A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression

SummarySignaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias

A Critical Role of c-Cbl-Interacting Protein of 85 kDa in the Development and Progression of Head and Neck Squamous Cell Carcinomas through the Ras-ERK Pathway12

Activation of the transforming growth factor (TGF) α/epidermal growth factor receptor (EGFR)-mediated signaling pathway is a common mechanism for dysregulated growth of head and neck squamous cell carcinoma (HNSCC). c-Cbl-interacting protein of 85 kDa (CIN85) is an adaptor protein that facilitates EGFR internalization. Little is known, however, about a role of CIN85 in EGFR signaling as well as its relevance to tumor development and progression of HNSCC. Here, we demonstrate that CIN85 is highly expressed in HNSCC tumor samples compared with adjacent normal tissues, and this overexpression is significantly correlated with advanced clinical stage. The experiments using CIN85-overexpressing and knockdown HNSCC cell lines showed that CIN85 promotes HNSCC growth and facilitates EGFR internalization without apparently affecting phosphorylation of EGFR. Moreover, CIN85 promoted TGF-α-induced activation of Ras and phosphorylation of downstream molecules such as c-Raf, MEK, and extracellular signal-regulated kinase, leading to expression of c-Myc that is critical for sustained proliferation of HNSCC. Taken together, these findings suggest that CIN85 not only controls EGFR internalization but also promotes the EGFR-mediated tumor development and progression, and thus, CIN85 may serve as a potential therapeutic target in a subset of HNSCC

MOESM2 of Musashi-1 is the candidate of the regulator of hair cell progenitors during inner ear regeneration

Additional file 2: Fig. S1. Representative images of hematoxylin–eosin–stained sections of the sensory epithelium from chicken utricles. (A) Epithelium from a control (saline-injected) chicken. (B) Epithelium from a gentamicin sulfate-injected chicken on day 14 postinjection. Extruded hair cells (arrowheads) and phagocytosis (arrows) are indicated. Fig. S2. Representative images of BrdU incorporation in the utricle as analyzed by immunohistochemistry in control chickens (A) and aminoglycoside-treated chickens on days 2 (B), 7 (C), and 14 (D) after the last gentamicin injection. Fig. S3 Relative expression of the ATOH1 gene. Increased ATOH1 mRNA levels were detected in supporting cells 3 h after aminoglycoside injection and continued for the next 14 days (*p < 0.05)

MOESM1 of Musashi-1 is the candidate of the regulator of hair cell progenitors during inner ear regeneration

Additional file 1: Table S1. Primers used for quantitative RT-PCR. Table S2. Genes upregulated more than fivefold in hair cell s than in supporting cells. Table S3. Genes upregulated more than 2.5-fold in supporting cells than in hair cells

The glycosylation design space for recombinant lysosomal replacement enzymes produced in CHO cells

Lysosomal replacement enzymes are taken up by cell surface receptors that recognize glycans, the effects of different glycan features are unknown. Here the authors present a gene engineering screen in CHO cells that allows custom N-glycan-decorated enzymes with improved circulation time and organ distribution

Additional file 3: Figure S2. of Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis

Phenotypic analysis of RANKL+ and RANKL− effector memory B cells. Purified switched-memory B cells from HC were stimulated with BCR/CD40 and IFN-γ for 48 hours. RANKL+ and RANKL− cells were analyzed for expression of CD20, CD21, CD95, CD11c, CCR1 and CCR5 using respective Abs (all from BioLegend). Representative data are shown (n = 3–4). (PDF 177 kb

Additional file 1: Table S1. of Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis

Clinical characterization of patients with RA included in the study. (DOCX 18 kb