Pan-histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2

Chemotherapy modestly prolongs survival of patients with advanced gastric cancer, but strategies are needed to increase its efficacy. Histone deacetylase (HDAC) inhibitors modify chromatin and can block cancer cell proliferation and promote apoptosis.

[Drug-independent blood pressure control through the autonomous nervous system]

Arterial hypertension is a chronic disease with a therapeutical challenge for the patient and the physician involved. Patient-independent techniques with good efficacy and tolerability are wanted. The autonomous nervous system insufficiently therapeutically exploited to date, is now approachable by two types of intervention: renal nerve ablation, an endovascular approach without remaining foreign body, and BAT, baroreflex activating therapy using an implantable device stimulating the carotid sinus. The blood pressure lowering potency of BAT appears more than with renal nerve ablation and also clinical study data are more prevalent. With both treatment options the patients having the most profit are insufficiently defined. Given this knowledge, any form of secondary hypertension needs to be excluded beforehand.

TGF-b2 induction regulates invasiveness of Theileria-transformed leukocytes and disease susceptibility

Theileria parasites invade and transform bovine leukocytes causing either East Coast fever (T. parva), or tropical theileriosis (T. annulata). Susceptible animals usually die within weeks of infection, but indigenous infected cattle show markedly reduced pathology, suggesting that host genetic factors may cause disease susceptibility. Attenuated live vaccines are widely used to control tropical theileriosis and attenuation is associated with reduced invasiveness of infected macrophages in vitro. Disease pathogenesis is therefore linked to aggressive invasiveness, rather than uncontrolled proliferation of Theileria-infected leukocytes. We show that the invasive potential of Theileria-transformed leukocytes involves TGF-b signalling. Attenuated live vaccine lines express reduced TGF-b2 and their invasiveness can be rescued with exogenous TGF-b. Importantly, infected macrophages from disease susceptible Holstein-Friesian (HF) cows express more TGF-b2 and traverse Matrigel with great efficiency compared to those from disease-resistant Sahiwal cattle. Thus, TGF-b2 levels correlate with disease susceptibility. Using fluorescence and time-lapse video microscopy we show that Theileria-infected, disease-susceptible HF macrophages exhibit increased actin dynamics in their lamellipodia and podosomal adhesion structures and develop more membrane blebs. TGF-b2-associated invasiveness in HF macrophages has a transcription-independent element that relies on cytoskeleton remodelling via activation of Rho kinase (ROCK). We propose that a TGF-b autocrine loop confers an amoeboid-like motility on Theileria-infected leukocytes, which combines with MMP-dependent motility to drive invasiveness and virulence.

Mapping the Operation of the Miniature Combustion Aerosol Standard (Mini-CAST) Soot Generator

The Jing Ltd. miniature combustion aerosol standard (Mini-CAST) soot generator is a portable, commercially available burner that is widely used for laboratory measurements of soot processes. While many studies have used the Mini-CAST to generate soot with known size, concentration, and organic carbon fraction under a single or few conditions, there has been no systematic study of the burner operation over a wide range of operating conditions. Here, we present a comprehensive characterization of the microphysical, chemical, morphological, and hygroscopic properties of Mini-CAST soot over the full range of oxidation air and mixing N-2 flow rates. Very fuel-rich and fuel-lean flame conditions are found to produce organic-dominated soot with mode diameters of 10-60nm, and the highest particle number concentrations are produced under fuel-rich conditions. The lowest organic fraction and largest diameter soot (70-130nm) occur under slightly fuel-lean conditions. Moving from fuel-rich to fuel-lean conditions also increases the O:C ratio of the soot coatings from similar to 0.05 to similar to 0.25, which causes a small fraction of the particles to act as cloud condensation nuclei near the Kelvin limit (kappa similar to 0-10(-3)). Comparison of these property ranges to those reported in the literature for aircraft and diesel engine soots indicates that the Mini-CAST soot is similar to real-world primary soot particles, which lends itself to a variety of process-based soot studies. The trends in soot properties uncovered here will guide selection of burner operating conditions to achieve optimum soot properties that are most relevant to such studies.

Energy harvesting from the beating heart by a mass imbalance oscillation generator

Energy-harvesting devices attract wide interest as power supplies of today's medical implants. Their long lifetime will spare patients from repeated surgical interventions. They also offer the opportunity to further miniaturize existing implants such as pacemakers, defibrillators or recorders of bio signals. A mass imbalance oscillation generator, which consists of a clockwork from a commercially available automatic wrist watch, was used as energy harvesting device to convert the kinetic energy from the cardiac wall motion to electrical energy. An MRI-based motion analysis of the left ventricle revealed basal regions to be energetically most favorable for the rotating unbalance of our harvester. A mathematical model was developed as a tool for optimizing the device's configuration. The model was validated by an in vitro experiment where an arm robot accelerated the harvesting device by reproducing the cardiac motion. Furthermore, in an in vivo experiment, the device was affixed onto a sheep heart for 1 h. The generated power in both experiments-in vitro (30 μW) and in vivo (16.7 μW)-is sufficient to power modern pacemakers.

Induction of the Neurokinin 1 Receptor by TNFα in Endometriotic Tissue Provides the Potential for Neurogenic Control Over Endometriotic Lesion Growth

Context: Endometriosis is characterized by the growth of ectopic endometrial tissue. Nerve fibers are frequently associated with ectopic lesions, and neurogenic inflammation may play a role in endometriosis. Objective: The purpose of this study was to determine the presence of tachykinin receptors in endometriotic lesions and the role of TNFα on their expression. Design: This study was an assessment of matching eutopic and ectopic endometrial tissue and peritoneal fluid from patients with endometriosis and an in vitro analysis of primary endometrial cells. Setting: The setting was a university hospital. Patients: Participants were premenopausal women undergoing laparoscopy. Interventions: Endometriotic lesions were removed surgically. Main Outcome Measures: Tachykinin mRNA (TACR1/2) and protein (neurokinin 1 receptor [NK1R]) expression in both eutopic and ectopic endometrial tissue from patients with endometriosis and the correlation to peritoneal fluid TNFα were measured. Primary endometrial epithelial and stromal cells were assessed in vitro to determine the induction of TACR1/2 and NK1R expression after TNFα treatment. Cell viability of endometrial stromal cells after substance P exposure was also assessed. Results: Expression of both TACR1 and TACR2 mRNA was significantly higher in the ectopic than in the eutopic tissue. Both TACR1 mRNA and NK1R protein expression was significantly correlated with peritoneal fluid TNFα, and in vitro studies confirmed that TNFα treatment induced both TACR1 mRNA and NK1R protein expression in endometrial stromal cells. In endometrial stromal cells, substance P treatment enhanced cell viability, which was inhibited by a specific NK1R antagonist. Conclusions: NK1R expression is induced in ectopic endometrial tissue by peritoneal TNFα. Induction of NK1R expression may permit endometriotic lesion maintenance via exposure to substance P.

Impaired innate interferon induction in severe therapy resistant atopic asthmatic children

Deficient type I interferon-β and type III interferon-λ induction by rhinoviruses has previously been reported in mild/moderate atopic asthmatic adults. No studies have yet investigated if this occurs in severe therapy resistant asthma (STRA). Here, we show that compared with non-allergic healthy control children, bronchial epithelial cells cultured ex vivo from severe therapy resistant atopic asthmatic children have profoundly impaired interferon-β and interferon-λ mRNA and protein in response to rhinovirus (RV) and polyIC stimulation. Severe treatment resistant asthmatics also exhibited increased virus load, which negatively correlated with interferon mRNA levels. Furthermore, uninfected cells from severe therapy resistant asthmatic children showed lower levels of Toll-like receptor-3 mRNA and reduced retinoic acid inducible gene and melanoma differentiation-associated gene 5 mRNA after RV stimulation. These data expand on the original work, suggesting that the innate anti-viral response to RVs is impaired in asthmatic tissues and demonstrate that this is a feature of STRA.

Anthracyclines during induction therapy in acute myeloid leukaemia: a systematic review and meta-analysis

This systematic review and meta-analysis compared the efficacy of different anthracyclines and anthracycline dosing schedules for induction therapy in acute myeloid leukaemia in children and adults younger than 60 years of age. Twenty-nine randomized controlled trials were eligible for inclusion in the review. Idarubicin (IDA), in comparison to daunorubicin (DNR), reduced remission failure rates (risk ratio (RR) 0·81; 95% confidence interval (CI), 0·66-0·99; P = 0·04), but did not alter rates of early death or overall mortality. Superiority of IDA for remission induction was limited to studies with a DNR/IDA dose ratio <5 (ratio <5: RR 0·65; 95% CI, 0·51-0·81; P < 0·001; ratio ≥5: RR 1·03; 95% CI, 0·91-1·16; P = 0·63). Higher-dose DNR, compared to lower-dose DNR, was associated with reduced rates for remission failure (RR 0·75; 95% CI, 0·60-0·94; P = 0·003) and overall mortality (RR 0·83; 95% CI, 0·75-0·93; P < 0·001), but not for early death. Comparisons of several other anthracycline derivates did not reveal significant differences in outcomes. Survival estimates in adults suggest that both high-dose DNR (90 mg/m(2) daily × 3 or 50 mg/m(2) daily × 5) and IDA (12 mg/m(2) daily × 3) can achieve 5-year survival rates of between 40 and 50 percent.

The Ideology, Politics and Autonomous Art of Richard Weiner: (An Event in Discourse)"

The first aim of the project was to compile documentation on the life and work of Richard Weiner, a Czech journalist, writer and poet who spent the best part of his life as Paris correspondent for Lidove noviny. Langerova looked at the contexts and the growing independence of certain parts of his work, the distribution of thematic compositional elements into different parts of discourse and their position in the autonomous space of a work of art. Looking at the features of minority literature and the contemporary contexts of Weiner's life and work Langerova focuses on the situation of the Jewish community (Wiener came from an assimilated Jewish family). For this minorities, the function of language as a medium of communication which is able to create an autonomous world became increasingly important. Literature, which is based on this function of language, is a political matter par excellence before it begins forming as an autonomous, independent and divergent place. This means that everything private and intimate is closely connected to political and social responsibility, while supposedly objective genres contain subjective features. Another important characteristic is "nomadism", which asks the question of "Where do I belong". This was very important in Czechoslovakia after World War I , as in the issue of Zionism. Although Weiner rejected Zionism, he asks this question in his writing and it is reflected at a symbolic level in his work, which shows a fundamental thematic and compositional plan of a journey, cross-roads and wandering. These theses were reflected in Weiner's life, which was a series of continuous transfers and unplanned moves, often when he thought he had found his place. As well as tracing the course of his life, and his relations with and views of other writers, Langerova looks at his writings in various areas. Her major focus is the divergence of trivial and great events into different types of discourse in Richard Weiner's work, their transfer (small into great, trivial into mythical) and their historical context.