Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide.

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.

Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy.

The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascular endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand factor and vascular cell adhesion molecule 1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in prevention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.

Virtual Training: Learning Transfer of Assembly Tasks.

In training assembly workers in a factory, there are often barriers such as cost and lost productivity due to shutdown. The use of virtual reality (VR) training has the potential to reduce these costs. This research compares virtual bimanual haptic training versus traditional physical training and the effectiveness for learning transfer. In a mixed experimental design, participants were assigned to either virtual or physical training and trained by assembling a wooden burr puzzle as many times as possible during a twenty minute time period. After training, participants were tested using the physical puzzle and were retested again after two weeks. All participants were trained using brightly colored puzzle pieces. To examine the effect of color, testing involved the assembly of colored physical parts and natural wood colored physical pieces. Spatial ability as measured using a mental rotation test, was shown to correlate with the number of assemblies they were able to complete in the training. While physical training outperformed virtual training, after two weeks the virtually trained participants actually improved their test assembly times. The results suggest that the color of the puzzle pieces helped the virtually trained participants in remembering the assembly process.

Arsenic exposure alters expression of cell cycle and lipid metabolism genes in the liver of adult zebrafish (Danio rerio).

Adult zebrafish (Danio rerio) were used to investigate mRNA expression in the liver following 7-day and 21-day exposures to 0, 10, 50, or 500 ppb sodium arsenite. Arsenic exposure has been linked to several human disorders including cancers and cardiovascular and metabolic diseases. Quantitative PCR was employed to determine the mRNA expression of genes involved in cell cycle regulation [cyclin E1 (ccne1), WEE1 A kinase (wee1)], DNA damage repair [breast cancer 2 (brca2)] and lipid transport and metabolism [carnitine O-octanoyltransferase (crot), fatty acid binding protein-3 (fabp3) and 3-hydroxy-3-methylglutaryl-CoA synthase 1 (hmgcs1)]. Results from the 7-day exposure showed sex- and dose-specific changes in expression of wee1, brca2, crot and hmgcs1. No significant differences from controls were observed in fish exposed for 21 days. Expression of all genes, except ccne1, was significantly different between the 7- and 21-day exposures. The results presented here correlate with prior findings from our lab and others, and offer further insight into potential mechanisms of low-dose arsenic exposure.

Proteomic analysis of arsenic-exposed zebrafish (Danio rerio) identifies altered expression in proteins involved in fibrosis and lipid uptake in a gender-specific manner.

The zebrafish (Danio rerio) was used to investigate protein expression in the liver following arsenic exposure. Several disorders have been linked to arsenic exposure, including cancer, diabetes, and cardiovascular disease. The mechanisms of arsenic toxicity are poorly understood. Prior studies have described altered gene expression, inflammation, and mitogenic signaling in acute or chronic exposure models. A proteomic approach was employed to investigate arsenic-induced alteration in the zebrafish liver proteome following a 7-day exposure to 50 ppb sodium arsenite. Over 740 unique proteins were identified, with fewer than 2% showing differential expression. Molecular pathway analysis software identified lipid metabolism and transport as potential molecular targets. Immunoblots were used to confirm protein expression changes, whereas qPCR was employed to investigate gene expression changes. Overall, 25 proteins were differentially expressed in a gender-specific manner, 11 in males and 14 in females. Of these 25, a single protein, hydroxysteroid dehydrogenase like 2, showed decreased expression in both males and females following arsenic exposure. These findings indicate that protein expression is altered following arsenic exposure. The changes presented here seem to be most prevalent in lipid transport and metabolic pathways, suggesting a potential increase in fibrosis in males and decreased lipid accumulation and uptake in females.