Peering into review.

Nat Med. 2010 Mar;16(3):239

Authors:

PMID: 20208482 [PubMed - in process]

FDA initiative may crack wall of secrecy.

Nat Med. 2010 Mar;16(3):244

Authors: Schubert C

PMID: 20208488 [PubMed - in process]

Vaccine funds will save lives.

Nat Med. 2010 Mar;16(3):243

Authors: Willyard C

PMID: 20208487 [PubMed - in process]

Pharma spends big to buy influence.

Nat Med. 2010 Mar;16(3):243

Authors:

PMID: 20208486 [PubMed - in process]

Obama's budget boosts biomedicine.

Nat Med. 2010 Mar;16(3):243

Authors:

PMID: 20208485 [PubMed - in process]

In Haiti, collapsed AIDS clinics fret over new challenges.

Nat Med. 2010 Mar;16(3):242

Authors: Dolgin E

PMID: 20208484 [PubMed - in process]

Rare opportunities appear on the horizon to treat rare diseases.

Nat Med. 2010 Mar;16(3):241

Authors: Torres C

PMID: 20208483 [PubMed - in process]

Patent disputes could trip up genome wide scans for disease.

Nat Med. 2010 Mar;16(3):245

Authors: Borrell B

PMID: 20208490 [PubMed - in process]

Industry's influence in biologics legislation examined.

Nat Med. 2010 Mar;16(3):245

Authors: Dolgin E

PMID: 20208489 [PubMed - in process]

A timeline of the Wakefield retraction.

Nat Med. 2010 Mar;16(3):248

Authors:

PMID: 20208494 [PubMed - in process]

New commissioner spells new direction for EU research funding.

Nat Med. 2010 Mar;16(3):247

Authors: Laursen L

PMID: 20208493 [PubMed - in process]

Researchers unite to improve Parkinson's drug discovery.

Nat Med. 2010 Mar;16(3):247

Authors: Dolgin E

PMID: 20208492 [PubMed - in process]

Patents draw new lines in the battle to commercialize stem cells.

Nat Med. 2010 Mar;16(3):246

Authors: Dolgin E

PMID: 20208491 [PubMed - in process]

Grassley probes health care technology.

Nat Med. 2010 Mar;16(3):250

Authors: May M

PMID: 20208498 [PubMed - in process]

Electronic records pose dilemma in developing countries.

Nat Med. 2010 Mar;16(3):249

Authors: Willyard C

PMID: 20208497 [PubMed - in process]

Comparative push concerns minorities.

Nat Med. 2010 Mar;16(3):249

Authors: Torres C

PMID: 20208496 [PubMed - in process]

State of denial.

Nat Med. 2010 Mar;16(3):248

Authors: Scudellari M

PMID: 20208495 [PubMed - in process]

News in brief.

Nat Med. 2010 Mar;16(3):252-3

Authors:

PMID: 20208502 [PubMed - in process]

Pharma sets its sights on secondary data use.

Nat Med. 2010 Mar;16(3):251

Authors: Torres C

PMID: 20208501 [PubMed - in process]

Small practices find little incentive to go electronic.

Nat Med. 2010 Mar;16(3):251

Authors: Torres C

PMID: 20208500 [PubMed - in process]

'HIPAA2' legislation means more delicate handling of data.

Nat Med. 2010 Mar;16(3):250

Authors: May M

PMID: 20208499 [PubMed - in process]

Straight talk with...Shlomo Yanai.

Nat Med. 2010 Mar;16(3):261

Authors: Watzman H

Shlomo Yanai has led the world's largest generic drug manufacturer, Teva Pharmaceutical Industries, as its chief executive officer since March 2007. Last year-barely his third in pharmaceuticals and his sixth in business-he was named the world's most influential pharma CEO by World Pharmaceutical Frontiers and Israel's top business executive by the Tel Aviv financial newspaper Calcalist. A twice-wounded veteran of the Yom Kippur War of 1973, Yanai served in the Israel Defense Forces for 32 years. This interview was conducted in Hebrew by Haim Watzman, who also translated the discussion into English.

PMID: 20208505 [PubMed - in process]

An apt approach.

Nat Med. 2010 Mar;16(3):258-60

Authors: Dove A

PMID: 20208504 [PubMed - in process]

The knockout rat pack.

Nat Med. 2010 Mar;16(3):254-7

Authors: Dolgin E

PMID: 20208503 [PubMed - in process]

Globalizing pharmaceutical trials.

Nat Med. 2010 Mar;16(3):262

Authors: Annas GJ

PMID: 20208506 [PubMed - in process]

A sweet target for innate immunity.

Nat Med. 2010 Mar;16(3):263-4

Authors: Liu FT, Bevins CL

PMID: 20208507 [PubMed - in process]

Ido brings down the pressure in systemic inflammation.

Nat Med. 2010 Mar;16(3):265-7

Authors: Hofmann F

PMID: 20208509 [PubMed - in process]

Rebuilding Humpty Dumpty with a serotonin inhibitor.

Nat Med. 2010 Mar;16(3):264-5

Authors: Seeman E

PMID: 20208508 [PubMed - in process]

Lipids control mucus production in cystic fibrosis.

Nat Med. 2010 Mar;16(3):267-8

Authors: Gulbins E

PMID: 20208510 [PubMed - in process]

HIV vaccines: mosaic approach to virus diversity.

Nat Med. 2010 Mar;16(3):268-70

Authors: Corey L, McElrath MJ

PMID: 20208511 [PubMed - in process]

New drugs may improve, complicate treatment for multiple sclerosis.

Nat Med. 2010 Mar;16(3):272

Authors:

PMID: 20208513 [PubMed - in process]

Spasticity: a switch from inhibition to excitation.

Nat Med. 2010 Mar;16(3):270-1

Authors: Edgerton VR, Roy RR

PMID: 20208512 [PubMed - in process]

Asthma and allergy: The early beginnings.

Nat Med. 2010 Mar;16(3):274-5

Authors: Hawrylowicz C, Ryanna K

PMID: 20208515 [PubMed - in process]

Asthma and allergy: The emerging epithelium.

Nat Med. 2010 Mar;16(3):273-4

Authors: Lloyd CM, Saglani S

PMID: 20208514 [PubMed - in process]

Research highlights.

Nat Med. 2010 Mar;16(3):276-7

Authors:

PMID: 20208516 [PubMed - in process]

HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs.

Nat Med. 2010 Mar 7;

Authors: Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J, Bixby D, Savona MR, Collins KL

HIV causes a chronic infection characterized by depletion of CD4(+) T lymphocytes and the development of opportunistic infections. Despite drugs that inhibit viral spread, HIV infection has been difficult to cure because of uncharacterized reservoirs of infected cells that are resistant to highly active antiretroviral therapy (HAART) and the immune response. Here we used CD34(+) cells from infected people as well as in vitro studies of wild-type HIV to show infection and killing of CD34(+) multipotent hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent infection that stably persisted in cell culture until viral gene expression was activated by differentiation factors. A unique reporter HIV that directly detects latently infected cells in vitro confirmed the presence of distinct populations of active and latently infected HPCs. These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection.

PMID: 20208541 [PubMed - as supplied by publisher]

Programmed death-1-induced interleukin-10 production by monocytes impairs CD4(+) T cell activation during HIV infection.

Nat Med. 2010 Mar 7;

Authors: Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP

Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4(+) T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4(+) T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.

PMID: 20208540 [PubMed - as supplied by publisher]

Kynurenine is an endothelium-derived relaxing factor produced during inflammation.

Nat Med. 2010 Feb 28;

Authors: Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR, Kapoor V, Celermajer DS, Mellor AL, Keaney JF, Hunt NH, Stocker R

Control of blood vessel tone is central to vascular homeostasis. Here we show that metabolism of tryptophan to kynurenine by indoleamine 2,3-dioxygenase (Ido) expressed in endothelial cells contributes to arterial vessel relaxation and the control of blood pressure. Infection of mice with malarial parasites (Plasmodium berghei) or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration and hypotension. Pharmacological inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or interferon-gamma, which is required for Ido induction. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium independent. The arterial relaxation induced by kynurenine was mediated by activation of the adenylate and soluble guanylate cyclase pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Our results identify tryptophan metabolism by Ido as a new pathway contributing to the regulation of vascular tone.

PMID: 20190767 [PubMed - as supplied by publisher]

Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury.

Nat Med. 2010 Feb 28;

Authors: Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L

Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABA(A)) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl(-)) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl(-) equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.

PMID: 20190766 [PubMed - as supplied by publisher]

Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys.

Nat Med. 2010 Feb 21;

Authors: Barouch DH, O'Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte A, Riggs AM, Lynch DM, Clark SL, Backus K, Perry JR, Seaman MS, Carville A, Mansfield KG, Szinger JJ, Fischer W, Muldoon M, Korber B

The worldwide diversity of HIV-1 presents an unprecedented challenge for vaccine development. Antigens derived from natural HIV-1 sequences have elicited only a limited breadth of cellular immune responses in nonhuman primate studies and clinical trials to date. Polyvalent 'mosaic' antigens, in contrast, are designed to optimize cellular immunologic coverage of global HIV-1 sequence diversity. Here we show that mosaic HIV-1 Gag, Pol and Env antigens expressed by recombinant, replication-incompetent adenovirus serotype 26 vectors markedly augmented both the breadth and depth without compromising the magnitude of antigen-specific T lymphocyte responses as compared with consensus or natural sequence HIV-1 antigens in rhesus monkeys. Polyvalent mosaic antigens therefore represent a promising strategy to expand cellular immunologic vaccine coverage for genetically diverse pathogens such as HIV-1.

PMID: 20173752 [PubMed - as supplied by publisher]

Mosaic vaccines elicit CD8(+) T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys.

Nat Med. 2010 Feb 21;

Authors: Santra S, Liao HX, Zhang R, Muldoon M, Watson S, Fischer W, Theiler J, Szinger J, Balachandran H, Buzby A, Quinn D, Parks RJ, Tsao CY, Carville A, Mansfield KG, Pavlakis GN, Felber BK, Haynes BF, Korber BT, Letvin NL

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8(+) T lymphocytes that control HIV replication and CD4(+) T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8(+) T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8(+) T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.

PMID: 20173754 [PubMed - as supplied by publisher]

Concerted action of cellular JNK and Pin1 restricts HIV-1 genome integration to activated CD4(+) T lymphocytes.

Nat Med. 2010 Feb 21;

Authors: Manganaro L, Lusic M, Gutierrez MI, Cereseto A, Del Sal G, Giacca M

Long-standing evidence indicates that quiescent human peripheral blood T lymphocytes (PBLs) do not support efficient HIV infection. In resting PBLs, reverse transcription of viral RNA takes longer than in activated cells, partially because formation of the late products of reverse transcription is decreased by RNA binding by apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G (APOBEC3G). In a subsequent step, integration of the viral complementary DNA that is eventually formed is markedly impaired. Here we show that cellular c-Jun N-terminal kinase (JNK), an enzyme that is not expressed in resting CD4(+) T cells, regulates permissiveness to HIV-1 infection, and we unravel a new, sequential post-translational pathway of protein modification that regulates viral DNA integration. We found that, in activated T lymphocytes, viral integrase, which mediates HIV-1 cDNA integration into the host cell genome, is phosphorylated by JNK on a highly conserved serine residue in its core domain. Phosphorylated integrase, in turn, becomes a substrate for the cellular peptidyl prolyl-isomerase enzyme Pin1, which catalyzes a conformational modification of integrase. These concerted activities increase integrase stability and are required for efficient HIV-1 integration and infection. Lack of these modifications restricts viral infection in nonactivated, primary CD4(+) T lymphocytes.

PMID: 20173753 [PubMed - as supplied by publisher]

Pharmacological correction of a defect in PPAR-gamma signaling ameliorates disease severity in Cftr-deficient mice.

Nat Med. 2010 Feb 14;

Authors: Harmon GS, Dumlao DS, Ng DT, Barrett KE, Dennis EA, Dong H, Glass CK

Cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (encoded by Cftr) that impair its role as an apical chloride channel that supports bicarbonate transport. Individuals with cystic fibrosis show retained, thickened mucus that plugs airways and obstructs luminal organs as well as numerous other abnormalities that include inflammation of affected organs, alterations in lipid metabolism and insulin resistance. Here we show that colonic epithelial cells and whole lung tissue from Cftr-deficient mice show a defect in peroxisome proliferator-activated receptor-gamma (PPAR-gamma, encoded by Pparg) function that contributes to a pathological program of gene expression. Lipidomic analysis of colonic epithelial cells suggests that this defect results in part from reduced amounts of the endogenous PPAR-gamma ligand 15-keto-prostaglandin E(2) (15-keto-PGE(2)). Treatment of Cftr-deficient mice with the synthetic PPAR-gamma ligand rosiglitazone partially normalizes the altered gene expression pattern associated with Cftr deficiency and reduces disease severity. Rosiglitazone has no effect on chloride secretion in the colon, but it increases expression of the genes encoding carbonic anhydrases 4 and 2 (Car4 and Car2), increases bicarbonate secretion and reduces mucus retention. These studies reveal a reversible defect in PPAR-gamma signaling in Cftr-deficient cells that can be pharmacologically corrected to ameliorate the severity of the cystic fibrosis phenotype in mice.

PMID: 20154695 [PubMed - as supplied by publisher]

Innate immune lectins kill bacteria expressing blood group antigen.

Nat Med. 2010 Feb 14;

Authors: Stowell SR, Arthur CM, Dias-Baruffi M, Rodrigues LC, Gourdine JP, Heimburg-Molinaro J, Ju T, Molinaro RJ, Rivera-Marrero C, Xia B, Smith DF, Cummings RD

The expression of ABO(H) blood group antigens causes deletion of cells that generate self-specific antibodies to these antigens but this deletion limits adaptive immunity toward pathogens bearing cognate blood group antigens. To explore potential defense mechanisms against such pathogens, given these limitations in adaptive immunity, we screened for innate proteins that could recognize human blood group antigens. Here we report that two innate immune lectins, galectin-4 (Gal-4) and Gal-8, which are expressed in the intestinal tract, recognize and kill human blood group antigen-expressing Escherichia coli while failing to alter the viability of other E. coli strains or other Gram-negative or Gram-positive organisms both in vitro and in vivo. The killing activity of both Gal-4 and Gal-8 is mediated by their C-terminal domains, occurs rapidly and independently of complement and is accompanied by disruption of membrane integrity. These results demonstrate that innate defense lectins can provide immunity against pathogens that express blood group-like antigens on their surface.

PMID: 20154696 [PubMed - as supplied by publisher]

An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB.

Nat Med. 2010 Feb 14;

Authors: Min J, Zaslavsky A, Fedele G, McLaughlin SK, Reczek EE, De Raedt T, Guney I, Strochlic DE, Macconaill LE, Beroukhim R, Bronson RT, Ryeom S, Hahn WC, Loda M, Cichowski K

Metastasis is responsible for the majority of prostate cancer-related deaths; however, little is known about the molecular mechanisms that underlie this process. Here we identify an oncogene-tumor suppressor cascade that promotes prostate cancer growth and metastasis by coordinately activating the small GTPase Ras and nuclear factor-kappaB (NF-kappaB). Specifically, we show that loss of the Ras GTPase-activating protein (RasGAP) gene DAB2IP induces metastatic prostate cancer in an orthotopic mouse tumor model. Notably, DAB2IP functions as a signaling scaffold that coordinately regulates Ras and NF-kappaB through distinct domains to promote tumor growth and metastasis, respectively. DAB2IP is suppressed in human prostate cancer, where its expression inversely correlates with tumor grade and predicts prognosis. Moreover, we report that epigenetic silencing of DAB2IP is a key mechanism by which the polycomb-group protein histone-lysine N-methyltransferase EZH2 activates Ras and NF-kappaB and triggers metastasis. These studies define the mechanism by which two major pathways can be simultaneously activated in metastatic prostate cancer and establish EZH2 as a driver of metastasis.

PMID: 20154697 [PubMed - as supplied by publisher]

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8(+) T cell immunity.

Nat Med. 2010 Feb 7;

Authors: Flatz L, Hegazy AN, Bergthaler A, Verschoor A, Claus C, Fernandez M, Gattinoni L, Johnson S, Kreppel F, Kochanek S, Broek MV, Radbruch A, Lévy F, Lambert PH, Siegrist CA, Restifo NP, Löhning M, Ochsenbein AF, Nabel GJ, Pinschewer DD

Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8(+) T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4(+) T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.

PMID: 20139992 [PubMed - as supplied by publisher]

Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis.

Nat Med. 2010 Feb 7;

Authors: Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P

Osteoporosis is a disease of low bone mass most often caused by an increase in bone resorption that is not sufficiently compensated for by a corresponding increase in bone formation. As gut-derived serotonin (GDS) inhibits bone formation, we asked whether hampering its biosynthesis could treat osteoporosis through an anabolic mechanism (that is, by increasing bone formation). We synthesized and used LP533401, a small molecule inhibitor of tryptophan hydroxylase-1 (Tph-1), the initial enzyme in GDS biosynthesis. Oral administration of this small molecule once daily for up to six weeks acts prophylactically or therapeutically, in a dose-dependent manner, to treat osteoporosis in ovariectomized rodents because of an isolated increase in bone formation. These results provide a proof of principle that inhibiting GDS biosynthesis could become a new anabolic treatment for osteoporosis.

PMID: 20139991 [PubMed - as supplied by publisher]

China leaps higher in research share.

Nat Med. 2010 Feb;16(2):136

Authors: Torres C

PMID: 20134441 [PubMed - in process]

Gawande floats idea for health delivery institute.

Nat Med. 2010 Feb;16(2):135

Authors: Dolgin E

PMID: 20134440 [PubMed - in process]

'Cure acceleration' funds woven into health reform legislation.

Nat Med. 2010 Feb;16(2):135

Authors: Wadman M

PMID: 20134439 [PubMed - in process]

Slump in UK trials blamed on strict rules.

Nat Med. 2010 Feb;16(2):134

Authors: Laursen L

PMID: 20134438 [PubMed - in process]

Hazardous microbe rules raise biosecurity debate to a new level.

Nat Med. 2010 Feb;16(2):134

Authors: Hutson S

PMID: 20134437 [PubMed - in process]

WHO report on drug development marred by big pharma leak.

Nat Med. 2010 Feb;16(2):133

Authors: Mullard A

PMID: 20134436 [PubMed - in process]

Supporting data.

Nat Med. 2010 Feb;16(2):131

Authors:

PMID: 20134435 [PubMed - in process]

A good year for biologics.

Nat Med. 2010 Feb;16(2):139

Authors:

PMID: 20134447 [PubMed - in process]

Funding shortfall threatens Australian medical training.

Nat Med. 2010 Feb;16(2):138

Authors: Grose S

PMID: 20134446 [PubMed - in process]

Enforcement of new ethics rules pondered in India.

Nat Med. 2010 Feb;16(2):138

Authors: Jayaraman KS

PMID: 20134445 [PubMed - in process]

New vaccine tailored to the weakened elderly immune system.

Nat Med. 2010 Feb;16(2):137

Authors: Schubert C

PMID: 20134444 [PubMed - in process]

Mandatory registration required for Korean stem cell lines.

Nat Med. 2010 Feb;16(2):137

Authors: Wohn DY

PMID: 20134443 [PubMed - in process]

Companies throw their weight behind new antiobesity drugs.

Nat Med. 2010 Feb;16(2):136

Authors: Cahoon L

PMID: 20134442 [PubMed - in process]

Sacked drugs advisor launches private panel.

Nat Med. 2010 Feb;16(2):143

Authors: Laursen L

PMID: 20134455 [PubMed - in process]

Doping at the winter games.

Nat Med. 2010 Feb;16(2):142

Authors: Torres C

PMID: 20134454 [PubMed - in process]

Passport control to prevent athlete doping.

Nat Med. 2010 Feb;16(2):142

Authors: Torres C

PMID: 20134453 [PubMed - in process]

Elusive claims data hold promise for healthcare research.

Nat Med. 2010 Feb;16(2):141

Authors: Scudellari M

PMID: 20134452 [PubMed - in process]

Troubles beset Thai health ministry.

Nat Med. 2010 Feb;16(2):141

Authors: Grose S

PMID: 20134451 [PubMed - in process]

Destroying newborn blood samples threatens birth defect research.

Nat Med. 2010 Feb;16(2):140

Authors: May M

PMID: 20134450 [PubMed - in process]

New retrospective analysis of drugs gives pregnant pause.

Nat Med. 2010 Feb;16(2):140

Authors: Opar A

PMID: 20134449 [PubMed - in process]

Outsourcing challenges FDA to strengthen oversight abroad.

Nat Med. 2010 Feb;16(2):139

Authors: Torres C

PMID: 20134448 [PubMed - in process]

Calcium-modulating cyclophilin ligand does not restrict retrovirus release.

Nat Med. 2010 Feb;16(2):155-6

Authors: Kühl A, Münch J, Sauter D, Bertram S, Glowacka I, Steffen I, Specht A, Hofmann H, Schneider H, Behrens G, Pöhlmann S

PMID: 20134461 [PubMed - in process]

Straight talk with...Ken Getz.

Nat Med. 2010 Feb;16(2):154

Authors: Willyard C

How should clinical trials be improved? Ken Getz, a senior fellow at the Tufts Center for the Study of Drug Development, has been thinking up answers to this question for two decades. In 2003, Getz took on a new challenge when he launched the Center for Information & Study on Clinical Research, a nonprofit focused on providing education and outreach on clinical research to the public. Cassandra Willyard asked Getz for his thoughts on trial recruitment, financial conflicts of interest and keeping trial participants safe.

PMID: 20134460 [PubMed - in process]

The search beyond statins.

Nat Med. 2010 Feb;16(2):150-3

Authors: Wenner Moyer M

PMID: 20134459 [PubMed - in process]

From pond scum to pharmacy shelf.

Nat Med. 2010 Feb;16(2):146-9

Authors: Dance A

PMID: 20134458 [PubMed - in process]

News in brief.

Nat Med. 2010 Feb;16(2):144-5

Authors:

PMID: 20134457 [PubMed - in process]

NIH goes back to college for peer review.

Nat Med. 2010 Feb;16(2):143

Authors: Dolgin E

PMID: 20134456 [PubMed - in process]

How epidemics happen.

Nat Med. 2010 Feb;16(2):159

Authors: Murray M

PMID: 20134465 [PubMed - in process]

Reply to "Calcium-modulating cyclophilin ligand does not restrict retrovirus release".

Nat Med. 2010 Feb;16(2):157

Authors: Varthakavi V, Heimann-Nichols E, Smith RM, Rose J

PMID: 20134464 [PubMed - in process]

Reply to "On the origin of glioneural neoplasms after neural cell transplantation".

Nat Med. 2010 Feb;16(2):157-8

Authors: Jandial R, Snyder EY

PMID: 20134463 [PubMed - in process]

On the origin of glioneural neoplasms after neural cell transplantation.

Nat Med. 2010 Feb;16(2):157

Authors: Amariglio N, Rechavi G

PMID: 20134462 [PubMed - in process]

Gene therapy activates EVI1, destabilizes chromosomes.

Nat Med. 2010 Feb;16(2):163-5

Authors: Dunbar CE, Larochelle A

PMID: 20134468 [PubMed - in process]

Inflammatory proteinase slips into tumor cells.

Nat Med. 2010 Feb;16(2):161-3

Authors: Fingleton B

PMID: 20134467 [PubMed - in process]

Gut microbes extend reach to systemic innate immunity.

Nat Med. 2010 Feb;16(2):160-1

Authors: Philpott DJ, Girardin SE

PMID: 20134466 [PubMed - in process]

Muscling in: Uncovering the origins of rhabdomyosarcoma.

Nat Med. 2010 Feb;16(2):171-3

Authors: Hettmer S, Wagers AJ

PMID: 20134473 [PubMed - in process]

Muscling in: Gene therapies for muscular dystrophy target RNA.

Nat Med. 2010 Feb;16(2):170-1

Authors: Chamberlain JR, Chamberlain JS

PMID: 20134472 [PubMed - in process]

Burning fat not so sweet.

Nat Med. 2010 Feb;16(2):169

Authors:

PMID: 20134471 [PubMed - in process]

Empowering T helper 17 cells in autoimmunity.

Nat Med. 2010 Feb;16(2):166-8

Authors: Veldhoen M, Seddon B

PMID: 20134470 [PubMed - in process]

Angiotensin II and JAK2 put on the pressure.

Nat Med. 2010 Feb;16(2):165-6

Authors: Bernstein KE, Fuchs S

PMID: 20134469 [PubMed - in process]

Retraction: Identification of calcium-modulating cyclophilin ligand as a human host restriction to HIV-1 release overcome by Vpu.

Nat Med. 2010 Feb;16(2):238

Authors: Varthakavi V, Heimann-Nichols E, Smith RM, Sun Y, Bram RJ, Ali S, Rose J, Ding L, Spearman P

PMID: 20134478 [PubMed - in process]

Addendum: Neuronal PTP1B regulates body weight, adiposity and leptin action.

Nat Med. 2010 Feb;16(2):237

Authors: Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB

PMID: 20134477 [PubMed - in process]

Erratum: Reducing endoplasmic reticulum stress through a macrophage lipid chaperone alleviates atherosclerosis.

Nat Med. 2010 Feb;16(2):237

Authors: Erbay E, Babaev VR, Mayers JR, Makowski L, Charles KN, Snitow ME, Fazio S, Wiest MM, Watkins SM, Linton MF, Hotamisligil GS

PMID: 20134476 [PubMed - in process]

Corrigendum: Neuronal PTP1B regulates body weight, adiposity and leptin action.

Nat Med. 2010 Feb;16(2):237

Authors: Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG, Kahn BB

PMID: 20134475 [PubMed - in process]

Research highlights.

Nat Med. 2010 Feb;16(2):174-5

Authors:

PMID: 20134474 [PubMed - in process]

A virus-like particle vaccine for epidemic Chikungunya virus protects nonhuman primates against infection.

Nat Med. 2010 Jan 28;

Authors: Akahata W, Yang ZY, Andersen H, Sun S, Holdaway HA, Kong WP, Lewis MG, Higgs S, Rossmann MG, Rao S, Nabel GJ

Chikungunya virus (CHIKV) has infected millions of people in Africa, Europe and Asia since this alphavirus reemerged from Kenya in 2004. The severity of the disease and the spread of this epidemic virus present a serious public health threat in the absence of vaccines or antiviral therapies. Here, we describe a new vaccine that protects against CHIKV infection of nonhuman primates. We show that selective expression of viral structural proteins gives rise to virus-like particles (VLPs) in vitro that resemble replication-competent alphaviruses. Immunization with these VLPs elicited neutralizing antibodies against envelope proteins from alternative CHIKV strains. Monkeys immunized with VLPs produced high-titer neutralizing antibodies that protected against viremia after high-dose challenge. We transferred these antibodies into immunodeficient mice, where they protected against subsequent lethal CHIKV challenge, indicating a humoral mechanism of protection. Immunization with alphavirus VLP vaccines represents a strategy to contain the spread of CHIKV and related pathogenic viruses in humans.

PMID: 20111039 [PubMed - as supplied by publisher]

Amplification of LAPTM4B and YWHAZ contributes to chemotherapy resistance and recurrence of breast cancer.

Nat Med. 2010 Jan 24;

Authors: Li Y, Zou L, Li Q, Haibe-Kains B, Tian R, Li Y, Desmedt C, Sotiriou C, Szallasi Z, Iglehart JD, Richardson AL, Wang ZC

Adjuvant chemotherapy for breast cancer after surgery has effectively lowered metastatic recurrence rates. However, a considerable proportion of women suffer recurrent cancer at distant metastatic sites despite adjuvant treatment. Identification of the genes crucial for tumor response to specific chemotherapy drugs is a challenge but is necessary to improve outcomes. By using integrated genomics, we identified a small number of overexpressed and amplified genes from chromosome 8q22 that were associated with early disease recurrence despite anthracycline-based adjuvant chemotherapy. We confirmed the association in an analysis of multiple independent cohorts. SiRNA-mediated knockdown of either of two of these genes, the antiapoptotic gene YWHAZ and a lysosomal gene LAPTM4B, sensitized tumor cells to anthracyclines, and overexpression of either of the genes induced anthracycline resistance. Overexpression of LAPTM4B resulted in sequestration of the anthracycline doxorubicin, delaying its appearance in the nucleus. Overexpression of these two genes was associated with poor tumor response to anthracycline treatment in a neoadjuvant chemotherapy trial in women with primary breast cancer. Our results suggest that 8q22 amplification and overexpression of LAPTM4B and YWHAZ contribute to de novo chemoresistance to anthracyclines and are permissive for metastatic recurrence. Overexpression of these two genes may predict anthracycline resistance and influence selection of chemotherapy.

PMID: 20098429 [PubMed - as supplied by publisher]

Nature Medicine, reloaded.

Nat Med. 2010 Jan;16(1):1

Authors:

PMID: 20057388 [PubMed - indexed for MEDLINE]

Transferrin therapy ameliorates disease in beta-thalassemic mice.

Nat Med. 2010 Jan 24;

Authors: Li H, Rybicki AC, Suzuka SM, von Bonsdorff L, Breuer W, Hall CB, Cabantchik ZI, Bouhassira EE, Fabry ME, Ginzburg YZ

Individuals with beta-thalassemia develop progressive systemic iron overload, resulting in high morbidity and mortality. These complications are caused by labile plasma iron, which is taken up by parenchymal cells in a dysregulated manner; in contrast, erythropoiesis depends on transferrin-bound iron uptake via the transferrin receptor. We hypothesized that the ineffective erythropoiesis and anemia observed in beta-thalassemia might be ameliorated by increasing the amount of circulating transferrin. We tested the ability of transferrin injections to modulate iron metabolism and erythropoiesis in Hbb(th1/th1) mice, an experimental model of beta-thalassemia. Injected transferrin reversed or markedly improved the thalassemia phenotype in these mice. Specifically, transferrin injections normalized labile plasma iron concentrations, increased hepcidin expression, normalized red blood cell survival and increased hemoglobin production; this treatment concomitantly decreased reticulocytosis, erythropoietin abundance and splenomegaly. These results indicate that transferrin is a limiting factor contributing to anemia in these mice and suggest that transferrin therapy might be beneficial in human beta-thalassemia.

PMID: 20098432 [PubMed - as supplied by publisher]

Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease.

Nat Med. 2010 Jan 24;

Authors: Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B, Kinner A, Schmidt M, Krämer A, Schwäble J, Glimm H, Koehl U, Preiss C, Ball C, Martin H, Göhring G, Schwarzwaelder K, Hofmann WK, Karakaya K, Tchatchou S, Yang R, Reinecke P, Kühlcke K, Schlegelberger B, Thrasher AJ, Hoelzer D, Seger R, von Kalle C, Grez M

Gene-modified autologous hematopoietic stem cells (HSC) can provide ample clinical benefits to subjects suffering from X-linked chronic granulomatous disease (X-CGD), a rare inherited immunodeficiency characterized by recurrent, often life-threatening bacterial and fungal infections. Here we report on the molecular and cellular events observed in two young adults with X-CGD treated by gene therapy in 2004. After the initial resolution of bacterial and fungal infections, both subjects showed silencing of transgene expression due to methylation of the viral promoter, and myelodysplasia with monosomy 7 as a result of insertional activation of ecotropic viral integration site 1 (EVI1). One subject died from overwhelming sepsis 27 months after gene therapy, whereas a second subject underwent an allogeneic HSC transplantation. Our data show that forced overexpression of EVI1 in human cells disrupts normal centrosome duplication, linking EVI1 activation to the development of genomic instability, monosomy 7 and clonal progression toward myelodysplasia.

PMID: 20098431 [PubMed - as supplied by publisher]

The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.

Nat Med. 2010 Jan 24;

Authors: Guilluy C, Brégeon J, Toumaniantz G, Rolli-Derkinderen M, Retailleau K, Loufrani L, Henrion D, Scalbert E, Bril A, Torres RM, Offermanns S, Pacaud P, Loirand G

Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II-induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II-dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II-dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.

PMID: 20098430 [PubMed - as supplied by publisher]

Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth.

Nat Med. 2010 Jan 17;

Authors: Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, Stolz DB, Land SR, Marconcini LA, Kliment CR, Jenkins KM, Beaulieu KA, Mouded M, Frank SJ, Wong KK, Shapiro SD

Lung cancer is the leading cause of cancer death worldwide. Recent data suggest that tumor-associated inflammatory cells may modify lung tumor growth and invasiveness. To determine the role of neutrophil elastase (encoded by Elane) on tumor progression, we used the loxP-Stop-loxP K-ras(G12D) (LSL-K-ras) model of mouse lung adenocarcinoma to generate LSL-K-ras-Elane(-/-) mice. Tumor burden was markedly reduced in LSL-K-ras-Elane(-/-) mice at all time points after induction of mutant K-ras expression. Kaplan-Meier survival analysis showed that whereas all LSL-K-ras-Elane(+/+) mice died, none of the mice lacking neutrophil elastase died. Neutrophil elastase directly induced tumor cell proliferation in both human and mouse lung adenocarcinomas by gaining access to an endosomal compartment within tumor cells, where it degraded insulin receptor substrate-1 (IRS-1). Immunoprecipitation studies showed that, as neutrophil elastase degraded IRS-1, there was increased interaction between phosphatidylinositol 3-kinase (PI3K) and the potent mitogen platelet-derived growth factor receptor (PDGFR), thereby skewing the PI3K axis toward tumor cell proliferation. The inverse relationship identified between neutrophil elastase and IRS-1 in LSL-K-ras mice was also identified in human lung adenocarcinomas, thus translating these findings to human disease. This study identifies IRS-1 as a key regulator of PI3K within malignant cells. Additionally, to our knowledge, this is the first description of a secreted proteinase gaining access to the inside of a cell and altering intracellular signaling.

PMID: 20081861 [PubMed - as supplied by publisher]

Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell-mediated immunity.

Nat Med. 2010 Jan 17;

Authors: Liu L, Zhong Q, Tian T, Dubin K, Athale SK, Kupper TS

Variola major (smallpox) infection claimed hundreds of millions lives before it was eradicated by a simple vaccination strategy: epicutaneous application of the related orthopoxvirus vaccinia virus (VACV) to superficially injured skin (skin scarification, s.s.). However, the remarkable success of this strategy was attributed to the immunogenicity of VACV rather than to the unique mode of vaccine delivery. We now show that VACV immunization via s.s., but not conventional injection routes, is essential for the generation of superior T cell-mediated immune responses that provide complete protection against subsequent challenges, independent of neutralizing antibodies. Skin-resident effector memory T cells (T(EM) cells) provide complete protection against cutaneous challenge, whereas protection against lethal respiratory challenge requires both respiratory mucosal T(EM) cells and central memory T cells (T(CM) cells). Vaccination with recombinant VACV (rVACV) expressing a tumor antigen was protective against tumor challenge only if delivered via the s.s. route; it was ineffective if delivered by hypodermic injection. The clinically safer nonreplicative modified vaccinia Ankara virus (MVA) also generated far superior protective immunity when delivered via the s.s. route compared to intramuscular (i.m.) injection as used in MVA clinical trials. Thus, delivery of rVACV-based vaccines, including MVA vaccines, through physically disrupted epidermis has clear-cut advantages over conventional vaccination via hypodermic injection.

PMID: 20081864 [PubMed - as supplied by publisher]

Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity.

Nat Med. 2010 Jan 17;

Authors: Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN

Humans are colonized by a large and diverse bacterial flora (the microbiota) essential for the development of the gut immune system. A broader role for the microbiota as a major modulator of systemic immunity has been proposed; however, evidence and a mechanism for this role have remained elusive. We show that the microbiota are a source of peptidoglycan that systemically primes the innate immune system, enhancing killing by bone marrow-derived neutrophils of two major pathogens: Streptococcus pneumoniae and Staphylococcus aureus. This requires signaling via the pattern recognition receptor nucleotide-binding, oligomerization domain-containing protein-1 (Nod1, which recognizes meso-diaminopimelic acid (mesoDAP)-containing peptidoglycan found predominantly in Gram-negative bacteria), but not Nod2 (which detects peptidoglycan found in Gram-positive and Gram-negative bacteria) or Toll-like receptor 4 (Tlr4, which recognizes lipopolysaccharide). We show translocation of peptidoglycan from the gut to neutrophils in the bone marrow and show that peptidoglycan concentrations in sera correlate with neutrophil function. In vivo administration of Nod1 ligands is sufficient to restore neutrophil function after microbiota depletion. Nod1(-/-) mice are more susceptible than wild-type mice to early pneumococcal sepsis, demonstrating a role for Nod1 in priming innate defenses facilitating a rapid response to infection. These data establish a mechanism for systemic immunomodulation by the microbiota and highlight potential adverse consequences of microbiota disruption by broad-spectrum antibiotics on innate immune defense to infection.

PMID: 20081863 [PubMed - as supplied by publisher]