Hot off the presses! Jul 01 Nat Med

The Jul 01 issue of the Nat Med is now up on Pubget (About Nat Med): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• The insider's guide to plagiarism
  - Nat Med 15(7):707 (2009)
  Scientific plagiarism—a problem as serious as fraud—has not received all the attention it deserves.
• Conflict of interest rules seen by some as too stringent
  - Nat Med 15(7):709 (2009)
  Increasing public and congressional scrutiny has in recent months led many major medical institutions to adopt stricter conflict of interest regulations such as gift bans and consulting restrictions. The new rules are intended to curtail industry influence in medicine.
• A close look at acid reflux drugs points to possible risks
  - Nat Med 15(7):710 (2009)
  For tens of millions of people, antacid tablets aren't enough to quell the burning chest pains from acid reflux. As a result, many turn to powerful proton pump inhibitors (PPIs) such as Nexium and Prevacid.
• Report details changes and challenges for women in biomedicine
  - Nat Med 15(7):711 (2009)
  In 1997, a year after becoming a full professor of otolaryngology and pediatrics at the State University of New York (SUNY) in Buffalo, Linda Brodsky offered to help her department chairman prepare for a review of their residency training program. As part of her duties, she reviewed a list of her colleagues' salaries.
• NIH pushes for rare disease drugs
  - Nat Med 15(7):711 (2009)
  The US National Institutes of Health (NIH) has announced a new $24 million program to develop drugs for rare diseases.Nearly 90% of potential drugs get ruled out via expensive testing during costly preclinical trials, often dubbed the 'Valley of Death'.
• New initiative launched to support research in Africa
  - Nat Med 15(7):712 (2009)
  Newton Kumwenda knows firsthand the barriers to conducting biomedical research in Africa's poorest countries.As an epidemiologist at the University of Malawi, he has produced more than a dozen papers on HIV within the last two years.
• Medical research charities brace for economic impact
  - Nat Med 15(7):712 (2009)
  The majority of charities that fund medical research are bracing for the impact of the current economic recession, and they're making an early call for help.According to a survey released on 27 May by the UK-based Association of Medical Research Charities (AMRC), three-quarters of the organization's affiliated charities expect the economic downturn to have a marked impact on their income.
• High-tech bandages lighten the load of light therapy
  - Nat Med 15(7):713 (2009)
  Tiny electronic lights embedded in a small, flexible bandage may provide a new way to zap tumor cells in people with skin cancer.The technology, emerging from two British companies, Polymertronics and Lumicure, harnesses a type of light source known as 'organic' light–emitting diodes (OLEDs).
• Nuclear watchdog and WHO move forward against cancer
  - Nat Med 15(7):713 (2009)
  A pilot project coordinated jointly by the World Health Organization (WHO) and the International Atomic Energy Agency to assist developing nations in setting up cancer programs specific to their needs is hoping to expand delivery of therapy within some of the world's poorest countries.The number of people with cancer in the developing world is expected to double from 5 million in 2000 to 10 million by the year 2020, a reality that no nation can afford to ignore.
• News in brief
  - Nat Med 15(7):714-715 (2009)
  May 21The Joint United Nations Programme on HIV/AIDS (UNAIDS) was joined by organizations such as the International AIDS Society in its call for the elimination of mother-to-child transmission of HIV by 2015 through timely administration of antiretroviral drugs to pregnant women with the virus.
• Straight talk with... Mauro Ferrari
  - Nat Med 15(7):716-717 (2009)
  Mauro Ferrari has Texas-size aspirations for using nanotechnology to treat illness. He teaches at both the University of Texas and Rice University — and at the same time serves as president for the Alliance of NanoHealth, a Houston-based body for promoting nanomedicine. This past June, Ferrari also became professor and chairman of the newly established Department of Nanomedicine and Biomedical Engineering (nBME) at the University of Texas Health Science Center at Houston. With this new department, Ferrari aims to bring researchers from a wide range of medical and scientific disciplines together under one roof to develop new nanomedicines. The department will also train the next generation of medical students, allowing nanomedicine to become an integral part of the medical curriculum at the University of Texas. During a visit to the UK in June to speak at the launch of Swansea University's Centre for NanoHealth, touted as Europe's first center devoted to nanomedicine, Ferrari met with Jon Evans to discuss nanomedicine, the importance of matching technology to therapeutic need and becoming a medical student in his mid-40s.
• Outpacing Cancer
  - Nat Med 15(7):718-722 (2009)
  In the late 1990s the drug gefitinib became a new tool in treating the most common type of lung cancer, called non–small cell lung cancer. But doctors found that even with continued gefitinib treatment, some patients experienced a cancer relapse within a year. For the past several years, researchers have been working to uncover why these patients lost sensitivity to gefitinib and seeking how to overcome resistance to the drug. Kirsten Dorans reports on the strategies scientists are developing to outpace continually evolving cancer.
• Australian funding overhaul set into motion
  - Nat Med 15(7):723 (2009)
  Australian medical researchers are looking for a share of an unprecedented boost to public research funding as the Australian government responds to the global financial crisis.Australia's 2009–2010 federal spending on science and innovation will soar 25% year on year, a commitment welcomed by the Federation of Australians Scientific and Technological Societies, a research industry association, as "exceptional" and "well above expectations.
• Lawsuit sparks calls for libel law reform
  - Nat Med 15(7):723 (2009)
  Last summer, the British Chiropractic Association filed a libel suit against science journalist Simon Singh for writing that the association "happily promotes bogus treatments." In May, the two parties met for a preliminary hearing.
• Indian universities face misconduct allegations
  - Nat Med 15(7):723 (2009)
  A report by the Times of India newspaper alleging that admissions to medical school might have been sold for money at two private institutions has stirred controversy in India. The newspaper has said it caught officials on tape demanding as much as Rs 4 million ($80,000) for admission to medical degree programs without providing receipts.
• Drug development's dark side
  - Nat Med 15(7):724 (2009)
  In the late 1980s, on the basis of psychoanalytic theory, child psychiatrists generally believed that children were incapable of becoming depressed. In spite of this, children as young as ten years old were hospitalized because of symptoms of severe depression.
• Antibody affinity maturation and respiratory syncytial virus disease
  - Nat Med 15(7):725 (2009)
  The mouse immunization experiments reported in Delgado et al.1 support the hypothesis that failure to elicit affinity-matured, neutralizing antibodies contributed to disease enhancement after immunization of children with a formalin-inactivated respiratory syncytial virus vaccine candidate (FI-RSV) in the 1960s. However, the authors' assertion that lack of protection by FI-RSV was "not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes" is not justified by the data presented.
• Reply to: "Antibody affinity maturation and respiratory syncytial virus disease"
  - Nat Med 15(7):725-726 (2009)
  Shaw et al.1 state that our observations indicate that a protective RSV vaccine must elicit affinity-matured neutralizing antibodies for enhanced respiratory disease (ERD) not to occur2. We agree with this statement.
• Will integrin inhibitors have proangiogenic effects in the clinic?
  - Nat Med 15(7):726 (2009)
  In a comprehensive analysis, Reynolds et al.1 recently reported that RGD-mimetic agents such as cilengitide may, under certain experimental conditions, promote rather than inhibit angiogenesis. They accordingly express their reservations regarding the clinical exploration of such agents in human patients with cancer.
• Reply to: "Will integrin inhibitors have proangiogenic effects in the clinic?"
  - Nat Med 15(7):727 (2009)
  Outcome in glioblastoma multiforme (GBM) is extremely poor, with median progression-free survival and overall survival of only 6.9 and 14.
• Receptors identified for hand, foot and mouth virus
  - Nat Med 15(7):728-729 (2009)
  Two receptors have now been identified for the virus behind severe hand, foot and mouth disease (pages 794–797 and 798–801).
• Coupling bone degradation to formation
  - Nat Med 15(7):729-731 (2009)
  To maintain skeletal integrity and prevent fractures, degradation and rebuilding of bone must occur in synchrony. Transforming growth factor-1 is now found to coordinate this restructuring process: the molecule is released during bone degradation and stimulates bone rebuilding (pages 757–765).
• Tumor immunotherapy: making an immortal army
  - Nat Med 15(7):731-732 (2009)
  Manipulation of cell renewal pathways creates T memory stem cells that can generate a sustained and targeted immune response. These findings have broad implications for vaccine development and immunotherapy (pages 808–813).
• Targeting lymphotoxin depletes pathogenic T cells
  - Nat Med 15(7):732-733 (2009)
  A monoclonal antibody directed against lymphotoxin- (LT-) expressed by pathogenic T cells can prompt the clearance of these cells from the body (pages 766–773). The findings bring us one step closer to targeting only the cell populations that cause harm in autoimmune diseases while leaving beneficial arms of the immune system largely intact.
• Hedgehog inhibitor pokes tumor
  - Nat Med 15(7):734 (2009)
  Patients with the most common form of pancreatic cancer, ductal adenocarcinoma, barely respond to therapy. A study in mice now opens the door to a new approach.
• Damage control in the nervous system: rehabilitation in a plastic environment
  - Nat Med 15(7):735-736 (2009)
  People with damage to the central nervous system often undergo rehabilitation therapy. James Fawcett and Armin Curt examine how such therapy might work in conjunction with experimental approaches that increase the ability of neurons to form new connections. They discuss how animal studies raise questions about how to test such approaches in people in a field where firm data are already hard to come by. Phillip Popovich and Dana McTigue take a look at a specific type of nervous system damage—spinal cord injury—and argue that the role of the immune system is underappreciated. They also suggest that one common therapy, application of glucocorticoids, might actually exacerbate the condition.
• Damage control in the nervous system: beware the immune system in spinal cord injury
  - Nat Med 15(7):736-737 (2009)
  Stroke and traumatic brain injury adversely affect the immune system. Immune suppression is well documented, denoted by apoptosis of splenocytes, impaired production of cytokines from leukocytes and leukopenia (low white blood cell count)1.
• Research Highlights
  - Nat Med 15(7):738-739 (2009)
  
• GOAT links dietary lipids with the endocrine control of energy balance
  - Nat Med 15(7):741-745 (2009)
  Central nervous system nutrient sensing and afferent endocrine signaling have been established as parallel systems communicating metabolic status and energy availability in vertebrates. The only afferent endocrine signal known to require modification with a fatty acid side chain is the orexigenic hormone ghrelin. We find that the ghrelin O-acyl transferase (GOAT), which is essential for ghrelin acylation, is regulated by nutrient availability, depends on specific dietary lipids as acylation substrates and links ingested lipids to energy expenditure and body fat mass. These data implicate the ghrelin-GOAT system as a signaling pathway that alerts the central nervous system to the presence of dietary calories, rather than to their absence as is commonly accepted.
• Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates
  - Nat Med 15(7):746-749 (2009)
  Memory T cells promote allograft rejection particularly in co-stimulation blockade–based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function–associated antigen-3–Ig; LFA -3–Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade–based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan–T cell depletion.
• A small molecule blocking oncogenic protein EWS-FLI1 interaction with RNA helicase A inhibits growth of Ewing's sarcoma
  - Nat Med 15(7):750-756 (2009)
  Many sarcomas and leukemias carry nonrandom chromosomal translocations encoding tumor-specific mutant fusion transcription factors that are essential to their molecular pathogenesis. Ewing's sarcoma family tumors (ESFTs) contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. EWS-FLI1 binding to RNA helicase A (RHA) is important for its oncogenic function. We therefore used surface plasmon resonance screening to identify compounds that bind EWS-FLI1 and might block its interaction with RHA. YK-4-279, a derivative of the lead compound from the screen, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular! binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents.
• TGF-1–induced migration of bone mesenchymal stem cells couples bone resorption with formation
  - Nat Med 15(7):757-765 (2009)
  Bone remodeling depends on the precise coordination of bone resorption and subsequent bone formation. Disturbances of this process are associated with skeletal diseases, such as Camurati-Engelmann disease (CED). We show using in vitro and in vivo models that active TGF-1 released during bone resorption coordinates bone formation by inducing migration of bone marrow stromal cells, also known as bone mesenchymal stem cells, to the bone resorptive sites and that this process is mediated through a SMAD signaling pathway. Analyzing mice carrying a CED-derived mutant TGFB1 (encoding TGF-1), which show the typical progressive diaphyseal dysplasia seen in the human disease, we found high levels of active TGF-1 in the bone marrow. Treatment with a TGF- type I receptor inhibitor partially rescued the uncoupled bone remodeling and prevented the fractures. Thus, as TGF-1 functions to couple bone resorption and formation, modulation of TGF-1 activity could be an effective treatment! for bone remodeling diseases.
• Targeted depletion of lymphotoxin-–expressing TH1 and TH17 cells inhibits autoimmune disease
  - Nat Med 15(7):766-773 (2009)
  Uncontrolled T helper type 1 (TH1) and TH17 cells are associated with autoimmune responses. We identify surface lymphotoxin- (LT-) as common to TH0, TH1 and TH17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-. Depleting LT-–specific mAb inhibited T cell–mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-–specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon- and tumor necrosis factor- (TNF-), whereas decoy lymphotoxin- receptor (LT-R) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fc receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6,! IL-1 and TNF- within joints. These data indicate that depleting LT-–expressing lymphocytes with LT-–specific mAb may be beneficial in the treatment of autoimmune disease.
• Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease
  - Nat Med 15(7):774-780 (2009)
  Although there have been major advances in the treatment of rheumatoid arthritis with the advent of biological agents, the mechanisms that drive cytokine production and sustain disease chronicity remain unknown. Tenascin-C (encoded by Tnc) is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. Here we show that mice that do not express tenascin-C show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra-articular injection of tenascin-C promotes joint inflammation in vivo in mice, and addition of exogenous tenascin-C induces cytokine synthesis in explant cultures from inflamed synovia of individuals with rheumatoid arthritis. Moreover, in human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis, tenascin-C induces synthesis of proinflammatory cytokines via activation of Toll-like receptor 4 (TLR4). Thus, we have identi! fied tenascin-C as a novel endogenous activator of TLR4-mediated immunity that mediates persistent synovial inflammation and tissue destruction in arthritic joint disease.
• A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
  - Nat Med 15(7):781-787 (2009)
  The immunoproteasome, a distinct class of proteasome found predominantly in monocytes and lymphocytes, is known to shape the antigenic repertoire presented on class I major histocompatibility complexes (MHC-I). However, a specific role for the immunoproteasome in regulating other facets of immune responses has not been established. We describe here the characterization of PR-957, a selective inhibitor of low–molecular mass polypeptide-7 (LMP7, encoded by Psmb8), the chymotrypsin-like subunit of the immunoproteasome. PR-957 blocked presentation of LMP7-specific, MHC-I–restricted antigens in vitro and in vivo. Selective inhibition of LMP7 by PR-957 blocked production of interleukin-23 (IL-23) by activated monocytes and interferon- and IL-2 by T cells. In mouse models of rheumatoid arthritis, PR-957 treatment reversed signs of disease and resulted in reductions in cellular infiltration, cytokine production and autoantibody levels. These studies reveal a unique role fo! r LMP7 in controlling pathogenic immune responses and provide a therapeutic rationale for targeting LMP7 in autoimmune disorders.
• Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system
  - Nat Med 15(7):788-793 (2009)
  Previous proteomic and transcriptional analyses of multiple sclerosis lesions1, 2, 3 revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice4, 5, 6, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-Nal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1-/-) C57BL/6 mice7 immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow–chimeric mice reconstituted with Bdkrb1-/- T lymphocytes, which showed enhanced T helper type 17 (TH17) cell invasion i! nto the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.
• Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71
  - Nat Med 15(7):794-797 (2009)
  Enterovirus 71 (EV71) is a major causative agent of hand, foot and mouth disease (HFMD), a common febrile disease occurring mainly in young children. Although clinical manifestations of HFMD are usually mild and self limiting, a severe EV71 outbreak can lead to a diverse array of neurological diseases. Identification of the specific cellular receptors is crucial for elucidating the mechanism of early virus-host interactions and the pathogenesis of enteroviruses1. Here we identify human P-selectin glycoprotein ligand-1 (PSGL-1; CD162), a sialomucin membrane protein expressed on leukocytes that has a major role in early stages of inflammation2, 3, 4, as a functional receptor for EV71 using an expression cloning method by panning5. The N-terminal region of PSGL-1 binds specifically to EV71. Stable PSGL-1 expression allowed EV71 entry and replication, and development of cytopathic effects in nonsusceptible mouse L929 cells. Five out of eight EV71 strains bound soluble PSGL! -1 and used intact PSGL-1 as the primary receptor for infection of Jurkat T cells. Three other EV71 strains did not use PSGL-1, suggesting the presence of strain-specific replication of EV71 in leukocytes. EV71 replicated in nonleukocyte cell lines in a PSGL-1–independent manner, indicating the presence of alternative receptor(s) for EV71. The identification of PSGL-1 as a receptor for EV71 sheds new light on a role for PSGL-1–positive leukocytes in cell tropism and pathogenesis during the course of HFMD and other EV71-mediated diseases.
• Scavenger receptor B2 is a cellular receptor for enterovirus 71
  - Nat Med 15(7):798-801 (2009)
  Enterovirus 71 (EV71) belongs to human enterovirus species A of the genus Enterovirus within the family Picornaviridae1. EV71, together with coxsackievirus A16 (CVA16), are most frequently associated with hand, foot and mouth disease (HFMD)1. Although HFMD is considered a mild exanthematous infection, infections involving EV71, but not CVA16, can progress to severe neurological disease, including fatal encephalitis, aseptic meningitis and acute flaccid paralysis2. In recent years, epidemic and sporadic outbreaks of neurovirulent EV71 infections have been reported in Taiwan, Malaysia, Singapore, Japan and China3, 4, 5, 6, 7. Here, we show that human scavenger receptor class B, member 2 (SCARB2, also known as lysosomal integral membrane protein II or CD36b like-2) is a receptor for EV71. EV71 binds soluble SCARB2 or cells expressing SCARB2, and the binding is inhibited by an antibody to SCARB2. Expression of human SCARB2 enables normally unsusceptible cell lines to suppo! rt EV71 propagation and develop cytopathic effects. EV71 infection is hampered by the antibody to SCARB2 and soluble SCARB2. SCARB2 also supports the infection of the milder pathogen CVA16. The identification of SCARB2 as an EV71 and CVA16 receptor contributes to a better understanding of the pathogenicity of these viruses.
• Hematopoietic colony–stimulating factors mediate tumor-nerve interactions and bone cancer pain
  - Nat Med 15(7):802-807 (2009)
  Pain is one of the most severe and debilitating symptoms associated with several forms of cancer1, 2. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves2. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood2. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells3 and tumor cells4. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF)3 are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led t! o reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve–specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.
• Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells
  - Nat Med 15(7):808-813 (2009)
  Self-renewing cell populations such as hematopoietic stem cells and memory B and T lymphocytes might be regulated by shared signaling pathways1. The Wnt–-catenin pathway is an evolutionarily conserved pathway that promotes hematopoietic stem cell self-renewal and multipotency by limiting stem cell proliferation and differentiation2, 3, but its role in the generation and maintenance of memory T cells is unknown. We found that induction of Wnt–-catenin signaling by inhibitors of glycogen sythase kinase-3 or the Wnt protein family member Wnt3a arrested CD8+ T cell development into effector cells. By blocking T cell differentiation, Wnt signaling promoted the generation of CD44lowCD62LhighSca-1highCD122highBcl-2high self-renewing multipotent CD8+ memory stem cells with proliferative and antitumor capacities exceeding those of central and effector memory T cell subsets. These findings reveal a key role for Wnt signaling in the maintenance of 'stemness' in mature memory ! CD8+ T cells and have major implications for the design of new vaccination strategies and adoptive immunotherapies.
• Validated germline-competent embryonic stem cell lines from nonobese diabetic mice
  - Nat Med 15(7):814-818 (2009)
  Nonobese diabetic (NOD) mice provide an excellent model of type 1 diabetes. The genetic contribution to this disease is complex, with more than 20 loci implicated in diabetes onset. One of the challenges for researchers using the NOD mouse model (and, indeed, other models of spontaneous autoimmune disease) has been the high density of sequence variation within candidate chromosomal segments. Furthermore, the scope for analyzing many putative disease loci via gene targeting has been hampered by the lack of NOD embryonic stem (ES) cells. We describe here the derivation of NOD ES cell lines capable of generating chimeric mice after stable genetic modification. These NOD ES cell lines also show efficient germline transmission, with offspring developing diabetes. The availability of these cells will not only enable the dissection of closely linked loci and the role they have in the onset of type 1 diabetes but also facilitate the generation of new transgenics.
• Erratum: Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer
  - Nat Med 15(7):819 (2009)
  Introduction Nat. Med. 15, 559–565 (2009); published online 12 April 2009; corrected after print 7 July 2009 In the version of this article initially published, some of the sample identifiers were missing from Figure 1e. The error has been corrected in the HTML and PDF versions of the article.
• Corrigendum: Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies
  - Nat Med 15(7):819 (2009)
  Introduction Nat. Med. 15, 528–536 (2009); published online 26 April 2009; corrected after print 7 July 2009 In the version of this article initially published, the two right histological sections in Figure 5a were duplicated in Figure 5b. The error has been corrected in the HTML and PDF versions of the article.