A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis.

The design of molecular catalysts typically involves reconciling multiple conflicting property requirements, largely relying on human intuition and local structural searches. However, the vast number of potential catalysts requires pruning of the candidate space by efficient property prediction with quantitative structure-property relationships. Data-driven workflows embedded in a library of potential catalysts can be used to build predictive models for catalyst performance and serve as a blueprint for novel catalyst designs. Herein we introduce kraken, a discovery platform covering monodentate organophosphorus(III) ligands providing comprehensive physicochemical descriptors based on representative conformer ensembles. Using quantum-mechanical methods, we calculated descriptors for 1558 ligands, including commercially available examples, and trained machine learning models to predict properties of over 300000 new ligands. We demonstrate the application of kraken to systematically explore the property space of organophosphorus ligands and how existing data sets in catalysis can be used to accelerate ligand selection during reaction optimization.

Data-Driven Strategies for Accelerated Materials Design.

The ongoing revolution of the natural sciences by the advent of machine learning and artificial intelligence sparked significant interest in the material science community in recent years. The intrinsically high dimensionality of the space of realizable materials makes traditional approaches ineffective for large-scale explorations. Modern data science and machine learning tools developed for increasingly complicated problems are an attractive alternative. An imminent climate catastrophe calls for a clean energy transformation by overhauling current technologies within only several years of possible action available. Tackling this crisis requires the development of new materials at an unprecedented pace and scale. For example, organic photovoltaics have the potential to replace existing silicon-based materials to a large extent and open up new fields of application. In recent years, organic light-emitting diodes have emerged as state-of-the-art technology for digital screens and portable devices and are enabling new applications with flexible displays. Reticular frameworks allow the atom-precise synthesis of nanomaterials and promise to revolutionize the field by the potential to realize multifunctional nanoparticles with applications from gas storage, gas separation, and electrochemical energy storage to nanomedicine. In the recent decade, significant advances in all these fields have been facilitated by the comprehensive application of simulation and machine learning for property prediction, property optimization, and chemical space exploration enabled by considerable advances in computing power and algorithmic efficiency.In this Account, we review the most recent contributions of our group in this thriving field of machine learning for material science. We start with a summary of the most important material classes our group has been involved in, focusing on small molecules as organic electronic materials and crystalline materials. Specifically, we highlight the data-driven approaches we employed to speed up discovery and derive material design strategies. Subsequently, our focus lies on the data-driven methodologies our group has developed and employed, elaborating on high-throughput virtual screening, inverse molecular design, Bayesian optimization, and supervised learning. We discuss the general ideas, their working principles, and their use cases with examples of successful implementations in data-driven material discovery and design efforts. Furthermore, we elaborate on potential pitfalls and remaining challenges of these methods. Finally, we provide a brief outlook for the field as we foresee increasing adaptation and implementation of large scale data-driven approaches in material discovery and design campaigns.

Consensus statement from the international consensus meeting on post-traumatic cranioplasty.

BACKGROUND: Due to the lack of high-quality evidence which has hindered the development of evidence-based guidelines, there is a need to provide general guidance on cranioplasty (CP) following traumatic brain injury (TBI), as well as identify areas of ongoing uncertainty via a consensus-based approach. METHODS: The international consensus meeting on post-traumatic CP was held during the International Conference on Recent Advances in Neurotraumatology (ICRAN), in Naples, Italy, in June 2018. This meeting was endorsed by the Neurotrauma Committee of the World Federation of Neurosurgical Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and several other neurotrauma organizations. Discussions and voting were organized around 5 pre-specified themes: (1) indications and technique, (2) materials, (3) timing, (4) hydrocephalus, and (5) paediatric CP. RESULTS: The participants discussed published evidence on each topic and proposed consensus statements, which were subject to ratification using anonymous real-time voting. Statements required an agreement threshold of more than 70% for inclusion in the final recommendations. CONCLUSIONS: This document is the first set of practical consensus-based clinical recommendations on post-traumatic CP, focusing on timing, materials, complications, and surgical procedures. Future research directions are also presented.

Preserving US microbe collections sparks future discoveries.

Collections of micro-organisms are a crucial element of life science research infrastructure but are vulnerable to loss and damage caused by natural or man-made disasters, the untimely death or retirement of personnel, or the loss of research funding. Preservation of biological collections has risen in priority due to a new appreciation for discoveries linked to preserved specimens, emerging hurdles to international collecting and decreased funding for new collecting. While many historic collections have been lost, several have been preserved, some with dramatic rescue stories. Rescued microbes have been used for discoveries in areas of health, biotechnology and basic life science. Suggestions for long-term planning for microbial stocks are listed, as well as inducements for long-term preservation.

Temporal trends and sources of variation in carbon flux from coarse woody debris in experimental forest canopy openings.

Pulses of respiration from coarse woody debris (CWD) have been observed immediately following canopy disturbances, but it is unclear how long these pulses are sustained. Several factors are known to influence carbon flux rates from CWD, but few studies have evaluated more than temperature and moisture. We experimentally manipulated forest structure in a second-growth northern hardwood forest and measured CO2 flux periodically for seven growing seasons following gap creation. We present an analysis of which factors, including the composition of the wood-decay fungal community influence CO2 flux. CO2 flux from CWD was strongly and positively related to wood temperature and varied significantly between substrate types (logs vs. stumps). For five growing seasons after treatment, the CO2 flux of stumps reached rates up to seven times higher than that of logs. CO2 flux of logs did not differ significantly between canopy-gap and closed-canopy conditions in the fourth through seventh post-treatment growing seasons. By the seventh season, the seasonal carbon flux of both logs and stumps had decreased significantly from prior years. Linear mixed models indicated the variation in the wood inhabiting fungal community composition explained a significant portion of variability in the CO2 flux along with measures of substrate conditions. CO2 flux rates were inversely related to fungal diversity, with logs hosting more species but emitting less CO2 than stumps. Overall, our results suggest that the current treatment of CWD in dynamic forest carbon models may be oversimplified, thereby hampering our ability to predict realistic carbon fluxes associated with wood decomposition.

PDE2-mediated cAMP hydrolysis accelerates cardiac fibroblast to myofibroblast conversion and is antagonized by exogenous activation of cGMP signaling pathways.

Recent studies suggest that the signal molecules cAMP and cGMP have antifibrotic effects by negatively regulating pathways associated with fibroblast to myofibroblast (MyoCF) conversion. The phosphodiesterase 2 (PDE2) has the unique property to be stimulated by cGMP, which leads to a remarkable increase in cAMP hydrolysis and thus mediates a negative cross-talk between both pathways. PDE2 has been recently investigated in cardiomyocytes; here we specifically addressed its role in fibroblast conversion and cardiac fibrosis. PDE2 is abundantly expressed in both neonatal rat cardiac fibroblasts (CFs) and cardiomyocytes. The overexpression of PDE2 in CFs strongly reduced basal and isoprenaline-induced cAMP synthesis, and this decrease was sufficient to induce MyoCF conversion even in the absence of exogenous profibrotic stimuli. Functional stress-strain experiments with fibroblast-derived engineered connective tissue (ECT) demonstrated higher stiffness in ECTs overexpressing PDE2. In regard to cGMP, neither basal nor atrial natriuretic peptide-induced cGMP levels were affected by PDE2, whereas the response to nitric oxide donor sodium nitroprusside was slightly but significantly reduced. Interestingly, despite persistently depressed cAMP levels, both cGMP-elevating stimuli were able to completely prevent the PDE2-induced MyoCF phenotype, arguing for a double-tracked mechanism. In conclusion, PDE2 accelerates CF to MyoCF conversion, which leads to greater stiffness in ECTs. Atrial natriuretic peptide- and sodium nitroprusside-mediated cGMP synthesis completely reverses PDE2-induced fibroblast conversion. Thus PDE2 may augment cardiac remodeling, but this effect can also be overcome by enhanced cGMP. The redundant role of cAMP and cGMP as antifibrotic meditators may be viewed as a protective mechanism in heart failure.

[Deep brain stimulation using simultaneous stereotactic electrode placement: an alternative to conventional functional stereotaxy?]. / Tiefe Hirnstimulation mittels simultaner stereotaktischer Elektrodenplatzierung : Eine Alternative zur konventionellen funktionellen Stereotaxie?

BACKGROUND: Deep brain stimulation (DBS) has become a reliable method in the treatment of movement disorders, e.g. idiopathic Parkinson's disease (IPD) and is technically based on stereotaxy. The Starfix® platform is a new type of stereotactic frame that allows an individualized and patient-optimized therapeutic regimen in IPD. OBJECTIVES: The aim of this study was to retrospectively compare the outcomes of IPD patients who underwent surgery with the use of conventional stereotactic frames (31 patients) to those who underwent implantation of DBS with the use of Starfix® frames (29 patients). MATERIAL AND METHODS: Surgery time, the unified Parkinson's disease rating scale III (UPDRS/III) score, L-dopa and L-dopa equivalent doses (LED) were compared prior to surgery as well as 4 weeks, 12 weeks, 6 months and 1 year postoperatively. RESULTS: The IPD-related symptoms improved significantly in both groups with respect to the UPDRS III score (conventional 69.6% vs. 72.4% Starfix®). After surgery significant reductions of L-dopa and LED were seen in both groups. Inherent advantages of the Starfix® platform included simultaneous positioning of the stimulating electrodes and a significant reduction in surgical time. CONCLUSION: In summary, both stereotactic procedures are reliable and safe procedures for the placement of stimulating electrodes as well as the stimulation effect achieved. The logistical uncoupling of presurgical planning from surgical therapy emphasizes the benefits of the individualized stereotactic procedure.

Polymer Functionalized Nanoparticles in Blue Phase LC: Effect of Particle Shape.

Ethylene oxide oligomers and polymers, free and tethered to gold nanoparticles, were dispersed in blue phase liquid crystals (BPLC). Gold nanospheres (AuNPs) and nanorods (AuNRs) were functionalized with thiolated ethylene oxide ligands with molecular weights ranging from 200 to 5000 g/mol. The BPLC mixture (ΔTBP ~6 °C) was based on the mesogenic acid heterodimers, n-hexylbenzoic acid (6BA) and n-trans-butylcyclohexylcarboxylic acid (4-BCHA) with the chiral dopant (R)-2-octyl 4-[4-(hexyloxy)benzoyloxy]benzoate. The lowest molecular weight oligomer lowered and widened the BP range but adding AuNPs functionalized with the same ligand had little effect. Higher concentrations or molecular weights of the ligands, free or tethered to the AuNPs, completely destabilized the BP. Mini-AuNRs functionalized with the same ligands lowered and widened the BP temperature range with longer mini-AuNRs having a larger effect. In contrast to the AuNPs, the mini-AuNRs with the higher molecular weight ligands widened rather than destabilized the BP, though the lowest MW ligand yielded the largest BP range, (ΔTBP > 13 °C). The different effects on the BP may be due to the AuNPs accumulating at singular defect sites whereas the mini-AuNRs, with diameters smaller than that of the disclination lines, can more efficiently fill in the BP defects.

Intra-tumoural extra-cellular pH: a useful parameter of response to chemotherapy in syngeneic tumour lines.

Reliable surrogate markers of response to anticancer therapy remain a desirable tool for preclinical modelling and clinical practice in oncology. Clinical evaluation is relatively unreliable when attempting to assess rapidly and prospectively the outcome of treatment. Fluxes in released or circulating tumour marker levels are a useful but inconsistent marker of cytotoxic response. Serial measurement of circulating tumour cells appears to have some utility as a surrogate marker, but assay systems are expensive, and many cancers are not associated with the presence of circulating tumour cells. Because tissue breakdown is associated with release of nucleic acids and other cellular products, we reasoned that serial measurement of intra-tumoural pH may correlate with the extent of tumour lysis, and thus with outcomes of cytotoxic chemotherapy. Doxorubicin-sensitive and doxorubicin-resistant sublines of P388 murine monocytic leukaemia in C57BL/6 mice were treated with increasing concentrations of doxorubicin. Tumours were serially measured by conventional bi-dimensional methods and pH was sampled using a bevelled tip electrode. Mean and median pH changes were statistically different in responsive and resistant tumours, and amplitude of change correlated with long-term responses to doxorubicin. Serial sampling of pH in tumour masses may provide a useful surrogate of long-term response to chemotherapy.

RAG mutations in human B cell-negative SCID.

Patients with human severe combined immunodeficiency (SCID) can be divided into those with B lymphocytes (B+ SCID) and those without (B- SCID). Although several genetic causes are known for B+ SCID, the etiology of B- SCID has not been defined. Six of 14 B- SCID patients tested were found to carry a mutation of the recombinase activating gene 1 (RAG-1), RAG-2, or both. This mutation resulted in a functional inability to form antigen receptors through genetic recombination and links a defect in one of the site-specific recombination systems to a human disease.

Lysophosphatidic acid downregulates tissue inhibitor of metalloproteinases, which are negatively involved in lysophosphatidic acid-induced cell invasion.

Ovarian cancer is a highly metastatic disease. Lysophosphatidic acid (LPA) levels are elevated in ascites from ovarian cancer patients, but its potential role in ovarian cancer metastasis has just begun to be revealed. In this work, we show that LPA stimulates invasion of primary ovarian cancer cells, but not ovarian epithelial or borderline ovarian tumor cells, although these benign cells indeed respond to LPA in cell migration. We have found that LPA downregulates tissue inhibitor of metalloproteinases (TIMPs). TIMP2 and TIMP3 play functional role in LPA-induced invasion as negative regulators. G(i) protein, phosphatidylinositol-3 kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), cytosolic phospholipase A(2) and urokinase type plasminogen activator (uPA) are required for LPA-induced cells invasion. TIMP3 may affect two independent downstream targets, vascular endothelial growth factor receptor and p38 MAPK. In vivo, LPA stimulates tumor metastasis in an orthotopic ovarian tumor model, which can be inhibited by a PI3K inhibitor, LY294002. In summary, LPA is likely a key component for promoting ovarian metastasis in vivo. LPA downregulates TIMP3, which may have targets other than metalloproteinases. Our in vivo metastasis mouse model is useful for studying the efficacy of therapeutic regimes of ovarian cancer.

Dynamic infrared thermography (DIRT) for assessment of skin blood perfusion in cranioplasty: a proof of concept for qualitative comparison with the standard indocyanine green video angiography (ICGA).

PURPOSE: Complications in wound healing after neurosurgical operations occur often due to scarred dehiscence with skin blood perfusion disturbance. The standard imaging method for intraoperative skin perfusion assessment is the invasive indocyanine green video angiography (ICGA). The noninvasive dynamic infrared thermography (DIRT) is a promising alternative modality that was evaluated by comparison with ICGA. METHODS: The study was carried out in two parts: (1) investigation of technical conditions for intraoperative use of DIRT for its comparison with ICGA, and (2) visual and quantitative comparison of both modalities in a proof of concept on nine patients. Time-temperature curves in DIRT and time-intensity curves in ICGA for defined regions of interest were analyzed. New perfusion parameters were defined in DIRT and compared with the usual perfusion parameters in ICGA. RESULTS: The visual observation of the image data in DIRT and ICGA showed that operation material, anatomical structures and skin perfusion are represented similarly in both modalities. Although the analysis of the curves and perfusion parameter values showed differences between patients, no complications were observed clinically. These differences were represented in DIRT and ICGA equivalently. CONCLUSIONS: DIRT has shown a great potential for intraoperative use, with several advantages over ICGA. The technique is passive, contactless and noninvasive. The practicability of the intraoperative recording of the same operation field section with ICGA and DIRT has been demonstrated. The promising results of this proof of concept provide a basis for a trial with a larger number of patients.

Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid.

Interferons (IFNs) and retinoids are potent biological response modifiers. By using JAK-STAT pathways, IFNs regulate the expression of genes involved in antiviral, antitumor, and immunomodulatory actions. Retinoids exert their cell growth-regulatory effects via nuclear receptors, which also function as transcription factors. Although these ligands act through distinct mechanisms, several studies have shown that the combination of IFNs and retinoids synergistically inhibits cell growth. We have previously reported that IFN-beta-all-trans-retinoic acid (RA) combination is a more potent growth suppressor of human tumor xenografts in vivo than either agent alone. Furthermore, the IFN-RA combination causes cell death in several tumor cell lines in vitro. However, the molecular basis for these growth-suppressive actions is unknown. It has been suggested that certain gene products, which mediate the antiviral actions of IFNs, are also responsible for the antitumor actions of the IFN-RA combination. However, we did not find a correlation between their activities and cell death. Therefore, we have used an antisense knockout approach to directly identify the gene products that mediate cell death and have isolated several genes associated with retinoid-IFN-induced mortality (GRIM). In this investigation, we characterized one of the GRIM cDNAs, GRIM-12. Sequence analysis suggests that the GRIM-12 product is identical to human thioredoxin reductase (TR). TR is posttranscriptionally induced by the IFN-RA combination in human breast carcinoma cells. Overexpression of GRIM-12 causes a small amount of cell death and further enhances the susceptibility of cells to IFN-RA-induced death. Dominant negative inhibitors directed against TR inhibit its cell death-inducing functions. Interference with TR enzymatic activity led to growth promotion in the presence of the IFN-RA combination. Thus, these studies identify a novel function for TR in cell growth regulation.

Assessment of ventricular reconfiguration after third ventriculostomy: what does shape analysis provide in addition to volumetry?

PURPOSE: From neuroradiologic experience, it is evident that the adaptation of the ventricular system secondary to pathologic processes or surgery is not uniform. To describe changes entirely, one must consider, in particular, information about volume and shape. In this study, we address specifically the information encoded in the change of shape. To exemplify the technique, we used time-series MR imaging examinations of patients with surgically treated chronic or acute occlusive hydrocephalus. METHODS: Preoperative and postoperative MR imaging at different time-steps was performed in 2 patients with occlusive hydrocephalus with a different time course of ventricular enlargement. The third and lateral ventricles were segmented with an automated classification scheme. Ventricular surfaces were binarized, mapped to a spheric coordinate system, and modeled by harmonic-basis functions. This approach allows simplification of the complex shape by stepwise filtering of the details that form the surface. The ventricles can be directly compared on the level of the simplified shape. RESULTS: Although the relative volumetric change was comparable between patients, analysis of shape revealed notable regional differences in the pattern of adaptation. Comparing subacute and chronic hydrocephalus, the analysis reflected fundamental differences in the pattern of ventricular enlargement. CONCLUSION: In addition to the mere volumetric description, this approach identifies regions that re-adjust differently to the altered pressure. The pattern of re-adaptation depends on the time course and history of the hydrocephalus. Furthermore, the different patterns of ventricular adaptation in patients with chronic or subacute hydrocephalus suggest a contiguity with properties of the surrounding parenchymal tissue.

Influence of hydrocortisone on the binding of nitrosoureas to nuclear chromatin subfractions.

The effects of steroid-induced modifications of chromatin structure on the extent and sites of chloroethylnitrosourea binding to chromatin were studied using log-phase HeLa cells. The cells were exposed to 0.1 to 2.0 microM hydrocortisone for 22 hr; this resulted in depressed DNA synthesis while transcriptional activity was stimulated. Hydrocortisone had no effect upon cellular or nuclear uptake of the two nitrosoureas under study, 0.6 mM chlorozotocin or 1-(2-chloroethyl-3-cyclohexyl-1-nitrosourea). Both drugs were found to alkylate transcriptional chromatin preferentially, as demonstrated by DNase II and DNase I digestion. This alkylation was stimulated 2-fold by the same micromolar concentrations of hydrocortisone, 0.1 to 2.0 microM, which stimulated transcription. The extent of nuclear RNA alkylation, determined using RNase T2 as a probe, was found to contribute less than 20% of total chromatin alkylation and was unaffected by steroid pretreatment. Instead, the increased alkylation within these chromatin subfractions was attributed to a steroid-induced alteration of chromatin structure. Electron microscopic examination of HeLa nuclear morphology revealed a hydrocortisone-induced disaggregation of nuclear membrane-associated heterochromatin resulting in a more heterogeneous, less condensed distribution of chromatin. Such data are consistent with a relaxation of the supercoiled chromatin structure, resulting in increased transcription and increased accessibility of potential target sites for nitrosourea alkylation.

Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination.

Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-beta and all-trans retinoic acid combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic approach we have recently identified several Genes associated with Retinoid-IFN induced Mortality (GRIM) that mediate the cell death effect of IFN/RA combination. One of the GRIMs, GRIM-12, was identical to human thioredoxin reductase (TR), an enzyme that controls intracellular redox state. To define the participants of TR mediated death pathway we have examined the role of thioredoxin (Trx), its downstream substrate, and its influence on IFN/RA-induced death regulation. Inhibition of the thioredoxin expression by antisense RNA suppressed cell death. Similarly, a mutant Trx1 lacking the critical cysteine residues blocked cell death. In contrast, overexpression of wildtype thioredoxin augmented cell death. This effect of Trx1 was in part due to its ability to augment cell death via caspase-8. The redox inactive Trx1 mutant inhibits the cell death induced by caspase-8 but not caspase-3. These studies identify a novel mechanism of cell death regulation by IFN/RA combination involving redox enzymes.

Modulation of p53 dependent gene expression and cell death through thioredoxin-thioredoxin reductase by the Interferon-Retinoid combination.

We have shown earlier that the IFN-beta and all-trans retinoic acid (RA) combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic technique we have identified several Genes associated with Retinoid-IFN induced Mortality (GRIM). One of the GRIMs was human thioredoxin reductase (TR), a redox enzyme. Since the overexpressed TR augments IFN/RA stimulated cell death, we explored the mechanisms of TR-mediated death. Here we show that TR augments cell death by upregulating the transcriptional activity of p53 tumor suppressor. This process does not involve a physical increase in levels of p53. Using redox inactive mutants of TR and its substrate, thioredoxin (Trx), we demonstrate that IFN/RA-induced regulation of p53 dependent gene expression requires TR and Trx. In contrast-over-expression of wildtype TR or Trx augment the p53 dependent gene expression in response to IFN/RA treatment. Consistent with these results an increased DNA binding activity of p53 was noted in the presence of TR. These studies identify a novel mechanism of p53 mediated cell death regulation involving redox enzymes.

The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin reductase.

Interferons (IFNs) suppress cell growth by inducing cellular genes. The anti-estrogen tamoxifen (Tam), binds to estrogen receptor and inhibits transcription of estrogen stimulated genes. In cells resistant to IFN-induced growth suppression, IFN/Tam combination causes cell death. We previously reported that the combination of IFN-beta and Tam was a more potent growth suppressor of human tumor xenografts than either agent alone. The IFN/Tam combination acts in a manner similar to the IFN/retinoic acid combination. Using a genetic technique, we have recently identified several genes associated with retinoid-IFN-induced mortality (GRIM). One such gene, GRIM-12, was identical to human thioredoxin reductase (TR). In the present study we have examined whether the IFN/Tam combination also requires GRIM-12 for inducing cell death. We report here that GRIM-12 is necessary for mediating the cell death effects of IFN/Tam, and its expression is induced by IFN/Tam at a post-transcriptional stage. Repression of GRIM-12 levels either by antisense expression or by dominant negative inhibitors caused resistance to IFN/Tam induced death and promoted cell growth. Overexpression of GRIM-12 increased IFN/Tam induced apoptosis. Thus, these studies have identified a critical role for GRIM-12 (TR) in apoptosis.

Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis.

Melanoma cells are relatively resistant to Apo2L/TRAIL (TNF-related apoptosis-inducing ligand). We postulated that resistance might result from higher expression of inhibitors of apoptosis including Bcl-2, FLIP (FLICE-like inhibitory protein) or IAPs such as XIAP (X-linked inhibitor of apoptosis) or survivin. Compared to scrambled or mismatch controls, targeting individual inhibitors with siRNA (si-Bcl-2, si-XIAP, si-FLIP or si-Surv), followed by Apo2L/TRAIL resulted in marked increase in apoptosis in melanoma cells. Compared to Bcl-2 or FLIP, siRNAs against XIAP and survivin were most potent in sensitizing melanoma cells. A similar substantial increase in apoptosis was seen in renal carcinoma cells (SKRC-45, Caki-2), following the inhibition of either XIAP or survivin by siRNAs. Apo2L/TRAIL treatment in IAP-targeted cells resulted in cleavage of Bid, activation of caspase-9 and cleavage of PARP (poly ADP-ribose polymerase). Thus, Apo2L/TRAIL resistance can be overcome by interfering with expression of inhibitors of apoptosis regulating both extrinsic (death receptor) or intrinsic (mitochondrial) pathways of apoptosis in melanoma cells.

Evaluation of intra-operative ultrasound imaging in brain tumor resection: a prospective study.

AIMS: The purpose of our study was to evaluate intra-operative ultrasound (IOUS) as a tool of resection control after brain tumor surgery. In addition, we looked for tumor species suitable for ultrasound representation. METHODS: Using a Siemens Omnia Sonoline Ultrasound, 36 tumors were examined, high-grade gliomas (62%), metastases (22%) and others (16%). We focused on tumor imaging by ultrasound with regard to its reliability of tumor expansion and margins. Evaluation of the images was carried out by correlating the ultrasound-based intra-operative measured tumor volume before and after resection with a pre- and post-operative (within 48 hours) measured volume by MRI. The IOUS measurements were performed by the neurosurgeon and the MRI measurements by the neuroradiologist. Thus, the measurement procedures were blinded. Corresponding to a deviation of the ultrasound volume by 10, 20 and > 20% from the MRI volume, the correlation was ranked good, moderate and poor. For assessing the agreement between these two methods of imaging, the statistical analysis was conducted using a method described by Bland and Altman. RESULTS: High-grade gliomas mostly showed a moderate or poor correlation in comparing IOUS- and MRI-tumor volumetry resulting in incomplete resection. Metastases resulted in a good to moderate correlation with a satisfactory extent of resection. The other tumors had poor images with larger tumor residues. The MRI measured volumes tended to be larger on average; the deviation grew with tumor size . CONCLUSION: The reliability of IOUS depends on tumor type. It is beneficial to use IOUS for the resection of metastases and a few high-grade gliomas. Concerning the volumetric accuracy, the value of IOUS is worse than its value of navigation and resection control.