Search

Mutations of the Janus family kinase JAK3 gene cause severe combined immunodeficiency (SCID). JAK3 deficiency in humans is characterized by the absence of circulating T cells and natural killer (NK) cells with normal numbers of poorly functioning B cells (T–B+NK–). Using SCID patient-specific induced pluripotent stem cells (iPSCs) and a T cell in vitro differentiation system, we demonstrate a complete block in early T cell development of JAK3-deficient cells. Correction of the JAK3 mutation by CRISPR/Cas9-enhanced gene targeting restores normal T cell development, including the production of mature T cell populations with a broad T cell receptor (TCR) repertoire. Whole-genome sequencing of corrected cells demonstrates no CRISPR/Cas9 off-target modifications. These studies describe an approach for the study of human lymphopoiesis and provide a foundation for gene correction therapy in humans with immunodeficiencies.

We designed multimodal tumor vaccine that consists of irradiated tumor cells infected with the oncolytic IL-12-expressing HSV-1 virus, M002. This vaccine was tested against the syngeneic neuroblastoma mouse model Neuro 2a injected into the right caudate nucleus of the immunocompetent A/J mice. Mice were vaccinated via intramuscular injection of multimodal vaccine or uninfected irradiated tumor cells at seven and 14 days after tumor establishment. While there was no survival difference between groups vaccinated with cell-based vaccine applied following tumor injection, a premunition prime/boost vaccination strategy produced a significant survival advantage in both groups and sustained immune response to an intracranial rechallenge of the same tumor. The syngeneic but unrelated H6 hepatocellular tumor cell line grew unrestricted in vaccinated mice, indicative of vaccine-mediated specific immunity to Neuro 2a tumors. Longitudinal analyses of tumor-infiltrating lymphocytes revealed a primary adaptive T cell response involving both CD4+ and CD8+ T cell subsets. Spleen cell mononuclear preparations from vaccinated mice were significantly more cytotoxic to Neuro 2a tumor cells than spleen cells from control mice as demonstrated in a four-hour in vitro cytotoxicity assay. These results strongly suggest that an irradiated whole cell tumor vaccine incorporating IL-12-expressing M002 HSV can produce a durable, specific immunization in a murine model of intracranial tumor.

Qualitative, quantitative, and ratio estimate randomized response models were tested in comparison with a conventional interview technique in the measurement of a sensitive issue with known true values. Results show that the randomized response model is successful in minimizing measurement error and provides more accurate estimates of sensitive behavior than conventional interview techniques. [ABSTRACT FROM AUTHOR]

The use of comparative advertising has escalated from an occasional, partially disguised acknowledgement of the competition to direct, point-by-point comparisons of the sponsored and competing brands. This article presents a conceptual framework for classifying and evaluating different comparison advertising formats. The framework identifies different formats along two multi-level dimensions. Examples of several research questions that could be addressed using the framework are presented. [ABSTRACT FROM AUTHOR]

The article analyzes the contribution of telemarketing in selling concept, services and goods. The term telemarketing refers to a systematic and continuous program of communicating with customers and prospects via telephone and other person-to-person electronic media. Telemarketing includes more than passive receipt of inbound calls, which characteristically occur at telephone order desks maintained by many firms. The role of telemarketing in the institutional seller, trade servicer, and trade seller job categories is to supplement field selling efforts. The more routinized the selling process, the more likely telemarketing can make an important supplemental contribution to face-to-face selling. Telemarketing can provide a complete sales and customer support effort for selling situations in which face-to-face contact is not required. Organizations which may benefit from this strategy are ones with large and widely dispersed customer bases whose purchasers range from very small amounts to very large amounts.

One of the fastest growing methods for increasing salesforce efficiency is telemarketing. Telemarketing is no longer limited to business-to-consumer sales. Business-to-business telemarketing is growing at a rate of 30 to 40 percent each year. It has been estimated that business-to-business telemarketing will generate over $97 billion in sales during 1986; a 33 percent increase over 1985. Telemarketing offers several other potential benefits including the opportunity to increase sales revenue and profits. Telemarketers can normally conduct prospecting calls much more quickly and more efficiently than their counterparts in the field. They are also better prepared to handle incoming calls since they do not have to divide their time between the office and the field. Telemarketers can be used in service centers to handle problems with delayed or lost orders. The service center can act as a buffer for field representatives by handling routine problems and releasing the field representatives to spend more of their time selling.

Human induced pluripotent stem cells (hiPSCs) have enormous potential for the treatment of inherited and acquired disorders. Recently, antigen-specific T lymphocytes derived from hiPSCs have been reported. However, T lymphocyte populations with broad T cell receptor (TCR) diversity have not been generated. We report that hiPSCs derived from skin biopsy are capable of producing T lymphocyte populations with a broad TCR repertoire. In vitro T cell differentiation follows a similar developmental program as observed in vivo, indicated by sequential expression of CD7, intracellular CD3 and surface CD3. The γδ TCR locus is rearranged first and is followed by rearrangement of the αβ locus. Both γδ and αβ T cells display a diverse TCR repertoire. Upon activation, the cells express CD25, CD69, cytokines (TNF-α, IFN-γ, IL-2) and cytolytic proteins (Perforin and Granzyme-B). These results suggest that most, if not all, mechanisms required to generate functional T cells with a broad TCR repertoire are intact in our in vitro differentiation protocol. These data provide a foundation for production of patient-specific T cells for the treatment of acquired or inherited immune disorders and for cancer immunotherapy. [ABSTRACT FROM AUTHOR]