Gastrointestinal stromal tumors (GISTs): Point mutations matter in management, a review

The therapeutic implications of the genomic alterations seen within the drivers of gastrointestinal stromal tumors (GIST) are among the best understood in all of solid tumors. Sequencing of cKIT and PDGFRα should be considered standard practice for the treatment of GIST patients. In this article, we will review the common mutations and how they are utilized in clinical management. In addition, we will review the rare D842V PDGFRα mutation and the diverse molecular group that lacks a mutation in either cKIT or PDGFRα (wild-type GIST) which are best treated on clinical trial. Finally, we will look forward at the future therapies that are ever evolving for management of GIST. Taken together, the scientific advances in understanding the molecular basis of GIST validates the importance of knowing and understanding the mutations that are present in any one patient

A retrospective analysis of the efficacy of immunotherapy in metastatic soft-tissue sarcomas

Although checkpoint inhibitors have been approved in multiple cancers, they are still under investigation in soft tissue sarcoma (STS). We conducted a retrospective review to report the safety, efficacy, and prognostic factors related to checkpoint inhibitors in STS. A sequential cohort of metastatic STS patients from four institutions treated with checkpoint inhibitors was assembled. Logistic and Cox regression models were applied to determine the effect of patient characteristics, prior treatment, and baseline factors on achieving the best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by the treating physician. Eighty-eight patients with two median prior therapies received checkpoint inhibitors. Treatments included pembrolizumab in 47, nivolumab in 6, ipilimumab in 1, combination ipilimumab/nivolumab in 27, and other combination immunotherapies in 7 patients. Immunotherapy was discontinued in 54 patients-72.2% for progression, 16.7% for toxicity, and 11.1% for other reasons. Median progression-free survival (PFS) was 4.1 months and median overall survival was 19.1 months. One patient with undifferentiated pleomorphic sarcoma (UPS) achieved a CR, while 20 patients had a PR, including 7 UPS, 9 leiomyosarcoma (LMS), and 1 each with alveolar soft part sarcoma, fibroblastic sarcoma, sclerosing epithelioid fibrosarcoma, and myxofibrosarcoma. Forty-five percent (9 of 20) of LMS patients achieved a PR. Twenty-eight patients had SD. Our results confirm the activity and safety of anti-PD-1 therapy in metastatic STS. A notable response rate was observed in UPS and LMS subtypes. This study expands the knowledge base beyond what is currently available from clinical trials involving checkpoint inhibitors in metastatic STS

Aplicação do modelo de precificação de ativo de capital para Companhia Siderúrgica Nacional

O objetivo desta pesquisa é avaliar a relação taxa de retorno x risco das ações d Companhia Siderúrgica Nacional em relação às empresas da amostra, que possuem açõe negociáveis na bolsa e que mais agregam valor para o Produto Interno Bruto do Brasil. pesquisa será descritiva, bibliográfica e documental. A coleta de dados será realizad utilizando diversas publicações relacionadas ao tema em questão e sites da  CV  BOVESPA e do IBGE. A amostra será selecionada através do cálculo de uma próxi do valo agregado das empresas listadas na Bovespa (preferencialmente as ações mai negociadas) obedecendo aos critérios: as somas do valor agregado das empresas do seto serviços deverão compor, por exemplo, 64% da amostra; as empresas do setor industri deverão compor 31% da amostra; as empresas do setor agrícola deverão compor 5% d amostra, percentuais equivalentes ao PIB. Em seguida, serão coletados os valore mensais dos títulos em bolsa do ano de 2006 até o presente mês da amostra e aplicando se o modelo CAPM. Analisar o CAPM das ações da Companhia Siderúrgica Nacional e relação as outras empresas que compõem a amostra concluindo a pesquisa

Single shot cathode transverse momentum imaging in high brightness photoinjectors

In state of the art photoinjector electron sources, thermal emittance from photoemission dominates the final injector emittance. Therefore, low thermal emittance cathode developments and diagnostics are very important. Conventional thermal emittance measurements for the high gradient gun are time-consuming and thus thermal emittance is not measured as frequently as quantum efficiency during the lifetime of photocathodes, although both are important properties for the photoinjector optimizations. In this paper, a single shot measurement of photoemission transverse momentum, i.e., thermal emittance per rms laser spot size, is proposed for photocathode rf guns. By tuning the gun solenoid focusing, the electrons' transverse momenta at the cathode are imaged to a downstream screen, which enables a single shot measurement of both the rms value and the detailed spectra of the photoelectrons' transverse momenta. Both simulations and proof of principle experiments are reported

Empirical comparison of high gradient achievement for different metals in DC and pulsed mode

For the SwissFEL project, an advanced high gradient low emittance gun is under development. Reliable operation with an electric field, preferably above 125 MV/m at a 4 mm gap, in the presence of an UV laser beam, has to be achieved in a diode configuration in order to minimize the emittance dilution due to space charge effects. In the first phase, a DC breakdown test stand was used to test different metals with different preparation methods at voltages up to 100 kV. In addition high gradient stability tests were also carried out over several days in order to prove reliable spark-free operation with a minimum dark current. In the second phase, electrodes with selected materials were installed in the 250 ns FWHM, 500 kV electron gun and tested for high gradient breakdown and for quantum efficiency using an ultra-violet laser.Comment: 25 pages, 13 figures, 5 tables. Follow up from FEL 2008 conference (Geyongju Korea 2008) New Title in JVST A (2010) : Vacuum breakdown limit and quantum efficiency obtained for various technical metals using DC and pulsed voltage source

Suppression subtractive hybridization analysis reveals expression of conserved and novel genes in male accessory glands of the ant Leptothorax gredleri

Background: During mating, insect males eject accessory gland proteins (Acps) into the female genital tract. These substances are known to affect female post-mating behavior and physiology. In addition, they may harm the female, e. g., in reducing its lifespan. This is interpreted as a consequence of sexual antagonistic co-evolution. Whereas sexual conflict abounds in non-social species, the peculiar life history of social insects (ants, bees, wasps) with lifelong pair-bonding and no re-mating aligns the reproductive interests of the sexes. Harming the female during mating would negatively affect male fitness and sexual antagonism is therefore not expected. Indeed, mating appears to increase female longevity in at least one ant species. Acps are presumed to play a role in this phenomenon, but the underlying mechanisms are unknown. In this study, we investigated genes, which are preferentially expressed in male accessory glands of the ant Leptothorax gredleri, to determine which proteins might be transferred in the seminal fluid. Results: By a suppression subtractive hybridization protocol we obtained 20 unique sequences (USs). Twelve had mutual best matches with genes predicted for Apis mellifera and Nasonia vitripennis. Functional information (Gene Ontology) was available only for seven of these, including intracellular signaling, energy-dependent transport and metabolic enzyme activities. The remaining eight USs did not match sequences from other species. Six genes were further analyzed by quantitative RT-PCR in three life cycle stages of male ants. A gene with carboxy-lyase activity and one of unpredicted function were significantly overexpressed in accessory glands of sexually mature males. Conclusions: Our study is the first one to investigate differential gene expression in ants in a context related to mating. Our findings indicate that male accessory glands of L. gredleri express a series of genes that are unique to this species, possibly representing novel genes, in addition to conserved ones for which functions can be predicted. Identifying differentially expressed genes might help to better understand molecular mechanisms involved in reproductive processes in eusocial Hymenoptera. While the novel genes could account for rapidly evolving ones driven by intra-sexual conflict between males, conserved genes imply that rather beneficial traits might get fixed by a process described as inter-sexual cooperation between males and females.Deutsche Forschungsgemeinschaft - DFG[He 1623/19]CAPES/(DAAD) Deutscher Akademischer Austausch Dienst, Germany[261/07]FAPESPDSMA by CNP

Studies on charge production from Cs2Te photocathodes in the PITZ L-band normal conducting radio frequency photo injector

This paper discusses the behavior of electron bunch charge produced in an L-band normal conducting radio frequency cavity (RF gun) from Cs2Te photocathodes illuminated with ps-long UV laser pulses when the laser transverse distribution consists of a flat-top core with Gaussian-like decaying halo. The produced charge shows a linear dependence at low laser pulse energies as expected in the quantum efficiency limited emission regime, while its dependence on laser pulse energy is observed to be much weaker for higher values, due to space charge limited emission. However, direct plug-in of experimental parameters into the space charge tracking code ASTRA yields lower output charge in the space charge limited regime compared to measured values. The rate of increase of the produced charge at high laser pulse energies close to the space charge limited emission regime seems to be proportional to the amount of halo present in the radial laser profile since the charge from the core has saturated already. By utilizing core + halo particle distributions based on measured radial laser profiles, ASTRA simulations and semi-analytical emission models reproduce the behavior of the measured charge for a wide range of RF gun and laser operational parameters within the measurement uncertainties.Comment: 15 pages, 16 figures, 2 table

Commissioning of the SPARC Movable Emittance Meter and Its First Operation at PITZ

For the SPARC Project a novel diagnostic device, called "Emittance-meter", has been conceived and constructed to perform a detailed study of the emittance compensation process in the SPARC photo-injector and to optimize the RF-gun and the accelerator working point. It consists of a movable emittance measurement system, based on the 1D pepper-pot method, installed between two long bellows with the possibility to scan a region 1.2 m long downstream the RF-gun. The construction of the device was completed in the first part of this year and a series of laboratory tests, to evaluate its performances, were carried out in Spring 2005. At the beginning of the summer the complete system was moved to DESY at Zeuthen to be installed on the Photo Injector Test Facility PITZ. After the commissioning it will used for measurements of the PITZ electron beam in the framework of a collaboration between the SPARC and PITZ Projects aiming on studies and operations with photo injectors

Emittance Reduction of RF Photoinjector Generated Electron Beams by Transverse Laser Beam Shaping

Laser pulse shaping is one of the key elements to generate low emittance electron beams with RF photoinjectors. Ultimately high performance can be achieved with ellipsoidal laser pulses, but 3-dimensional shaping is challenging. High beam quality can also be reached by simple transverse pulse shaping, which has demonstrated improved beam emittance compared to a transversely uniform laser in the 'pancake' photoemission regime. In this contribution we present the truncation of a Gaussian laser at a radius of approximately one sigma in the intermediate (electron bunch length directly after emission about the same as radius) photoemission regime with high acceleration gradients (up to 60 MV/m). This type of electron bunch is used e.g. at the European XFEL and FLASH free electron lasers at DESY, Hamburg site and is being investigated in detail at the Photoinjector Test facility at DESY in Zeuthen (PITZ). Here we present ray-tracing simulations and experimental data of a laser beamline upgrade enabling variable transverse truncation. Initial projected emittance measurements taken with help of this setup are shown, as well as supporting beam dynamics simulations. Additional simulations show the potential for substantial reduction of slice emittance at PITZ. © Published under licence by IOP Publishing Ltd