Voice stress analysis

In a study of the validity of eight candidate voice measures (fundamental frequency, amplitude, speech rate, frequency jitter, amplitude shimmer, Psychological Stress Evaluator scores, energy distribution, and the derived measure of the above measures) for determining psychological stress, 17 males age 21 to 35 were subjected to a tracking task on a microcomputer CRT while parameters of vocal production as well as heart rate were measured. Findings confirm those of earlier studies that increases in fundamental frequency, amplitude, and speech rate are found in speakers involved in extreme levels of stress. In addition, it was found that the same changes appear to occur in a regular fashion within a more subtle level of stress that may be characteristic, for example, of routine flying situations. None of the individual speech measures performed as robustly as did heart rate

Gene Therapy for Pediatric Cancer: State of the Art and Future Perspectives

While modern treatments have led to a dramatic improvement in survival for pediatric malignancy, toxicities are high and a significant proportion of patients remain resistant. Gene transfer offers the prospect of highly specific therapies for childhood cancer. “Corrective” genes may be transferred to overcome the genetic abnormalities present in the precancerous cell. Alternatively, genes can be introduced to render the malignant cell sensitive to therapeutic drugs. The tumor can also be attacked by decreasing its blood supply with genes that inhibit vascular growth. Another possible approach is to modify normal tissues with genes that make them more resistant to conventional drugs and/or radiation, thereby increasing the therapeutic index. Finally, it may be possible to attack the tumor indirectly by using genes that modify the behavior of the immune system, either by making the tumor more immunogenic, or by rendering host effector cells more efficient. Several gene therapy applications have already been reported for pediatric cancer patients in preliminary Phase 1 studies. Although no major clinical success has yet been achieved, improvements in gene delivery technologies and a better understanding of mechanisms of tumor progression and immune escape have opened new perspectives for the cure of pediatric cancer by combining gene therapy with standard therapeutic available treatments

The next-in-line effect

Subjects performed a free recall task while seated in a square. One by one, alternate subjects exposed a word card and read the word out loud to the group. The remaining subjects simply listened. All subjects were tested for recall. Subjects who performed tended not to recall words read 9 sec before and after their performance ("scallop effect"), and this loss increased with performance difficulty. Incidental evidence suggested high recall for material performed by particular subjects ("peak effects") and channel capacity. When subjects are next in line they may ignore cues not related to performing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33869/1/0000130.pd

Chimeric Antigen Receptors for T-Cell Malignancies

Development of chimeric antigen receptor (CAR)-modified T cells for the treatment of T-lineage leukemia and lymphoma has encountered several unique challenges. The most widely expressed tumor antigen targets for malignant T cells are often also expressed on non-malignant T cells. Transducing T cells with CARs targeted to these shared antigens can therefore promote over-activation or fratricide of CAR T cells, reducing their therapeutic potency. If fratricide is resolved, clinical CAR T cell activity may eliminate normal T-cell subsets and cause temporary immunosuppression. In this review, we summarize the preclinical development of CAR-based therapies for T-cell malignancies and discuss strategies to minimize toxicities associated with on-target fratricide and off-tumor activity

Engineered CAR T cell therapy for solid tumors

The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced impressive clinical responses in patients with hematologic malignances. However the successful extension of this therapy to solid tumors has proven challenging due to i) the paucity of target antigens that are tumor selective, leading to a heightened risk of “on-target, off-tumor” toxicities and, ii) the suppressive tumor microenvironment, which subverts T cell effector function. Therefore, to overcome these limitations we have programmed T cells with a combination of receptors that recognize a gene expression pattern that is unique to the tumor site and whose endodomains deliver intracellular signals 1, 2 and 3 (antigen, co-stimulation and cytokine) required for optimal T cell activation and protection from suppressive factors present at the tumor site. The current presentation will not only highlight our T cell engineering improvements but also our process optimization, including the incorporation of the G-Rex device, to facilitate the clinical and commercial development of potentially curative therapie

Evidence for the Presentation of Major Histocompatibility Complex Class I–restricted Epstein-Barr Virus Nuclear Antigen 1 Peptides to CD8+ T Lymphocytes

The Epstein-Barr virus (EBV)-encoded nuclear antigen 1 (EBNA1) is expressed in all EBV-associated tumors, making it an important target for immunotherapy. However, evidence for major histocompatibility complex (MHC) class I–restricted EBNA1 peptides endogenously presented by EBV-transformed B and tumor cells remains elusive. Here we describe for the first time the identification of an endogenously processed human histocompatibility leukocyte antigen (HLA)-B8–restricted EBNA1 peptide that is recognized by CD8+ T cells. T cell recognition could be inhibited by the treatment of target cells with proteasome inhibitors that block the MHC class I antigen processing pathway, but not by an inhibitor (chloroquine) of MHC class II antigen processing. We also demonstrate that new protein synthesis is required for the generation of the HLA-B8 epitope for T cell recognition, suggesting that defective ribosomal products (DRiPs) are the major source of T cell epitopes. Experiments with protease inhibitors indicate that some serine proteases may participate in the degradation of EBNA1 DRiPs before they are further processed by proteasomes. These findings not only provide the first evidence of the presentation of an MHC class I–restricted EBNA1 epitope to CD8+ T cells, but also offer new insight into the molecular mechanisms involved in the processing and presentation of EBNA1

Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch

Safety switches are becoming relevant for the clinical translation of T-cell-based immunotherapies. In patients receiving an allogeneic hematopoietic stem cell transplant, the inducible caspase-9 gene (iC9) safety switch expressed by donor-derived T lymphocytes efficiently controls acute graft versus host disease (GvHD). However, in vivo elimination of iC9-T cells by the chemical inducer of dimerization (CID) that activates the iC9 protein is incomplete. To study this effect, we characterized the clonal diversity and dynamics of vector insertion sites (VIS) in iC9-T cells pre- and post-CID administration in four patients who developed GvHD. We identified 3,203 VIS among four patients and followed their in vivo clonal dynamics up to 161 days post-CID. VIS were categorized by their proximity to host genome elements, gene associations, and cis-modulatory relationship to mapped promoters. We found that VIS are preferentially located near open chromatin and promoter regions; furthermore, there was no evidence for selection bias among VIS surviving the CID treatment. The majority of iC9-T cells with high normalized VIS copy number at the time of GvHD onset were eliminated by CID, while iC9-T cells detectable post-CID generally have low normalized VIS copy number. We propose that suboptimal iC9 transgene expression is responsible for the incomplete elimination of iC9-T cells and illustrate here by simple model how cis-modulatory influences of local genome context and T-cell receptor activation status at time of CID treatment contribute to stochastic sparing of iC9-T cells

Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation

Activation of the inducible caspase 9 (iC9) safety gene by a dimerizing drug (chemical inducer of dimerization (CID) AP1903) effectively resolves the symptoms and signs of graft-versus-host disease (GvHD) in haploidentical stem cell transplant (HSCT) recipients. However, after CID treatment, 1% of iC9-T cells remain and can regrow over time; although these resurgent T cells do not cause recurrent GvHD, it remains unclear whether repeat CID treatments are a safe and feasible way to further deplete residual gene-modified T cells should any other adverse effects associated with them occur. Here, we report a patient who received an infusion of haploidentical iC9-T cells after HSCT and subsequently received three treatments with AP1903. There was a mild (grade 2) and transient pancytopenia following each AP1903 administration but no non-hematological toxicity. Ninety five percent of circulating iC9-T cells (CD3+CD19+) were eliminated after the first AP1903 treatment. Three months later, the residual cells had expanded more than eightfold and had a lower level of iC9 expression. Each repeated AP1903 administration eliminated a diminishing percentage of the residual repopulating cells, but elimination could be enhanced by T-cell activation. These data support the safety and efficiency of repeated CID treatments for persistent or recurring toxicity from T-cell therapies