Hot off the presses! Oct 01 Nature medicine

The Oct 01 issue of the Nature medicine is now up on Pubget (About Nature medicine): 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 twain shall meet
  - Nature Medicine 15(10):1095 (2009)
  Announcing an initiative to connect commercially oriented academics with their local business community.
• Large trial to examine parasites' influence on global killers
  Willyard C - Nature Medicine 15(10):1097 (2009)
  In the controlled confines of a laboratory, researchers can study the impact of a single pathogen on a single outcome. In the real world, things are messier; research subjects may be infected with a host of bacteria, viruses and parasites, all of which interact with the immune system and may also interact with each other.
• Survey of medical centers points to funding gaps
  Westly E - Nature Medicine 15(10):1098 (2009)
  Improved patient care has always been the primary goal of biomedical research. But as the debate over health care reform intensifies, questions about exactly how such research translates to patient care and how this research should be funded have moved to the forefront.
• Infections linked to prostate cancer
  Brower V - Nature Medicine 15(10):1098 (2009)
  New research strengthens a possible link between a recently identified human retrovirus and prostate cancer—though a causal connection is far from certain. Scientists at the University of Utah in Salt Lake found evidence of the xenotropic murine leukemia virus–related virus, XMRV, in 27% of 334 prostate cancer biopsies.
• Value of health interventions underestimated by governments
  Siva N - Nature Medicine 15(10):1099 (2009)
  As the healthcare debate fiercely continues in the US and President Obama desperately tries to persuade his country that their troubled health care system is in need of a major overhaul, a new study suggests that health intervention programs are less expensive when one takes a longer view than the conventional ten-year time window of cost prediction.The US Congressional Budget Office (CBO) and Office of the Actuary at the Department of Health and Human Services (HHS) advise the government on the value of medical interventions; these institutions' reports can in turn have substantial impact on US policy.
• Closing Army pathology lab bristles at replacement attempt
  Westly E - Nature Medicine 15(10):1099 (2009)
  In an 8 September press release, the Virginia-based company Bostwick Laboratories announced the opening of the American International Pathology Laboratories (AIPL), a "world-class facility providing positions to more than 40 civilian pathologists and staff formerly of the Armed Forces Institute of Pathology (AFIP) laboratories." It was a slightly revised version of the press release the company had published a month earlier.
• Harvard Medical School rescinds controversial media rules
  May M - Nature Medicine 15(10):1100 (2009)
  On 25 August, students at Harvard Medical School (HMS) received an e-mail message about changes to the student handbook, including a new policy about interacting with the news media that triggered a controversy. The wording of the policy suggested that students could only talk to the media after approval from administrative officials.
• 'Propaganda index' proposed for medical literature
  Jones N - Nature Medicine 15(10):1100-1101 (2009)
  The inappropriate 'spin' of biomedical results is rife and could be countered in part by using a 'propaganda index', said experts at the sixth international congress of the Peer Review and Biomedical Publication in Vancouver this September.Some papers make a drug look better than the data really supports, says Doug Altman of the Centre for Statistics in Medicine in Oxford, UK.
• Analysis of retractions puts spotlight on academia
  Jones N - Nature Medicine 15(10):1101 (2009)
  About half of the medical papers retracted over the past few decades were pulled because of misconduct rather than an innocent mistake, according to two new studies. And that fraction is on the increase.
• News in brief
  - Nature Medicine 15(10):1102-1103 (2009)
  Aug 24The multinational company Proctor & Gamble announced that Warner Chilcott, a drug company based in Ireland, would acquire its global pharmaceuticals business for an up-front cash payment of $3.1 billion.
• Straight talk with...Christopher Murray
  Schubert C - Nature Medicine 15(10):1104-1105 (2009)
  Hard numbers can be difficult to come by in the current debate about health care in the US. Even rarer are accurate assessments of health care systems in less developed countries. But policy makers are not completely groping in the dark when it comes to data—thanks in part to Christopher Murray. Two years ago, Murray, a physician and health economist with experience at the World Health Organization (WHO), took the helm of the newly created Institute for Health Metrics and Evaluation at the University of Washington. Since 2007, the institute, funded largely by the Bill & Melinda Gates Foundation and the state of Washington, has grown to a staff of 75 people and has begun churning out studies that that are shaping the debate on health care reform. For instance, Murray's group—along with colleagues at his former base, Harvard University in Cambridge, Massachusetts—have documented huge disparities in life expectancy and mortality in parts of the US. In some pockets of the country, life expectancy for women is even on the decline (PLoS Med. 27, e66; 2008). Murray spoke with Charlotte Schubert about how having accurate numbers can add up to progress in health care.
• The most transparent research
  Wenner M - Nature Medicine 15(10):1106-1109 (2009)
  Biomedicine would be a breeze if organisms were transparent. With the ability to see through tissues, scientists could spot the development of tumors more easily in study animals. And biologists could study exactly how an animal's organs develop by observing them as they grow. In effect, the secrets of the body would be out there for everyone to see. The thought of peering into our tissues may sound like science fiction, but one day it could be science. Using ideas from genetics, electrical engineering, chemistry and solid-state physics, a handful of researchers are working on ways to render biological tissues transparent. Some have already succeeded: in 2007, Richard White, a biologist at the Dana Farber Cancer Institute in Boston, used careful breeding techniques to create a transparent adult zebrafish named casper, evoking a reference to the famous cartoon ghost by the same name. Now, more than 100 labs around the world are using these transparent fish to study cancer pathology and development in real time. "The field of in vivo imaging—looking at things that are happening inside an actual organism—is growing rapidly," White says. Researchers are even making strides toward turning human tissue transparent. The primary reason we can't see what's inside of us is that light scatters when it passes through tissue. The body is densely packed with many types of substances, such as bone and fat, and light travels through them at different speeds because they have what physicists refer to as different refractive indices. The result is that light can't pass through biological tissues in a straight line, much as car headlights don't pass through dense fog. To fix this problem, scientists are working on developing ways to stop tissues from scattering light. Indeed, "if you take away the scattering properties of human tissues, we would look more or less like jellyfish," explains Changhuei Yang, an electrical engineer and bioengineer at the California Institute of Technology. Though their approaches (described in the following pages) are diverse, these researchers share the common goal of making it one day possible to see what's going on deep inside of the body—a feat that would provide new insights into our biology and help doctors diagnose and treat disease much more easily. "We're trying to push the limits in terms of what can we uncover," says Bernard Choi, a bioengineer at the University of California–Irvine.
• CCL3L1 and HIV/AIDS susceptibility
  Urban TJ Weintrob AC Fellay J Colombo S Shianna KV Gumbs C Rotger M Pelak K Dang KK Detels R Martinson JJ O'Brien SJ Letvin NL McMichael AJ Haynes BF Carrington M Telenti A Michael NL Goldstein DB - Nature Medicine 15(10):1110-1112 (2009)
  We read with interest the recent article in Nature Medicine describing the influence of variation in CCL3L1 copy number and CCR5 genotype on immune recovery during highly active antiretroviral therapy (HAART) in HIV-1–infected individuals1. The chemotactic cytokine CCL3L1 (encoding the macrophage inflammatory protein-1P (MIP-1P) protein) is a potent ligand for the HIV-1 co-receptor CCR5, which is essential for viral entry into human host cells2.
• CCL3L1 and HIV/AIDS susceptibility
  Bhattacharya T Stanton J Kim EY Kunstman KJ Phair JP Jacobson LP Wolinsky SM - Nature Medicine 15(10):1112-1115 (2009)
  A selective advantage against infectious diseases such as HIV/AIDS is associated with differences in the genes relevant to immunity and virus replication. The CC chemokine receptor-5 (CCR5), the principal co-receptor for HIV, and its chemokine ligands, including CC chemokine ligand-3–like-1 (CCL3L1), influence the susceptibility of the CD4+ target cell to infection1.
• Experimental aspects of copy number variant assays at CCL3L1
  Field SF Howson JM Maier LM Walker S Walker NM Smyth DJ Armour JA Clayton DG Todd JA - Nature Medicine 15(10):1115-1117 (2009)
  Copy number variants (CNVs) are duplicated or deleted segments of the genome that vary in size from a few bases to several kilobases and comprise a substantial proportion of normal genomic variation1. The role of population-wide CNVs in disease has only recently come under investigation2, 3.
• Reply to: "CCL3L1 and HIV/AIDS susceptibility" and "Experimental aspects of copy number variant assays at CCL3L1"
  He W Kulkarni H Castiblanco J Shimizu C Aluyen U Maldonado R Carrillo A Griffin M Lipsitt A Beachy L Shostakovich-Koretskaya L Mangano A Sen L Nibbs RJ Tiemessen CT Bolivar H Bamshad MJ Clark RA Burns JC Dolan MJ Ahuja SK - Nature Medicine 15(10):1117-1120 (2009)
  We read with interest the three correspondences1, 2, 3 that are directly or indirectly related to our previous publication in Nature Medicine4. Because of methodological concerns with their own C-C chemokine ligand-3–like-1 (CCL3L1) gene quantitative PCR (qPCR) assay, Urban et al.1 assume that similar limitations apply to the assay that we and others have used and, by extension, infer that all of the several reported associations for CCL3L1 copy number with HIV/AIDS suceptibility (Supplementary Table 1) are spurious.
• Smallpox outfoxed
  - Nature Medicine 15(10):1121 (2009)
  The global eradication of smallpox has been rightly called the "greatest life-saving achievement in the history of medicine," as pointed out by Richard Preston in the foreword to the new book Smallpox—The Death of a Disease: The Inside Story of Eradicating a Worldwide Killer. This personal account of the eradication effort, written by its director Donald A.
• Gateway to the diseased brain
  Mingozzi F High KA - Nature Medicine 15(10):1123-1124 (2009)
  The blood-brain barrier constitutes a major obstacle to effective treatment of diseases affecting the central nervous system. A new strategy to target specifically the endothelium of diseased brain may allow the development of more effective gene-based therapies (pages 1215–1218).
• Preserving fertility during cancer treatment
  Woodruff TK - Nature Medicine 15(10):1124-1125 (2009)
  Imatinib (trade name Gleevec) preserves fertility in female mice treated with the common chemotherapeutic agent cisplatin. Imatinib seems to block an apoptotic pathway activated by cisplatin in ovarian germ cells (pages 1179–1185). The findings could lead to new ways to protect germ cells from the damaging effects of cancer treatment.
• Epilepsy: synapses stuck in childhood
  Caleo M - Nature Medicine 15(10):1126-1127 (2009)
  Mouse experiments show how mutation of a gene involved in human epilepsy causes hyperexcitability of the neuronal network (pages 1208–1214). The mutations interfere with the maturation of excitatory synapses during postnatal development.
• Gene copy number: learning to count past two
  Shrestha S Tang J Kaslow RA - Nature Medicine 15(10):1127-1129 (2009)
  The number of copies of the gene encoding a ligand for an HIV co-receptor have been found to influence the susceptibility to HIV infection and AIDS progression. New studies dispute this conclusion. The studies are contested by the authors of the original findings, and highlight the inherent difficulties in accurately measuring gene copy numbers (pages 1110–1112, 1112–1115, 1115–1117 and 1117–1120).
• Biomarkers for Alzheimer's disease: the dilemma of silent disease
  - Nature Medicine 15(10):1130 (2009)
  Alzheimer's disease researchers have homed in on a few molecules in the cerebrospinal fluid (CSF) that may help diagnose Alzheimer's disease before clear-cut symptoms emerge. Niklas Mattsson et al.1 have now conducted the largest trial of such biomarkers in 1,583 subjects—including 750 people with mild cognitive impairment who were followed for at least two years after measurement of the markers.
• Bleeding in the brain: Killer waves of depolarization in subarachnoid bleed
  Iadecola C - Nature Medicine 15(10):1131-1132 (2009)
  Hemorrhages in the brain are responsible for about 15% of strokes and are particularly difficult to treat. Costantino Iadecola assesses a new clinical study that may change the view of why a common form of hemorrhage, subarachnoid hemorrhage, often leads to death. Massive brain lesions often develop days after the initial event, a dangerous complication previously attributed to vasospasm, narrowing of the arteries. The study suggests that these lesions may instead by caused by neuronal depolarization, extending in waves across the brain. Gregory del Zoppo explores the connection between deposition of toxic amyloid- peptides in the brain and hemorrhage. He discusses studies suggesting that the peptides inactivate proteins in the blood that can stop hemorrhage.
• Bleeding in the brain: Amyloid- may keep clots away
  Del Zoppo GJ - Nature Medicine 15(10):1132-1133 (2009)
  Deposition of amyloid in the parenchymal tissues and the blood vessels of the brain accompanies Alzheimer's disease. In the elderly, vascular deposition of amyloid can also have another impact: it can be associated with brain hemorrhage.
• Research Highlights
  - Nature Medicine 15(10):1134-1135 (2009)
  
• Lasker Awards and papal portraiture: turning fields upside down
  Goldstein JL - Nature Medicine 15(10):1137-1140 (2009)
  Picasso has been quoted as saying "my mother said to me, 'If you are a soldier, you will become a general. If you are a monk, you will become a Pope.
• Nuclear reprogramming in eggs
  Gurdon J - Nature Medicine 15(10):1141-1144 (2009)
  I must have been born with a strong attraction toward, and possibly even an aptitude for, doing things on a small scale. I remember that, at an early age, I spent many months making a three-masted sailing boat with rigging in a half-walnut shell.
• Ekiden to iPS Cells
  Yamanaka S - Nature Medicine 15(10):1145-1148 (2009)
  When I started a long ekiden—a relay marathon by multiple runners—toward cellular reprogramming about a decade ago, not many teams joined the start of the race. At the time, many laboratories were trying to differentiate embryonic stem (ES) cells into various functional cells, inspired by the report on the isolation of human ES cells1.
• Perspectives on the development of imatinib and the future of cancer research
  Druker BJ - Nature Medicine 15(10):1149-1152 (2009)
  I am incredibly fortunate. To receive an award from the Lasker Foundation, with its preeminent jury, is indeed an honor.
• Attacking cancer at its foundation
  Lydon N - Nature Medicine 15(10):1153-1157 (2009)
  Foundational discoveries connecting the fields of viral oncogenes and human protein kinases stimulated a number of groups to begin drug discovery programs targeting these kinases. The clinical success of some of these programs has created much interest in protein kinase inhibitors in almost all pharmaceutical companies.
• Shifting paradigms: the seeds of oncogene addiction
  Sawyers CL - Nature Medicine 15(10):1158-1161 (2009)
  Thomas Kuhn's The Structure of Scientific Revolutions argues that new insights often come from scientific renegades who champion new paradigms to account for observations that cannot be adequately explained by existing theory1. His views intrigued me while I was a Princeton undergraduate interested in the history of science.
• An integrin v3–c-Src oncogenic unit promotes anchorage-independence and tumor progression
  Desgrosellier JS Barnes LA Shields DJ Huang M Lau SK Prévost N Tarin D Shattil SJ Cheresh DA - Nature Medicine 15(10):1163-1169 (2009)
  Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin v3 is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin v3 in pancreatic cancer and other carcinomas. Specifically, v3 expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the 3 integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous v3 integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migra! tion or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an v3–c-Src signaling module may account for the aggressive behavior of integrin v3–expressing tumors in humans.
• Activation of the NLRP3 inflammasome in dendritic cells induces IL-1–dependent adaptive immunity against tumors
  Ghiringhelli F Apetoh L Tesniere A Aymeric L Ma Y Ortiz C Vermaelen K Panaretakis T Mignot G Ullrich E Perfettini JL Schlemmer F Tasdemir E Uhl M Génin P Civas A Ryffel B Kanellopoulos J Tschopp J André F Lidereau R McLaughlin NM Haynes NM Smyth MJ Kroemer G Zitvogel L - Nature Medicine 15(10):1170-1178 (2009)
  The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon- (IFN-)–producing T lymphocytes. Here we show that dying tumor cells release ATP, which then acts on P2X7 purinergic receptors from DCs and triggers the NOD-like receptor family, pyrin domain containing-3 protein (NLRP3)-dependent caspase-1 activation complex ('inflammasome'), allowing for the secretion of interleukin-1 (IL-1). The priming of IFN-–producing CD8+ T cells by dying tumor cells fails in the absence of a functional IL-1 receptor 1 and in Nlpr3-deficient (Nlrp3-/-) or caspase-1–deficient (Casp-1-/-) mice unless exogenous IL-1 is provided. Accordingly, anticancer chemotherapy turned out to be inefficient against tumors established in purinergic receptor P2rx7-/- or Nlrp3-/- or Casp1-/- hosts. Anthracycline-treated individuals with breast cancer carrying a loss-of-function allele of P! 2RX7 developed metastatic disease more rapidly than individuals bearing the normal allele. These results indicate that the NLRP3 inflammasome links the innate and adaptive immune responses against dying tumor cells.
• Inhibition of the c-Abl–TAp63 pathway protects mouse oocytes from chemotherapy-induced death
  Gonfloni S Di Tella L Caldarola S Cannata SM Klinger FG Di Bartolomeo C Mattei M Candi E De Felici M Melino G Cesareni G - Nature Medicine 15(10):1179-1185 (2009)
  Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl–TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63-dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes ! of the follicle reserve during chemotherapeutic treatments.
• Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis
  Roepke TK King EC Reyna-Neyra A Paroder M Purtell K Koba W Fine E Lerner DJ Carrasco N Abbott GW - Nature Medicine 15(10):1186-1194 (2009)
  Thyroid dysfunction is a global health concern, causing defects including neurodevelopmental disorders, dwarfism and cardiac arrhythmia. Here, we show that the potassium channel subunits KCNQ1 and KCNE2 form a thyroid-stimulating hormone–stimulated, constitutively active, thyrocyte K+ channel required for normal thyroid hormone biosynthesis. Targeted disruption of Kcne2 in mice impaired thyroid iodide accumulation up to eightfold, impaired maternal milk ejection, halved milk tetraiodothyronine (T4) content and halved litter size. Kcne2-deficient mice had hypothyroidism, dwarfism, alopecia, goiter and cardiac abnormalities including hypertrophy, fibrosis, and reduced fractional shortening. The alopecia, dwarfism and cardiac abnormalities were alleviated by triiodothyronine (T3) and T4 administration to pups, by supplementing dams with T4 before and after they gave birth or by feeding the pups exclusively from Kcne2+/+ dams; conversely, these symptoms were elicited in ! Kcne2+/+ pups by feeding exclusively from Kcne2-/- dams. These data provide a new potential therapeutic target for thyroid disorders and raise the possibility of an endocrine component to previously identified KCNE2- and KCNQ1-linked human cardiac arrhythmias.
• The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake
  Plum L Lin HV Dutia R Tanaka J Aizawa KS Matsumoto M Kim AJ Cawley NX Paik JH Loh YP Depinho RA Wardlaw SL Accili D - Nature Medicine 15(10):1195-1201 (2009)
  Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity after weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by the transcription factor FoxO1. We show that FoxO1 ablation in pro-opiomelanocortin (Pomc)-expressing neurons in mice (here called Pomc-Foxo1-/- mice) increases Carboxypeptidase E (Cpe) expression, resulting in selective increases of -melanocyte–stimulating hormone (-Msh) and carboxy-cleaved -endorphin, the products of Cpe-dependent processing of Pomc. This neuropeptide profile is associated with decreased food intake and normal energy expenditure in Pomc-Foxo1-/- mice. We show that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. ! The dissociation of food intake from energy expenditure in Pomc-Foxo1-/- mice represents a model for therapeutic intervention in obesity and raises the possibility of targeting Cpe to develop weight loss medications.
• Inhibition of calpain increases LIS1 expression and partially rescues in vivo phenotypes in a mouse model of lissencephaly
  Yamada M Yoshida Y Mori D Takitoh T Kengaku M Umeshima H Takao K Miyakawa T Sato M Sorimachi H Wynshaw-Boris A Hirotsune S - Nature Medicine 15(10):1202-1207 (2009)
  Lissencephaly is a devastating neurological disorder caused by defective neuronal migration. LIS1 (official symbol PAFAH1B1, for platelet-activating factor acetylhydrolase, isoform 1b, subunit 1) was identified as the gene mutated in individuals with lissencephaly, and it was found to regulate cytoplasmic dynein function and localization. Here we show that inhibition or knockdown of calpains protects LIS1 from proteolysis, resulting in the augmentation of LIS1 amounts in Lis1+/- mouse embryonic fibroblast cells and rescue of the aberrant distribution of cytoplasmic dynein, mitochondria and -COP–positive vesicles. We also show that calpain inhibitors improve neuronal migration of Lis1+/- cerebellar granular neurons. Intraperitoneal injection of the calpain inhibitor ALLN to pregnant Lis1+/- dams rescued apoptotic neuronal cell death and neuronal migration defects in Lis1+/- offspring. Furthermore, in utero knockdown of calpain by short hairpin RNA rescued defective co! rtical layering in Lis1+/- mice. Thus, calpain inhibition is a potential therapeutic intervention for lissencephaly.
• Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy
  Zhou YD Lee S Jin Z Wright M Smith SE Anderson MP - Nature Medicine 15(10):1208-1214 (2009)
  A subset of central glutamatergic synapses are coordinately pruned and matured by unresolved mechanisms during postnatal development. We report that the human epilepsy gene LGI1, encoding leucine-rich, glioma-inactivated protein-1 and mutated in autosomal dominant lateral temporal lobe epilepsy (ADLTE), mediates this process in hippocampus. We created transgenic mice either expressing a truncated mutant LGI1 (835delC) found in ADLTE or overexpressing a wild-type LGI1. We discovered that the normal postnatal maturation of presynaptic and postsynaptic functions was arrested by the 835delC mutant LGI1, and contrastingly, was magnified by excess wild-type LGI1. Concurrently, mutant LGI1 inhibited dendritic pruning and increased the spine density to markedly increase excitatory synaptic transmission. Inhibitory transmission, by contrast, was unaffected. Furthermore, mutant LGI1 promoted epileptiform discharge in vitro and kindling epileptogenesis in vivo with partial -amino! butyric acidA (GABAA) receptor blockade. Thus, LGI1 represents a human gene mutated to promote epilepsy through impaired postnatal development of glutamatergic circuits (pages 1126–1127).
• Molecular signatures of disease brain endothelia provide new sites for CNS-directed enzyme therapy
  Chen YH Chang M Davidson BL - Nature Medicine 15(10):1215-1218 (2009)
  The brain vasculature forms an immense network such that most neural cells are in contact with a microvessel. Here we tested the hypothesis that endothelia lining these vessels can be harnessed to create a cellular reservoir of enzyme replacement therapy to diseased brain. As a model system, we used mice with central nervous system (CNS) deficits due to lysosomal storage disease (LSD mice). The basic premise of this work is that recombinant enzyme expressed in, and secreted from, the vascular endothelia will be endocytosed by underlying neurons and glia, decreasing neuropathology. We screened a phage library in vivo by panning to identify peptides that bound the vascular endothelia in diseased and wild-type mice. Epitopes binding diseased brain were distinct from those panned from normal brain. Moreover, different epitopes were identified in two distinct LSD disease models, implying a unique vascular signature imparted by the disease state. Presentation of these epitop! es on the capsid of adeno-associated virus (AAV) expanded the biodistribution of intravenously injected AAV from predominantly liver to include the CNS. Peripheral injection of the epitope-modified AAVs expressing the enzymes lacking in LSD mice reconstituted enzyme activity throughout the brain and improved disease phenotypes in two distinct disease models (pages 1123–1124).
• Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging
  Vakoc BJ Lanning RM Tyrrell JA Padera TP Bartlett LA Stylianopoulos T Munn LL Tearney GJ Fukumura D Jain RK Bouma BE - Nature Medicine 15(10):1219-1223 (2009)
  Intravital multiphoton microscopy has provided powerful mechanistic insights into health and disease and has become a common instrument in the modern biological laboratory. The requisite high numerical aperture and exogenous contrast agents that enable multiphoton microscopy, however, limit the ability to investigate substantial tissue volumes or to probe dynamic changes repeatedly over prolonged periods. Here we introduce optical frequency domain imaging (OFDI) as an intravital microscopy that circumvents the technical limitations of multiphoton microscopy and, as a result, provides unprecedented access to previously unexplored, crucial aspects of tissue biology. Using unique OFDI-based approaches and entirely intrinsic mechanisms of contrast, we present rapid and repeated measurements of tumor angiogenesis, lymphangiogenesis, tissue viability and both vascular and cellular responses to therapy, thereby demonstrating the potential of OFDI to facilitate the exploration! of physiological and pathological processes and the evaluation of treatment strategies.
• Development of universal antidotes to control aptamer activity
  Oney S Lam RT Bompiani KM Blake CM Quick G Heidel JD Liu JY Mack BC Davis ME Leong KW Sullenger BA - Nature Medicine 15(10):1224-1228 (2009)
  With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may! be a particularly safe class of therapeutics.

Hot off the presses! Oct 01 Nature biotechnology

The Oct 01 issue of the Nature biotechnology is now up on Pubget (About Nature biotechnology): 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 twain shall meet
  - Nature Biotechnology 27(10):869 (2009)
  Announcing an initiative to connect commercially oriented academics with their local business community.
• Expanded access rules pose quandary for drug developers
  Mack GS - Nature Biotechnology 27(10):871-872 (2009)
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• FDA penalizes trial misconduct
  Shaffer C - Nature Biotechnology 27(10):872 (2009)
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• Test tube meat on the menu?
  Fox JL - Nature Biotechnology 27(10):873 (2009)
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• Europe plans for drug-making plants
  Wolfson W - Nature Biotechnology 27(10):874 (2009)
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• Pfizer lured to Sweden
  Aldridge S - Nature Biotechnology 27(10):874 (2009)
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• Spotlight focuses on protein-misfolding therapies
  Ratner M - Nature Biotechnology 27(10):874 (2009)
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• Regulation of consumer genomic tests remains in limbo
  Allison M - Nature Biotechnology 27(10):875-877 (2009)
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• Golden Triangle taps Boston
  Aldridge S - Nature Biotechnology 27(10):877 (2009)
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• Fits and starts for Geron
  Defrancesco L - Nature Biotechnology 27(10):877 (2009)
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• Firms seek new models to access public equity
  Mitchell P - Nature Biotechnology 27(10):878-879 (2009)
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• Sanofi's Shantha boost
  Jayaraman K - Nature Biotechnology 27(10):879 (2009)
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• Gulf beckons biotech
  Birch H - Nature Biotechnology 27(10):879 (2009)
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• Under wraps
  Waltz E - Nature Biotechnology 27(10):880-882 (2009)
  Are the crop industry's strong-arm tactics and close-fisted attitude to sharing seeds holding back independent research and undermining public acceptance of transgenic crops? Emily Waltz investigates.
• Credibility: your most important asset
  - Nature Biotechnology 27(10):883-885 (2009)
  
• Is it virtuous to be virtual? The VC viewpoint
  Chakma J Calcagno JL Behbahani A Mojtahedian S - Nature Biotechnology 27(10):886-888 (2009)
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• The power of social networking in medicine
  Brownstein CA Brownstein JS Williams DS Wicks P Heywood JA - Nature Biotechnology 27(10):888-890 (2009)
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• Creating a mouse academic research commons
  Einhorn D Heimes R - Nature Biotechnology 27(10):890-891 (2009)
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• Cofactor-mediated protein promiscuity
  Dimitrov JD Vassilev TL - Nature Biotechnology 27(10):892 (2009)
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• Healthcare-biotech symbiosis
  Ahmed K Ashrafian H - Nature Biotechnology 27(10):892-893 (2009)
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• Improved genome annotation for Zymomonas mobilis
  Yang S Pappas KM Hauser LJ Land ML Chen GL Hurst GB Pan C Kouvelis VN Typas MA Pelletier DA Klingeman DM Chang YJ Samatova NF Brown SD - Nature Biotechnology 27(10):893-894 (2009)
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• Can web 2.0 reboot clinical trials?
  Allison M - Nature Biotechnology 27(10):895-902 (2009)
  Dozens of companies are trying to leverage social networking and other software tools to accelerate trials and reduce their cost.
• Legal uncertainty in the area of genetic diagnostic testing
  Huys I Berthels N Matthijs G Van Overwalle G - Nature Biotechnology 27(10):903-909 (2009)
  A patent landscape analysis of 22 common genetic diagnostic tests shows substantially fewer claims on genes per se than initially suggested but raises questions of legal uncertainty as to the claims' scope.
• Recent patent applications in RNA interference
  - Nature Biotechnology 27(10):910 (2009)
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• siRNA delivery not Toll-free
  Gantier MP Williams BR - Nature Biotechnology 27(10):911-912 (2009)
  Activating the tumor-associated immune system with an siRNA conjugated to a Toll-like receptor 9 ligand is a promising anticancer strategy.
• Snapshots of kinase activities
  Muñoz J Heck AJ - Nature Biotechnology 27(10):912-913 (2009)
  A mass spectrometry–based strategy facilitates sensitive and rapid detection of kinase activities in small amounts of cell lysate.
• Stem cell biology meets p53
  Puzio-Kuter AM Levine AJ - Nature Biotechnology 27(10):914-915 (2009)
  Often called "the guardian of the genome," p53 may also be the guardian of stable development.
• Cancer's insatiable appetite
  Locasale JW Cantley LC Heiden MG - Nature Biotechnology 27(10):916-917 (2009)
  Seemingly unrelated mutations that drive cancer share the ability to promote nutrient uptake and metabolism conducive to cell growth.
• Introducing the acetylome
  Smith KT Workman JL - Nature Biotechnology 27(10):917-919 (2009)
  Mass spectrometry reveals protein acetylation to be as widespread as phosphorylation.
• Research highlights
  Aschheim K Elsner M Hare P Mak C - Nature Biotechnology 27(10):920 (2009)
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• How to visually interpret biological data using networks
  Merico D Gfeller D Bader GD - Nature Biotechnology 27(10):921-924 (2009)
  Networks in biology can appear complex and difficult to decipher. We illustrate how to interpret biological networks with the help of frequently used visualization and analysis patterns.
• In vivo delivery of siRNA to immune cells by conjugation to a TLR9 agonist enhances antitumor immune responses
  Kortylewski M Swiderski P Herrmann A Wang L Kowolik C Kujawski M Lee H Scuto A Liu Y Yang C Deng J Soifer HS Raubitschek A Forman S Rossi JJ Pardoll DM Jove R Yu H - Nature Biotechnology 27(10):925-932 (2009)
  Efficient delivery of small interfering (si)RNA to specific cell populations in vivo remains a formidable challenge to its successful therapeutic application. We show that siRNA synthetically linked to a CpG oligonucleotide agonist of toll-like receptor (TLR)9 targets and silences genes in TLR9+ myeloid cells and B cells, both of which are key components of the tumor microenvironment. When a CpG-conjugated siRNA that targets the immune suppressor gene Stat3 is injected in mice either locally at the tumor site or intravenously, it enters tumor-associated dendritic cells, macrophages and B cells. Silencing of Stat3 leads to activation of tumor-associated immune cells and ultimately to potent antitumor immune responses. Our findings demonstrate the potential of TLR agonist–siRNA conjugates for targeted gene silencing coupled with TLR stimulation and immune activation in the tumor microenvironment.
• Sensitive multiplexed analysis of kinase activities and activity-based kinase identification
  Kubota K Anjum R Yu Y Kunz RC Andersen JN Kraus M Keilhack H Nagashima K Krauss S Paweletz C Hendrickson RC Feldman AS Wu CL Rush J Villén J Gygi SP - Nature Biotechnology 27(10):933-940 (2009)
  Constitutive activation of one or more kinase signaling pathways is a hallmark of many cancers. Here we extend the previously described mass spectrometry–based KAYAK approach by monitoring kinase activities from multiple signaling pathways simultaneously. This improved single-reaction strategy, which quantifies the phosphorylation of 90 synthetic peptides in a single mass spectrometry run, is compatible with nanogram to microgram amounts of cell lysate. Furthermore, the approach enhances kinase monospecificity through substrate competition effects, faithfully reporting the signatures of many signaling pathways after mitogen stimulation or of basal pathway activation differences across a panel of well-studied cancer cell lines. Hierarchical clustering of activities from related experiments groups peptides phosphorylated by similar kinases together and, when combined with pathway alteration using pharmacological inhibitors, distinguishes underlying differences in poten! cy, off-target effects and genetic backgrounds. Finally, we introduce a strategy to identify the kinase, and even associated protein complex members, responsible for phosphorylation events of interest.
• A proteomics approach to discovering natural products and their biosynthetic pathways
  Bumpus SB Evans BS Thomas PM Ntai I Kelleher NL - Nature Biotechnology 27(10):951-956 (2009)
  Many natural products with antibiotic, anticancer and antifungal properties are synthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs)1. Although genome sequencing has revealed the diversity of these enzymes, identifying new products and their biosynthetic pathways remains challenging2. By taking advantage of the size of these enzymes (often >2,000 amino acids) and unique marker ions derived from their common phosphopantetheinyl cofactor, we adapted mass spectrometry–based proteomics to selectively detect NRPS and PKS gene clusters in microbial proteomes without requiring genome sequence information. We detected known NRPS systems in members of the genera Bacillus and Streptomyces, and screened 22 environmental isolates to uncover production of unknown natural products from the hybrid NRPS-PKS zwittermicin A biosynthetic gene cluster3. We also discovered an NRPS cluster that generates a seven-residue lipopeptide. This 'protein-first' ! strategy complements bioassay- and sequence-based approaches by finding expressed gene clusters that produce new natural products.
• Automated design of synthetic ribosome binding sites to control protein expression
  Salis HM Mirsky EA Voigt CA - Nature Biotechnology 27(10):946-950 (2009)
  Microbial engineering often requires fine control over protein expression—for example, to connect genetic circuits1, 2, 3, 4, 5, 6, 7 or control flux through a metabolic pathway8, 9, 10, 11, 12, 13. To circumvent the need for trial and error optimization, we developed a predictive method for designing synthetic ribosome binding sites, enabling a rational control over the protein expression level. Experimental validation of >100 predictions in Escherichia coli showed that the method is accurate to within a factor of 2.3 over a range of 100,000-fold. The design method also correctly predicted that reusing identical ribosome binding site sequences in different genetic contexts can result in different protein expression levels. We demonstrate the method's utility by rationally optimizing protein expression to connect a genetic sensor to a synthetic circuit. The proposed forward engineering approach should accelerate the construction and systematic optimization of large g! enetic systems.
• Induction of protein-protein interactions in live cells using light
  Yazawa M Sadaghiani AM Hsueh B Dolmetsch RE - Nature Biotechnology 27(10):941-945 (2009)
  Protein-protein interactions are essential for many cellular processes. We have developed a technology called light-activated dimerization (LAD) to artificially induce protein hetero- and homodimerization in live cells using light. Using the FKF1 and GIGANTEA (GI) proteins of Arabidopsis thaliana, we have generated protein tags whose interaction is controlled by blue light. We demonstrated the utility of this system with LAD constructs that can recruit the small G-protein Rac1 to the plasma membrane and induce the local formation of lamellipodia in response to focal illumination. We also generated a light-activated transcription factor by fusing domains of GI and FKF1 to the DNA binding domain of Gal4 and the transactivation domain of VP16, respectively, showing that this technology is easily adapted to other systems. These studies set the stage for the development of light-regulated signaling molecules for controlling receptor activation, synapse formation and other s! ignaling events in organisms.
• Erratum: Sanofi Aventis grooms its ranks for biotech partnering
  Moran N - Nature Biotechnology 27(10):957 (2009)
  Introduction Nat. Biotechnol. 27, 581–582 (2009); published online 8 July 2009; corrected after print 8 October 2009 In the version of this article initially published, the writer incorrectly states that "BiPar was spun out of Genentech to develop small-molecule inhibitors...." The text should have read "BiPar was set up to develop small-molecule inhibitors...." The error has been corrected in the HTML and PDF versions of the article.
• Erratum: Diagnostics firms face new patent claim worries
  Allison M - Nature Biotechnology 27(10):957 (2009)
  Introduction Nat. Biotechnol. 27, 586–587 (2009); published online 8 July 2009; corrected after print 8 October 2009 In the version of this article initially published, on page 587, left column, last paragraph, it states incorrectly that GeneDX holds a patent to certain mutations in the connexin 26 gene related to keratitis-ichthyosis-deafness syndrome. GeneDX does not own that patent. The error has been corrected in the HTML and PDF versions of the article.
• Erratum: Novo awaits green light for diabetes drug
  May M - Nature Biotechnology 27(10):957 (2009)
  Introduction Nat. Biotechnol. 27, 682–685 (2009); published online 7 August 2009; corrected after print 8 October 2009 In the version of this article initially published, GLP-1 was incorrectly described as "glucose-lowering peptide-1"; the correct definition is "glucagon-like peptide-1." The article also stated incorrectly that Amylin and Lilly "filed a new drug application for this drug in July..." referring to Exenatide Once Weekly. This should be corrected to "their new drug application was accepted for review by the FDA in July...." The error has been corrected in the HTML and PDF versions of the article.
• People
  - Nature Biotechnology 27(10):958 (2009)
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