Both the brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) play multiple roles in various aspects of neurons, including cell survival synaptic function. BDNF its receptor TrkB are extensively expressed neurons central nervous system (CNS), contribution BDNF/TrkB to neuronal function is evident; thus, downregulation has been considered be involved pathogenesis Alzheimer’s disease (AD). GCs, stress-related molecules, glucocorticoid receptors (GRs) also associated with AD...

Background Dendritic cells (DCs) play critical roles in regulating the innate and adaptive immune responses, have long been a major focus of cancer immunotherapy. Accumulating evidence suggests that conventional type 1 DCs (cDC1s) excel cross-presentation exogenous antigens on MHC-I molecules induction antitumor CD8 + T cell immunity; however, obtaining large numbers cDC1s is difficult. The use reprogramming differentiation technology advantageous for unlimited autologous especially...

Background Dendritic cells (DCs) are a promising therapeutic target in cancer immunotherapy given their ability to prime antigen-specific T cells, and initiate antitumor immune response. A major obstacle for DC-based is the difficulty obtain sufficient number of functional DCs. Theoretically, this limitation can be overcome by using induced pluripotent stem (iPSCs); however, strategies engage iPSC-derived DCs (iPSC-DCs) into remain elucidated. Accumulating evidence showing that induction...

Lack of reliable predictive biomarkers is a major limitation combination therapy with chemotherapy and anti–programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/PD-L1) (chemo-immunotherapy). We previously observed that the increase peripheral blood CD8+ T cells expressing CX3CR1, marker differentiation, correlates response to anti–PD-1 therapy; however, prognostic value T-cell CX3CR1 expression during chemo-immunotherapy unknown. Here, we evaluated utility circulating...

Evidence has shown that T-cell receptors (TCRs) recognize the same epitopes may not be exact TCR clonotypes but have slightly different sequences. However, changes in genomic and transcriptomic signatures of these highly homologous T cells during immunotherapy remain unknown. Here, we examined evolutionary features circulating observed tumors (tumor-infiltrating lymphocyte (TIL)-TCRs) by combining single-cell RNA/TCR sequencing longitudinal blood samples tumor tissue from a patient treated...

Tay–Sachs disease (TSD) is a GM2 gangliosidosis lysosomal storage caused by loss of hexosaminidase-A (HEXA) activity and characterized progressive neurodegeneration due to the massive accumulation ganglioside in brain. Here, we generated iPSCs derived from patients with TSD, found similar potential for neural differentiation between TSD-iPSCs normal iPSCs, although progenitor cells (NPCs) exhibited enlarged lysosomes upregulation marker, LAMP1, ganglioside. The NPCs also had an increased...

GM1 gangliosidosis is a lysosomal storage disease caused by loss of β-galactosidase activity and characterized progressive neurodegeneration due to massive accumulation ganglioside in the brain. Here, we generated induced pluripotent stem cells (iPSCs) derived from patients with gangliosidosis, resultant neurons showed impaired neurotransmitter release as presynaptic function ganglioside. Treatment normal also disturbed function. A high-content drug-screening system was then established...

Abstract Crosslinking BCR in the immature B cell line WEHI-231 causes apoptosis. We found that Bcl-xL was degraded by polyubiquitination upon crosslinking and this study explored mechanism controls degradation of Bcl-xL. Ser62 phosphorylated JNK to trigger polyubiquitination, opposed serine/threonine protein phosphatase 6 (PP6) physically associated with show decreased PP6 activity allow phosphorylation CD40 rescues BCR-induced apoptosis, we activation response CD40. Our data suggest is...

Neoadjuvant immunotherapy, given before surgical resection, is a promising approach to develop systemic antitumor immunity for the treatment of high-risk resectable disease. Here, using syngeneic and orthotopic mouse models triple-negative breast cancer, we have tested hypothesis that generation tumor-specific T-cell responses by induction activation tumor-residing Batf3-dependent conventional type 1 dendritic cells (cDC1) resection improves control distant metastatic disease survival. Mice...

Intralesional therapy is a promising approach for remodeling the immunosuppressive tumor microenvironment while minimizing systemic toxicities. A combinatorial in situ immunomodulation (ISIM) regimen with intratumoral administration of Fms-like tyrosine kinase 3 ligand (Flt3L), local irradiation, and TLR3/CD40 stimulation induces activates conventional type 1 dendritic cells elicits de novo adaptive T cell immunity poorly cell-inflamed tumors. However, impact ISIM on myeloid-derived...

Abstract Despite recent progress in therapeutic strategies, prognosis of metastatic triple-negative breast cancer (TNBC) remains dismal. Evidence suggests that the induction and activation tumor-residing conventional type-1 dendritic cells (cDC1s) is critical for generation CD8 + T mediate regression mammary tumors potentiate anti-PD-1/PD-L1 efficacy. However, it unknown whether this strategy effective against TNBC, which poorly responsive to immunotherapy. Here, using a mouse model we...

In order to investigate genetic impact of a large amount radionuclides released by the Fukushima Dai-ichi Nuclear Power Plant accident in 2011, we surveyed 2,304 haploid genomes Drosophila melanogaster collected three localities 2012 and 2013 for chromosomal inversions. No unique inversion was found 298 only two 2,006 2013. The observed frequencies were even lower than long-term average frequency inversions Japan. common cosmopolitan also examined Fukushima, Kyoto, Iriomote (Okinawa) 2012....

Sialidosis is a neuropathic lysosomal storage disease caused by deficiency in the NEU1 gene-encoding neuraminidase and characterized abnormal accumulation of undigested sialyl-oligoconjugates systemic organs including brain. Although patients exhibit neurological symptoms, underlying neuropathological mechanism remains unclear. Here, we generated induced pluripotent stem cells (iPSCs) from skin fibroblasts with sialidosis differentiation into neural progenitor (NPCs) neurons. NPCs neurons...

Both brain-derived neurotrophic factor (BDNF) and glucocorticoids (GCs) have multiple roles in the various aspects of neurons, including cell survival synaptic function. BDNF its receptor TrkB express central nervous system (CNS) neurons extensively, contribution BDNF/TrkB neuronal function is evident, thus, downregulation has been considered to be involved pathogenesis Alzheimer’s disease (AD). GCs, a stress-related molecule, glucocorticoid (GR) are also associated with AD, addition mental...

Human induced pluripotent stem cells (iPSCs) and their progeny displaying tissue-specific characteristics have paved the way for regenerative medicine research in various fields such as elucidation of pathological mechanism diseases discovery drug candidates. iPSC-derived neurons are particularly valuable it is difficult to analyze neural obtained from central nervous system humans. For neuronal induction with iPSCs, one commonly used approaches isolation expansion rosettes, following...

Among neurotrophins, which are composed of nerve growth factor (NGF), brain-derived neurotrophic (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5), BDNF has been extensively studied for its physiological role in cell survival synaptic regulation the central nervous system (CNS) neurons. binds to TrkB (a tyrosine kinase) with high affinity resulting downstream intracellular signaling cascades play crucial roles determining fate, including neuronal differentiation maturation CNS It...

<p>Supplementary Figure 4. Related to Fig. 2, 3 and Supplementary 5-7. 68-year-old female with bilateral lung metastases multiple mediastinal lymph node metastasis was treated chemo-immunotherapy (carboplatin, pemetrexed, pembrolizumab). PD-L1 expression in the pre-treatment tumor specimen 2%. The patient had stable disease for 621 days overall survival > years. A Contrast-enhanced cross-sectional imaging obtained at prior during treatment. B Expression of CX3CR1 peripheral blood...