All-trans retinoic acid works synergistically with the γ-secretase inhibitor crenigacestat to augment BCMA on multiple myeloma and the efficacy of BCMA-CAR T cells.

B-cell maturation antigen (BCMA) is the lead antigen for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). A challenge is inter- and intra-patient heterogeneity in BCMA expression on MM cells and BCMA downmodulation under therapeutic pressure. Accordingly, there is a desire to augment and sustain BCMA expression on MM cells in patients that receive BCMA-CAR T-cell therapy.

Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) is an attractive entity for the development of chimeric antigen receptor (CAR) T-cell immunotherapy because AML blasts are susceptible to T-cell-mediated elimination. Here, we introduce sialic acid-binding immunoglobulin-like lectin 6 (Siglec-6) as a novel target for CAR T cells in AML. We designed a Siglec-6-specific CAR with a targeting domain derived from the human monoclonal antibody JML-1.

The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells.

Immunotherapy with chimeric antigen receptor (CAR)-engineered T cells can be effective against advanced malignancies. CAR T cells are "living drugs" that require technologies to enable physicians (and patients) to maintain control over the infused cell product. Here, we demonstrate that the tyrosine kinase inhibitor dasatinib interferes with the lymphocyte-specific protein tyrosine kinase (LCK) and thereby inhibits phosphorylation of CD3ζ and ζ-chain of T cell receptor-associated protein kinase 70 kDa (ZAP70), ablating signaling in CAR constructs containing either CD28_CD3ζ or 4-1BB_CD3ζ activation modules.

CAR T cells targeting αβ integrin are effective against advanced cancer in preclinical models.

Objective: Integrins are heterodimeric receptors that convey cell-to-cell and cell-to-matrix interactions. Integrin αβ is expressed in several tumour entities including melanoma, glioblastoma, breast, pancreatic and prostate cancer, where it promotes tumour cell survival and metastasis. Here, we generated αβ-specific chimeric antigen receptor (CAR) T-cells and analysed their antitumour function in pre-clinical models and .

Cochlear nucleus whole mount explants promote the differentiation of neuronal stem cells from the cochlear nucleus in co-culture experiments.

The cochlear nucleus is the first brainstem nucleus to receive sensory input from the cochlea. Depriving this nucleus of auditory input leads to cellular and molecular disorganization which may potentially be counteracted by the activation or application of stem cells. Neuronal stem cells (NSCs) have recently been identified in the neonatal cochlear nucleus and a persistent neurogenic niche was demonstrated in this brainstem nucleus until adulthood.

Mosaic pattern of Cre recombinase expression in cochlear outer hair cells of the Brn3.1 Cre mouse.

The Brn3.1 gene encodes for the protein Brn3.1, which is a member of the POU-IV class of transcription factors.

Effects of the neurotrophic factors BDNF, NT-3, and FGF2 on dissociated neurons of the cochlear nucleus.

The cochlear nucleus is the first relay station for acoustic information in the auditory pathway and its cellular integrity is affected by hearing loss. Neurotrophic factors, which are known to regulate fundamental processes in the brain, are expressed in the cochlear nucleus and are regulated by the changes in the stimulation. The aim of this study was to evaluate the effect of the neurotrophins Brain derived neurotrophic factor (BDNF) and Neurotrophin 3 (NT-3) and the neurotrophic factor Fibroblast growth factor 2 (FGF2) on primary cultured cells of the mouse cochlear nucleus.

Mutation of the TBCE gene causes disturbance of microtubules in the auditory nerve and cochlear outer hair cell degeneration accompanied by progressive hearing loss in the pmn/pmn mouse.

The progressive motor neuronopathy (pmn/pmn) mouse, an animal model for a fast developing human motor neuron disorder, is additionally characterized by simultaneous progressive sensorineural hearing loss. The gene defect in the pmn/pmn mouse is localized to a missense mutation in the tubulin-specific chaperone E (TBCE) gene on mouse chromosome 13, which is one of the five tubulin-specific chaperons involved in tubulin folding and dimerization. The missense mutation leads to a disturbance of tubulin structures in the auditory nerve and a progressive outer hair cell loss due to apoptosis, which is accompanied by highly elevated ABR-thresholds and loss of DPOAEs.

Dynamic changes of the neurogenic potential in the rat cochlear nucleus during post-natal development.

Neuronal stem cells have been described in the post-natal cochlear nucleus recently. The aim of the study was to analyse the neurogenic potential in the cochlear nucleus from the early post-natal days until adulthood. Cochlear nuclei from Sprague-Dawley rats from post-natal day P3 up to P40 were examined.