Adaptation of HIV-1 envelope gp120 to humoral immunity at a population level.

Nat Med. 2010 Aug 29;

Authors: Bunnik EM, Euler Z, Welkers MR, Boeser-Nunnink BD, Grijsen ML, Prins JM, Schuitemaker H

By comparing HIV-1 variants from people who became infected at the beginning of the epidemic and from people who have recently contracted the virus, we observed an enhanced resistance of the virus to antibody neutralization over time, accompanied by an increase in the length of the variable loops and in the number of potential N-linked glycosylation sites on the HIV-1 envelope gp120 subunit. The enhanced neutralization resistance of HIV-1 in contemporary seroconverters coincided with the poorer elicitation of neutralizing antibody responses, which may have implications for vaccine design.

PMID: 20802498 [PubMed - as supplied by publisher]

Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance.

Nat Med. 2010 Aug 29;

Authors: López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, Morgan DA, Schoenmakers E, Agassandian K, Lage R, de Morentin PB, Tovar S, Nogueiras R, Carling D, Lelliott C, Gallego R, Orešič M, Chatterjee K, Saha AK, Rahmouni K, Diéguez C, Vidal-Puig A

Thyroid hormones have widespread cellular effects; however it is unclear whether their effects on the central nervous system (CNS) contribute to global energy balance. Here we demonstrate that either whole-body hyperthyroidism or central administration of triiodothyronine (T3) decreases the activity of hypothalamic AMP-activated protein kinase (AMPK), increases sympathetic nervous system (SNS) activity and upregulates thermogenic markers in brown adipose tissue (BAT). Inhibition of the lipogenic pathway in the ventromedial nucleus of the hypothalamus (VMH) prevents CNS-mediated activation of BAT by thyroid hormone and reverses the weight loss associated with hyperthyroidism. Similarly, inhibition of thyroid hormone receptors in the VMH reverses the weight loss associated with hyperthyroidism. This regulatory mechanism depends on AMPK inactivation, as genetic inhibition of this enzyme in the VMH of euthyroid rats induces feeding-independent weight loss and increases expression of thermogenic markers in BAT. These effects are reversed by pharmacological blockade of the SNS. Thus, thyroid hormone-induced modulation of AMPK activity and lipid metabolism in the hypothalamus is a major regulator of whole-body energy homeostasis.

PMID: 20802499 [PubMed - as supplied by publisher]

Clinical microfluidics for neutrophil genomics and proteomics.

Nat Med. 2010 Aug 29;

Authors: Kotz KT, Xiao W, Miller-Graziano C, Qian WJ, Russom A, Warner EA, Moldawer LL, De A, Bankey PE, Petritis BO, Camp DG, Rosenbach AE, Goverman J, Fagan SP, Brownstein BH, Irimia D, Xu W, Wilhelmy J, Mindrinos MN, Smith RD, Davis RW, Tompkins RG, Toner M, , Baker HV, Balis UG, Billiar TR, Calvano SE, Cobb JP, Cuschieri J, Finnerty CC, Gamelli RL, Gibran NS, Harbrecht BG, Hayden DL, Hennessy L, Herndon DN, Jeschke MG, Johnson JL, Klein MB, Lowry SF, Maier RV, Mason PH, McDonald-Smith GP, Minei JP, Moore EE, Nathens AB, O Keefe GE, Rahme LG, Remick DG, Schoenfeld DA, Shapiro MB, Sperry J, Storey JD, Tibshirani R, Warren HS, West MA, Wispelwey B, Wong WH

Neutrophils have key roles in modulating the immune response. We present a robust methodology for rapidly isolating neutrophils directly from whole blood with 'on-chip' processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and by comparison with standard bulk isolation methodologies. Last, we implement this tool as part of a near-patient blood processing system within a multi-center clinical study of the immune response to severe trauma and burn injury. The preliminary results from a small cohort of subjects in our study and healthy controls show a unique time-dependent gene expression pattern clearly demonstrating the ability of this tool to discriminate temporal transcriptional events of neutrophils within a clinical setting.

PMID: 20802500 [PubMed - as supplied by publisher]

Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease.

Nat Med. 2010 Aug 22;

Authors: Lee BD, Shin JH, Vankampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.

PMID: 20729864 [PubMed - as supplied by publisher]

Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease.

Nat Med. 2010 Aug 22;

Authors: Lee BD, Shin JH, Vankampen J, Petrucelli L, West AB, Ko HS, Lee YI, Maguire-Zeiss KA, Bowers WJ, Federoff HJ, Dawson VL, Dawson TM

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.

PMID: 20729864 [PubMed - as supplied by publisher]

Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.

Nat Med. 2010 Aug 22;

Authors: Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

PMID: 20729865 [PubMed - as supplied by publisher]

Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.

Nat Med. 2010 Aug 22;

Authors: Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I

There is no effective treatment for cocaine addiction despite extensive knowledge of the neurobiology of drug addiction. Here we show that a selective aldehyde dehydrogenase-2 (ALDH-2) inhibitor, ALDH2i, suppresses cocaine self-administration in rats and prevents cocaine- or cue-induced reinstatement in a rat model of cocaine relapse-like behavior. We also identify a molecular mechanism by which ALDH-2 inhibition reduces cocaine-seeking behavior: increases in tetrahydropapaveroline (THP) formation due to inhibition of ALDH-2 decrease cocaine-stimulated dopamine production and release in vitro and in vivo. Cocaine increases extracellular dopamine concentration, which activates dopamine D2 autoreceptors to stimulate cAMP-dependent protein kinase A (PKA) and protein kinase C (PKC) in primary ventral tegmental area (VTA) neurons. PKA and PKC phosphorylate and activate tyrosine hydroxylase, further increasing dopamine synthesis in a positive-feedback loop. Monoamine oxidase converts dopamine to 3,4-dihydroxyphenylacetaldehyde (DOPAL), a substrate for ALDH-2. Inhibition of ALDH-2 enables DOPAL to condense with dopamine to form THP in VTA neurons. THP selectively inhibits phosphorylated (activated) tyrosine hydroxylase to reduce dopamine production via negative-feedback signaling. Reducing cocaine- and craving-associated increases in dopamine release seems to account for the effectiveness of ALDH2i in suppressing cocaine-seeking behavior. Selective inhibition of ALDH-2 may have therapeutic potential for treating human cocaine addiction and preventing relapse.

PMID: 20729865 [PubMed - as supplied by publisher]

Advanced antisense therapies for postexposure protection against lethal filovirus infections.

Nat Med. 2010 Aug 22;

Authors: Warren TK, Warfield KL, Wells J, Swenson DL, Donner KS, Van Tongeren SA, Garza NL, Dong L, Mourich DV, Crumley S, Nichols DK, Iversen PL, Bavari S

Currently, no vaccines or therapeutics are licensed to counter Ebola or Marburg viruses, highly pathogenic filoviruses that are causative agents of viral hemorrhagic fever. Here we show that administration of positively charged phosphorodiamidate morpholino oligomers (PMOplus), delivered by various dosing strategies initiated 30-60 min after infection, protects >60% of rhesus monkeys against lethal Zaire Ebola virus (ZEBOV) and 100% of cynomolgus monkeys against Lake Victoria Marburg virus (MARV) infection. PMOplus may be useful for treating these and other highly pathogenic viruses in humans.

PMID: 20729866 [PubMed - as supplied by publisher]

Therapeutic cell engineering with surface-conjugated synthetic nanoparticles.

Nat Med. 2010 Aug 15;

Authors: Stephan MT, Moon JJ, Um SH, Bershteyn A, Irvine DJ

A major limitation of cell therapies is the rapid decline in viability and function of the transplanted cells. Here we describe a strategy to enhance cell therapy via the conjugation of adjuvant drug-loaded nanoparticles to the surfaces of therapeutic cells. With this method of providing sustained pseudoautocrine stimulation to donor cells, we elicited marked enhancements in tumor elimination in a model of adoptive T cell therapy for cancer. We also increased the in vivo repopulation rate of hematopoietic stem cell grafts with very low doses of adjuvant drugs that were ineffective when given systemically. This approach is a simple and generalizable strategy to augment cytoreagents while minimizing the systemic side effects of adjuvant drugs. In addition, these results suggest therapeutic cells are promising vectors for actively targeted drug delivery.

PMID: 20711198 [PubMed - as supplied by publisher]

Transgenic mice with a diverse human T cell antigen receptor repertoire.

Nat Med. 2010 Aug 8;

Authors: Li LP, Lampert JC, Chen X, Leitao C, Popović J, Müller W, Blankenstein T

Because of tolerance mechanisms, it has been hard to identify the T cell receptors (TCRs) of high-avidity T cells against self (for example, tumor) antigens. TCRs that are specific for foreign human antigens from the nontolerant T cell repertoire can be identified in mice. Moreover, if mice are constructed to express the human TCR repertoire, they can be used to analyze the unskewed repertoire against human self antigens. Here we generated transgenic mice with the entire human TCRalphabeta gene loci (1.1 and 0.7 Mb), whose T cells express a diverse human TCR repertoire that compensates for mouse TCR deficiency. A human major histocompatibility class I transgene increases the generation of CD8(+) T cells with human compared to mouse TCRs. Functional CD8(+) T cells against several human tumor antigens were induced, and those against the Melan-A melanoma antigen used similar TCRs to those that have been detected in T cell clones from individuals with autoimmune vitiligo or melanoma. These mice will allow researchers to identify pathogenic and therapeutic human TCRs.

PMID: 20693993 [PubMed - as supplied by publisher]

A cure for cancer research.

Nat Med. 2010 Aug;16(8):829

Authors:

PMID: 20689526 [PubMed - in process]

After Avandia, some seek split in drug approval and monitoring.

Nat Med. 2010 Aug;16(8):831

Authors: Dolgin E

PMID: 20689527 [PubMed - in process]

Fewer shots proposed to increase uptake of HPV vaccine.

Nat Med. 2010 Aug;16(8):832-3

Authors: Dorans K

PMID: 20689528 [PubMed - in process]

Chronic controversy continues over mysterious XMRV virus.

Nat Med. 2010 Aug;16(8):832

Authors: Dolgin E

PMID: 20689529 [PubMed - in process]

Fight for subject confidentiality threatens disaster research.

Nat Med. 2010 Aug;16(8):833

Authors: Hutson S

PMID: 20689530 [PubMed - in process]

Lab-grown organs seen as remedy for long donor waitlists.

Nat Med. 2010 Aug;16(8):834

Authors: Palmer R

PMID: 20689531 [PubMed - in process]

Gap in stem cell funding could drive Australian brain drain.

Nat Med. 2010 Aug;16(8):834

Authors: Dolgin E

PMID: 20689532 [PubMed - in process]

Stem cells serve as new platform for biodefense preparedness.

Nat Med. 2010 Aug;16(8):835

Authors: May M

PMID: 20689533 [PubMed - in process]

Teaching hospitals urged to disclose clinical conflicts of interest.

Nat Med. 2010 Aug;16(8):836

Authors: Palmer R

PMID: 20689534 [PubMed - in process]

Educators dissect the future of medical training.

Nat Med. 2010 Aug;16(8):836

Authors: Palmer R

PMID: 20689535 [PubMed - in process]

Advocates to bring rare disease philanthropy under one umbrella.

Nat Med. 2010 Aug;16(8):837

Authors: Dolgin E

PMID: 20689536 [PubMed - in process]

Big pharma moves from 'blockbusters' to 'niche busters'.

Nat Med. 2010 Aug;16(8):837

Authors: Dolgin E

PMID: 20689537 [PubMed - in process]

News in brief.

Nat Med. 2010 Aug;16(8):838-9

Authors:

PMID: 20689538 [PubMed - in process]

Straight talk with ... Peter Piot.

Nat Med. 2010 Aug;16(8):840

Authors: Mullard A

Peter Piot was a freshly minted doctor, still working toward his PhD in microbiology, when he co-discovered Ebola virus. The experience launched him on a successful career in global health, including a 12-year stint as Executive Director of UNAIDS until 2008. More recently, he was appointed director of the London School of Hygiene and Tropical Medicine (LSHTM), where he is due to start next month. Speaking with Asher Mullard, he discusses the world's failed pledge to deliver universal access to AIDS treatments by 2010, the advances that have nevertheless been made and the changing paradigm of AIDS programs.

PMID: 20689539 [PubMed - in process]

Parse the salt, please.

Nat Med. 2010 Aug;16(8):841-3

Authors: Strauss S

PMID: 20689540 [PubMed - in process]

Tech meets bio.

Nat Med. 2010 Aug;16(8):844-7

Authors: Heger M

PMID: 20689541 [PubMed - in process]

Prepare for the long haul of drug monitoring.

Nat Med. 2010 Aug;16(8):848

Authors: Gliklich R

PMID: 20689542 [PubMed - in process]

What's in a name?

Nat Med. 2010 Aug;16(8):849

Authors: Rubinsztein D

PMID: 20689543 [PubMed - in process]

Neutrophils release brakes of coagulation.

Nat Med. 2010 Aug;16(8):851-2

Authors: Ruf W, Ruggeri ZM

PMID: 20689544 [PubMed - in process]

Turning on the angiogenic microswitch.

Nat Med. 2010 Aug;16(8):853-4

Authors: Eilken HM, Adams RH

PMID: 20689545 [PubMed - in process]

A needle in the 'cancer vaccine' haystack.

Nat Med. 2010 Aug;16(8):854-6

Authors: Gallois A, Bhardwaj N

PMID: 20689546 [PubMed - in process]

Glutamate joins the ranks of immunomodulators.

Nat Med. 2010 Aug;16(8):856-8

Authors: Hansen AM, Caspi RR

PMID: 20689547 [PubMed - in process]

Targeting dendritic cell metabolism in cancer.

Nat Med. 2010 Aug;16(8):858-9

Authors: Zitvogel L, Kroemer G

PMID: 20689548 [PubMed - in process]

Mutant mice challenged as models of injury in the central nervous system.

Nat Med. 2010 Aug;16(8):860

Authors:

PMID: 20689549 [PubMed - in process]

A double agent in cancer: Deciphering macrophage roles in human tumors.

Nat Med. 2010 Aug;16(8):861-2

Authors: Ruhrberg C, De Palma M

PMID: 20689550 [PubMed - in process]

A double agent in cancer: Stopping macrophages wounds tumors.

Nat Med. 2010 Aug;16(8):863-4

Authors: Qualls JE, Murray PJ

PMID: 20689551 [PubMed - in process]

Research highlights.

Nat Med. 2010 Aug;16(8):866-7

Authors:

PMID: 20689552 [PubMed - in process]

MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis.

Nat Med. 2010 Aug 1;

Authors: Anand S, Majeti BK, Acevedo LM, Murphy EA, Mukthavaram R, Scheppke L, Huang M, Shields DJ, Lindquist JN, Lapinski PE, King PD, Weis SM, Cheresh DA

Although it is well established that tumors initiate an angiogenic switch, the molecular basis of this process remains incompletely understood. Here we show that the miRNA miR-132 acts as an angiogenic switch by targeting p120RasGAP in the endothelium and thereby inducing neovascularization. We identified miR-132 as a highly upregulated miRNA in a human embryonic stem cell model of vasculogenesis and found that miR-132 was highly expressed in the endothelium of human tumors and hemangiomas but was undetectable in normal endothelium. Ectopic expression of miR-132 in endothelial cells in vitro increased their proliferation and tube-forming capacity, whereas intraocular injection of an antagomir targeting miR-132, anti-miR-132, reduced postnatal retinal vascular development in mice. Among the top-ranking predicted targets of miR-132 was p120RasGAP, which we found to be expressed in normal but not tumor endothelium. Endothelial expression of miR-132 suppressed p120RasGAP expression and increased Ras activity, whereas a miRNA-resistant version of p120RasGAP reversed the vascular response induced by miR-132. Notably, administration of anti-miR-132 inhibited angiogenesis in wild-type mice but not in mice with an inducible deletion of Rasa1 (encoding p120RasGAP). Finally, vessel-targeted nanoparticle delivery of anti-miR-132 restored p120RasGAP expression in the tumor endothelium, suppressed angiogenesis and decreased tumor burden in an orthotopic xenograft mouse model of human breast carcinoma. We conclude that miR-132 acts as an angiogenic switch by suppressing endothelial p120RasGAP expression, leading to Ras activation and the induction of neovascularization, whereas the application of anti-miR-132 inhibits neovascularization by maintaining vessels in the resting state.

PMID: 20676106 [PubMed - as supplied by publisher]

Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.

Nat Med. 2010 Aug 1;

Authors: Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT, Engelmann B

Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo. The serine proteases and extracellular nucleosomes enhance tissue factor- and factor XII-dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

PMID: 20676107 [PubMed - as supplied by publisher]

Combined treatment with oral metronidazole and N-acetylcysteine is effective in ethylmalonic encephalopathy.

Nat Med. 2010 Jul 25;

Authors: Viscomi C, Burlina AB, Dweikat I, Savoiardo M, Lamperti C, Hildebrandt T, Tiranti V, Zeviani M

Ethylmalonic encephalopathy is caused by mutations in ETHE1, a mitochondrial matrix sulfur dioxygenase, leading to failure to detoxify sulfide, a product of intestinal anaerobes and, in trace amounts, tissues. Metronidazole, a bactericide, or N-acetylcysteine, a precursor of sulfide-buffering glutathione, substantially prolonged the lifespan of Ethe1-deficient mice, with the combined treatment being additive. The same dual treatment caused marked clinical improvement in five affected children, with hardly any adverse or side effects.

PMID: 20657580 [PubMed - as supplied by publisher]

Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation.

Nat Med. 2010 Jul 25;

Authors: Fallarino F, Volpi C, Fazio F, Notartomaso S, Vacca C, Busceti C, Bicciato S, Battaglia G, Bruno V, Puccetti P, Fioretti MC, Nicoletti F, Grohmann U, Di Marco R

High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper (T(H)17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased T(H) cell commitment to the T(H)17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (T(reg)) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.

PMID: 20657581 [PubMed - as supplied by publisher]

CIB1 is a regulator of pathological cardiac hypertrophy.

Nat Med. 2010 Jul 18;

Authors: Heineke J, Auger-Messier M, Correll RN, Xu J, Benard MJ, Yuan W, Drexler H, Parise LV, Molkentin JD

Hypertrophic heart disease is a leading health problem in Western countries. Here we identified the small EF hand domain-containing protein Ca(2+) and integrin-binding protein-1 (CIB1) in a screen for previously unknown regulators of cardiomyocyte hypertrophy. Yeast two-hybrid screening for CIB1-interacting partners identified a related EF hand domain-containing protein, calcineurin B, the regulatory subunit of the prohypertrophic protein phosphatase calcineurin. CIB1 localizes primarily to the sarcolemma in mouse and human myocardium, where it anchors calcineurin to control its activation in coordination with the L-type Ca(2+) channel. CIB1 protein amounts and membrane association were enhanced in cardiac pathological hypertrophy, but not in physiological hypertrophy. Consistent with these observations, Cib1-deleted mice showed a marked reduction in myocardial hypertrophy, fibrosis, cardiac dysfunction and calcineurin-nuclear factor of activated T cells (NFAT) activity after pressure overload, whereas the degree of physiologic hypertrophy after swimming exercise was not altered. Transgenic mice with inducible and cardiac-specific overexpression of CIB1 showed enhanced cardiac hypertrophy in response to pressure overload or calcineurin signaling. Moreover, mice lacking Ppp3cb (encoding calcineurin A, beta isozyme) showed no enhancement in cardiac hypertrophy associated with CIB1 overexpression. Thus, CIB1 functions as a previously undescribed regulator of cardiac hypertrophy through its ability to regulate the association of calcineurin with the sarcolemma and its activation.

PMID: 20639889 [PubMed - as supplied by publisher]

A molecularly engineered split reporter for imaging protein-protein interactions with positron emission tomography.

Nat Med. 2010 Jul 18;

Authors: Massoud TF, Paulmurugan R, Gambhir SS

Improved techniques to noninvasively image protein-protein interactions (PPIs) are essential. We molecularly engineered a positron emission tomography (PET)-based split reporter (herpes simplex virus type 1 thymidine kinase), cleaved between Thr265 and Ala266, and used this in a protein-fragment complementation assay (PCA) to quantify PPIs in mammalian cells and to microPET image them in living mice. An introduced point mutation (V119C) markedly enhanced thymidine kinase complementation in PCAs, on the basis of rapamycin modulation of FKBP12-rapamycin-binding domain (FRB) and FKBP12 (FK506 binding protein), the interaction of hypoxia-inducible factor-1alpha with the von Hippel-Lindau tumor suppressor, and in an estrogen receptor intramolecular protein folding assay. Applications of this unique split thymidine kinase are potentially far reaching, including, for example, considerably more accurate monitoring of immune and stem cell therapies, allowing for fully quantitative and tomographic PET localization of PPIs in preclinical small- and large-animal models of disease.

PMID: 20639890 [PubMed - as supplied by publisher]

Dissolving polymer microneedle patches for influenza vaccination.

Nat Med. 2010 Jul 18;

Authors: Sullivan SP, Koutsonanos DG, Del Pilar Martin M, Lee JW, Zarnitsyn V, Choi SO, Murthy N, Compans RW, Skountzou I, Prausnitz MR

Influenza prophylaxis would benefit from a vaccination method enabling simplified logistics and improved immunogenicity without the dangers posed by hypodermic needles. Here we introduce dissolving microneedle patches for influenza vaccination using a simple patch-based system that targets delivery to skin's antigen-presenting cells. Microneedles were fabricated using a biocompatible polymer encapsulating inactivated influenza virus vaccine for insertion and dissolution in the skin within minutes. Microneedle vaccination generated robust antibody and cellular immune responses in mice that provided complete protection against lethal challenge. Compared to conventional intramuscular injection, microneedle vaccination resulted in more efficient lung virus clearance and enhanced cellular recall responses after challenge. These results suggest that dissolving microneedle patches can provide a new technology for simpler and safer vaccination with improved immunogenicity that could facilitate increased vaccination coverage.

PMID: 20639891 [PubMed - as supplied by publisher]

Regeneration and orthotopic transplantation of a bioartificial lung.

Nat Med. 2010 Jul 13;

Authors: Ott HC, Clippinger B, Conrad C, Schuetz C, Pomerantseva I, Ikonomou L, Kotton D, Vacanti JP

About 2,000 patients now await a donor lung in the United States. Worldwide, 50 million individuals are living with end-stage lung disease. Creation of a bioartificial lung requires engineering of viable lung architecture enabling ventilation, perfusion and gas exchange. We decellularized lungs by detergent perfusion and yielded scaffolds with acellular vasculature, airways and alveoli. To regenerate gas exchange tissue, we seeded scaffolds with epithelial and endothelial cells. To establish function, we perfused and ventilated cell-seeded constructs in a bioreactor simulating the physiologic environment of developing lung. By day 5, constructs could be perfused with blood and ventilated using physiologic pressures, and they generated gas exchange comparable to that of isolated native lungs. To show in vivo function, we transplanted regenerated lungs into orthotopic position. After transplantation, constructs were perfused by the recipient's circulation and ventilated by means of the recipient's airway and respiratory muscles, and they provided gas exchange in vivo for up to 6 h after extubation.

PMID: 20628374 [PubMed - as supplied by publisher]

Lipid accumulation and dendritic cell dysfunction in cancer.

Nat Med. 2010 Jul 11;

Authors: Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, Corzo A, Cho HI, Celis E, Lennox B, Knight SC, Padhya T, McCaffrey TV, McCaffrey JC, Antonia S, Fishman M, Ferris RL, Kagan VE, Gabrilovich DI

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.

PMID: 20622859 [PubMed - as supplied by publisher]

Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia.

Nat Med. 2010 Jul 8;

Authors: Kharas MG, Lengner CJ, Al-Shahrour F, Bullinger L, Ball B, Zaidi S, Morgan K, Tam W, Paktinat M, Okabe R, Gozo M, Einhorn W, Lane SW, Scholl C, Fröhling S, Fleming M, Ebert BL, Gilliland DG, Jaenisch R, Daley GQ

RNA-binding proteins of the Musashi (Msi) family are expressed in stem cell compartments and in aggressive tumors, but they have not yet been widely explored in the blood. Here we demonstrate that Msi2 is the predominant form expressed in hematopoietic stem cells (HSCs), and its knockdown leads to reduced engraftment and depletion of HSCs in vivo. Overexpression of human MSI2 in a mouse model increases HSC cell cycle progression and cooperates with the chronic myeloid leukemia-associated BCR-ABL1 oncoprotein to induce an aggressive leukemia. MSI2 is overexpressed in human myeloid leukemia cell lines, and its depletion leads to decreased proliferation and increased apoptosis. Expression levels in human myeloid leukemia directly correlate with decreased survival in patients with the disease, thereby defining MSI2 expression as a new prognostic marker and as a new target for therapy in acute myeloid leukemia (AML).

PMID: 20616797 [PubMed - as supplied by publisher]

Seeking transparency.

Nat Med. 2010 Jul;16(7):723

Authors:

PMID: 20613727 [PubMed - in process]

Correction: In vision trial, some researchers would rather see double.

Nat Med. 2010 Jul;16(7):726

Authors:

PMID: 20613729 [PubMed - in process]

Lack of microarray uptake compromises diagnosis of young.

Nat Med. 2010 Jul;16(7):725

Authors: Hughes V

PMID: 20613728 [PubMed - in process]

Pharma fesses up to freebies.

Nat Med. 2010 Jul;16(7):726

Authors:

PMID: 20613730 [PubMed - in process]

Legalese creates consent 'conundrum' in clinical trials.

Nat Med. 2010 Jul;16(7):727

Authors: Dolgin E

PMID: 20613732 [PubMed - in process]

Austerity threatens pharma beyond borders of cost cutters.

Nat Med. 2010 Jul;16(7):726

Authors: Mullard A

PMID: 20613731 [PubMed - in process]

FDA strengthens its stance against unethical researchers.

Nat Med. 2010 Jul;16(7):728

Authors: Palmer R

PMID: 20613734 [PubMed - in process]

Gene test kit oversight could prove a mixed blessing for research.

Nat Med. 2010 Jul;16(7):728

Authors: Scudellari M

PMID: 20613733 [PubMed - in process]

Pharmacogenetics raises new legal questions.

Nat Med. 2010 Jul;16(7):729

Authors: Hutson S

PMID: 20613735 [PubMed - in process]

Canadian beacon.

Nat Med. 2010 Jul;16(7):731

Authors:

PMID: 20613737 [PubMed - in process]

Australia reworks research philanthropy to fill unmet need.

Nat Med. 2010 Jul;16(7):730

Authors: Morgan B

PMID: 20613736 [PubMed - in process]

Researchers knock down gene to stop HIV in its tracks.

Nat Med. 2010 Jul;16(7):731

Authors: Weaver J

PMID: 20613738 [PubMed - in process]

Tech teams try to curate genetic data for future use.

Nat Med. 2010 Jul;16(7):733

Authors: Willyard C

PMID: 20613740 [PubMed - in process]

Family data underused to track disease.

Nat Med. 2010 Jul;16(7):732

Authors: May M

PMID: 20613739 [PubMed - in process]

News in brief.

Nat Med. 2010 Jul;16(7):734-5

Authors:

PMID: 20613741 [PubMed - in process]

Timing is everything.

Nat Med. 2010 Jul;16(7):737-9

Authors: Khamsi R

PMID: 20613743 [PubMed - in process]

Straight talk with...Carolyn Bertozzi.

Nat Med. 2010 Jul;16(7):736

Authors: Palmer R

Last month, Carolyn Bertozzi became the first woman to win the prestigious Massachusetts Institute of Technology (MIT)-Lemelson Prize, a $500,000 award that honors midcareer inventors. Bertozzi, a chemical biologist, works to understand how sugars mediate cell-to-cell communication. But she isn't content with just observing the process; her lab at the University of California-Berkeley has pioneered tools for labeling molecules inside living cells. Her biomedical inventions have contributed to the development of noninvasive methods for identifying disease tissue within the body-advances that could revolutionize both the diagnosis and the treatment of a host of diseases ranging from arthritis to cancer. Roxanne Palmer recently caught up with her by phone to discuss Bertozzi's sweet success with cell surface sugars.

PMID: 20613742 [PubMed - in process]

The inverse of immunity.

Nat Med. 2010 Jul;16(7):740-3

Authors: Dolgin E

PMID: 20613744 [PubMed - in process]

The heart of drug discovery.

Nat Med. 2010 Jul;16(7):745

Authors: Fisher EA

PMID: 20613746 [PubMed - in process]

The delay in sharing research data is costing lives.

Nat Med. 2010 Jul;16(7):744

Authors: Sommer J

PMID: 20613745 [PubMed - in process]

Antivenoms administered properly and swiftly save lives.

Nat Med. 2010 Jul;16(7):747

Authors: Murphy JC

PMID: 20613747 [PubMed - in process]

RAF translocations expand cancer targets.

Nat Med. 2010 Jul;16(7):749-50

Authors: McMahon M

PMID: 20613748 [PubMed - in process]

Telling kidneys to cease and decyst.

Nat Med. 2010 Jul;16(7):751-2

Authors: Takiar V, Caplan MJ

PMID: 20613749 [PubMed - in process]

VEGF and ephrin-B2: a bloody duo.

Nat Med. 2010 Jul;16(7):752-4

Authors: Germain S, Eichmann A

PMID: 20613750 [PubMed - in process]

Smoking and emphysema: the stress connection.

Nat Med. 2010 Jul;16(7):754-5

Authors: Ellisen LW

PMID: 20613751 [PubMed - in process]

Dynamic and transient cancer stem cells nurture melanoma.

Nat Med. 2010 Jul;16(7):758

Authors:

PMID: 20613753 [PubMed - in process]

Pregnancy hormones boost beta cells via serotonin.

Nat Med. 2010 Jul;16(7):756-7

Authors: Georgia S, Bhushan A

PMID: 20613752 [PubMed - in process]

Far from the Heart: Counteracting coagulation.

Nat Med. 2010 Jul;16(7):759-60

Authors: Esmon CT

PMID: 20613754 [PubMed - in process]

Research highlights.

Nat Med. 2010 Jul;16(7):764-5

Authors:

PMID: 20613756 [PubMed - in process]

Far from the Heart: Receptor cross-talk in remote conditioning.

Nat Med. 2010 Jul;16(7):760-2

Authors: Weber C

PMID: 20613755 [PubMed - in process]

Corrigendum: Autophagy enhances the efficacy of BCG vaccine by increasing peptide presentation in mouse dendritic cells.

Nat Med. 2010 Jul;16(7):828

Authors: Jagannath C, Lindsey DR, Dhandayuthapani S, Xu Y, Hunter RL, Eissa NT

PMID: 20613757 [PubMed - in process]

Corrigendum: Shifting HIFs in osteoarthritis.

Nat Med. 2010 Jul;16(7):828

Authors: Husa M, Liu-Bryan R, Terkeltaub R

PMID: 20613758 [PubMed - in process]

Modulation of histone H3 lysine 56 acetylation as an antifungal therapeutic strategy.

Nat Med. 2010 Jul 4;

Authors: Wurtele H, Tsao S, Lépine G, Mullick A, Tremblay J, Drogaris P, Lee EH, Thibault P, Verreault A, Raymond M

Candida albicans is a major fungal pathogen that causes serious systemic and mucosal infections in immunocompromised individuals. In yeast, histone H3 Lys56 acetylation (H3K56ac) is an abundant modification regulated by enzymes that have fungal-specific properties, making them appealing targets for antifungal therapy. Here we demonstrate that H3K56ac in C. albicans is regulated by the RTT109 and HST3 genes, which respectively encode the H3K56 acetyltransferase (Rtt109p) and deacetylase (Hst3p). We show that reduced levels of H3K56ac sensitize C. albicans to genotoxic and antifungal agents. Inhibition of Hst3p activity by conditional gene repression or nicotinamide treatment results in a loss of cell viability associated with abnormal filamentous growth, histone degradation and gross aberrations in DNA staining. We show that genetic or pharmacological alterations in H3K56ac levels reduce virulence in a mouse model of C. albicans infection. Our results demonstrate that modulation of H3K56ac is a unique strategy for treatment of C. albicans and, possibly, other fungal infections.

PMID: 20601951 [PubMed - as supplied by publisher]

Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity.

Nat Med. 2010 Jun 27;

Authors: Chibon F, Lagarde P, Salas S, Pérot G, Brouste V, Tirode F, Lucchesi C, de Reynies A, Kauffmann A, Bui B, Terrier P, Bonvalot S, Le Cesne A, Vince-Ranchère D, Blay JY, Collin F, Guillou L, Leroux A, Coindre JM, Aurias A

Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.

PMID: 20581836 [PubMed - as supplied by publisher]

Serotonin regulates pancreatic beta cell mass during pregnancy.

Nat Med. 2010 Jun 27;

Authors: Kim H, Toyofuku Y, Lynn FC, Chak E, Uchida T, Mizukami H, Fujitani Y, Kawamori R, Miyatsuka T, Kosaka Y, Yang K, Honig G, van der Hart M, Kishimoto N, Wang J, Yagihashi S, Tecott LH, Watada H, German MS

During pregnancy, the energy requirements of the fetus impose changes in maternal metabolism. Increasing insulin resistance in the mother maintains nutrient flow to the growing fetus, whereas prolactin and placental lactogen counterbalance this resistance and prevent maternal hyperglycemia by driving expansion of the maternal population of insulin-producing beta cells. However, the exact mechanisms by which the lactogenic hormones drive beta cell expansion remain uncertain. Here we show that serotonin acts downstream of lactogen signaling to stimulate beta cell proliferation. Expression of serotonin synthetic enzyme tryptophan hydroxylase-1 (Tph1) and serotonin production rose sharply in beta cells during pregnancy or after treatment with lactogens in vitro. Inhibition of serotonin synthesis by dietary tryptophan restriction or Tph inhibition blocked beta cell expansion and induced glucose intolerance in pregnant mice without affecting insulin sensitivity. Expression of the Galpha(q)-linked serotonin receptor 5-hydroxytryptamine receptor-2b (Htr2b) in maternal islets increased during pregnancy and normalized just before parturition, whereas expression of the Galpha(i)-linked receptor Htr1d increased at the end of pregnancy and postpartum. Blocking Htr2b signaling in pregnant mice also blocked beta cell expansion and caused glucose intolerance. These studies reveal an integrated signaling pathway linking beta cell mass to anticipated insulin need during pregnancy. Modulators of this pathway, including medications and diet, may affect the risk of gestational diabetes.

PMID: 20581837 [PubMed - as supplied by publisher]

Cancer vaccine approval could open floodgates.

Nat Med. 2010 Jun;16(6):615

Authors:

PMID: 20526296 [PubMed - indexed for MEDLINE]

Avandia outcome may signal change in epidemiologists' sway.

Nat Med. 2010 Jun;16(6):614

Authors: Wadman M

PMID: 20526293 [PubMed - indexed for MEDLINE]

Health reform unhealthy for pharma.

Nat Med. 2010 Jun;16(6):618

Authors:

PMID: 20526298 [PubMed - indexed for MEDLINE]

The state of clinical research in America.

Nat Med. 2010 Jun;16(6):621

Authors:

PMID: 20526305 [PubMed - indexed for MEDLINE]

Data handling errors spur debate over clinical trial.

Nat Med. 2010 Jun;16(6):618

Authors: Hutson S

PMID: 20526299 [PubMed - indexed for MEDLINE]

A mother's gift, minus mitochondria.

Nat Med. 2010 Jun;16(6):645

Authors:

PMID: 20526317 [PubMed - indexed for MEDLINE]

Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models.

Nat Med. 2010 Jun 20;

Authors: Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, Belenky A, Bukanov NO, Dackowski WR, Husson H, Russo RJ, Shayman JA, Ledbetter SR, Leonard JP, Ibraghimov-Beskrovnaya O

Polycystic kidney disease (PKD) represents a family of genetic disorders characterized by renal cystic growth and progression to kidney failure. No treatment is currently available for people with PKD, although possible therapeutic interventions are emerging. Despite genetic and clinical heterogeneity, PKDs have in common defects of cystic epithelia, including increased proliferation, apoptosis and activation of growth regulatory pathways. Sphingolipids and glycosphingolipids are emerging as major regulators of these cellular processes. We sought to evaluate the therapeutic potential for glycosphingolipid modulation as a new approach to treat PKD. Here we demonstrate that kidney glucosylceramide (GlcCer) and ganglioside GM3 levels are higher in human and mouse PKD tissue as compared to normal tissue, regardless of the causative mutation. Blockade of GlcCer accumulation with the GlcCer synthase inhibitor Genz-123346 effectively inhibits cystogenesis in mouse models orthologous to human autosomal dominant PKD (Pkd1 conditional knockout mice) and nephronophthisis (jck and pcy mice). Molecular analysis in vitro and in vivo indicates that Genz-123346 acts through inhibition of the two key pathways dysregulated in PKD: Akt protein kinase-mammalian target of rapamycin signaling and cell cycle machinery. Taken together, our data suggest that inhibition of GlcCer synthesis represents a new and effective treatment option for PKD.

PMID: 20562878 [PubMed - as supplied by publisher]

Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix.

Nat Med. 2010 Jun 13;

Authors: Uygun BE, Soto-Gutierrez A, Yagi H, Izamis ML, Guzzardi MA, Shulman C, Milwid J, Kobayashi N, Tilles A, Berthiaume F, Hertl M, Nahmias Y, Yarmush ML, Uygun K

Orthotopic liver transplantation is the only available treatment for severe liver failure, but it is currently limited by organ shortage. One technical challenge that has thus far limited the development of a tissue-engineered liver graft is oxygen and nutrient transport. Here we demonstrate a novel approach to generate transplantable liver grafts using decellularized liver matrix. The decellularization process preserves the structural and functional characteristics of the native microvascular network, allowing efficient recellularization of the liver matrix with adult hepatocytes and subsequent perfusion for in vitro culture. The recellularized graft supports liver-specific function including albumin secretion, urea synthesis and cytochrome P450 expression at comparable levels to normal liver in vitro. The recellularized liver grafts can be transplanted into rats, supporting hepatocyte survival and function with minimal ischemic damage. These results provide a proof of principle for the generation of a transplantable liver graft as a potential treatment for liver disease.

PMID: 20543851 [PubMed - as supplied by publisher]

Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos.

Nat Med. 2010 Jun 6;

Authors: Beronja S, Livshits G, Williams S, Fuchs E

Using ultrasound-guided in utero infections of fluorescently traceable lentiviruses carrying RNAi or Cre recombinase into mouse embryos, we have demonstrated noninvasive, highly efficient selective transduction of surface epithelium, in which progenitors stably incorporate and propagate the desired genetic alterations. We achieved epidermal-specific infection using small generic promoters of existing lentiviral short hairpin RNA libraries, thus enabling rapid assessment of gene function as well as complex genetic interactions in skin morphogenesis and disease in vivo. We adapted this technology to devise a new quantitative method for ascertaining whether a gene confers a growth advantage or disadvantage in skin tumorigenesis. Using alpha1-catenin as a model, we uncover new insights into its role as a widely expressed tumor suppressor and reveal physiological interactions between Ctnna1 and the Hras1-Mapk3 and Trp53 gene pathways in regulating skin cell proliferation and apoptosis. Our study illustrates the strategy and its broad applicability for investigations of tissue morphogenesis, lineage specification and cancers.

PMID: 20526348 [PubMed - as supplied by publisher]

In vision trial, some researchers would rather see double.

Nat Med. 2010 Jun;16(6):611

Authors: Dolgin E

PMID: 20526290 [PubMed - in process]

An unhealthy disregard.

Nat Med. 2010 Jun;16(6):609

Authors:

PMID: 20526289 [PubMed - in process]

Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma.

Nat Med. 2010 Jun 6;

Authors: Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pflueger D, Ramnarayanan K, Shankar S, Han B, Cao Q, Cao X, Suleman K, Kumar-Sinha C, Dhanasekaran SM, Chen YB, Esgueva R, Banerjee S, Lafargue CJ, Siddiqui J, Demichelis F, Moeller P, Bismar TA, Kuefer R, Fullen DR, Johnson TM, Greenson JK, Giordano TJ, Tan P, Tomlins SA, Varambally S, Rubin MA, Maher CA, Chinnaiyan AM

Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.

PMID: 20526349 [PubMed - as supplied by publisher]

Tool kit for translational research.

Nat Med. 2010 Jun;16(6):612-3

Authors: Schubert C

PMID: 20526292 [PubMed - in process]

Four years on, clinical partnerships program proves worth.

Nat Med. 2010 Jun;16(6):612-3

Authors: Schubert C

PMID: 20526291 [PubMed - in process]

Antivenoms needed, say officials, but companies won't bite.

Nat Med. 2010 Jun;16(6):615

Authors: Hutson S

PMID: 20526295 [PubMed - in process]

Diabetes drug woes spell trouble for the entire drug family.

Nat Med. 2010 Jun;16(6):614

Authors: Wadman M

PMID: 20526294 [PubMed - in process]

When natural disasters strike, tragedy can unfold in the lab.

Nat Med. 2010 Jun;16(6):616-7

Authors: Willyard C

PMID: 20526297 [PubMed - in process]

Committee planned to weigh misconduct in Australia.

Nat Med. 2010 Jun;16(6):620

Authors: Grose S

PMID: 20526302 [PubMed - in process]