphase reactions and emissions of volatile organic compounds, such as HCHO, highlighting the control local anthropogenic emissions have on the oxidizing capacity of the polluted wintertime atmosphere.

[Kinase inhibitors in oncology : What is new?] / Kinaseinhibitoren in der Onkologie : Was ist neu?

Kinase inhibitors are now among the most important drugs in targeted therapy and are used in particular for the treatment of different tumor entities. Since many kinase inhibitors inhibit various tyrosine kinases efficiently but not specifically, they are often characterized by their versatile use in a wide variety of entities and diseases. The diverse use of this group of drugs, as well as the challenge of their side-effect profile, continues to make kinase inhibitors the subject of numerous clinical studies. The following article provides an overview of recent new approvals in the field of kinase inhibitors and shows their importance for oncological therapy.

Coagulase-negative staphylococci are associated to the mild inflammatory pattern of healthcare-associated meningitis: a retrospective study.

The epidemiology of healthcare-associated meningitis (HAM) is dominated by commensal bacteria from the skin, as coagulase-negative staphylococci (CoNS). We hypothesized that the pauci-symptomatic and mild inflammatory patterns of HAM are related to the low pathogenic state of CoNS. Our aim was to describe clinical and biological features of CoNS HAM, compared to other HAM. All consecutive patients with HAM admitted in our hospital were retrospectively included from 2007 to 2014. HAM due to CoNS were compared to HAM caused by other bacteria (controls) for clinical and laboratory patterns. Seventy-one cases of HAM were included, comprising 18 CoNS and 53 controls. Patients were not different in terms of baseline characteristics. CoNS HAM occurred later after the last surgery than controls (17 vs. 12 days, p = 0.029) and had higher Glasgow Coma Scale (GCS) score (14 vs. 13, p = 0.038). Cerebrospinal fluid (CSF) analysis revealed a lower pleocytosis (25 vs. 1340/mm3, p < 0.001), a higher glucose level (3.75 vs. 0.8 mmol/L, p < 0.001), and a lower protein level (744 vs. 1751 mg/L, p < 0.001) in the CoNS group than in the control group, respectively. HAM due to CoNS was significantly less symptomatic and less inflammatory than HAM due to other bacteria.

Comparison of the Radiosensitizing Effect of ATR, ATM and DNA-PK Kinase Inhibitors on Cervical Carcinoma Cells.

Here, we compared the effects of inhibitors of three phosphatidylinositol-3-kinase-related kinases, ATM, ATR a DNA-PK, on radiosensitization of cervical carcinoma cells. We demonstrated that DNA-PK inhibitor NU7441 enhanced phosphorylation of Chk1 and Chk2 kinases 2 h after irradiation of HeLa cells at a dose of 8 Gy in contrast to ATM kinase inhibitor KU55933, which completely blocked the Chk2 kinase phosphorylation on threonine 68, and ATR kinase inhibitor VE-821, which blocked the Chk1 kinase phosphorylation on serine 345. Most HeLa cells were accumulated in G2 phase of the cell cycle 24 h after irradiation at a high dose of 15 Gy, which was even potentiated after adding the inhibitors NU7441 and KU55933. Compared to all other irradiated groups, inhibitor VE-821 increased the number of cells in S phase and reduced the number of cells in G2 phase 24 h after irradiation at the high dose of 15 Gy. HeLa cells entered the mitotic cycle with unrepaired DNA, which resulted in cell death and the radiosensitizing effect of VE-821. Short-term application of the inhibitors (2 h before and 30 min after the irradiation by the dose of 8 Gy) significantly decreased the colony-forming ability of HeLa cells. Using real-time monitoring of cell proliferation by the xCELLigence system we demonstrated that while the radiosensitizing effect of VE-821 (ATR inhibitor) is manifested early after the irradiation, the radiosensitizing effect of KU55933 (ATM inhibitor) and NU7441 (DNA-PK inhibitor) is only observed as late as 72 h after the irradiation.

Detection of DNA crosslinks in peripheral lymphocytes isolated from patients treated with platinum derivates using modified comet assay.

Platinum-based chemotherapeutic agents induce the formation of crosslinks in DNA, which are accepted as being responsible for the cytotoxicity of these agents. In this study, we used a modification of the alkaline comet assay for detection of the presence of DNA crosslinks in vitro caused by cisplatin, and in peripheral lymphocytes of patients with non-small cell lung carcinoma undergoing chemotherapy with platinum derivatives. The comet technique modified for the detection of DNA crosslinks was calibrated in vitro by treating HeLa cells and human lymphocytes from healthy donors with different concentrations of cisplatin. A cisplatin dose-dependent formation of DNA crosslinks was observed in in vitro measurements using 10-200 µM concentrations of cisplatin. Lymphocytes from cancer patients were also assayed for the formation and repair of DNA crosslinks. Evidence of crosslink formation and repair was observed in peripheral blood lymphocytes of all cancer patients in this study, although some inter-individual differences were observed in the response to chemotherapy and in repair of DNA crosslinks. We propose that monitoring the number of DNA crosslinks in peripheral blood lymphocytes might be a quick and sensitive method for monitoring a patient's sensitivity to this agent. Modification of the method by incubation of analysed cells with styrene oxide before crosslink analysis by comet assay extends the use of the method also to laboratories which have no facilities to use ionizing irradiation for introducing DNA breaks into the cells.

Pyrocumulonimbus affect average stratospheric aerosol composition.

Pyrocumulonimbus (pyroCb) are wildfire-generated convective clouds that can inject smoke directly into the stratosphere. PyroCb have been tracked for years, yet their apparent rarity and episodic nature lead to highly uncertain climate impacts. In situ measurements of pyroCb smoke reveal its distinctive and exceptionally stable aerosol properties and define the long-term influence of pyroCb activity on the stratospheric aerosol budget. Analysis of 13 years of airborne observations shows that pyroCb are responsible for 10 to 25% of the black carbon and organic aerosols in the "present-day" lower stratosphere, with similar impacts in both the North and South Hemispheres. These results suggest that, should pyroCb increase in frequency and/or magnitude in future climates, they could generate dominant trends in stratospheric aerosol.

Disorder-induced localization in crystalline phase-change materials.

Localization of charge carriers in crystalline solids has been the subject of numerous investigations over more than half a century. Materials that show a metal-insulator transition without a structural change are therefore of interest. Mechanisms leading to metal-insulator transition include electron correlation (Mott transition) or disorder (Anderson localization), but a clear distinction is difficult. Here we report on a metal-insulator transition on increasing annealing temperature for a group of crystalline phase-change materials, where the metal-insulator transition is due to strong disorder usually associated only with amorphous solids. With pronounced disorder but weak electron correlation, these phase-change materials form an unparalleled quantum state of matter. Their universal electronic behaviour seems to be at the origin of the remarkable reproducibility of the resistance switching that is crucial to their applications in non-volatile-memory devices. Controlling the degree of disorder in crystalline phase-change materials might enable multilevel resistance states in upcoming storage devices.

Reconciling Assumptions in Bottom-Up and Top-Down Approaches for Estimating Aerosol Emission Rates From Wildland Fires Using Observations From FIREX-AQ.

Accurate fire emissions inventories are crucial to predict the impacts of wildland fires on air quality and atmospheric composition. Two traditional approaches are widely used to calculate fire emissions: a satellite-based top-down approach and a fuels-based bottom-up approach. However, these methods often considerably disagree on the amount of particulate mass emitted from fires. Previously available observational datasets tended to be sparse, and lacked the statistics needed to resolve these methodological discrepancies. Here, we leverage the extensive and comprehensive airborne in situ and remote sensing measurements of smoke plumes from the recent Fire Influence on Regional to Global Environments and Air Quality (FIREX-AQ) campaign to statistically assess the skill of the two traditional approaches. We use detailed campaign observations to calculate and compare emission rates at an exceptionally high-resolution using three separate approaches: top-down, bottom-up, and a novel approach based entirely on integrated airborne in situ measurements. We then compute the daily average of these high-resolution estimates and compare with estimates from lower resolution, global top-down and bottom-up inventories. We uncover strong, linear relationships between all of the high-resolution emission rate estimates in aggregate, however no single approach is capable of capturing the emission characteristics of every fire. Global inventory emission rate estimates exhibited weaker correlations with the high-resolution approaches and displayed evidence of systematic bias. The disparity between the low-resolution global inventories and the high-resolution approaches is likely caused by high levels of uncertainty in essential variables used in bottom-up inventories and imperfect assumptions in top-down inventories.

Experimental and theoretical studies of the reaction of the OH radical with alkyl sulfides: 3. Kinetics and mechanism of the OH initiated oxidation of dimethyl, dipropyl, and dibutyl sulfides: reactivity trends in the alkyl sulfides and development of a predictive expression for the reaction of OH with DMS.

A pulsed laser photolysis-pulsed laser-induced fluorescence technique has been employed to measure rate coefficients for the OH-initiated oxidation of dimethyl sulfide (DMS), its deuterated analog (DMS-d(6)), dipropyl sulfide (DPS), and dibutyl sulfide (DBS). Effective rate coefficients have been measured as a function of the partial pressure of O(2) over the temperature range of 240-295 K and at 200 and 600 Torr total pressure. We report the first observations of an O(2) enhancement in the effective rate coefficients for the reactions of OH with DPS and DBS. All observations are consistent with oxidation proceeding via a two-channel oxidation mechanism involving abstraction and addition channels. Structures and thermochemistry of the DPSOH and DBSOH adducts were calculated. Calculated bond strengths of adducts increase with alkyl substitution but are comparable to that of the DMSOH adduct and are consistent with experimental observations. Reactivity trends across the series of alkyl sulfide (C(2)-C(8)) reactions are analyzed. All reactions proceed via a two-channel mechanism involving either an H-atom abstraction or the formation of an OH adduct that can then react with O(2). Measurements presented in this work, in conjunction with previous measurements, have been used to develop a predictive expression for the OH-initiated oxidation of DMS. This expression is based on the elementary rate coefficients in the two-channel mechanism. The expression can calculate the effective rate coefficient for the reaction of OH with DMS over the range of 200-300 K, 0-760 Torr, and 0-100% partial pressure of O(2). This expression expands on previously published work but is applicable to DMS oxidation throughout the troposphere.

The concept of hybrid molecules of tacrine and benzyl quinolone carboxylic acid (BQCA) as multifunctional agents for Alzheimer's disease.

Novel tacrine-benzyl quinolone carboxylic acid (tacrine-BQCA) hybrids were designed based on multi-target directed ligands (MTLDs) paradigm, synthesized and evaluated in vitro as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). Tacrine moiety is represented herein as 7-methoxytacrine, 6-chlorotacrine or unsubstituted tacrine forming three different families of seven members, i.e. 21 compounds in overall. Introducing BQCA, a positive modulator of M1 muscarinic acetylcholine receptors (mAChRs), the action of novel compounds on M1 mAChRs was evaluated via Fluo-4 NW assay on the Chinese hamster ovarian (CHO-M1WT2) cell line. All the novel tacrine-BQCA hybrids were able to block the action of hAChE and hBChE in micromolar to nanomolar range. The hAChE kinetic profile of 5p was found to be mixed-type which is consistent with our docking experiments. Moreover, selected ligands were assessed for their potential hepatotoxicity on HepG2 cell line and presumable permeation through the blood-brain barrier by PAMPA assay. Expected agonistic profile towards M1 mAChRs delivered by BQCA moiety was not confirmed. From all the hybrids, 5o can be highlighted as non-selective cholinesterase inhibitor (hAChE IC50 = 74.5 nM; hBChE IC50 = 83.3 nM) with micromolar antagonistic activity towards M1 mAChR (IC50 = 4.23 µM). A non-selective pattern of cholinesterase inhibition is likely to be valuable during the onset as well as later stages of AD.

First Report of Phakopsora pachyrhizi, the Causal Agent of Asian Soybean Rust, on Florida Beggarweed in the United States.

Phakopsora pachyrhizi Syd. & P. Syd., which causes Asian soybean rust (SBR), was observed on Florida beggarweed, Desmodium tortuosum (Sw) DC., in Attapulgus, GA during late October and early November 2005. Tan to brown lesions (<1.0 mm in diameter) consistent with symptoms of SBR (2) were observed on older leaves of several plants collected near an SBR-infected soybean trial. Dissection (40 to 60×) and compound microscopy (×200 to 400) revealed conical pustules and ellipsoid, echinulate urediniospores (average size 15 × 20 µm) on the abaxial leaf surface. Polymerase chain reaction (PCR) (primers Ppm1 and Ppa2) (1) was conducted on four samples to confirm identification of P. pachyrhizi or P. meibomiae. Three were positive for P. pachyrhizi, and one was negative for both species. Using morphology and real-time PCR, SBR was confirmed as P. pachyrhizi by the USDA/APHIS in Beltsville, MD. Six noninfected Florida beggarweed plants were transplanted to pots during December 2005 and grown at 22 to 24°C in a greenhouse. On 11 January 2006, a water suspension of urediniospores collected from SBR-infected soybeans (1 × 105 spores per ml) was spray inoculated on all leaves to almost runoff and incubated for 48 h in a plastic humidity chamber. Lesions, pustules, and urediniospores consistent with SBR (2) were observed on 3 February 2006. A PCR assay was conducted on six samples from the infected greenhouse plants and all were positive for P. pachyrhizi. Florida beggarweed is widespread in the southern United States and may serve as an additional overwintering source for P. pachyrhizi and a potential inoculum source for the soybean crop. References: (1) R. D. Fredrick et al. Phytopathology 92:217, 2002. (2) J. B. Sinclair and G. L. Hartman. Soybean rust. Pages 25-26 in: Compendium of Soybean Diseases. 4th ed. G. L. Hartman et al., eds. The American Phytopathological Society, St. Paul, MN, 1999.

Survival control of malignant lymphocytes by anti-apoptotic MCL-1.

Programmed apoptotic cell death is critical to maintain tissue homeostasis and cellular integrity in the lymphatic system. Accordingly, the evasion of apoptosis is a critical milestone for the transformation of lymphocytes on their way to becoming overt lymphomas. The anti-apoptotic BCL-2 family proteins are pivotal regulators of the mitochondrial apoptotic pathway and genetic aberrations in these genes are associated with lymphomagenesis and chemotherapeutic resistance. Pharmacological targeting of BCL-2 is highly effective in certain indolent B-cell lymphomas; however, recent evidence highlights a critical role for the BCL-2 family member MCL-1 in several lymphoma subtypes. MCL-1 is recurrently highly expressed in various kinds of cancer including non-Hodgkin's lymphoma of B- and T-cell origin. Moreover, both indolent and aggressive forms of lymphoma require MCL-1 for lymphomagenesis and for their continued survival. This review summarizes the role of MCL-1 in B- and T-cell lymphoma and discusses its potential as a therapeutic target.

A 7-methoxytacrine-4-pyridinealdoxime hybrid as a novel prophylactic agent with reactivation properties in organophosphate intoxication.

Chemical warfare agents constitute an increasing threat to both military and civilian populations. Therefore, effective prophylactic approaches are urgently needed. Herein, we present a novel hybrid compound which is able not only to keep acetylcholinesterase resistant to organophosphate (OP) inhibitors, but also to serve as an enzyme reactivator in the case of OP intoxication.

Blockade of BCL-2 proteins efficiently induces apoptosis in progenitor cells of high-risk myelodysplastic syndromes patients.

Deregulated apoptosis is an identifying feature of myelodysplastic syndromes (MDS). Whereas apoptosis is increased in the bone marrow (BM) of low-risk MDS patients, progression to high-risk MDS correlates with an acquired resistance to apoptosis and an aberrant expression of BCL-2 proteins. To overcome the acquired apoptotic resistance in high-risk MDS, we investigated the induction of apoptosis by inhibition of pro-survival BCL-2 proteins using the BCL-2/-XL/-W inhibitor ABT-737 or the BCL-2-selective inhibitor ABT-199. We characterized a cohort of 124 primary human BM samples from MDS/secondary acute myeloid leukemia (sAML) patients and 57 healthy, age-matched controls. Inhibition of anti-apoptotic BCL-2 proteins was specifically toxic for BM cells from high-risk MDS and sAML patients, whereas low-risk MDS or healthy controls remained unaffected. Notably, ABT-737 or ABT-199 treatment was capable of targeting the MDS stem/progenitor compartment in high-risk MDS/sAML samples as shown by the reduction in CD34(+) cells and the decreased colony-forming capacity. Elevated expression of MCL-1 conveyed resistance against both compounds. Protection by stromal cells only partially inhibited induction of apoptosis. Collectively, our data show that the apoptotic resistance observed in high-risk MDS/sAML cells can be overcome by the ABT-737 or ABT-199 treatment and implies that BH3 mimetics might delay disease progression in higher-risk MDS or sAML patients.

Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance.

T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.

Aqueous-phase mechanism for secondary organic aerosol formation from isoprene: application to the Southeast United States and co-benefit of SO2 emission controls.

Isoprene emitted by vegetation is an important precursor of secondary organic aerosol (SOA), but the mechanism and yields are uncertain. Aerosol is prevailingly aqueous under the humid conditions typical of isoprene-emitting regions. Here we develop an aqueous-phase mechanism for isoprene SOA formation coupled to a detailed gas-phase isoprene oxidation scheme. The mechanism is based on aerosol reactive uptake coefficients (γ) for water-soluble isoprene oxidation products, including sensitivity to aerosol acidity and nucleophile concentrations. We apply this mechanism to simulation of aircraft (SEAC4RS) and ground-based (SOAS) observations over the Southeast US in summer 2013 using the GEOS-Chem chemical transport model. Emissions of nitrogen oxides (NOx ≡ NO + NO2) over the Southeast US are such that the peroxy radicals produced from isoprene oxidation (ISOPO2) react significantly with both NO (high-NOx pathway) and HO2 (low-NOx pathway), leading to different suites of isoprene SOA precursors. We find a mean SOA mass yield of 3.3 % from isoprene oxidation, consistent with the observed relationship of total fine organic aerosol (OA) and formaldehyde (a product of isoprene oxidation). Isoprene SOA production is mainly contributed by two immediate gas-phase precursors, isoprene epoxydiols (IEPOX, 58% of isoprene SOA) from the low-NOx pathway and glyoxal (28%) from both low- and high-NOx pathways. This speciation is consistent with observations of IEPOX SOA from SOAS and SEAC4RS. Observations show a strong relationship between IEPOX SOA and sulfate aerosol that we explain as due to the effect of sulfate on aerosol acidity and volume. Isoprene SOA concentrations increase as NOx emissions decrease (favoring the low-NOx pathway for isoprene oxidation), but decrease more strongly as SO2 emissions decrease (due to the effect of sulfate on aerosol acidity and volume). The US EPA projects 2013-2025 decreases in anthropogenic emissions of 34% for NOx (leading to 7% increase in isoprene SOA) and 48% for SO2 (35% decrease in isoprene SOA). Reducing SO2 emissions decreases sulfate and isoprene SOA by a similar magnitude, representing a factor of 2 co-benefit for PM2.5 from SO2 emission controls.

Organic nitrate chemistry and its implications for nitrogen budgets in an isoprene- and monoterpene-rich atmosphere: constraints from aircraft (SEAC4RS) and ground-based (SOAS) observations in the Southeast US.

Formation of organic nitrates (RONO2) during oxidation of biogenic volatile organic compounds (BVOCs: isoprene, monoterpenes) is a significant loss pathway for atmospheric nitrogen oxide radicals (NOx), but the chemistry of RONO2 formation and degradation remains uncertain. Here we implement a new BVOC oxidation mechanism (including updated isoprene chemistry, new monoterpene chemistry, and particle uptake of RONO2) in the GEOS-Chem global chemical transport model with ∼25 × 25 km2 resolution over North America. We evaluate the model using aircraft (SEAC4RS) and ground-based (SOAS) observations of NOx, BVOCs, and RONO2 from the Southeast US in summer 2013. The updated simulation successfully reproduces the concentrations of individual gas- and particle-phase RONO2 species measured during the campaigns. Gas-phase isoprene nitrates account for 25-50% of observed RONO2 in surface air, and we find that another 10% is contributed by gas-phase monoterpene nitrates. Observations in the free troposphere show an important contribution from long-lived nitrates derived from anthropogenic VOCs. During both campaigns, at least 10% of observed boundary layer RONO2 were in the particle phase. We find that aerosol uptake followed by hydrolysis to HNO3 accounts for 60% of simulated gas-phase RONO2 loss in the boundary layer. Other losses are 20% by photolysis to recycle NOx and 15% by dry deposition. RONO2 production accounts for 20% of the net regional NOx sink in the Southeast US in summer, limited by the spatial segregation between BVOC and NOx emissions. This segregation implies that RONO2 production will remain a minor sink for NOx in the Southeast US in the future even as NOx emissions continue to decline.

The beta3-adrenergic agonist CL316,243 inhibits insulin signaling but not glucose uptake in primary human adipocytes.

Insulin resistance and obesity are central components of the metabolic syndrome which has become the leading cause of cardiovascular morbidity and mortality worldwide. Direct interactions of the beta (3)-adrenoceptor system with adipocyte signaling and function in humans remain poorly understood. However, this might have important consequences for the regulation of energy homeostasis and insulin resistance in states of hyperinsulinemia and sympatho-adrenergic overactivity. We therefore investigated beta (3)-adrenoceptor-mediated effects on insulin signaling and glucose uptake in mammary adipocytes of healthy women that underwent breast reduction surgery. Glucose uptake was strongly induced by insulin stimulation. This was paralleled by robust induction of insulin receptor kinase activity, insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity, and protein kinase B phosphorylation. Treatment with the beta (3)-adrenoceptor-selective agonist CL316,243 alone, neither induced alterations in the early insulin signaling cascade nor changed the basal level of glucose uptake. By contrast, pretreatment with the beta (3)-adrenoceptor agonist inhibited the insulin-induced insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity by 50 % and protein kinase B phosphorylation by 40 % without affecting insulin receptor kinase activity upstream. However, on the functional level insulin-induced glucose uptake remained unchanged by beta (3)-adrenoceptor stimulation. Our data demonstrate an insulin receptor-independent negative influence of beta (3)-adrenoceptor stimulation on proximal insulin signaling. This inhibition is apparently dissociated from glucose uptake in human adipocytes.

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015.

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.