Inhibition of HSP90 as a Strategy to Radiosensitize Glioblastoma: Targeting the DNA Damage Response and Beyond

Radiotherapy is an essential component of multi-modality treatment of glioblastoma (GBM). However, treatment failure and recurrence are frequent and give rise to the dismal prognosis of this aggressive type of primary brain tumor. A high level of inherent treatment resistance is considered to be the major underlying reason, stemming from constantly activated DNA damage response (DDR) mechanisms as a consequence of oncogene overexpression, persistent replicative stress, and other so far unknown reasons. The molecular chaperone heat shock protein 90 (HSP90) plays an important role in the establishment and maintenance of treatment resistance, since it crucially assists the folding and stabilization of various DDR regulators. Accordingly, inhibition of HSP90 represents a multi-target strategy to interfere with DDR function and to sensitize cancer cells to radiotherapy. Using NW457, a pochoxime-based HSP90 inhibitor with favorable brain pharmacokinetic profile, we show here that HSP90 inhibition at low concentrations with per se limited cytotoxicity leads to downregulation of various DNA damage response factors on the protein level, distinct transcriptomic alterations, impaired DNA damage repair, and reduced clonogenic survival in response to ionizing irradiation in glioblastoma cells in vitro. In vivo, HSP90 inhibition by NW457 improved the therapeutic outcome of fractionated CBCT-based irradiation in an orthotopic, syngeneic GBM mouse model, both in terms of tumor progression and survival. Nevertheless, in view of the promising in vitro results the in vivo efficacy was not as strong as expected, although apart from the radiosensitizing effects HSP90 inhibition also reduced irradiation-induced GBM cell migration and tumor invasiveness. Hence, our findings identify the combination of HSP90 inhibition and radiotherapy in principle as a promising strategy for GBM treatment whose performance needs to be further optimized by improved inhibitor substances, better formulations and/or administration routes, and fine-tuned treatment sequences

Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole

BACKGROUND: AIDS-associated cryptococcal meningitis has a high mortality. Fluconazole was the only systemic antifungal therapy available in our centre. From 1999–2001 we used low-dose fluconazole (200 mg daily initially), and did not offer therapy to patients perceived to have poor prognoses. In 2001 donated fluconazole became available, allowing us to use standard doses (400 mg daily initially). Antiretroviral therapy was not available during the study period. METHODS: Retrospective chart review of adult patients before and after the fluconazole donation. RESULTS: 205 patients fulfilled the inclusion criteria, 77 before and 128 after the donation. Following the donation fewer patients received no antifungal treatment (5% vs 19%, p = 0.002), and more patients received standard-dose fluconazole (90% vs 6%, p < 0.001). In-hospital mortality was 25%. Impaired consciousness, no antifungal treatment received and cerebrospinal fluid antigen titre > 1,000 were independent predictors of in-hospital mortality. Concomitant rifampicin did not affect in-hospital survival. Thirteen patients were referred to the tertiary referral hospital and received initial treatment with amphotericin B for a mean of 6 days – their in-hospital survival was not different from patients who received only fluconazole (p = 0.9). Kaplan-Meier analysis showed no differences in length of survival by initial treatment with standard or low doses of fluconazole (p = 0.27 log rank test); median survival was 76 and 82 days respectively. CONCLUSION: Outcome of AIDS-associated cryptococcal meningitis is similar with low or standard doses of fluconazole. The early mortality is high. Initial therapy with amphotericin B and other measures may be needed to improve outcome

Predictive Models for the Diagnostic of Human Visceral Leishmaniasis in Brazil

Visceral leishmaniasis (VL) is a neglected tropical disease endemic to 65 countries, including Brazil, where the disease frequently occurs in remote locations and treatment is often performed on the basis of clinical suspicion. Predictive models based on scoring systems could be a helpful tool for the clinical management of VL. Based on clinical signs and symptoms, and five different serological tests of 213 patients with parasitologically confirmed (cases) and 119 with clinical suspicion of VL but with another confirmed etiology (non-cases), twelve prediction models using logistic regression and classification and regression trees (CART) for VL diagnosis were developed. The model composed of the clinical-laboratory variables and the rk39 rapid test showed the best performance in both logistic regression and CART (Sensitivity of 90.1% and specificity ranging from 97.2–97.4%). The scoring system is simple and based on the clinical-laboratory findings that are easily available in most clinical settings. The results suggest that those models might be useful in locations where access to available diagnostic methods is difficult, contributing to more efficient and more rational allocation of healthcare resources

Successful surgical excision of primary right atrial angiosarcoma

Primary cardiac angiosarcoma is a rare and aggressive tumor with a high incidence of metastatic spread (up to 89%) at the time of diagnosis, which restricts the indication for surgical resection to a small number of patients. We report the case of a 50-year old Caucasian woman with non-metastatic primary right atrial angiosarcoma, who underwent successful surgical excision of the tumor (with curative intent) and reconstruction of the right atrium with a porcine pericardial patch. However, after a symptom-free survival of five months the patient presented with bone and liver metastases without evidence of local tumor recurrence

My Hand or Yours? Markedly Different Sensitivity to Egocentric and Allocentric Views in the Hand Laterality Task

In the hand laterality task participants judge the handedness of visually presented stimuli – images of hands shown in a variety of postures and views - and indicate whether they perceive a right or left hand. The task engages kinaesthetic and sensorimotor processes and is considered a standard example of motor imagery. However, in this study we find that while motor imagery holds across egocentric views of the stimuli (where the hands are likely to be one's own), it does not appear to hold across allocentric views (where the hands are likely to be another person's). First, we find that psychophysical sensitivity, d', is clearly demarcated between egocentric and allocentric views, being high for the former and low for the latter. Secondly, using mixed effects methods to analyse the chronometric data, we find high positive correlation between response times across egocentric views, suggesting a common use of motor imagery across these views. Correlations are, however, considerably lower between egocentric and allocentric views, suggesting a switch from motor imagery across these perspectives. We relate these findings to research showing that the extrastriate body area discriminates egocentric (‘self’) and allocentric (‘other’) views of the human body and of body parts, including hands

Glutamate receptor-like channels are essential for chemotaxis and reproduction in mosses

The deposited article version is a "Accelerated Article Preview" provided by Nature Publishing Group, and it contains attached the supplementary materials within the pdf.». This publication hasn't any creative commons license associated.Glutamate receptors are well characterized channels that mediate cell-to-cell communication during neurotransmission in animals. Nevertheless, information regarding their functional role in organisms without nervous systems is still limited. In plants, Glutamate Receptor-like (GLR) genes have been implicated in defence against pathogens, reproduction, control of stomata aperture and light signal transduction(1-5). However, the numerous GLR genes present in angiosperm genomes (20 to 70)(6) has prevented the observation of strong phenotypes in loss-of-function mutants. Here, we show that in the moss Physcomitrella patens, a basal land plant, mutation of GLR genes cause sperm failure in targeting the female reproductive organs. In addition, we show that GLR genes encode non-selective Ca(2+) permeable channels that can regulate cytoplasmic Ca(2+) and are needed to induce the expression of a BELL1-like transcription factor essential for zygote development. Our work reveals novel functions for GLRs in sperm chemotaxis and transcriptional regulation. Sperm chemotaxis is essential for fertilization in both animals and early land plants like bryophytes and pteridophytes. Therefore, our results are suggestive that ionotropic glutamate receptors may have been conserved throughout plant evolution to mediate cell-to-cell communication during sexual reproduction.Phillips University; Oxford University; University of Marburg; University of Muenster; MarieCurie ITN-Plant Origins grant: (FP7-PEOPLE-ITN-2008); FCT grants: (BEX-BCM/0376/2012; PTDC/BIA-PLA/4018/2012); NSF-US grant: (MCB 1616437/2016).info:eu-repo/semantics/acceptedVersio

DISCOVERY AND EARLY MULTI-WAVELENGTH MEASUREMENTS OF THE ENERGETIC TYPE IC SUPERNOVA PTF12GZK: A MASSIVE-STAR EXPLOSION IN A DWARF HOST GALAXY

We present the discovery and extensive early-time observations of the Type Ic supernova (SN) PTF12gzk. Our light curves show a rise of 0.8 mag within 2.5 hr. Power-law fits (f(t)∝(t – t 0) n ) to these data constrain the explosion date to within one day. We cannot rule out a quadratic fireball model, but higher values of n are possible as well for larger areas in the fit parameter space. Our bolometric light curve and a dense spectral sequence are used to estimate the physical parameters of the exploding star and of the explosion. We show that the photometric evolution of PTF12gzk is slower than that of most SNe Ic. The high ejecta expansion velocities we measure (~30, 000 km s–1 derived from line minima four days after explosion) are similar to the observed velocities of broad-lined SNe Ic associated with gamma-ray bursts (GRBs) rather than to normal SN Ic velocities. Yet, this SN does not show the persistent broad lines that are typical of broad-lined SNe Ic. The host-galaxy characteristics are also consistent with GRB-SN hosts, and not with normal SN Ic hosts. By comparison with the spectroscopically similar SN 2004aw, we suggest that the observed properties of PTF12gzk indicate an initial progenitor mass of 25-35 M ☉ and a large ((5-10) × 1051 erg) kinetic energy, the later being close to the regime of GRB-SN properties

BRAF(E600)-associated senescence-like cell cycle arrest of human naevi

Most normal mammalian cells have a finite lifespan(1), thought to constitute a protective mechanism against unlimited proliferation(2-4). This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes(6); however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi ( moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations ( predominantly V600E, where valine is substituted for glutamic acid) in BRAF(7), a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma)(8-10). This raises the question of whether naevi undergo BRAF(V600E)- induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence- associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)- driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62941/1/nature03890.pd

Facebook's Mobile Career

At the end of its first decade, Facebook’s identity, popularity, and characteristics are shaped in important ways by its becoming a form of mobile media, as much as it as platform associated with Internet and social media. This paper seeks to explore and understand Facebook as the important force in mobile media and communication it now is. It draws upon and combines perspectives from technology production, design, and economy, as well as user adoption, consumption, practices, affect, emotion, and resistance. The paper discusses the beginnings of mobile Facebook, and the early adoption of mobile Facebook associated with the rise of smartphones. The second part of the paper explores Facebook’s integration with photography (with Instagram) and social games (such as Zynga’s Farmville). The paper argues that Facebook’s mobile career is an accomplishment that has distinctively melded evolving affordances, everyday use across a wide range of settings, as well as political economies, corporate strategy, and design.Australian Research Counci