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Molecular diagnostics of sarcoma subtypes commonly involve the identification of characteristic oncogenic fusions. EWSR1-PATZ1is a rare fusion partnering in sarcoma, with few cases reported in the literature. In the current study, a series of 11 cases of EWSR1-PATZ1fusion positive malignancies are described. EWSR1-PATZ1-related sarcomas occur across a wide age range and have a strong predilection for chest wall primary site. Secondary driver mutations in cell-cycle genes, and in particular CDKN2A(71%), are common in EWSR1-PATZ1sarcomas in this series. In a subset of cases, an extended clinical and histopathological review was performed, as was confirmation and characterization of the fusion breakpoint revealing a novel intronic pseudoexon sequence insertion. Unified by a shared gene fusion, EWSR1-PATZ1sarcomas otherwise appear to exhibit divergent morphology, a polyphenotypic immunoprofile, and variable clinical behavior posing challenges for precise classification.

Photocatalytic water splitting from solar H2generation systems is of great interest as a sustainable fuel and an environmentally benign approach. A photocatalyst should be cost-efficient and highly productive to obtain a green H2fuel. Thus, photocatalytic water splitting is significant for real-world applications. In the present work, we have successfully synthesized MoO3@rGO nanocomposite material with heterojunction as a stable and high-performance photocatalyst for the H2evolution reaction in deionized (DI) water and natural seawater. First, MoO3was prepared through a low-temperature hydrothermal method and composites with graphene oxide (GO) and reduced graphene oxide (rGO) precursors, followed by ultrasonication. rGO was obtained from GO, which is obtained from the spent graphite (anode material) by the modified Hummer’s method. The rGO powder was reduced by an ascorbic acid-reducing agent under microwave irradiation using GO. The nanocomposite materials were characterized using XRD, Raman spectra, XPS, photoluminescence, FE-SEM, HR-TEM, and BET. The photocatalytic water splitting ability of MoO3@rGO was measured under visible light (λ ≥ 420 nm) irradiation with the TEOA sacrificial reagent. The H2generation rate in DI water and natural seawater was found to be 2183.41 and 2294.26 μmol g–1h–1, with an apparent quantum efficiency (AQE) of 5.72 and 5.98%, respectively. Such a high rate of H2generated is ascribed to the novel surface contact between MoO3and the rGO sheet as evident from HR-TEM images, wherein the rGO sheet is seen wrapped around MoO3. Consequently, the synergistic effect between MoO3and rGO sheets is expected without the use of any other cocatalysts. Thus, electron–hole recombination is significantly minimized during the water reduction reaction. We believe that the MoO3@rGO nanocomposite is a potential photocatalyst for energy production.

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More than 20% of the Amazon rainforest has been cleared in the past three decades, triggering important hydroclimatic changes. Small-scale (a few kilometres) deforestation in the 1980s has caused thermally triggered atmospheric circulations that increase regional cloudiness and precipitation frequency. However, these circulations are predicted to diminish as deforestation increases. Here we use multi-decadal satellite records and numerical model simulations to show a regime shift in the regional hydroclimate accompanying increasing deforestation in Rondônia, Brazil. Compared with the 1980s, present-day deforested areas in downwind western Rondônia are found to be wetter than upwind eastern deforested areas during the local dry season. The resultant precipitation change in the two regions is approximately ±25% of the deforested area mean. Meso-resolution simulations robustly reproduce this transition when forced with increasing deforestation alone, showing that large-scale climate variability plays a negligible role. Furthermore, deforestation-induced surface roughness reduction is found to play an essential role in the present-day dry-season hydroclimate. Our study illustrates the strong scale sensitivity of the climatic response to Amazonian deforestation and suggests that deforestation is sufficiently advanced to have caused a shift from a thermally to a dynamically driven hydroclimatic regime.

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A tripodal system for anchoring photochromic dithienylethenes on gold surfaces is reported. The self-assembled monolayers of a tripod-functionalized dithienylethene were characterized by cyclic voltammetry, surface-enhanced Raman spectroscopy (SERS), and X-ray photoelectron spectroscopy (XPS). These data are compared with solution studies, solid state Raman spectroscopy, and density functional theory (DFT) calculations. We show that the tripod-functionalized dithienylethene forms stable monolayers on gold in which all three legs of the tripod are adsorbed via the thiol units, thus providing a fixed position and orientation of the dithienylethene moiety with respect to the surface. Importantly, immobilization in this way allows for retention of both the photochemical and electrochemical functionality of the dithienylethene unit and reduces photochemical fatigue observed in solution.

Danger-associated molecular patterns (DAMPs) are nuclear or cytoplasmic proteins that are released from the injured tissues and activate the innate immune system. Mitochondrial DNA (mtDNA) is a novel DAMP that is released into the extracellular milieu subsequent to cell death and injury. We hypothesized that cell death within the central nervous system in children with traumatic brain injury (TBI) would lead to the release of mtDNA into the cerebrospinal fluid (CSF) and has the potential to predict the outcome after trauma. Cerebrospinal fluid was collected from children with severe TBI who required intracranial pressure monitoring with Glasgow Coma Scale (GCS) scores of 8 or less via an externalized ventricular drain. Control CSF was obtained in children without TBI or meningoencephalitis who demonstrated no leukocytes in the diagnostic lumbar puncture. The median age for patients with TBI was 6.3 years, and 62 were male. The common mechanisms of injury included motor vehicle collision (35.8), followed by falls (21.5) and inflicted TBI (19); six children (14.2) died during their intensive care unit course. The mean CSF mtDNA concentration was 1.10E05 ± 2.07E05 and 1.63E03 ± 1.80E03 copiesL in the pediatric TBI and control populations, respectively. Furthermore, the mean CSF mtDNA concentration in pediatric patients who later died or had severe disability was significantly higher than that of the survivors (1.63E05 ± 2.77E05 vs. 5.05E04 ± 6.21E04 copiesL) (P< 0.0001). We found a significant correlation between CSF mtDNA and high mobility group box 1, another prototypical DAMP, concentrations (= 0.574, P< 0.05), supporting the notion that both DAMPs are increased in the CSF after TBI. Our data suggest that CSF mtDNA is a novel DAMP in TBI and appears to be a useful biomarker that correlates with neurological outcome after TBI. Further inquiry into the components of mtDNA that modulate the innate immune response will be helpful in understanding the mechanism of local and systemic inflammation after TBI.

Sorafenib, a tyrosine kinase inhibitor, is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and advanced renal cell carcinoma (RCC). Sorafenib is currently being evaluated in phase II and III trials in various malignancies as a single agent (locally advanced/metastatic radioactive iodine-refractory differentiated thyroid cancer [DTC]), as part of multimodality care (HCC), and in combination with chemotherapies (metastatic breast cancer). Grade 1 and 2 adverse events (AEs) that commonly occur during treatment (ie, dermatologic manifestations, diarrhea, fatigue, and hypertension) should be proactively managed. The goal is to allow patients to remain on their full dose of sorafenib for as long as their treatment is indicated. A combination of early recognition of and intervention for AEs, patient education, and an open dialogue between patients and their multidisciplinary healthcare team, with timely reporting of AEs, will allow for effective management of AEs and minimize the need for sorafenib dose reduction or discontinuation.

A pediatric study has established a maximum tolerated dose (MTD) for temsirolimus (Tem) of more than 150 mgm2intravenouslyweek. A phase I trial was conducted to establish the MTD for Tem in combination with valproic acid (VPA) in children and adolescents with refractory solid tumors. The secondary aims included expression of mammalian target of rapamycin (mTOR) markers on archival tumor tissue; Tem pharmacokinetics; assessment of histone acetylation (HA); and tumor response. Patients were treated with VPA (5 mgkg orally three times daily) with a target serum level of 75–100 mcgml. Tem was started at an initial dose of 60 mgm2week. Pharmacokinetics and HA measurements were performed during weeks 1 and 5. Two of the first three patients experienced dose-limiting toxicity (grade 3 mucositis). Tem at 35 mgm2week was found to be tolerable. Peak Tem concentrations were higher in all patients compared with those in previously published reports of single agent Tem. Increases in HA are correlated with VPA levels. All tumor samples expressed mTORC1 and mTORC2. An objective response was observed in one patient (melanoma), whereas transient stable disease was observed in four other patients (spinal cord ependymoma, alveolar soft part sarcoma, medullary thyroid carcinoma, and hepatocellular carcinoma). The MTD of Tem when administered with VPA is considerably lower than when used as a single agent, with mucositis the major dose-limiting toxicity. The combination merits further study and may have activity in melanoma. Attention to drug–drug interactions will be important in future multiagent trials including Tem.

Plectin 1c (P1c), an intermediate filament-associated cytolinker protein, antagonizes the microtubule (MT)-stabilizing function of MT-associated proteins. Lack of P1c in keratinocytes leads to the stabilization of MTs and alters basic cellular features and functions, including cell shape, polarized migration, metabolism, and mitotic spindle formation.

Atmospheric models usually demand high processing power and generate large amounts of data. As the degree of parallelism grows, the I/O operations may become the major impacting factor of their performance. This work shows that a hybrid MPI/OpenMP implementation can improve the performance of the atmospheric model ocean–land–atmosphere model (OLAM) on a multicore cluster environment. We show that the hybrid MPI/OpenMP version of OLAM decreases the number of output files, resulting in better performance for I/O operations. We have evaluated OLAM on the parallel file system PVFS and shown that storing the files on PVFS results in lower performance than using the local disks of the cluster nodes due as a consequence of file creation and network concurrency. We have also shown that further parallel optimisations should be included in the hybrid version in order to improve the parallel execution time of OLAM.

Photographs of several works of visual artist Sarah Walko are presented.

Determining the correct dosage for the majority of chemotherapeutic agents presents a challenge for clinicians because there is a fine balance between doses that cause significant drug toxicity and loss of efficacy. This Review discusses the current limitations of body surface area-based dosing, provides examples of successful pharmacogenomics investigations that have used drug-metabolizing enzymes to decrease drug toxicity or improve efficacy, and highlights promising advances in pharmacogenomic-directed pharmacotherapy.

Predicting response and limiting drug-induced toxicity are 2 important challenges faced by clinicians in the treatment of colorectal cancer (CRC). The introduction of genetic testing to individualize treatment regimens will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes. This review discusses the role of the predictive genetic tests associated with the major therapeutic agents used in the treatment of CRC and their clinical significance in the determination of patient-specific treatment regimens.

The introduction of dibenzocyclohepten‐5‐ylidene as part of a unidirectional light‐driven molecular motor allows a more complete picture of the pathway of thermal helix inversion to be developed. The most stable conformation is similar to that found in related motors in that it has, overall, an anti‐folded structure with the substituent at the stereogenic centre adopting an axial orientation. Photochemical cis/transisomerisation at −40 °C results in the formation of an isomer in a syn‐folded conformation with the methyl group in an axial orientation. This contrasts with previous studies on related molecular rotary motors. The conformation of the higher energy intermediate typically observed for this class of compound is the anti‐folded conformation, in which the methyl group is in an equatorial orientation. This conformation is available through an energetically uphill upper half ring inversion of the observed photochemical product. However, this pathway competes with a second process that leads to the more stable anti‐folded conformation in which the methyl group is oriented axially. It has been shown that the conformations and pathways available for second‐generation molecular motors can be described by using similar overall geometries. Differences in the metastable high‐energy species are attributable to the relative energy and position on the reaction coordinate of the transition states. Kinetic studies on these new molecular motors thus provide important insights into the conformational dynamics of the rotation cycle.

Objective: To evaluate the safety and efficacy of ixabepilone as a new antimitotic chemotherapeutic agent for the treatment of breast cancer.Data Sources: Data were identified by searches of MEDLINE, PubMed, and American Society of Clinical Oncology abstracts from 1966 to March 2008, using the primary search terms ixabepilone, epothilones, BMS-247550, and breast cancer.Study Selection And Data Extraction: Phase 1, Phase 2, and Phase 3 clinical trials examining the safely and efficacy of ixabepilone and its place in cancer treatment were reviewed. Preference was given to large Phase 2 and 3 clinical trials in the breast cancer population. Manufacturer product information was used to supplement data lacking in published trials.Data Synthesis: Ixabepilone belongs to a novel class of drugs, the epothilones, which are nontaxano microtubule-stabilizing agents. Ixabepilone, in combination with capecitabine, has been approved by the Food and Drug Administration for treatment in patients with metastatic or locally advanced breast cancer that progresses after anthracycline and taxane therapy, or in patients with taxane-resistant cancer with contraindication to further anthracycline therapy. Ixabepilone has also been approved as monotherapy in patients with metastatic and locally advanced breast cancer refractory to taxanes, anthracyclines, and capecitabine. The most common adverse reactions reported by 20% or more of the patients receiving ixabepilone were peripheral sensory neuropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain. The most common hematologic abnormalities seen in more than 40% of the patients include neutropenia, leukopenia, anemia, and thrombocytopenia. Premedication with histamine H1and H2antagonists is recommended to prevent hypersensitivity reactions.Conclusions: Based on the clinical trials reviewed here and the current information available, ixabepilone is a welcome addition to the options available for the treatment of patients with metastatic breast cancer refractory to standard therapy.

Dithienylethene-based molecular switches have been extensively studied in solution and are considered excellent candidates in the design of molecular-based electronic devices. However, for most foreseeable applications they have to be integrated in the solid state, namely as building blocks in bottom-up approaches to prepare functional and addressable surfaces. Here we present a study of the electronic structure and chemical nature of dithienylethene switch thin films on Au(111) by X-ray photoemission spectroscopy, which proves to be a powerful technique to distinguish between the “open” and “closed” forms of the switch and gives information on the interactions between molecules and substrate. We explored the switching behavior of thin films when irradiated with UV and visible light. It is demonstrated that, despite the quenching effect that can be induced by the metal substrate, dithienylethenes can reversibly switch from open to closed form in thin solid films deposited on metal surfaces. We also showed that illumination of the closed form of dithienylethene with visible light induces not only the switching process in molecules isolated from the metal surface but also chemisorption of dithienylethene molecules that are in contact with Au(111). These results provide rationalization of the phenomena that take place while switching dithienylethenes at metal surfaces.

This protocol details the chemical modification of the mechanosensitive channel of large-conductance (MscL) channel protein into a light-activated nanovalve and its utilization for triggered delivery in synthetic liposomal vesicles. It is based on charge-induced activation of this otherwise mechanosensitive channel by covalent attachment to the protein of rationally designed synthetic functionalities. In the dark, these functionalities will be uncharged and the channel will stay closed, but UV illumination will cause their ionization and trigger channel activity. In the case of reversible activation, subsequent illumination with visible light will neutralize the charge, causing the channel to close. The protocol includes synthesis of light-responsive compounds, protein isolation and its chemical labeling, reconstitution of the protein into artificial membranes, its analysis at the single-molecule level and its application in liposomal delivery. The whole protocol takes 4 days. Unlike mutagenesis, this method allows the introduction of custom-designed functional groups.

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The electrochemical and spectroelectrochemical properties of a series of C5‐substituted dithienylhexahydro‐ and dithienylhexafluorocyclopentenes are reported. The effect of substitution at C5 of the thienyl moiety on the redox properties is quite dramatic, in contrast to the effect on their photochemical properties. The efficiency of electrochemical switching is dependent both on the central cyclopentene unit and on the nature of the substituents, whereby electron‐donating moieties favour oxidative electrochemical ring‐closure and vice versa. Asymmetrically substituted dithienylcyclopentenes were investigated to explore the ring‐closure process in more detail. The results indicate that electrochemically induced ring‐closure occurs via the monocation of the open form. In the presence of electroactive groups at C5 of the thienyl ring (e.g., methoxyphenyl) initial oxidation of these groups is followed by intermolecular electron transfer, which drives ring‐closure of the open forms.

The electro‐ and spectroelectrochemical properties of dithienylhexahydro‐ and dithienyhexafluorocyclopentenes are reported. The large effect of variation in the central cyclopentene moieties on the redox properties of the dithienylcyclopentenes is in striking contrast to the minor effect on their photochemical properties. The electronic properties of the oxidised compounds in the +1 and +2 oxidation state are reported, and the possibility of electrochemical cyclisation and cycloreversion were explored by UV/Vis spectroelectrochemistry. The efficiency of electrochemical switching is found to be dependent both on the central cyclopentene unit and on the nature of the substituents at C5 of the thienyl rings. For the hexahydrocyclopentene‐based compounds oxidative ring closure of the ring‐open form is observed, while for the hexafluorocyclopentene‐based compounds oxidative ring opening of the ring‐closed form is observed. However, the introduction of electroactive groups such as methoxyphenyl allows oxidative ring closure to occur in the hexafluoro compounds. The effect of electrolyte, solvent and temperature on the spectroelectrochemical properties were examined, and the switching process was found to be sensitive to the donor properties of the solvent/electrolyte system employed. In addition, thermally activated reversible isomerisation of the dicationic closed form was observed. The driving force for electrochemical ring opening and closure appears to be dependent on the relative stabilisation of the dicationic ring‐open and ring‐closed states. This study provides insight into the factors which determine the direction of cyclisation.

OAS1 is the small form and OAS2 is the medium form of the human interferon‐induced 2′‐5′ oligoadenylate synthetases. The p42 isoform of OAS1 and the p69 isoform of OAS2 have been expressed in insect cells and purified to give pure, highly active 2′‐5′ oligoadenylate synthetase. The catalysis of 2′‐5′ oligoadenylate synthesis is strictly dependent on double‐stranded RNA and magnesium ions. We have examined the effect of a series of divalent metal ions: copper, iron and zinc ions strongly inhibited the enzymatic activity, cobalt and nickel ions were partly inhibitory whereas calcium and manganese ions were without effect. However, manganese ions can replace magnesium ions as activator. The inhibitory effect of zinc ions was characterised in detail. The inhibitory constants of Zn2+were estimated to be 0.10 mM for OAS1p42 and to 0.02 mM for OAS2p69. Cross‐linking experiments showed that zinc ions can control the oligomerisation by enhancing the formation of tetrameric forms of OAS1p42