ABSTRACT
A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.
Subject(s)
Melanoma , Receptors, Chimeric Antigen , Uveal Neoplasms , Humans , Mice , Animals , Melanoma/therapy , Melanoma/drug therapy , Immunotherapy, Adoptive , Uveal Neoplasms/therapy , Uveal Neoplasms/drug therapy , Cell- and Tissue-Based Therapy , Membrane Glycoproteins , OxidoreductasesABSTRACT
Transgenic chickpeas expressing high levels of a truncated version of the cry1Ac (trcry1Ac) gene conferred complete protection to Helicoverpa armigera in the greenhouse. Homozygous progeny of two lines, Cry1Ac.1 and Cry1Ac.2, had similar growth pattern and other morphological characteristics, including seed yield, compared to the non-transgenic counterpart; therefore, seed compositional analysis was carried out. These selected homozygous chickpea lines were selfed for ten generations along with the non-transgenic parent under contained conditions. A comparative seed composition assessment, seed storage proteins profiling, and in vitro protein digestibility were performed to confirm that these lines do not have significant alterations in seed composition compared to the parent. Our analyses showed no significant difference in primary nutritional composition between transgenic and non-transgenic chickpeas. In addition, the seed storage protein profile also showed no variation between the transgenic chickpea lines. Seed protein digestibility assays using simulated gastric fluid revealed a similar rate of digestion of proteins from the transgenic trcry1Ac lines compared to the non-transgenic line. Thus, our data suggest no unintended changes in the seed composition of transgenic chickpea expressing a trcry1Ac gene.
Subject(s)
Cicer/genetics , Moths , Animals , Bacterial Proteins/genetics , Endotoxins , Hemolysin Proteins/genetics , Larva , Pest Control, Biological , Plants, Genetically ModifiedABSTRACT
Cherubism is a rare benign, autosomal-dominant inherited fibro-osseous lesion of jaw characterized by excessive bone degradation of the upper and lower jaws followed by the development of fibrous tissue masses. It is usually self-limiting; it starts in early childhood and involutes by puberty. The purpose of this clinical report is to describe a nonfamilial case of cherubism on a teenager female patient first treated by calcitonin nasal spray followed by surgical resection and recontouring after puberty.
ABSTRACT
A new method for separation of several amino acids using mobile phases (MPs) containing mixed micelles as well as 1-butanol and aprotic organic solvents as modifying additives has been developed. The effect of experimental factors (the ratio of MP components, nature of stationary phase) on separation of amino acids is investigated and all conditions for separation are optimized. It was found that separation of three amino acids l-lysine, l-histidine and l-tryptophan on silica gel stationary phase in the interval from micrograms to milligrams is available. The proposed method is simple and allows determining the amino acids in the linear interval of 0.1-1.5mg.
