Hot off the presses! May 01 Nat Med

The May 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:

• A really serious conflict
  - Nat Med 15(5):463-464 (2009)
  Not all financial interests in drug discovery are detrimental, and many are essential for its success. But focusing on perceived conflicts of interest may cause true scientific corruption to go unnoticed.
• Autism and other developmental brain disorders
  - Nat Med 15(5):464 (2009)
  The Second Roche–Nature Medicine Translational Neuroscience Symposium on Autism and other developmental brain disorders was a resounding success.
• A master's degree with a business spin gains popularity
  - Nat Med 15(5):465 (2009)
  Working as a quality control tester in a juice factory, Brendan Tierney knew he wanted to go back to school and pursue science. But Tierney faced two problems: he did not know which specific area of biomedical science to focus on, nor did he have a sense of how he could eventually use graduate training to land a better job.
• FDA leadership picks may stress safety over swift approval
  - Nat Med 15(5):466 (2009)
  Industry leaders and consumer advocates anticipate a shift in the focus of the US Food and Drug Administration (FDA) under the leadership of Margaret Hamburg as commissioner of the agency.Hamburg was nominated by US President Barack Obama on 14 March, but as Nature Medicine went to press, she was still awaiting Senate confirmation.
• Profit-hungry pharma sees some biotechs as ripe for the picking
  - Nat Med 15(5):466 (2009)
  In late March, pharmaceutical giant Roche completed its takeover of Genentech, the company credited with founding the biotech industry more than three decades ago. The deal cost Roche nearly $47 billion.
• Flush with new funds, NIH faces challenges of distribution
  - Nat Med 15(5):467 (2009)
  According to many economists, the US is in the midst of the worst economic slump since the Great Depression. But instead of slowing down, the biomedical research community is ramping up.
• Will a robot steal your job?
  - Nat Med 15(5):467 (2009)
  A robot named Adam that can design, implement, interpret and modify its own experiments has uncovered previously unknown functions of several genes involved in yeast metabolism, British scientists have reported (Science 324, 85–89; 2009). To the authors' knowledge, Adam is the first machine to make scientific discoveries on its own.
• Studies comparing treatment options receive a boost
  - Nat Med 15(5):468 (2009)
  US scientists are trying to answer a question that has long nagged doctors and patients alike: which treatment works best for a given illness?The US National Institutes of Health will support studies toward an answer, thanks to $400 million it received from the economic stimulus package to support research for the next two years on the comparative effectiveness of treatment options for a range of diseases from Alzheimer's to asthma.
• Battle lines drawn as US moves toward generic biologics
  - Nat Med 15(5):468 (2009)
  In late March, a bipartisan group of US senators introduced a bill that would open the US market to generic versions of biologic drugs, which have until now been the all-but-exclusive province of brand-name makers.Senator Charles Schumer, the bill's leading sponsor, bemoaned the price tags of biologic drugs, large proteins that are produced by a complicated process involving living cell cultures, rather than straightforward chemistry.
• New center aims to speed drug discovery
  - Nat Med 15(5):468 (2009)
  Last month, the UK's Medical Research Council (MRC) and its related commercialization company, MRC Technology (MRCT), opened a new center designed to expedite the discovery and development of new drugs. The MRCT Centre for Therapeutics Discovery (CTD) in London opened on 2 April.
• Regulators confront blind spots in research oversight
  - Nat Med 15(5):469 (2009)
  Investigators of scientific misconduct have had their hands full in recent months. So far this year, a regional hospital in western Massachusetts has announced the discovery of what may be the biggest case of research fraud in history, scientists in Texas have used a new computer algorithm to uncover thousands of apparently plagiarized papers in peer-reviewed journals and a congressional subcommittee questioned the consistency of institutional and independent review boards (IRBs) that oversee clinical trials (see 'Coast IRB hits treacherous waters' on page 470 of this issue).
• Corrigendum: The curious case of clioquinol
  - Nat Med 15(5):469 (2009)
  Nat. Med. 15, 356–359 (2009); published online 6 April 2009; corrected after print 7 May 2009
• Unique TB-HIV research institute planned in South Africa
  - Nat Med 15(5):470 (2009)
  At a time when the dangers of HIV and tuberculosis (TB) co-infection are increasingly apparent, the Howard Hughes Medical Institute (HHMI) has teamed up with the University of KwaZulu-Natal in South Africa, to create a new international research facility dedicated entirely to studying these two diseases, as well as how they interact. The KwaZulu-Natal Research Institute for Tuberculosis and HIV will be housed within the grounds of the Nelson Mandela School of Medicine in Durban.
• Coast IRB hits treacherous waters
  - Nat Med 15(5):470 (2009)
  In early March, Coast IRB, a company based in Colorado Springs, Colorado that offers independent review board services for clinical trials, issued an unusual pair of press releases. The first claimed that the company had uncovered an inappropriate clinical trial and immediately alerted the authorities.
• Amidst scientific unrest, France mulls an institutional alliance
  - Nat Med 15(5):471 (2009)
  The French government last month announced a new alliance among several major scientific institutes as part of its proposed strategy to overhaul the country's current national research system. The proposal paves the way for the possible creation of a single linking institution: the National Alliance for Life and Health Sciences (Alliance nationale pour les sciences de la vie et de la santé).
• New animal directive moves forward
  - Nat Med 15(5):471 (2009)
  European politicians have altered key provisions in draft legislation that will eventually govern all animal experiments in the EU.The European Parliament's agriculture committee voted on 31 March to amend many of the rules that had most worried academic and industry groups when the first draft of a new Europe-wide directive was unveiled last year.
• News in brief
  - Nat Med 15(5):472-473 (2009)
  Mar 18Nearly one year after the open access policy of the US National Institutes of Health (NIH) went into effect, the faculty of the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts voted to make their scholarly articles available on a free online open source software platform known as DSpace developed in part at MIT.
• Straight talk with...Harvey Fineberg
  - Nat Med 15(5):474-475 (2009)
  In 1970, the US government chartered the Institute of Medicine (IOM), a component of the National Academies, to serve as an independent counsel on issues concerning health policy. Today, the IOM has become a leading adviser on an array of topics from vaccine safety to the organizational structure of the National Institutes of Health (NIH). The institute has nearly 1,600 members who carry out studies, conduct workshops, hold public forums and publish influential reports. Harvey Fineberg, former provost of Harvard University, has served at the helm of the IOM as the institute's president since 2002. During his tenure at the institute, Fineberg has overseen a raft of studies on topics ranging from AIDS prevention to new medical technologies. He spoke to Prashant Nair about the role of the IOM in biomedical research in the US.
• Breakthroughs Within Reach
  - Nat Med 15(5):476-479 (2009)
  Basic laboratory procedures can present physical challenges for biomedical researchers with disabilities. But a cadre of innovators has come up with technological solutions that make the laboratory bench more accessible to scientists with impaired sight or movement. Stu Hutson reports on how these adaptive research tools help people with disabilities by using everything from computer screen readers to security lasers.
• Studying insomnia
  - Nat Med 15(5):481 (2009)
  
• Interleukin-17A is not expressed by CD207+ cells in Langerhans cell histiocytosis lesions
  - Nat Med 15(5):483-484 (2009)
  In a recent issue of Nature Medicine, Coury et al.1 identified a potentially interesting role for interleukin-17 (IL-17A), a proinflammatory cytokine, in the pathogenesis of Langerhans cell histiocytosis (LCH). LCH is a disease characterized by lesions containing CD207+ (langerin+) histiocytes.
• Interleukin-17A is not expressed by CD207+ cells in Langerhans cell histiocytosis lesions
  - Nat Med 15(5):484-485 (2009)
  In our previous report in Nature Medicine1, we found interleukin-17A (IL-17A) in samples from humans with active childhood Langerhans cell histiocytosis (LCH) by performing studies at the protein level. We neutralized serum IL-17A activity in biological assays with two antibodies (from either eBiosciences (clone eBio64CAP17) or Dendritics (clone IL512G6.
• One size does fit all
  - Nat Med 15(5):485 (2009)
  Your December 2008 editorial1 on the proposal to revise the animal experiments directive of the EU acknowledges that the use of animals in research has long been a matter of concern to the public, that animal welfare must not take a backseat to economic considerations and that leveling the playing field across the EU is important—but then argues that all of that is trumped by the desire of poorer countries to build up their science base.This would imply that animal research standards, instead of being ratcheted up to those of the best countries, be allowed to drop to those of the worst—something hardly consistent with promoting animal welfare.
• Blood pressure control: salt gets under your skin
  - Nat Med 15(5):487-488 (2009)
  After an increase in dietary salt, the excess sodium is stored under the skin—stimulating lymphatic growth through the activity of macrophages (pages 545–552). The findings should recast thinking about how blood pressure is regulated.
• Breaking the gene barrier in schizophrenia
  - Nat Med 15(5):488-490 (2009)
  Studies of schizophrenia have been plagued by shortcomings such as weak genetic association with disease, inadequate animal models and limited replication of gene expression findings. Future success may lie not in overcoming any one of these limitations but in a broad approach strengthening the evidence in each area. Using such an approach, neuroscientists have uncovered a new gene behind the disease (pages 509–518).
• Chaos in the embryo
  - Nat Med 15(5):490-491 (2009)
  The chromosomes of human embryos seem to be more unstable than previously thought. An analysis of embryos derived from in vitro fertilization reveals high rates of structural abnormalities (pages 577–583).
• Angiogenesis: escape from hypoxia
  - Nat Med 15(5):491-493 (2009)
  Current attempts to block angiogenesis during cancer and other diseases are limited partly by their effects on normal angiogenic processes. Could a more targeted approach emerge from the identification of a factor required for pathological angiogenesis under conditions of hypoxia (pages 553–558)?
• Follicle of youth
  - Nat Med 15(5):495 (2009)
  Adult and neonatal mouse ovaries contain a population of cells that, after passage in culture, can give rise to viable oocytes. With this finding, Kang Zou et al.1 wade into the long-running controversy over whether adult mammals can produce new oocytes, or whether their number is fixed by birth.
• The sepsis seesaw: tilting toward immunosuppression
  - Nat Med 15(5):496-497 (2009)
  The immune response goes haywire during sepsis, a deadly condition triggered by infection. Richard S. Hotchkiss and his colleagues take the focus off of the prevailing view that the key aspect of this response is an exuberant inflammatory reaction. They assess recent human studies bolstering the notion that immunosuppression is also a major contributor to the disease. Many people with sepsis succumb to cardiac dysfunction, a process examined by Peter Ward. He showcases the factors that cause cardiomyocyte contractility to wane during the disease.
• The sepsis seesaw: seeking a heart salve
  - Nat Med 15(5):497-498 (2009)
  Sepsis in humans frequently follows the body's attempt to thwart infectious agents such as bacteria, viruses and fungi. In many respects, the development of sepsis represents the harmful consequences of exuberant innate immune responses, resulting in high levels of proinflammatory mediators that are associated with organ failure, primarily in the heart, lungs, liver and kidneys.
• Research Highlights
  - Nat Med 15(5):500-501 (2009)
  
• Open innovation networks between academia and industry: an imperative for breakthrough therapies
  - Nat Med 15(5):502-507 (2009)
  The demand to bring transformative therapeutics to patients and the escalating costs of doing so are driving the life science industry to seek collaborations with academia to stimulate innovation. Despite the opportunities afforded by working together, companies and universities lack a systematic approach for capturing the full potential of such relationships.
• A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia
  - Nat Med 15(5):509-518 (2009)
  Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go–related K+ channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a dom! ain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.
• Endothelial basement membrane laminin alpha5 selectively inhibits T lymphocyte extravasation into the brain
  - Nat Med 15(5):519-527 (2009)
  Specific inhibition of the entry of encephalitogenic T lymphocytes into the central nervous system in multiple sclerosis would provide a means of inhibiting disease without compromising innate immune responses. We show here that targeting lymphocyte interactions with endothelial basement membrane laminins provides such a possibility. In mouse experimental autoimmune encephalomyelitis, T lymphocyte extravasation correlates with sites expressing laminin alpha4 and small amounts of laminin alpha5. In mice lacking laminin alpha4, laminin alpha5 is ubiquitously expressed along the vascular tree, resulting in marked and selective reduction of T lymphocyte infiltration into the brain and reduced disease susceptibility and severity. Vessel phenotype and immune response were not affected in these mice. Rather, laminin alpha5 directly inhibited integrin alpha6beta1–mediated migration of T lymphocytes through laminin alpha4. The data indicate that T lymphocytes use mechanisms d! istinct from other immune cells to penetrate the endothelial basement membrane barrier, permitting specific targeting of this immune cell population.
• Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies
  - Nat Med 15(5):528-536 (2009)
  Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the! cellular and molecular level has major implications for immunotherapy in the treatment of tumors.
• Synthetic EthR inhibitors boost antituberculous activity of ethionamide
  - Nat Med 15(5):537-544 (2009)
  The side effects associated with tuberculosis therapy bring with them the risk of noncompliance and subsequent drug resistance. Increasing the therapeutic index of antituberculosis drugs should thus improve treatment effectiveness. Several antituberculosis compounds require in situ metabolic activation to become inhibitory. Various thiocarbamide-containing drugs, including ethionamide, are activated by the mycobacterial monooxygenase EthA, the production of which is controlled by the transcriptional repressor EthR. Here we identify drug-like inhibitors of EthR that boost the bioactivation of ethionamide. Compounds designed and screened for their capacity to inhibit EthR-DNA interaction were co-crystallized with EthR. We exploited the three-dimensional structures of the complexes for the synthesis of improved analogs that boosted the ethionamide potency in culture more than tenfold. In Mycobacterium tuberculosis–infected mice, one of these analogs, BDM31343, enabled a! substantially reduced dose of ethionamide to lessen the mycobacterial load as efficiently as the conventional higher-dose treatment. This provides proof of concept that inhibiting EthR improves the therapeutic index of thiocarbamide derivatives, which should prompt reconsideration of their use as first-line drugs.
• Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C–dependent buffering mechanism
  - Nat Med 15(5):545-552 (2009)
  In salt-sensitive hypertension, the accumulation of Na+ in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na+ accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD! . Our data show that TonEBP–VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension.
• Histone H2AX is integral to hypoxia-driven neovascularization
  - Nat Med 15(5):553-558 (2009)
  H2A histone family member X (H2AX, encoded by H2AFX) and its C-terminal phosphorylation (gamma-H2AX) participates in the DNA damage response and mediates DNA repair1, 2, 3, 4, 5, 6. Hypoxia is a physiological stress that induces a replication-associated DNA damage response7. Moreover, hypoxia is the major driving force for neovascularization8, as the hypoxia-mediated induction of vascular growth factors triggers endothelial cell proliferation8. Here we studied the role of the hypoxia-induced DNA damage response in endothelial cell function and in hypoxia-driven neovascularization in vivo. Hypoxia induced replication-associated generation of gamma-H2AX in endothelial cells in vitro and in mice. Both in cultured cells and in mice, endothelial cell proliferation under hypoxic conditions was reduced by H2AX deficiency. Whereas developmental angiogenesis was not affected in H2afx-/- mice, hypoxia-induced neovascularization during pathologic proliferative retinopathy, in res! ponse to hind limb ischemia or during tumor angiogenesis was substantially lower in H2afx-/- mice. Moreover, endothelial-specific H2afx deletion resulted in reduced hypoxia-driven retina neovascularization and tumor neovascularization. Our findings establish that H2AX, and hence activation of the DNA repair response, is needed for endothelial cells to maintain their proliferation under hypoxic conditions and is crucial for hypoxia-driven neovascularization.
• Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer
  - Nat Med 15(5):559-565 (2009)
  Many studies have shown that primary prostate cancers are multifocal1, 2, 3 and are composed of multiple genetically distinct cancer cell clones4, 5, 6. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis7 and recent single-locus genetic data in prostate and other metastatic cancers8, 9, 10, ! these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.
• Nanofluidic proteomic assay for serial analysis of oncoprotein activation in clinical specimens
  - Nat Med 15(5):566-571 (2009)
  Current methods of protein detection are insensitive to detecting subtle changes in oncoprotein activation that underlie key cancer signaling processes. The requirement for large numbers of cells precludes serial tumor sampling for assessing a response to therapeutics. Therefore, we have developed a nanofluidic proteomic immunoassay (NIA) to quantify total and low-abundance protein isoforms in nanoliter volumes. Our method can quantify amounts of MYC oncoprotein and B cell lymphoma protein-2 (BCL2) in Burkitt's and follicular lymphoma; identify changes in activation of extracellular signal–related kinases-1 (ERK1) and ERK2, mitogen-activated kinase-1 (MEK), signal transducer and activator of transcription protein-3 (STAT3) and STAT5, c-Jun N-terminal kinase (JNK) and caspase-3 in imatinib-treated chronic myelogeneous leukemia (CML) cells; measure an unanticipated change in the phosphorylation of an ERK2 isomer in individuals with CML who responded to imatinib; and de! tect a decrease in STAT3 and STAT5 phosphorylation in individuals with lymphoma who were treated with atorvastatin. Therefore, we have described a new and highly sensitive method for determining oncoprotein expression and phosphorylation in clinical specimens for the development of new therapeutics for cancer.
• The parametric response map is an imaging biomarker for early cancer treatment outcome
  - Nat Med 15(5):572-576 (2009)
  Here we describe the parametric response map (PRM), a voxel-wise approach for image analysis and quantification of hemodynamic alterations during treatment for 44 patients with high-grade glioma. Relative cerebral blood volume (rCBV) and flow (rCBF) maps were acquired before treatment and after 1 and 3 weeks of therapy. We compared the standard approach using region-of-interest analysis for change in rCBV or rCBF to the change in perfusion parameters on the basis of PRM (PRMrCBV and PRMrCBF) for their accuracy in predicting overall survival. Neither the percentage change of rCBV or rCBF predicted survival, whereas the regional response evaluations made on the basis of PRM were highly predictive of survival. Even when accounting for baseline rCBV, which is prognostic, PRMrCBV proved more predictive of overall survival.
• Chromosome instability is common in human cleavage-stage embryos
  - Nat Med 15(5):577-583 (2009)
  Chromosome instability is a hallmark of tumorigenesis. This study establishes that chromosome instability is also common during early human embryogenesis. A new array-based method allowed screening of genome-wide copy number and loss of heterozygosity in single cells. This revealed not only mosaicism for whole-chromosome aneuploidies and uniparental disomies in most cleavage-stage embryos but also frequent segmental deletions, duplications and amplifications that were reciprocal in sister blastomeres, implying the occurrence of breakage-fusion-bridge cycles. This explains the low human fecundity and identifies post-zygotic chromosome instability as a leading cause of constitutional chromosomal disorders.
• Corrigendum: Regulation of cardiovascular development and integrity by the heart of glass– cerebral cavernous malformation protein pathway
  - Nat Med 15(5):584 (2009)
  Introduction Nat. Med. 15, 169–176 (2009); published online 18 January 2009; corrected after print 12 February 2009 In the version of this article initially published, Shawn M. Sweeney was not included in the list of authors. The error has been corrected in the HTML and PDF versions of the article.
• Corrigendum: A pivotal role for galectin-1 in fetomaternal tolerance
  - Nat Med 15(5):584 (2009)
  Introduction Nat. Med. 13, 1450–1457 (2007); published online 18 November 2007; corrected after print 7 May 2009 In the version of this article initially published, the plot labeled "Stress + Gal-1" duplicated the plot labeled "Control" for the IL-12p70 staining in Figure 2f. The corrected plots have now been provided in the HTML and PDF versions of the article. Two sentences were omitted from the section on purification of uterine DCs in the Methods. The sentences should have read: "We obtained purified DCs from uterine tissue in very low numbers. Thus, we pooled isolated cells from each group and used this cell cocktail for the isotype control staining." The error has been corrected in the HTML and PDF versions of the article. In Figure 4f, the lanes of the western blot were merged inappropriately. The properly presented blot, in which the gel lanes have been separated to indicate that the samples were not originally run side by side, has been provided in the PDF and HTML versions of the article. The standard curve of the cytometric bead array kit used to generate the cytokine data c! an be found in the revised Supplementary information available online.