Characterization Of The Effect Of Braf Inhibitors On Melanoma Metabolism In Vitro And In Vivo

Vemurafenib is the first FDA-approved personalized treatment for metastatic melanoma to show an improvement in survival. This serine threonine kinase inhibitor targets the mutated BRAF V600E protein, which occurs in approximately 50% of melanomas. The downstream effect of BRAF V600E blockade is inhibition of cell proliferation. Little is known about the effect of vemurafenib on glucose metabolism in melanoma cells. The Warburg effect, or the use aerobic glycolysis to generate energy and building blocks for cell proliferation, is a hallmark of cancer. Normal cells, in contrast, metabolize glucose through oxidative phosphorylation in the presence of oxygen and through glycolysis in anaerobic environments. Vemurafenib decreases glucose uptake in sensitive human melanoma cell lines but not in intrinsically resistant lines or lines that have been passaged to become resistant. The Braf/Pten mouse model of melanoma shows no major decrease in glucose uptake with treatment with PLX4720, an analog of vemurafenib, of up to 28 days perhaps because PTEN deletion removes the negative feedback on the PI3K/mTOR pathway of cell metabolism. The decrease in uptake seen in vitro is associated with a decrease in hexokinase (HK) activity, which is required for entrapment of glucose as glucose-6-phosphate inside the cell, but not with significant changes in mRNA levels of glucose transporters or hexokinases (GLUT1, GLUT2, GLUT3, HK1, or HK2). The global effect of vemurafenib on glucose metabolism is decreased flux through glycolysis as shown by decreased lactate levels. These observations indicate vemurafenib targets the deregulated metabolism of human melanoma cells. This finding may lead to the discovery and development of novel therapeutics that specifically target the abnormal metabolism of cancer cells

VALIDATION OF A BIOANALYTICAL REVERSE-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD FOR THE QUANTITATION OF NYSTATIN IN AN ANIMAL MODEL AFTER INTRANASAL IN SITU GEL ADMINISTRATION

Objective: The aim of the study was to develop and validate a bioanalytical reverse-phase high-performance liquid chromatographic (HPLC) method for the estimation of nystatin in rat plasma after intranasal administration. Methods: The reversed-phase HPLC system was equipped with a Luna C18 column, the mobile system comprised of methanol, water, and dimethylformamide (55:30:15) and the flow rate was set at 0.9 ml/min. Results: The elution time for nystatin was 4.096±0.025 min. The calibration curves constructed in rat plasma were linear from 0.25 to 50 μg/ml. The lower limit of quantification (LOQ) was found to be 0.25 μg/ml. The standards for accuracy and precision of the intra- and inter-day variation studies were in the acceptable ranges as per the FDA guidelines. Conclusion: The LOQ value determined by the proposed method was noted to be satisfactory for inspecting the plasma pharmacokinetics of nystatin in rats’ post-administration of a nasal in situ gelling liquid crystalline precursor formulation in an in vivo study

ANALISIS KINERJA KEUANGAN PERUSAHAAN DITINJAU DARI RASIO LIKUIDITAS DAN RASIO PROFITABILITAS PADA PT GUDANG GARAM Tbk PERIODE 2009-2013

Untuk mengetahui kesehatan suatu perusahan selayaknya apabila suatu perusahaan dilakukan pengukuran ataupun penilaian kinerja perusahaan tersebut. Kinerja adalah prestasi yang dicapai oleh perusahaan dalam periode tertentu yang mencerminkan tingkat kesehatan perusahaan. Tujuannya adalah menemukan kelemahan di dalam kinerja perusahaan yang dapat menyebabkan masalah pada perusahaan tersebut. Demikian juga dengan PT Gudang Garam Tbk yang merupakan sebuah perusahaan yang tentunya selalu ingin mengetahui tingkat kesehatan usahanya dari tahun ke tahun, yaitu dengan cara menilai kinerja manajemen perusahaannya. PT Gudang Garam Tbk tentunya membutuhkan pengelolaan manajemen yang baik tentang permodalan, persediaan barang dan laba yang akan diperoleh. Sehingga perusahaan dapat terhindar dari adanya kekurangan aktiva lancar yang akan digunakan untuk melunasi hutang lancar. Serta perusahaan mampu menjalankan kegiatan operasionalnya dengan lebih efisien sehingga tujuan yang telah ditetapkan dapat tercapai. Penelitian ini merupakan penelitian kualitatif dengan pendekatan deskriptif yang dilakukan dengan menggunakan perhitungan terhadap data-data kuantitatif yang berupa laporan keuangan. Laporan keuangan tersebut merupakan data sekunder yang diperoleh dari www.gudanggaramtbk.com. Sedangkan alat analisis yang digunakan dalam penelitian ini adalah dengan menggunakan analisis rasio keuangan yang meliputi rasio likuiditas dan rasio profitabilitas dengan metode time series analysis. Secara umum dari hasil analisis tersebut menunjukkan bahwa kondisi keuangan PT Gudang Garam Tbk berfluktuasi namun secara keseluruhan dinilai baik. Rasio lancar rata-rata selama periode 5 tahun memiliki nilai 246 %. Angka ini dinilai baik karena berada diatas parameter nilai rasio lancar yang baik yaitu 200 %. Rasio cepat menunjukkan angka 34,31 %, angka ini dinilai kurang baik karena berada dibawah 100 % yang menjadi parameter rasio cepat yang baik. Untuk nilai ROE juga menunjukkan nilai yang baik karena memiliki nilai sebesar 17,64 %. Angka ini dinilai baik karena berada diatas bunga bank yang berkisar 8 % hingga 12 % per tahun. Nilai ROA juga dinilai baik, berada pada nilai 11,38 %, angka ini jauh diatas parameter nilai ROA yang baik yaitu > 2. Kata Kunci : Rasio Likuiditas, Rasio Profitabilitas, Kinerja Keuanga

Planeamiento estratégico del sistema económico financiero de la Marina de Guerra del Perú

La presente tesis desarrolla el Plan Estratégico del Sistema Económico Financiero de la Marina de Guerra del Perú y tiene como objetivo primordial establecer las estrategias que aseguren la eficaz, óptima, oportuna y eficiente utilización y articulación del presupuesto económico asignado y de los fondos económicos generados por esta, para satisfacer los requerimientos operativos y necesidades para su funcionamiento administrativo. La metodología empleada se basó en entrevistas con expertos profesionales del área economía y financiera de la institución y la revisión bibliográfica asociada con el tema en mención. En este documento se analizan los entornos interno y externo, asociados al Sistema Económico Financiero desde donde se deducen las fortalezas, oportunidades, debilidades y amenazas. Al analizar estos entornos se plantean las estrategias necesarias para el cumplimiento de la visión planteada, las cuales proponen el reto de incrementar el presupuesto mejorando la productividad de los recursos directamente recaudados, generar proyectos de inversión pública aprovechando la coyuntura política favorable, suscribir convenios con organismos de interés con el fin de generar recursos y beneficios por reciprocidad, actualizar la plataforma informática y capacitar al personal que pertenece al sistema. El reto es hacer al Sistema Económico Financiero más eficiente en la utilización de los recursos económicos asignados para satisfacer la demanda institucional.The present thesis explains the Strategic Plan of the Economic and Financial System of the Peruvian Navy which main objective is to establish strategies that ensure the effective, optimal, appropriate and efficient use and coordination of the assigned economic budget and the economic funds generated by the same in order to satisfy the operating requirements and needs for its administrative procedure. The methodology used was based on interviews carried out among professional experts in economy and finance of this institution and bibliographic review associated to the mentioned subject. This document analyzes the internal and external environments related to the Economic and Financial System where the strengths, weaknesses, opportunities and threats (SWOT) are inferred. Required strategies are suggested when analyzing these environments in order to fulfill the proposed vision, these strategies set out the task of increasing the budget improving the productivity of the directly raised resources, generate projects of public investment taking advantage of the favorable politics situation, celebrate agreements with organisms of interest in order to generate resources and benefits by reciprocity, update the IT platform and train the personnel who belongs to the system. The task is to make the Economic and Financial System more efficient when using the economic resources assigned to satisfy the institutional demand.Tesi

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma

Catalytic hydrogenation of benzene and toluene

The reaction takes Place in liquid phase in a batch reactor, at temperature between 393 K and 433 K. Partial hydrogen pressure is varied between 1.1 MPa and 3.0 MPa. Catalytic activity is expressed in mol of aromatic compund which react per gram of catalyst and per second. The general mechanism proposed for this kind of reaction assumes that there is no competitive adsorption between the aromatic compound and hydrogen. Reaction occurs between two molecules that are absorbed on two different sites. The kinetic model which describes the hydrogenation process of aromatic compounds in liquid phase is the following:   Activation energy and adsorption heat increase with the increase of the number of substituents, and with length of the chain in the benzene ring, while reaction velocity decreases.&nbsp