An Abridgment of Chapter 9, Vocational Services, in Improving Services to Handicapped Children and Book Review

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Engineered CAR19 T-cells to Demonstrate in vitro Antileukemia Activity

Abstract The Chimeric Antigen Receptor T-cells, also known as CAR T-cells, are a revolutionary approach to cancer treatment. They are engineered Tlymphocytes and recombinant receptors for specific antigens. They are mainly responsible for redirecting specificity, activation, and function of T lymphocytes and other immune cells in a single molecule. It attaches to the cancer cells, thereby leading to the destruction of the tumor. The CAR Tcells are made up of different domains, which include Antigen Binding Domain (CD19), Hinge, and Transmembrane Region, followed by Co- Stimulatory Domain (CD28) and T-cell Activation Domain (CD3). The Antigen Binding Domain recognizes the specific target of cancer cells. The Hinge and Transmembrane Region is responsible for the CAR signaling threshold and the amount of CAR signaling by controlling the CAR expression level. The T-cell Activation Domain regulates the activation of Tcells, whereas the Co-stimulatory Domain plays a role in giving secondary signals for T-cell activation. The designing of CAR T-cells involves various steps, which include a collection of the patient’s blood, followed by isolation of T-cells from it, activation/stimulation of patient’s T-cells using CD3/CD28 activation beads, along with the addition of interleukin 2, which is used to enhance the efficiency of T-cell stimulation. Then, the T-cells are genetically modified with CAR complex, thereby forming CAR T-cells, which are then expanded in the laboratory and infused back into the patient’s body to fight against leukemia

Intermediate Mass Black Hole Induced Quenching of Mass Segregation in Star Clusters

In many theoretical scenarios it is expected that intermediate-mass black holes (IMBHs, with masses M ~ 100-10000 solar masses) reside at the centers of some globular clusters. However, observational evidence for their existence is limited. Several previous numerical investigations have focused on the impact of an IMBH on the cluster dynamics or brightness profile. Here we instead present results from a large set of direct N-body simulations including single and binary stars. These show that there is a potentially more detectable IMBH signature, namely on the variation of the average stellar mass between the center and the half-light radius. We find that the existence of an IMBH quenches mass segregation and causes the average mass to exhibit only modest radial variation in collisionally relaxed star clusters. This differs from when there is no IMBH. To measure this observationally requires high resolution imaging at the level of that already available from the Hubble Space Telescope (HST) for the cores of a large sample of galactic globular clusters. With a modest additional investment of HST time to acquire fields around the half-light radius, it will be possible to identify the best candidate clusters to harbor an IMBH. This test can be applied only to globulars with a half-light relaxation time less than or equal to 1 Gyr, which is required to guarantee efficient energy equipartition due to two-body relaxation.Comment: 15 pages, 3 figures, ApJ, in pres

The ACS Survey Of Globular Clusters. V. Generating A Comprehensive Star Catalog For Each Cluster

The ACS Survey of Globular Clusters has used Hubble Space Telescope's Wide-Field Channel to obtain uniform imaging of 65 of the nearest globular clusters to provide an extensive homogeneous data set for a broad range of scientific investigations. The survey goals required not only a uniform observing strategy, but also a uniform reduction strategy. To this end, we designed a sophisticated software program to process the cluster data in an automated way. The program identifies stars simultaneously in the multiple dithered exposures for each cluster and measures them using the best available point-spread function models. We describe here in detail the program's rationale, algorithms, and output. The routine was also designed to perform artificial-star tests, and we ran a standard set of similar to 10(5) tests for each cluster in the survey. The catalog described here will be exploited in a number of upcoming papers and will eventually be made available to the public via the World Wide Web.Astronom

The ACS survey of globular clusters. XIII. Photometric calibration in comparison with Stetson standards

In this study we compare the photometric data of 34 Milky Way globular clusters, observed within the ACS Treasury Program (PI: Ata Sarajedini) with the corresponding ground-based data, provided by the Photometric Standard Field Catalogs of Stetson (2000, 2005). We focus on the transformation between the HST/ACS F606W to V-band and F814W to I-band only. The goal is to assess the validity of the filter transformation equations by Sirianni et al.(2005) with respect to their dependence on metallicity, Horizontal Branch morphology, mass and integrated (V-I) colour of the various globular clusters. Such a dependence is expected due to the fact that the transformation equations are based on the observations of only one globular cluster, i.e., NGC 2419. Surprisingly, the correlation between offset and metallicity is found to be weak, with a low level significance. The correlation between offset and Horizontal Branch structure, as well as total cluster mass is still weaker. Based on the available data we do not find the photometric offset to be linked to multiple stellar populations, e.g., as found in NGC 0288, NGC 1851, and NGC 5139. The results of this study show that there are small systematic offsets between the transformed ACS- and observed ground based photometry, and that these are only weakly correlated, if at all, with various cluster parameters and their underlying stellar populations. As a result, investigators wishing to transform globular cluster photometry from the Sirianni et al.(2005) ground-based V, I system onto the Stetson (2000) system simply need to add 0.040 (+/-0.012) to the V-band magnitudes and 0.047 (+/-0.011) to the I-band magnitudes. This in turn means that the transformed ACS (V-I) colours match the ground-based values from Stetson (2000) to within ~0.01 mag.Comment: 28 pages, 14 figures, accepted for publication in ApJ

The ACS Survey Of Galactic Globular Clusters. VI. NGC 6366: A Heavily Stripped Galactic Globular Cluster

We have used observations obtained as part of the Hubble Space Telescope/ACS Survey of Galactic globular clusters (GCs) to construct a color-magnitude diagram for the bulge cluster, NGC 6366. The luminosity function derived from those data extends to M(F606W) similar to 9, or masses of similar to 0.3 M(circle dot). Unlike most GCs, the mass function peaks near the main-sequence turnoff with significantly fewer low-mass stars even after correction for completeness and mass segregation. Using a multimass King model, we extrapolate the global cluster behavior and find the global mass function to be poorly matched by a power law, with a particular deficit of stars with masses between 0.5 and 0.7 M(circle dot). We briefly discuss this interesting anomaly within the context of tidal stripping.NASA GO-10775, 5-26555Space Telescope Science InstituteInstituto de Astrofisica de Canarias P3-94Ministry of Education and Science of the Kingdom of Spain AYA-2008-67913Astronom

The ACS Survey of Galactic Globular Clusters. IX. Horizontal Branch Morphology and the Second Parameter Phenomenon

The horizontal branch (HB) morphology of globular clusters (GCs) is most strongly influenced by metallicity. The second parameter phenomenon acknowledges that metallicity alone is not enough to describe the HB morphology of all GCs. In particular, the outer Galactic halo contains GCs with redder HBs at a given metallicity than are found inside the Solar circle. Thus, at least a second parameter is required to characterize HB morphology. Here we analyze the median color difference between the HB and the red giant branch (RGB), d(V-I), measured from HST ACS photometry of 60 GCs within ~20 kpc of the Galactic Center. Analysis of this homogeneous data set reveals that, after the influence of metallicity has been removed, the correlation between d(V-I) and age is stronger than that of any other parameter considered. Expanding the sample to include HST photometry of the 6 most distant Galactic GCs lends additional support to the correlation between d(V-I) and age. This result is robust with respect to the adopted metallicity scale and the method of age determination, but must bear the caveat that high quality, detailed abundance information is not available for a significant fraction of the sample. When a subset of GCs with similar metallicities and ages are considered, a correlation between d(V-I) and central luminosity density is exposed. With respect to the existence of GCs with anomalously red HBs at a given metallicity, we conclude that age is the second parameter and central density is most likely the third. Important problems related to HB morphology in GCs, notably multi-modal distributions and faint blue tails, remain to be explained. (Abridged)Comment: Accepted for publication in ApJ; 49 pages, 19 figure

Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients

BACKGROUND: Differences in tacrolimus dosing across ancestries is partly attributable to polymorphisms in CYP3A5 genes that encode tacrolimus-metabolizing cytochrome P450 3A5 enzymes. The CYP3A5*1 allele, preponderant in African Americans, is associated with rapid metabolism, subtherapeutic concentrations, and higher dose requirements for tacrolimus, all contributing to worse outcomes. Little is known about the relationship between CYP3A5 genotype and the tacrolimus pharmacokinetic area under the curve (AUC) profile in African Americans or whether pharmacogenetic differences exist between conventional twice-daily, rapidly absorbed, immediate-release tacrolimus (IR-Tac) and once-daily extended-release tacrolimus (LifeCycle Pharma Tac [LCPT]) with a delayed absorption profile. STUDY DESIGN: Randomized prospective crossover study. SETTING & PARTICIPANTS: 50 African American maintenance kidney recipients on stable IR-Tac dosing. INTERVENTION: Recipients were randomly assigned to continue IR-Tac on days 1 to 7 and then switch to LCPT on day 8 or receive LCPT on days 1 to 7 and then switch to IR-Tac on day 8. The LCPT dose was 85% of the IR-Tac total daily dose. OUTCOMES: Tacrolimus 24-hour AUC (AUC MEASUREMENTS: CYP3A5 genotype, 24-hour tacrolimus pharmacokinetic profiles. RESULTS: ∼80% of participants carried the CYP3A5*1 allele (CYP3A5 expressers). There were no significant differences in AUC LIMITATIONS: This was primarily a pharmacogenetic study rather than an efficacy study; the follow-up period was too short to capture clinical outcomes. CONCLUSIONS: Achieving therapeutic tacrolimus trough concentrations with IR-Tac in most African Americans results in significantly higher peak concentrations, potentially magnifying the risk for toxicity and adverse outcomes. This pharmacogenetic effect is attenuated by delayed tacrolimus absorption with LCPT. TRIAL REGISTRATION: Registered at ClinicalTrials.gov, with study number NCT01962922