New hints towards a precision medicine strategy for IDH wild-type glioblastoma.

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.

Bag of Patterns for Nearest Neighbour Neonatal EEG Recall.

Clinical neurophysiologists often find it difficult to recall rare EEG patterns despite the fact that this information could be diagnostic and help with treatment intervention. Traditional search methods may take time to retrieve the archived EEGs that could provide the meaning or cause of the specific pattern, which is undesirable as time can be critical for sick neonates. If neurophysiologists had the ability to quickly recall similar patterns, the prior occurrence of the pattern may help make an earlier diagnosis. This paper presents a system that may be used to assist a clinical neurophysiologist in the recall of neonatal EEG patterns. This paper compares two brute force approaches for the task of neonatal EEG recall and looks at the performance accuracy, speed and memory requirements. This system was tested on six different neonatal EEG pattern types with 430 events in total and the results are presented in this paper.

An Approximate Nearest Neighbour System For Neonatal EEG Recall.

Clinical neurophysiologists often find it difficult to recall rare EEG patterns despite the fact that this information could be diagnostic and help with treatment intervention. Traditional search methods may take time to retrieve the archived EEGs that could provide the meaning or cause of the specific pattern which is not acceptable as time can be critical for sick neonates. If neurophysiologists had the ability to quickly recall similar patterns, the prior occurrence of the pattern may help make an earlier diagnosis. This paper presents a system that may be used to assist a clinical neurophysiologist in the recall of neonatal EEG patterns. The proposed system consists of an alignment technique followed by an approximate nearest neighbour search algorithm called locality sensitive hashing. The system was tested on six different neonatal EEG pattern types with 430 events in total and the results are presented in this paper.

Continuous Uptake or Saturation-Investigation of Concentration and Surface-Packing-Specific Hemin Interaction with Lipid Membranes.

Drug design and targeted delivery in cells serve as a flourishing area not only for scientific inquiry, owing to numerous clinical applications, but also for understanding cell interaction with exogenous materials. The membrane localization of heme and its analog hemin, one of the most biologically relevant planar organic molecule, is very important to understand the molecular mechanism of intercalation and adsorption of this cytotoxic molecule after its dissociation from proteins such as hemoglobin. Herein, we investigate the differential behavior of hemin on the soft membrane surfaces of phospholipids by synchrotron-based X-ray scattering techniques, Langmuir monolayer measurements, and molecular dynamics simulation. A continuous hemin uptake from the subphase and intercalation into and/or adsorption on to the membrane surface have been witnessed in a strong membrane surface packing-specific manner. Competitive interactions between hemin-membrane and hemin-hemin are proposed to be responsible for the critical hemin concentration. Up to the limit, a continuous hemin uptake is possible and beyond that the hemin-hemin interaction dominates, effectively reducing the hemin intercalation into the membrane. This structural model of the hemin-uptake process can be generalized to understand the localization and transport across membranes and also for the development and design of new drugs.

Platinum(iv) oxaliplatin-peptide conjugates targeting memHsp70+ phenotype in colorectal cancer cells.

Novel Pt(iv) tumour penetrating peptide (TPP) conjugates are reported. They are the first example of metallodrugs to target a membrane bound heat shock protein 70 positive (memHSP70+) phenotype in cancer cells. The conjugates exhibit superior cytotoxicity as compared to oxaliplatin alone in Pt resistant colorectal cancer cells with relatively high memHSP70+ expression. Substitution of TPP in Pt(iv) peptide conjugates with scrambled peptide (ScP) essentially abolishes the observed cytotoxicity.

Photoinduced Enhancement of the Charge Density Wave Amplitude.

Symmetry breaking and the emergence of order is one of the most fascinating phenomena in condensed matter physics. It leads to a plethora of intriguing ground states found in antiferromagnets, Mott insulators, superconductors, and density-wave systems. Exploiting states of matter far from equilibrium can provide even more striking routes to symmetry-lowered, ordered states. Here, we demonstrate for the case of elemental chromium that moderate ultrafast photoexcitation can transiently enhance the charge-density-wave (CDW) amplitude by up to 30% above its equilibrium value, while strong excitations lead to an oscillating, large-amplitude CDW state that persists above the equilibrium transition temperature. Both effects result from dynamic electron-phonon interactions, providing an efficient mechanism to selectively transform a broad excitation of the electronic order into a well-defined, long-lived coherent lattice vibration. This mechanism may be exploited to transiently enhance order parameters in other systems with coupled degrees of freedom.

The Atomic scale structure of liquid metal-electrolyte interfaces.

Electrochemical interfaces between immiscible liquids have lately received renewed interest, both for gaining fundamental insight as well as for applications in nanomaterial synthesis. In this feature article we demonstrate that the atomic scale structure of these previously inaccessible interfaces nowadays can be explored by in situ synchrotron based X-ray scattering techniques. Exemplary studies of a prototypical electrochemical system - a liquid mercury electrode in pure NaCl solution - reveal that the liquid metal is terminated by a well-defined atomic layer. This layering decays on length scales of 0.5 nm into the Hg bulk and displays a potential and temperature dependent behaviour that can be explained by electrocapillary effects and contributions of the electronic charge distribution on the electrode. In similar studies of nanomaterial growth, performed for the electrochemical deposition of PbFBr, a complex nucleation and growth behaviour is found, involving a crystalline precursor layer prior to the 3D crystal growth. Operando X-ray scattering measurements provide detailed data on the processes of nanoscale film formation.

Application of audio fingerprinting to neonatal EEG.

A clinical neurophysiologist must recognize patterns in EEG signals to evaluate the health of a patient's brain activity. Rare or unusual patterns may take time to correctly identify. The ability to automatically assist this recall would be beneficial in ensuring that appropriate measures could be taken in a timely fashion. Audio fingerprinting is a method used to identify songs using only a snippet of the song. Fingerprints are extracted from a sub-section of the song and matched against a database of previously computed fingerprints. In this paper, a fingerprint quantization technique is implemented on neonatal EEG data to attempt to identify sections of EEG data when only seeing a sub-section of the data. The impact of signal distortions is investigated and results from a database of one hour recordings from 40 newborns are presented.

Stream computing for biomedical signal processing: A QRS complex detection case-study.

Recent developments in "Big Data" have brought significant gains in the ability to process large amounts of data on commodity server hardware. Stream computing is a relatively new paradigm in this area, addressing the need to process data in real time with very low latency. While this approach has been developed for dealing with large scale data from the world of business, security and finance, there is a natural overlap with clinical needs for physiological signal processing. In this work we present a case study of streams processing applied to a typical physiological signal processing problem: QRS detection from ECG data.

Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis.

Glioblastoma (GBM) is the most aggressive form of primary brain tumour, with dismal patient outcome. Treatment failure is associated with intrinsic or acquired apoptosis resistance and the presence of a highly tumourigenic subpopulation of cancer cells called GBM stem cells. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) has emerged as a promising novel therapy for some treatment-resistant tumours but unfortunately GBM can be completely resistant to TRAIL monotherapy. In this study, we identified Mcl-1, an anti-apoptotic Bcl-2 family member, as a critical player involved in determining the sensitivity of GBM to TRAIL-induced apoptosis. Effective targeting of Mcl-1 in TRAIL resistant GBM cells, either by gene silencing technology or by treatment with R-roscovitine, a cyclin-dependent kinase inhibitor that targets Mcl-1, was demonstrated to augment sensitivity to TRAIL, both within GBM cells grown as monolayers and in a 3D tumour model. Finally, we highlight that two separate pathways are activated during the apoptotic death of GBM cells treated with a combination of TRAIL and R-roscovitine, one which leads to caspase-8 and caspase-3 activation and a second pathway, involving a Mcl-1:Noxa axis. In conclusion, our study demonstrates that R-roscovitine in combination with TRAIL presents a promising novel strategy to trigger cell death pathways in glioblastoma.

Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. GBM cells are highly resistant to apoptosis induced by antitumor drugs and radiotherapy resulting in cancer progression. We assessed whether a systems medicine approach, analysing the ability of tumor cells to execute apoptosis could be utilized to predict the response of GBM patients to treatment. Concentrations of the key proapoptotic proteins procaspase-3, procaspase-9, Smac and Apaf-1 and the antiapopotic protein XIAP were determined in a panel of GBM cell lines and GBM patient tumor resections. These values were used as input for APOPTO-CELL, a systems biological based mathematical model built to predict cellular susceptibility to undergo caspase activation. The modeling was capable of accurately distinguishing between GBM cells that die or survive in response to treatment with temozolomide in 10 of the 11 lines analysed. Importantly the results obtained using GBM patient samples show that APOPTO-CELL was capable of stratifying patients according to their progression-free survival times and predicted the ability of tumor cells to support caspase activation in 16 of the 21 GBM patients analysed. Calculating the susceptibility to apoptosis execution may be a potent tool in predicting GBM patient therapy responsiveness and may allow for the use of APOPTO-CELL in a clinical setting.

Targeting the anti-apoptotic Bcl-2 family members for the treatment of cancer.

Most cells express a variety of both anti-apoptotic and pro-apoptotic Bcl-2 proteins and the interaction within this family dictates whether a cell survives or dies. The dysregulation of the anti-anti-apoptotic Bcl-2 family members is one of the defining features of cancer cells in comparison to normal cells, and significantly contributes to the resistance of cancer cells to current treatment modalities. This anti-apoptotic subfamily of proteins is now a major target in the development of new methods to improve treatment outcomes for cancer patients. Several drugs directed at inhibiting Bcl-2 and related anti-apoptotic proteins have been developed with some showing considerable promise in the clinic. This Review presents the current knowledge of the role of the anti-apoptotic Bcl-2 family in cancer cells, as well as current and future perspectives on targeting this subfamily of proteins for therapeutic intervention in human malignancies. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

The high-resolution diffraction beamline P08 at PETRA III.

The new third-generation synchrotron radiation source PETRA III located at the Deutsches Elektronen-Synchrotron DESY in Hamburg, Germany, has been operational since the second half of 2009. PETRA III is designed to deliver hard X-ray beams with very high brilliance. As one of the first beamlines of PETRA III the high-resolution diffraction beamline P08 is fully operational. P08 is specialized in X-ray scattering and diffraction experiments on solids and liquids where extreme high resolution in reciprocal space is required. The resolving power results in the high-quality PETRA III beam and unique optical elements such as a large-offset monochromator and beryllium lens changers. A high-precision six-circle diffractometer for solid samples and a specially designed liquid diffractometer are installed in the experimental hutch. Regular users have been accepted since summer 2010.

Comment on "30,000-year-old wild flax fibers".

Kvavadze et al. (Brevia, 11 September 2009, p. 1359) identified fiber samples as 30,000-year-old flax based on a comparison with modern flax fibers analyzed by compound microscope and on the presence of dislocations/nodes in the fibers. We argue that this evidence is not sufficient to identify the fibers as flax.

Surface layering at the mercury-electrolyte interface.

X-ray reflectometry reveals atomic layering at a liquid-liquid interface--mercury in a 0.01 M NaF solution. The interface width exceeds capillary wave theory predictions and displays an anomalous dependence on the voltage applied across it, displaying a minimum positive of the potential of zero charge. The latter is explained by electrocapillary effects and an additional intrinsic broadening of the interface profile, tentatively assigned to polarization of the conduction electrons due to the electric field of the electrochemical double layer at the interface.

Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus.

Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3-only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed that expression of the BH3-only protein, Bcl-2 interacting mediator of cell death (Bim), increased in the rat hippocampus but not in the neocortex after focal-onset status epilepticus. In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and posttranslational activation of Bim, such as CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Upregulation of bim mRNA was evident after 2 h and Bim protein increased between 4 and 24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared with wild-type animals after seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death after KA treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim-deficient mice was comparable with that in wild-type animals. These results show region-specific differential contributions of Bim to seizure-induced neuronal death.

Apoptosis induced by proteasome inhibition in cancer cells: predominant role of the p53/PUMA pathway.

The proteasome has emerged as a novel target for antineoplastic treatment of hematological malignancies and solid tumors, including those of the central nervous system. To identify cell death pathways activated in response to inhibition of the proteasome system in cancer cells, we treated human SH-SY5Y neuroblastoma cells with the selective proteasome inhibitor (PI) epoxomicin (Epoxo). Prolonged exposure to Epoxo was associated with increased levels of poly-ubiquitinylated proteins and p53, release of cytochrome c from the mitochondria, and activation of caspases. Analysis of global gene expression using high-density oligonucleotide microarrays revealed that Epoxo triggered transcriptional activation of the two Bcl-2-homology domain-3-only (BH3-only) genes p53 upregulated modulator of apoptosis (PUMA) and Bim. Subsequent studies in PUMA- and Bim-deficient cells indicated that Epoxo-induced caspase activation and apoptosis was predominantly PUMA-dependent. Further characterization of the transcriptional response to Epoxo in HCT116 human colon cancer cells demonstrated that PUMA induction was p53-dependent; with deficiency in either p53 or PUMA significantly protected HCT116 cells against Epoxo-induced apoptosis. Our data suggest that p53 activation and the transcriptional induction of its target gene PUMA play an important role in the sensitivity of cancer cells to apoptosis induced by proteasome inhibition, and imply that antineoplastic therapies with PIs might be especially useful in cancers with functional p53.

Phonon modes at the 2H-NbSe2 surface observed by grazing incidence inelastic x-ray scattering.

We have determined the dispersion of acoustic and optical surface phonon modes 2H-NbSe2 at the by inelastic x-ray scattering under grazing incidence conditions. Already, at room temperature, an anomaly is observed close to the charge density wave -vector position located at about one-third along the Gamma-M direction of the Brillouin zone. Our results indicate that the anomaly for the surface mode occurs at a lower energy than that measured in bulk sensitive geometry in the same experiment, showing evidence of a modified behavior in the uppermost layers. We demonstrate that inelastic x-ray scattering in grazing incidence conditions provides a unique tool to selectively study either surface or bulk lattice dynamics in a single experiment.

Clinical similarities in siblings with schizophrenia.

Three symptom groups, identified by factor analysis of schizophrenic symptoms, together with other clinical variables, were compared among 80 sibships (169 individuals) containing two or more members affected with schizophrenia. The three factors, which were labelled negative symptom disorganization, and reality distortion, all showed a moderate but significant degree of correlation between siblings. Age at onset was also significantly correlated. Such a familial pattern of clinical heterogeneity suggests underlying common familial aetiologies that influence the clinical form of the disorder. Whether these are genetic or environmental requires further investigation. This finding confers some external validation on the three factor model. It may be feasible to develop familial symptom patterns as the basis for an a priori approach to linkage heterogeneity.

Pathways to suicide prevention.

Society places a responsibility on the medical profession for the prevention of suicide. In this article, current trends in suicide, social prevention strategies and the role and limitations of medical intervention are reviewed.