New genetic markers for treatment personalization in pediatric acute lymphoblastic leukemia

La Leucemia Linfoblástica Aguda (LLA) es el cáncer pediátrico más común. Es un desorden de las células linfoblásticas, que son las precursoras de las células linfáticas, y se caracteriza por la acumulación en médula ósea y sangre de pequeñas células blásticas con poco citoplasma y cromatina dispersa. En las últimas décadas, se ha conseguido aumentar la supervivencia del 10% al 80% pero todavía hay un 20% de pacientes que no responden al tratamiento. Esta mejoría se ha conseguido mediante la implantación de terapias combinadas y la adecuación de la terapia a grupos de riesgo. Los pacientes se separan en tres grupos de riesgo, Riesgo Estándar (RE), Alto Riesgo (AR) y Muy Alto Riesgo (MAR), en base a marcadores pronósticos, entre los que se incluyen alteraciones citogenéticas. Sin embargo, a lo largo del tratamiento, nos encontramos con dos problemas:1) Por un lado, algunos de los pacientes incluidos en el grupo de RE y AR no responden bien al tratamiento y pasan AR y MAR respectivamente. Esto quiere decir que los grupos de riesgo no están bien definidos. Por lo tanto, sería de interés poder caracterizar los pacientes que realmente son RE y AR y aquéllos que desde un principio deberían haber sido considerados como de mayor riesgo.2) Por otro lado, un alto porcentaje de pacientes experimenta toxicidad, que puede llegar a ser muy grave en algunos casos, siendo necesario parar el tratamiento. Por este motivo, sería altamente beneficioso poder reconocer a los pacientes que van a ser más sensibles al tratamiento para, de ese modo, poder ajustar la dosis.Por todo esto, creemos que una mejor asignación de los pacientes de LLA a grupos de riesgo y la personalización de la dosis, mediante nuevos marcadores genéticos, permitiría mejorar la respuesta al tratamiento.En este estudio nos planteamos, por lo tanto, dos objetivos: 1) Llevar a cabo la identificación de nuevas alteraciones genéticas presentes en el tumor para una mejor caracterización del riesgo y 2) Realizar una caracterización genética del individuo que permita predecir la respuesta al tratamiento.

Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial

Background The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. Methods A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. Results The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. Conclusions In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation.

Dextran and protamine-based solid lipid nanoparticles as potential vectors for the treatment of X-linked juvenile retinoschisis

This is a copy of an article published in the Human gene therapy © 2012 copyright Mary Ann Liebert, Inc.; Human gene therapy is available online at: http://online.liebertpub.com.

Euler Solution Using Adaptive Cartesian Grid With A Gridless Boundary Treatment

A quadtree-based adaptive Cartesian grid generator and flow solver were developed. The grid adaptation based on pressure or density gradient was performed and a gridless method based on the least-square fashion was used to treat the wall surface boundary condition, which is generally difficult to be handled for the common Cartesian grid. First, to validate the technique of grid adaptation, the benchmarks over a forward-facing step and double Mach reflection were computed. Second, the flows over the NACA 0012 airfoil and a two-element airfoil were calculated to validate the developed gridless method. The computational results indicate the developed method is reasonable for complex flows.

The effects of dietary treatment on the morphometrics and haematological characteristics in Clarias gariepinus

Fingerling of Clarias gariepinus have been reported to have an optimal protein requirement of 40%. Not much is known about the effect that varying this protein level has in the haematological characteristics (i.e packed cell volume, red blood cell count, haemoglobin concentration and mean corpuscular haemoglobin concentration) and on some landmarks measured along the fish's body. The haematological parameter are useful in assessing the effect of dietary treatment on leanness or robustness in the fish. The results of these experiment reveals that of the 17 landmarks measured on the bodies of the fish species fed dietary protein levels of no protein 11% (low protein), 29% (sub optimal) and 40% (optimal), only four of the landmarks show significant difference. Also, analysis of the haematological characteristics show significant difference in haematoant (PCV) and erthroycte count (RBC) in all the treatments

Plasma-Arc Technology For The Thermal Treatment Of Chemical Wastes

Plasma-arc technology was developed to dispose of chemical wastes from a chemical plant by the Institute of Mechanics, Chinese Academy of Sciences (CAS-IMECH). A pilot plant system with this technology was constructed to destroy two types of chemical wastes. The system included shredding, mixing, and feeding subsystems, a plasma-arc reactor of 150 kW, an off-gas burning subsystem, and a scrubbing subsystem. The additives (CaO, SiO2, and Fe) were added into the reactor to form vitrified slag and capture the hazardous elements. The molten slag was quickly quenched to form an amorphous glassy structure. A direct current (DC) experimental facility of 30kW with plasma-arc technology was also set up to study the pyrolysis process in the laboratory, and the experimental results showed the cooling speed is the most important factor for good vitrified structure of the slag. According to previous tests, the destruction and removal efficiency (DRE) for these chemical wastes was more than 99.999%, and the polychlorinated biphenyls (PCBs) concentration in the solid residues was in the range of 1.28 to 12.9mg/kg, which is far below the Chinese national emission limit for the hazardous wastes. A simplified electromagneto model for numerical simulation was developed to predict the temperature and velocity fields. This model can make satisfactory maximum temperature and velocity distributions in the arc region, as well as the results by the magneto hydrodynamic approach.

The formation mechanism of low leaching glassy slag during plasma arc vitrification treatment of fly ash

In this paper, the glass formation theory is applied to study the formation mechanism of the low leaching glassy slag during the process of plasma waste treatment. The research shows that SiO2 acts as network former to form a 3-dimensional Si-O tetrahedral network in which heavy metals are bonded or encapsulated, so the Si-O tetrahedron protect heavy metals against leaching from the vitrified slag or acid corrosion. For given chemical compositions of waste, the formation ability of the vitrified slag can be represented by the ratio of the whole oxygen ions to the whole network former ions in glass (O/Si) which is appropriate in the range of 2~3. A plasma arc reactor is used to conduct the vitrification experiments of two kinds of fly ashes with additives in which effects of various parameters including arc power, cooling speed, treatment temperature are studied. The chemical compositions of fly ashes are analyzed by X-ray fluorescence (XRF) spectrometry. The experimental results show that both cooling speed and O/Si have important influence on the formation of the vitrified slag, which is qualitatively in accordance with the predictions of the glass formation theory.

THE FORMATION MECHANISM OF THE VITRIFIED SLAG IN A PLASMA ARC REACTOR FOR HAZARDOUS WASTE TREATMENT

Various hazardous wastes with additives have been vitrified to investigate the formation mechanism of the glassy slag by a 30 kW DC plasma-arc reactor developed by the Institute of Mechanics, Chinese Academy of Sciences. The average temperature in the reaction area is controlled at 1500°C. The chemical compositions of three sorts of fly ashes are analyzed by XRF (X-Ray Fluorescence). Fly ashes with vitrifying additives can be vitrified to form glassy slag, which show that the ratio of the whole oxygen ions to the whole network former ions in glass (R) is appropriate in the range of 2~3 to form durable vitrified slag. In this experiment, the arc power is controlled below 5 kW to inhibit waste evaporation. To enhance the effects of heat transfer to wastes, ferrous powder has been added into the graphite crucible, which aggregates as ingot below the molten silicate after vitrification. The slag fails to form glass if the quenching rate is less than 1 K/min. Therefore, the slag will break into small chips due to the sharp quenching rate, which is more than 100 K/sec.

A probabilistic treatment of uncertainty in nonlinear dynamical systems

In this work, computationally efficient approximate methods are developed for analyzing uncertain dynamical systems. Uncertainties in both the excitation and the modeling are considered and examples are presented illustrating the accuracy of the proposed approximations.

For nonlinear systems under uncertain excitation, methods are developed to approximate the stationary probability density function and statistical quantities of interest. The methods are based on approximating solutions to the Fokker-Planck equation for the system and differ from traditional methods in which approximate solutions to stochastic differential equations are found. The new methods require little computational effort and examples are presented for which the accuracy of the proposed approximations compare favorably to results obtained by existing methods. The most significant improvements are made in approximating quantities related to the extreme values of the response, such as expected outcrossing rates, which are crucial for evaluating the reliability of the system.

Laplace's method of asymptotic approximation is applied to approximate the probability integrals which arise when analyzing systems with modeling uncertainty. The asymptotic approximation reduces the problem of evaluating a multidimensional integral to solving a minimization problem and the results become asymptotically exact as the uncertainty in the modeling goes to zero. The method is found to provide good approximations for the moments and outcrossing rates for systems with uncertain parameters under stochastic excitation, even when there is a large amount of uncertainty in the parameters. The method is also applied to classical reliability integrals, providing approximations in both the transformed (independently, normally distributed) variables and the original variables. In the transformed variables, the asymptotic approximation yields a very simple formula for approximating the value of SORM integrals. In many cases, it may be computationally expensive to transform the variables, and an approximation is also developed in the original variables. Examples are presented illustrating the accuracy of the approximations and results are compared with existing approximations.

Statistical and econometric analysis of the treatment of HIV/AIDS

The epidemic of HIV/AIDS in the United States is constantly changing and evolving, starting from patient zero to now an estimated 650,000 to 900,000 Americans infected. The nature and course of HIV changed dramatically with the introduction of antiretrovirals. This discourse examines many different facets of HIV from the beginning where there wasn't any treatment for HIV until the present era of highly active antiretroviral therapy (HAART). By utilizing statistical analysis of clinical data, this paper examines where we were, where we are and projections as to where treatment of HIV/AIDS is headed.

Chapter Two describes the datasets that were used for the analyses. The primary database utilized was collected by myself from an outpatient HIV clinic. The data included dates from 1984 until the present. The second database was from the Multicenter AIDS Cohort Study (MACS) public dataset. The data from the MACS cover the time between 1984 and October 1992. Comparisons are made between both datasets.

Chapter Three discusses where we were. Before the first anti-HIV drugs (called antiretrovirals) were approved, there was no treatment to slow the progression of HIV. The first generation of antiretrovirals, reverse transcriptase inhibitors such as AZT (zidovudine), DDI (didanosine), DDC (zalcitabine), and D4T (stavudine) provided the first treatment for HIV. The first clinical trials showed that these antiretrovirals had a significant impact on increasing patient survival. The trials also showed that patients on these drugs had increased CD4+ T cell counts. Chapter Three examines the distributions of CD4 T cell counts. The results show that the estimated distributions of CD4 T cell counts are distinctly non-Gaussian. Thus distributional assumptions regarding CD4 T cell counts must be taken, into account when performing analyses with this marker. The results also show the estimated CD4 T cell distributions for each disease stage: asymptomatic, symptomatic and AIDS are non-Gaussian. Interestingly, the distribution of CD4 T cell counts for the asymptomatic period is significantly below that of the CD4 T cell distribution for the uninfected population suggesting that even in patients with no outward symptoms of HIV infection, there exists high levels of immunosuppression.

Chapter Four discusses where we are at present. HIV quickly grew resistant to reverse transcriptase inhibitors which were given sequentially as mono or dual therapy. As resistance grew, the positive effects of the reverse transcriptase inhibitors on CD4 T cell counts and survival dissipated. As the old era faded a new era characterized by a new class of drugs and new technology changed the way that we treat HIV-infected patients. Viral load assays were able to quantify the levels of HIV RNA in the blood. By quantifying the viral load, one now had a faster, more direct way to test antiretroviral regimen efficacy. Protease inhibitors, which attacked a different region of HIV than reverse transcriptase inhibitors, when used in combination with other antiretroviral agents were found to dramatically and significantly reduce the HIV RNA levels in the blood. Patients also experienced significant increases in CD4 T cell counts. For the first time in the epidemic, there was hope. It was hypothesized that with HAART, viral levels could be kept so low that the immune system as measured by CD4 T cell counts would be able to recover. If these viral levels could be kept low enough, it would be possible for the immune system to eradicate the virus. The hypothesis of immune reconstitution, that is bringing CD4 T cell counts up to levels seen in uninfected patients, is tested in Chapter Four. It was found that for these patients, there was not enough of a CD4 T cell increase to be consistent with the hypothesis of immune reconstitution.

In Chapter Five, the effectiveness of long-term HAART is analyzed. Survival analysis was conducted on 213 patients on long-term HAART. The primary endpoint was presence of an AIDS defining illness. A high level of clinical failure, or progression to an endpoint, was found.

Chapter Six yields insights into where we are going. New technology such as viral genotypic testing, that looks at the genetic structure of HIV and determines where mutations have occurred, has shown that HIV is capable of producing resistance mutations that confer multiple drug resistance. This section looks at resistance issues and speculates, ceterus parabis, where the state of HIV is going. This section first addresses viral genotype and the correlates of viral load and disease progression. A second analysis looks at patients who have failed their primary attempts at HAART and subsequent salvage therapy. It was found that salvage regimens, efforts to control viral replication through the administration of different combinations of antiretrovirals, were not effective in 90 percent of the population in controlling viral replication. Thus, primary attempts at therapy offer the best change of viral suppression and delay of disease progression. Documentation of transmission of drug-resistant virus suggests that the public health crisis of HIV is far from over. Drug resistant HIV can sustain the epidemic and hamper our efforts to treat HIV infection. The data presented suggest that the decrease in the morbidity and mortality due to HIV/AIDS is transient. Deaths due to HIV will increase and public health officials must prepare for this eventuality unless new treatments become available. These results also underscore the importance of the vaccine effort.

The final chapter looks at the economic issues related to HIV. The direct and indirect costs of treating HIV/AIDS are very high. For the first time in the epidemic, there exists treatment that can actually slow disease progression. The direct costs for HAART are estimated. It is estimated that the direct lifetime costs for treating each HIV infected patient with HAART is between $353,000 to $598,000 depending on how long HAART prolongs life. If one looks at the incremental cost per year of life saved it is only $101,000. This is comparable with the incremental costs per year of life saved from coronary artery bypass surgery.

Policy makers need to be aware that although HAART can delay disease progression, it is not a cure and HIV is not over. The results presented here suggest that the decreases in the morbidity and mortality due to HIV are transient. Policymakers need to be prepared for the eventual increase in AIDS incidence and mortality. Costs associated with HIV/AIDS are also projected to increase. The cost savings seen recently have been from the dramatic decreases in the incidence of AIDS defining opportunistic infections. As patients who have been on HAART the longest start to progress to AIDS, policymakers and insurance companies will find that the cost of treating HIV/AIDS will increase.