Interoceptive awareness is the conscious perception of sensations that create a sense of the physiological condition of the body. A validation study for the Japanese translation of the Multidimensional Assessment of Interoceptive Awareness (MAIA) surprised with a factor structure different from the original Englishlanguage version by eliminating two of eight scales. This prompted an exploration of the similarities and differences in interoceptive bodily awareness between Japanese and European Americans. Bicultural Japanese-Americans discussed concepts and experiences in the two cultures. We conducted focus groups and qualitative thematic analyses of transcribed recordings. 16 participants illustrated cross-cultural differences in interoceptive bodily awareness: switching between languages changes embodied experience; external versus internal attention focus; social expectations and body sensations; emphasis on form versus self-awareness; personal space; mind-body relationship; context dependency of bodily awareness and selfconstrual. The participants explained key concepts that present challenges for a Japanese cultural adaptation of the MAIA, specifically the concept of self-regulation lost in the factor analysis. In Japanese culture, self-regulation serves the purpose of conforming to social expectations, rather than achieving an individual self-comforting sense of homeostasis. Our findings will inform the next phase of improving the MAIA's cross-cultural adaptation.
Amphotropic retroviral replicating vector (RRV) Toca 511, expressing the yeast cytosine deaminase (CD) prodrug activator gene, showed promising evidence of therapeutic benefit and increased survival in early-phase trials for recurrent high-grade glioma. While a multi-center Phase 3 trial did not meet its overall endpoints, highly statistically significant survival was observed within predetermined patient subgroups compared to matched randomized control patients, and clinical investigation is on-going. Hence it is worthwhile to consider strategies aimed at enhancing therapeutic efficacy, such as delivering combinations of multiple transgenes. However, RRVs encoated with the same envelope compete for the same cancer cell surface receptors. We have now developed novel RRV encoated (‘pseudotyped’) with a heterologous envelope derived from Gibbon ape leukemia virus (GALV), which utilizes a different cell surface receptor from the native amphotropic retrovirus envelope for cellular entry. RRV(GALV) vectors expressing either GFP or HSV thymidine kinase (TK) were constructed, and efficient replication and transgene expression was observed in > 90% of both established and primary human glioblastoma cells within 14 days after initial infection at 0.01 (1%) multiplicity of infection (MOI). Genomic stability of RRV(GALV) vectors was also confirmed over prolonged propagation. Established and primary human glioblastoma cells infected with RRV(GALV)-TK vector showed ≥ 50%-90% reduction in cell viability after exposure to Ganciclovir prodrug in the range of 1µM-100µM for 5 days, as compared to uninfected control cells or cells infected with RRV(GALV)-GFP control vector. Furthermore, dual infection with RRV(GALV)-TK and amphotropic RRV-CD (Toca 511) resulted in synergistic cytotoxicity upon simultaneous exposure to their respective prodrugs. Further data will be presented from on-going studies evaluating these vectors in intracerebral glioblastoma models. These results indicate that GALV envelope-pseudotyped RRV can efficiently deliver prodrug activator gene therapy in experimental glioma models, and open the door to combinatorial gene therapy regimens with this vector platform.
Prodrug activator gene therapy with a retroviral replicating vector (RRV) has shown a highly favorable safety profile and long-term survival in early-phase trials for recurrent high-grade glioma. Overall endpoints were not met in a recent Phase 3 trial, but highly statistically significant survival was observed in prespecified patient subgroups as compared to randomized matched control patients receiving standard-of-care treatments, and further clinical evaluation is being focused on these subgroups. Additional strategies to enhance therapeutic potency may require two or more RRVs to deliver multiple transgenes simultaneously, but RRVs encoated with the same envelope protein will compete for the same cellular receptors, interfering with efficient co-infection. The current clinical vector (formerly Toca511, now DB107) is encoated by amphotropic murine leukemia virus (MLV) envelope, which binds to inorganic phosphate transporter PiT-2/SLC20A2. To switch RRV tropism, we developed RRVs pseudotyped with a heterologous envelope from Gibbon ape leukemia virus (GALV), which utilizes an alternative phosphate transporter, PiT-1/SLC20A1, for cell entry. Efficient co-infection of established and primary human glioblastoma cells with MLV- and GALV-pseudotyped RRV was achieved, without receptor competition. However, human hematopoietic stem/progenitor cells (HSPC) also express high levels of PiT-1, which may increase potential genotoxicity of GALV-pseudotyped RRV. Accordingly, as a novel strategy to restrict gene expression and replication in HSPC, we have developed and tested new RRV designs incorporating microRNA target sequences (miRT). Insertion of miRT recognized by hematopoietic lineage-specific microRNA-142-3p resulted in complete suppression of RRV replication in primary human CD34+ HSPC, with the percentage of infected cells below 1% after vector inoculation at multiplicities of infection (MOI) 0.05 and 0.1, and remaining below 3% even after inoculation at MOI 0.5 and 1.0. In vivo models have been developed for on-going studies to evaluate miRT-mediated restriction strategies for avoidance of potential genotoxicity by RRV in normal hematopoietic cells.
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