Increasing the Clinical Efficacy of NK and Antibody-Mediated Cancer Immunotherapy: Potential Predictors of Successful Clinical Outcome Based on Observations in High-Risk Neuroblastoma

Disease recurrence is frequent in high-risk neuroblastoma (NBL) patients even after multi-modality aggressive treatment [a combination of chemotherapy, surgical resection, local radiation therapy, autologous stem cell transplantation, and cis-retinoic acid (CRA)]. Recent clinical studies have explored the use of monoclonal antibodies (mAbs) that bind to disialoganglioside (GD2), highly expressed in NBL, as a means to enable immune effector cells to destroy NBL cells via antibody-dependent cell-mediated cytotoxicity (ADCC). Preclinical data indicate that ADCC can be more effective when appropriate effector cells are activated by cytokines. Clinical studies have pursued this by administering anti-GD2 mAb in combination with ADCC-enhancing cytokines (IL2 and GM-CSF), a regimen that has demonstrated improved cancer-free survival. More recently, early clinical studies have used a fusion protein that consists of the anti-GD2 mAb directly linked to IL2, and anti-tumor responses were seen in the Phase II setting. Analyses of genes that code for receptors that influence ADCC activity and natural killer (NK) cell function [Fc receptor (FcR), killer immunoglublin-like receptor (KIR), and KIR-ligand (KIR-L)] suggest patients with anti-tumor activity are more likely to have certain genotype profiles. Further analyses will need to be conducted to determine whether these genotypes can be used as predictive markers for favorable therapeutic outcome. In this review, we discuss factors that affect response to mAb-based tumor therapies such as hu14.18-IL2. Many of our observations have been made in the context of NBL; however, we will also include some observations made with mAbs targeting other tumor types that are consistent with results in NBL. Therefore, we hypothesize that the NBL observations discussed here may also be relevant to mAb therapy for other cancers, in which ADCC is known to play a role

Diversity oriented biosynthesis via accelerated evolution of modular gene clusters.

Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular polyketide synthase multienzymes by an assembly-line process in which each module of enzymes in turn specifies attachment of a particular chemical unit. Although polyketide synthase encoding genes have been successfully engineered to produce novel analogues, the process can be relatively slow, inefficient, and frequently low-yielding. We now describe a method for rapidly recombining polyketide synthase gene clusters to replace, add or remove modules that, with high frequency, generates diverse and highly productive assembly lines. The method is exemplified in the rapamycin biosynthetic gene cluster where, in a single experiment, multiple strains were isolated producing new members of a rapamycin-related family of polyketides. The process mimics, but significantly accelerates, a plausible mechanism of natural evolution for modular polyketide synthases. Detailed sequence analysis of the recombinant genes provides unique insight into the design principles for constructing useful synthetic assembly-line multienzymes

Absorption in Sport: A Cross-Validation Study.

Absorption has been identified as readiness for experiences of deep involvement in the task. Conceptually, absorption is a key psychological construct, incorporating experiential, cognitive, and motivational components. Although, no operationalization of the construct has been provided to facilitate research in this area, the purpose of this research was the development and examination of the psychometric properties of a sport-specific measure of absorption that evolved from the use of the modified Tellegen Absorption Scale (MODTAS; Jamieson, 2005) in mainstream psychology. The study aimed to provide evidence of the psychometric properties, reliability, and validity of the Measure of Absorption in Sport Contexts (MASCs). The psychometric examination included a calibration sample from Scotland and a cross-validation sample from Australia using a cross-sectional design. The item pool was developed based on existing items from the modified Tellegen Absorption Scale (Jamieson, 2005). The MODTAS items were reworded and translated into a sport context. The Scottish sample consisted of 292 participants and the Australian sample of 314 participants. Congeneric model testing and confirmatory factor analysis for both samples and multi-group invariance testing across samples was used. In the cross-validation sample the MASC subscales showed acceptable internal consistency and construct reliability (≥0.70). Excellent fit indices were found for the final 18-item, six-factor measure in the cross-validation sample, [Formula: see text] = 197.486, p {\textless} 0.001; CFI = 0.957; TLI = 0.945; RMSEA = 0.045; SRMR = 0.044. Multi-group invariance testing revealed no differences in item meaning, except for two items. The MASC and the Dispositional Flow Scale-2 showed moderate-to-strong positive correlations in both samples, r = 0.38, p {\textless} 0.001 and r = 0.42, p {\textless} 0.001, supporting the external validity of the MASC. This article provides initial evidence in support of the psychometric properties, reliability, and validity of the sport-specific measure of absorption. The MASC provides rich research opportunities in sport psychology that can enhance the theoretical understanding between absorption and related constructs and facilitate future intervention studies

Measurement of charged-particle multiplicities in gluon and quark jets in p(p)over-bar collisions at root s=1.8 TeV

We report the first largely model independent measurement of charged particle multiplicities in quark and gluon jets, N-q and N-g, produced at the Fermilab Tevatron in p (p) over bar collisions with a center-of-mass energy of 1.8 TeV and recorded by the Collider Detector at Fermilab. The measurements are made for jets with average energies of 41 and 53 GeV by counting charged particle tracks in cones with opening angles of θ(c)=0.28, 0.36, and 0.47 rad around the jet axis. The corresponding jet hardness Q=E-jetθ(c) varies in the range from 12 to 25 GeV. At Q=19.2 GeV, the ratio of multiplicities r=N-g/N-q is found to be 1.64± 0.17, where statistical and systematic uncertainties are added in quadrature. The results are in agreement with resummed perturbative QCD calculations