Regulation of the Catabolic Cascade in Osteoarthritis by the Zinc-ZIP8-MTF1 Axis

SummaryOsteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn2+-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis

Discovery of a Supercluster at z ~ 0.91 and Testing the ΛCDM Cosmological Model

The ΛCDM cosmological model successfully reproduces many aspects of the galaxy and structure formation of the universe. However, the growth of large-scale structures (LSSs) in the early universe is not well tested yet with observational data. Here, we have utilized wide and deep optical–near-infrared data in order to search for distant galaxy clusters and superclusters (0.8 < z < 1.2). From the spectroscopic observation with the Inamori Magellan Areal Camera and Spectrograph (IMACS) on the Magellan telescope, three massive clusters at z ~ 0.91 are confirmed in the SSA22 field. Interestingly, all of them have similar redshifts within Δ z ~ 0.01 with velocity dispersions ranging from 470 to 1300 km s−1. Moreover, as the maximum separation is ~15 Mpc, they compose a supercluster at z ~ 0.91, meaning that this is one of the most massive superclusters at this redshift to date. The galaxy density map implies that the confirmed clusters are embedded in a larger structure stretching over ~100 Mpc. ΛCDM models predict about one supercluster like this in our surveyed volume, consistent with our finding so far. However, there are more supercluster candidates in this field, suggesting that additional studies are required to determine if the ΛCDM cosmological model can successfully reproduce the LSSs at high redshift

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma.

Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor-associated protein CD79B

What Shapes Environmental Responsibility Perceptions? Measuring Value Orientations as a Predictor of Situational Motivations and Communicative Action

This study investigates individuals' cognitive, motivational, and communication responses regarding an environmental CSR issue using arguments from the situational theory of problem-solving (STOPS) with a cross-situational factor as an antecedent. Survey results provide empirical support for the application of the STOPS in a CSR communication context and suggest that a collectivistic orientation predicts individuals' situational perceptions and cognitive reactions toward organizations' environmental CSR efforts. Theoretical and practical implications for strategic communicators are discussed

Usefulness of Contrast-Enhanced CT in a Patient with Acute Phlegmonous Esophagitis: A Case Report and Literature Review

Acute phlegmonous esophagitis is a very rare, life-threatening form of esophagitis, characterized by diffuse bacterial infection and pus formation within the submucosal and muscularis layers of the esophagus. We describe a case in which contrast-enhanced chest CT was useful for evaluating the severity of phlegmonous esophagitis, which was overlooked and underestimated by endoscopy

Protein Kinase C-delta-Mediated Recycling of Active KIT in Colon Cancer

Purpose: Abnormal signaling through receptor tyrosine kinase (RTK) moieties is important in tumorigenesis and drug targeting of colorectal cancers. Wild-type KIT (WT-KIT), a RTK that is activated upon binding with stem cell factor (SCF), is highly expressed in some colon cancers; however, little is known about the functional role of SCF-dependent KIT activation in colon cancer pathogenesis. We aimed to elucidate the conditions and roles of WT-KIT activation in colon cancer tumorigenesis.Experimental Design: Colorectal cancers with KIT expression were characterized by immunoblotting and immunohistochemistry. The biologic alterations after KIT-SCF binding were analyzed with or without protein kinase C (PKC) activation.Results: We found that WT-KIT was expressed in a subset of colon cancer cell lines and was activated by SCF, leading to activation of downstream AKT and extracellular signal-regulated kinase (ERK) signaling pathways. We also showed that KIT expression gradually decreased, after prolonged SCF stimulation, due to lysosomal degradation. Degradation of WT-KIT after SCF binding was significantly rescued when PKC was activated. We also showed the involvement of activated PKC-delta in the recycling of WT-KIT. We further showed that a subset of colorectal cancers exhibit expressions of both WT-KIT and activated PKC-delta and that expression of KIT is correlated with poor patient survival (P = 0.004).Conclusions: Continuous downstream signal activation after KIT-SCF binding is accomplished through PKC-delta-mediated recycling of KIT. This sustained KIT activation may contribute to tumor progression in a subset of colon cancers with KIT expression and might provide the rationale for a therapeutic approach targeting KIT. (C) 2013 AACR.OAIID:oai:osos.snu.ac.kr:snu2013-01/102/0000030226/2SEQ:2PERF_CD:SNU2013-01EVAL_ITEM_CD:102USER_ID:0000030226ADJUST_YN:YEMP_ID:A076075DEPT_CD:3344CITE_RATE:7.837DEPT_NM:생명과학부SCOPUS_YN:YCONFIRM: