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Carnegie, NJ, United States

Yamaguchi J.,University of Tokyo | Tanaka T.,University of Tokyo | Eto N.,Kyowa Hakko Kirin Pharma Inc. | Nangaku M.,University of Tokyo
Kidney International | Year: 2015

Tubulointerstitial hypoxia plays a critical role in the pathogenesis of kidney injury, and hypoxia-inducible factor (HIF)-1 is a master regulator of cellular adaptation to hypoxia. Aside from oxygen molecules, factors that modify HIF-1 expression and functional operation remain obscure. Therefore, we sought to identify novel HIF-1-regulating genes in kidney. A short-hairpin RNA library consisting of 150 hypoxia-inducible genes was derived from a microarray analysis of the rat renal artery stenosis model screened for the effect on HIF-1 response. We report that CCAAT/enhancer-binding protein δ (CEBPD), a transcription factor and inflammatory response gene, is a novel HIF-1 regulator in kidney. CEBPD was induced in the nuclei of tubular epithelial cells in both acute and chronic hypoxic kidneys. In turn, CEBPD induction augmented HIF-1α expression and its transcriptional activity. Mechanistically, CEBPD directly bound to the HIF-1α promoter and enhanced its transcription. Notably, CEBPD was rapidly induced by inflammatory cytokines, such as IL-1β in a nuclear factor-κB-dependent manner, which not only increased HIF-1α expression during hypoxia, but was also indispensable for the non-hypoxic induction of HIF-1α. Thus our study provides novel insight into HIF-1 regulation in tubular epithelial cells and offers a potential hypoxia and inflammation link relevant in both acute and chronic kidney diseases. © 2015 International Society of Nephrology.

Dalbeth N.,University of Auckland | Lauterio T.J.,URL Pharma Inc. | Wolfe H.R.,Kyowa Hakko Kirin Pharma Inc.
Clinical Therapeutics | Year: 2014

Purpose The aims of this article were to systematically review the literature about the mechanism of action of colchicine in the multimodal pathology of acute inflammation associated with gout and to consider the clinical utility of colchicine in other chronic inflammatory diseases.Methods The English-language literature on PubMed was searched for articles published between 1990 and October 2013, with a cross-reference to citations across all years. Relevant articles pertaining to the mechanism of action of colchicine and the clinical applications of colchicine in gout and other inflammatory conditions were identified and reviewed.Findings The molecular pathology of acute inflammation associated with gouty arthritis involves several concurrent pathways triggered by a variety of interactions between monosodium urate crystals and the surface of cells. Colchicine modulates multiple pro- and antiinflammatory pathways associated with gouty arthritis. Colchicine prevents microtubule assembly and thereby disrupts inflammasome activation, microtubule-based inflammatory cell chemotaxis, generation of leukotrienes and cytokines, and phagocytosis. Many of these cellular processes can be found in other diseases involving chronic inflammation. The multimodal mechanism of action of colchicine suggests potential efficacy of colchicine in other comorbid conditions associated with gout, such as osteoarthritis and cardiovascular disease.Implications Colchicine has multiple mechanisms of action that affect inflammatory processes and result in its utility for treating and preventing acute gout flare. Other chronic inflammatory diseases that invoke these molecular pathways may represent new therapeutic applications for colchicine. © 2014 The Authors. Published by Elsevier HS Journals, Inc.

Yamada T.,Kanazawa University | Bando H.,Kanazawa University | Takeuchi S.,Kanazawa University | Kita K.,Kanazawa University | And 6 more authors.
Cancer Science | Year: 2011

Small-cell lung cancer (SCLC) grows rapidly and metastasizes to multiple organs. We examined the antimetastatic effects of the humanized anti-ganglioside GM2 (GM2) antibodies, BIW-8962 and KM8927, compared with the chimeric antibody KM966, in a SCID mouse model of multiple organ metastases induced by GM2-expressing SCLC cells. BIW-8962 and KM8927 induced higher antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity than KM966 against the GM2-expressing SCLC cell line SBC-3 in vitro. These humanized antibodies inhibited the production of multiple organ metastases, increased the number of apoptotic cells, and prolonged the survival of the SCID mice. Histological analyses using clinical specimens showed that SCLC cells expressed GM2. These findings suggest that humanized anti-GM2 antibodies could be therapeutically useful for controlling multiple organ metastases of GM2-expressing SCLC. © 2011 Japanese Cancer Association.

News Article | July 29, 2015
Site: www.xconomy.com

In what may be a sign of the times, an independent, nonprofit biomedical research institute in San Diego that is focused on immune diseases and disorders has officially established ties with the UC San Diego Health System. The agreement signed by the La Jolla Institute for Allergy & Immunology and the UC San Diego Health System formalizes an informal relationship that began when the institute was founded 27 years ago. The institute’s first board included prominent leaders from UC San Diego and The Scripps Research Institute, and informal agreements with the UCSD Medical Center allowed joint research activities, consultation, and training in allergy and immunology. But as federal research funding has come under pressure in recent years, the institute has sought to bolster its funding by seeking other partnerships, according to Mitchell Kronenberg, who has served as the institute’s president and chief scientific officer since 2003. The institute, which has 272 scientists and a total headcount of 375, usually gets about $51 million in annual funding, mostly through federal grants from the National Institutes of Health and from the Japanese pharmaceutical company Kyowa Hakko Kirin. As part of the new agreement, UCSD will provide $36 million over the next 12 years, enabling the La Jolla institute to recruit and retain leading scientists. That will provide an extra $3 million a year for the institute, “so that’s really helpful,” Kronenberg said. He anticipates the institute will get about $53 million in funding in the coming fiscal year. All of the institute’s scientists will become adjunct professors at UC San Diego, dramatically expanding the university’s focus on the immune system. That includes the development of therapeutic vaccines to inhibit the inflammatory response in coronary heart disease, and new approaches to treating cancers by engineering a patients’ own immune cells to recognize and attack their tumors. The institute’s Center for Infectious Disease also has been working to identify antibodies that could be used to defend people against bioterrorism.. “We had interest from several academic centers,” Kronenberg said of the new partnership. “We had extensive discussions with two other entities besides UC San Diego.” One of those other entities was the University of Southern California, according to The San Diego Union-Tribune. With $4.5 billion in private donations raised to heighten USC’s academic profile, the school has been aggressively expanding its capabilities in life sciences research and development, and spending freely to recruit prominent scientists in biomedical research. Kronenberg declined to confirm the Union-Tribune report in an interview with me, explaining that he was bound to maintain the confidentiality of his discussions with other centers. Nevertheless, many UC San Diego leaders have been angry and defensive since a fight erupted last month between USC and UCSD over a program that coordinates research in Alzheimer’s disease (including many clinical trials) among scores of sites throughout the United States and Canada. UCSD founded the program with the National Institute on Aging (NIA) in 1991 as a kind of joint venture to facilitate the discovery, development, and testing of new drugs for the treatment of Alzheimer’s disease. “All of the institutions in San Diego collaborate; there’s a very collegial atmosphere,” David Brenner, dean of the UC San Diego School of Medicine, told Union-Tribune reporter Gary Robbins. “USC doesn’t want that. It wants to buy, rather than build, academic programs.” In 2014, USC attempted to join forces with The Scripps Research Institute—reportedly offering $15 million a year for 40 years for a partnership or wholesale acquisition of the biomedical research center. The proposal triggered a revolt among Scripps’ scientists, who stridently opposed the idea. The universities’ feud over the Alzheimer’s program led UC San Diego to sue USC, former UCSD scientist Paul Aisen, and others—alleging that they conspired to “misappropriate” the Alzheimer’s study while USC was recruiting Aisen to lead a new San Diego-based Alzheimer’s research institute for USC. After hearing arguments in the dispute at a hearing Friday, San Diego Superior Court Judge Judith Hayes granted UCSD’s request for a preliminary injunction against USC, Aisen, and other defendants in the dispute. The order represents the first step in restoring ownership of the Alzheimer’s program to UC San Diego, as well as control over a computer network and database that holds 24 years’ worth of Alzheimer’s research data. But arguments in the case have continued, and a final resolution of the dispute remains unclear. Meanwhile, Kronenberg said the La Jolla immunology institute determined that UC San Diego is “our natural partner” because of proximity (the institute is a few hundred feet east of UCSD’s Moores Cancer Center) and the institute’s longstanding ties with UCSD. “We don’t have any debt, and we weren’t in a rescue situation,” he said. Research at the institute includes work on autoimmune diseases like Type 1 (juvenile) diabetes and rheumatoid arthritis, developing immunotherapies to trigger an immune response to cancer, creating new vaccines, dampening harmful immune reactions to allergies and asthma, and finding new ways to battle infectious diseases. Under the institute’s new agreement with UC San Diego, the CEO of UC San Diego’s Health System will join the institute’s board as an ex officio member, and the dean of UCSD’s medical school will join the institute’s scientific advisory board. As the institute’s president, Kronenberg also will serve as an unpaid adviser to UCSD’s vice president of health sciences.

Carpenter T.O.,Yale University | Imel E.A.,Indiana University | Ruppe M.D.,Methodist Hospital | Weber T.J.,Duke University | And 8 more authors.
Journal of Clinical Investigation | Year: 2014

Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674.

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