Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor.

Rhabdomyosarcomas are the most frequent malignant soft tissue tumors of childhood; however, because current multimodality treatments fail to improve the poor survival rate of children with metastatic rhabdomyosarcoma, new treatments are required. We previously identified the gamma-subunit of the fetal acetylcholine receptor (fAChR) as a specific cell surface target in rhabdomyosarcoma. Here, we engineered human T lymphocytes to express chimeric receptors composed of the antigen-binding domain of a human anti-fAChR antibody joined to the signaling domain of the human T-cell receptor zeta-chain. The interaction of fAChRzeta-transduced T cells with fAChR-positive rhabdomyosarcoma cell lines, but not with fAChR-negative control cells, induced T-cell activation characterized by strong secretion of IFN-gamma and delayed lysis of tumor cells. Importantly, we found that in six of six rhabdomyosarcoma patients, chemotherapy increased fAChR expression on residual tumor cells in vivo. Our observations suggest that these fully human chimeric fAChRzeta-transduced T cells, which should be well tolerated by the patient, have potential use in vivo both as a primary treatment for rhabdomyosarcoma and as a complementary approach to eradicate residual tumor cells after chemotherapy

Rhabdomyosarcoma lysis by T cells expressing a human autoantibody-based chimeric receptor targeting the fetal acetylcholine receptor.

Rhabdomyosarcomas are the most frequent malignant soft tissue tumors of childhood; however, because current multimodality treatments fail to improve the poor survival rate of children with metastatic rhabdomyosarcoma, new treatments are required. We previously identified the gamma-subunit of the fetal acetylcholine receptor (fAChR) as a specific cell surface target in rhabdomyosarcoma. Here, we engineered human T lymphocytes to express chimeric receptors composed of the antigen-binding domain of a human anti-fAChR antibody joined to the signaling domain of the human T-cell receptor zeta-chain. The interaction of fAChRzeta-transduced T cells with fAChR-positive rhabdomyosarcoma cell lines, but not with fAChR-negative control cells, induced T-cell activation characterized by strong secretion of IFN-gamma and delayed lysis of tumor cells. Importantly, we found that in six of six rhabdomyosarcoma patients, chemotherapy increased fAChR expression on residual tumor cells in vivo. Our observations suggest that these fully human chimeric fAChRzeta-transduced T cells, which should be well tolerated by the patient, have potential use in vivo both as a primary treatment for rhabdomyosarcoma and as a complementary approach to eradicate residual tumor cells after chemotherapy

Tree line advance reduces mixing and oxygen concentrations in arctic-alpine lakes through wind sheltering and organic carbon supply

Oxygen depletion in lake bottom waters has adverse impacts on ecosystem health including decreased water quality from release of nutrients and reduced substances from sediments, and the reduction of fish growth and reproduction. Depletion occurs when oxygen is consumed during decomposition of organic matter, and oxygen replenishment is limited by water column stratification. Arctic-alpine lakes are often well mixed and oxygenated, but rapid climate change in these regions is an important driver of shifts in catchment vegetation that could affect the mixing and oxygen dynamics of lakes. Here, we analyze high-resolution time series of dissolved oxygen concentration and temperature profiles in 40 Swedish arctic-alpine lakes across the tree line ecotone. The lakes stratified for 1-125 days, and during stratification, near-bottom dissolved oxygen concentrations changed by -0.20 to +0.15 mg L-1 day(-1), resulting in final concentrations of 1.1-15.5 mg L-1 at the end of the longest stratification period. Structural equation modeling revealed that lakes with taller shoreline vegetation relative to lake area had higher dissolved organic carbon concentrations and oxygen consumption rates, but also lower wind speeds and longer stratification periods, and ultimately, lower near-bottom dissolved oxygen concentrations. We use an index of shoreline canopy height and lake area to predict variations among our study lakes in near-bottom dissolved oxygen concentrations at the end of the longest stratification period (R-2 = 0.41). Upscaling this relationship to 8392 Swedish arctic-alpine lakes revealed that near-bottom dissolved oxygen concentrations drop below 3, 5, and 7 mg L-1 in 15%, 32%, and 53% of the lakes and that this proportion is sensitive (5%-22%, 13%-45%, and 29%-69%) to hypothetical tree line shifts observed in the past century or reconstructed for the Holocene (+/- 200 m elevation; +/- 0.5 degrees latitude). Assuming space-for-time substitution, we predict that tree line advance will decrease near-bottom dissolved oxygen concentrations in many arctic-alpine lakes