Journal: Nat Med

Sorted by: date / impact
Abstract

Myeloid cell contributions to cardiovascular health and disease.

Nahrendorf M
Recent advances in cell tracing and sequencing technologies have expanded our knowledge on leukocyte behavior. As a consequence, inflammatory cells, such as monocyte-derived macrophages, and their actions and products are increasingly being considered as potential drug targets for treatment of atherosclerosis, myocardial infarction and heart failure. Particularly promising developments are the identification of harmful arterial and cardiac macrophage subsets, the cells\' altered, sometimes even clonal production in hematopoietic organs, and epigenetically entrained memories of myeloid progenitors and macrophages in the setting of cardiovascular disease. Given the roles of monocytes and macrophages in host defense, intricately understanding the involved cellular subsets, sources and functions is essential for the design of precision therapeutics that preserve protective innate immunity. Here I review how new clinical and preclinical data, often linking the cardiovascular, immune and other organ systems, propel conceptual advances to a point where cardiovascular immunotherapy appears within reach.

Nat Med: 03 Jun 2018; epub ahead of print
Nahrendorf M
Nat Med: 03 Jun 2018; epub ahead of print | PMID: 29867229
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genomic diversity in autopsy samples reveals within-host dissemination of HIV-associated Mycobacterium tuberculosis.

Lieberman TD, Wilson D, Misra R, Xiong LL, ... Cohen T, Kishony R
Mycobacterium tuberculosis remains a leading cause of death worldwide, especially among individuals infected with HIV. Whereas phylogenetic analysis has revealed M. tuberculosis spread throughout history and in local outbreaks, much less is understood about its dissemination within the body. Here we report genomic analysis of 2,693 samples collected post mortem from lung and extrapulmonary biopsies of 44 subjects in KwaZulu-Natal, South Africa, who received minimal antitubercular treatment and most of whom were HIV seropositive. We found that purifying selection occurred within individual patients, without the need for patient-to-patient transmission. Despite negative selection, mycobacteria diversified within individuals to form sublineages that co-existed for years. These sublineages, as well as distinct strains from mixed infections, were differentially distributed throughout the lung, suggesting temporary barriers to pathogen migration. As a consequence, samples taken from the upper airway often captured only a fraction of the population diversity, challenging current methods of outbreak tracing and resistance diagnostics. Phylogenetic analysis indicated that dissemination from the lungs to extrapulmonary sites was as frequent as between lung sites, supporting the idea of similar migration routes within and between organs, at least in subjects with HIV. Genomic diversity therefore provides a record of pathogen diversification and repeated dissemination across the body.

Nat Med: 30 Oct 2016; epub ahead of print
Lieberman TD, Wilson D, Misra R, Xiong LL, ... Cohen T, Kishony R
Nat Med: 30 Oct 2016; epub ahead of print | PMID: 27798613
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes.

Babon JA, DeNicola ME, Blodgett DM, Crèvecoeur I, ... Harlan DM, Kent SC
A major therapeutic goal for type 1 diabetes (T1D) is to induce autoantigen-specific tolerance of T cells. This could suppress autoimmunity in those at risk for the development of T1D, as well as in those with established disease who receive islet replacement or regeneration therapy. Because functional studies of human autoreactive T cell responses have been limited largely to peripheral blood-derived T cells, it is unclear how representative the peripheral T cell repertoire is of T cells infiltrating the islets. Our knowledge of the insulitic T cell repertoire is derived from histological and immunohistochemical analyses of insulitis, the identification of autoreactive CD8(+) T cells in situ, in islets of human leukocyte antigen (HLA)-A2(+) donors and isolation and identification of DQ8 and DQ2-DQ8 heterodimer-restricted, proinsulin-reactive CD4(+) T cells grown from islets of a single donor with T1D. Here we present an analysis of 50 of a total of 236 CD4(+) and CD8(+) T cell lines grown from individual handpicked islets or clones directly sorted from handpicked, dispersed islets from nine donors with T1D. Seventeen of these T cell lines and clones reacted to a broad range of studied native islet antigens and to post-translationally modified peptides. These studies demonstrate the existence of a variety of islet-infiltrating, islet-autoantigen reactive T cells in individuals with T1D, and these data have implications for the design of successful immunotherapies.

Nat Med: 30 Oct 2016; epub ahead of print
Babon JA, DeNicola ME, Blodgett DM, Crèvecoeur I, ... Harlan DM, Kent SC
Nat Med: 30 Oct 2016; epub ahead of print | PMID: 27798614
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Human antibody repertoire after VSV-Ebola vaccination identifies novel targets and virus-neutralizing IgM antibodies.

Khurana S, Fuentes S, Coyle EM, Ravichandran S, Davey RT, Beigel JH
Development of an effective vaccine against Ebola virus is of high priority. However, knowledge about potential correlates of protection and the durability of immune response after vaccination is limited. Here, we elucidate the human antibody repertoire after administration of vesicular stomatitis virus (VSV)-Ebola vaccine at 3 million, 20 million and 100 million plaque-forming units (PFU) and homologous VSV-Ebola vaccine boost in healthy adult volunteers. Whole genome-fragment phage display libraries, expressing linear and conformational epitopes of Ebola glycoprotein (GP), showed higher diversity of antibody epitopes in individuals vaccinated with 20 million PFU than in those vaccinated with 3 million or 100 million PFU. Surface plasmon resonance kinetics showed higher levels of GP-binding antibodies after a single vaccination with 20 million or 100 million PFU than with 3 million PFU, and these correlated strongly with neutralization titers. A second vaccination did not boost antibody or virus neutralization titers, which declined rapidly, and induced only minimal antibody affinity maturation. Isotype analysis revealed a predominant IgM response even after the second vaccination, which contributed substantially to virus neutralization in vitro. These findings may help identify new vaccine targets and aid development and evaluation of effective countermeasures against Ebola.

Nat Med: 30 Oct 2016; epub ahead of print
Khurana S, Fuentes S, Coyle EM, Ravichandran S, Davey RT, Beigel JH
Nat Med: 30 Oct 2016; epub ahead of print | PMID: 27798615
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with... Eric Green.

Westly E
Eric Green, the new head of the US National Human Genome Research Institute (NHGRI), has been involved with genomics since the term was first coined in the 1980s. He started at the US National Institutes of Health (NIH) as a postdoc and was a key contributor to the Human Genome Project. Nearly a decade ago, when Green was part of a team that produced one of the first human genome sequences, the potential for genomics-related medical applications seemed limitless. But most disorders have proved to be too complex to benefit from our current understanding of genomics, and some critics have argued that researchers have put too much emphasis on uncovering the genetic underpinnings of diseases. Recent demand for comparative effectiveness research in medicine has further complicated the debate, leading former head of NHGRI Francis Collins to worry that genomic differences could get "lost in the wash." Erica Westly spoke with Green about where he sees the genomics field heading and what role he thinks the NHGRI should have in the American health care system.

Nat Med: 08 Jan 2010; 16:16-7
Westly E
Nat Med: 08 Jan 2010; 16:16-7 | PMID: 20057411
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...Donna Ambrosino.

Dolgin E
In the 1890s, a diphtheria epidemic was killing thousands of children across the US, prompting many state health departments to create laboratories to start extracting antiserum from horses\' blood. More than a century later, however, only one of these public labs is still in operation: the Massachusetts Biologic Laboratories, known simply as MassBiologics. Established in 1894 as the Massachusetts Public Health Laboratories, it is now the only nonprofit, licensed vaccine and biologics manufacturer and research center in the country-which gives the lab a unique position to tackle diseases that \'big pharma\' isn\'t willing to touch. Leading the charge is Executive Director Donna Ambrosino, who took the helm in 1998 after a 20-year career at the Dana Farber Cancer Institute in Boston. On a snowy day in January, Elie Dolgin sat down to chat with Ambrosino at MassBiologics\'s brand new research center, opened last summer in the outskirts of Boston.

Nat Med: 08 Mar 2011; 17:240
Dolgin E
Nat Med: 08 Mar 2011; 17:240 | PMID: 21383712
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cancer epigenetics reaches mainstream oncology.

Rodríguez-Paredes M, Esteller M
Epigenetics is one of the most promising and expanding fields in the current biomedical research landscape. Since the inception of epigenetics in the 1940s, the discoveries regarding its implications in normal and disease biology have not stopped, compiling a vast amount of knowledge in the past decade. The field has moved from just one recognized marker, DNA methylation, to a variety of others, including a wide spectrum of histone modifications. From the methodological standpoint, the successful initial single gene candidate approaches have been complemented by the current comprehensive epigenomic approaches that allow the interrogation of genomes to search for translational applications in an unbiased manner. Most important, the discovery of mutations in the epigenetic machinery and the approval of the first epigenetic drugs for the treatment of subtypes of leukemias and lymphomas has been an eye-opener for many biomedical scientists and clinicians. Herein, we will summarize the progress in the field of cancer epigenetics research that has reached mainstream oncology in the development of new biomarkers of the disease and new pharmacological strategies.

Nat Med: 09 Mar 2011; 17:330-9
Rodríguez-Paredes M, Esteller M
Nat Med: 09 Mar 2011; 17:330-9 | PMID: 21386836
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The role of vaccines in preventing bacterial antimicrobial resistance.

Jansen KU, Knirsch C, Anderson AS
Antimicrobial resistance (AMR) and the associated morbidity and mortality due to bacterial pathogens have been increasing globally to alarming levels. The World Health Organization (WHO) has called for global action on AMR, supported worldwide by governments, health ministries and health agencies. Many potential solutions to stem AMR are being discussed and implemented. These include increases in antimicrobial stewardship, investment in research and development to design new classes of antibiotics, and reduction of antibiotic use in rearing of livestock. However, vaccines as tools to reduce AMR have historically been under-recognized in these discussions, even though their effectiveness in reducing disease and AMR is well documented. This review article seeks to highlight the value of vaccines as an additional modality to combat AMR globally, using select examples. It also will provide perspectives on how vaccines could be more effectively used in this effort.

Nat Med: 08 Jan 2018; 24:10-19
Jansen KU, Knirsch C, Anderson AS
Nat Med: 08 Jan 2018; 24:10-19 | PMID: 29315295
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Kinase suppressor of Ras-1 protects against pulmonary Pseudomonas aeruginosa infections.

Zhang Y, Li X, Carpinteiro A, Goettel JA, Soddemann M, Gulbins E
Pseudomonas aeruginosa is a Gram-negative pathogen that causes severe infections in immunocompromised individuals and individuals with cystic fibrosis or chronic obstructive pulmonary disease (COPD). Here we show that kinase suppressor of Ras-1 (Ksr1)-deficient mice are highly susceptible to pulmonary P. aeruginosa infection accompanied by uncontrolled pulmonary cytokine release, sepsis and death, whereas wild-type mice clear the infection. Ksr1 recruits and assembles inducible nitric oxide (NO) synthase (iNOS) and heat shock protein-90 (Hsp90) to enhance iNOS activity and to release NO upon infection. Ksr1 deficiency prevents lung alveolar macrophages and neutrophils from activating iNOS, producing NO and killing bacteria. Restoring NO production restores the bactericidal capability of Ksr1-deficient lung alveolar macrophages and neutrophils and rescues Ksr1-deficient mice from P. aeruginosa infection. Our findings suggest that Ksr1 functions as a previously unknown scaffold that enhances iNOS activity and is therefore crucial for the pulmonary response to P. aeruginosa infections.

Nat Med: 07 Feb 2011; epub ahead of print
Zhang Y, Li X, Carpinteiro A, Goettel JA, Soddemann M, Gulbins E
Nat Med: 07 Feb 2011; epub ahead of print | PMID: 21297617
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.

Wang Z, Zhang XJ, Ji YX, Zhang P, ... Li H, Wang Y
Epigenetic reprogramming is a critical process of pathological gene induction during cardiac hypertrophy and remodeling, but the underlying regulatory mechanisms remain to be elucidated. Here we identified a heart-enriched long noncoding (lnc)RNA, named cardiac-hypertrophy-associated epigenetic regulator (Chaer), which is necessary for the development of cardiac hypertrophy. Mechanistically, Chaer directly interacts with the catalytic subunit of polycomb repressor complex 2 (PRC2). This interaction, which is mediated by a 66-mer motif in Chaer, interferes with PRC2 targeting to genomic loci, thereby inhibiting histone H3 lysine 27 methylation at the promoter regions of genes involved in cardiac hypertrophy. The interaction between Chaer and PRC2 is transiently induced after hormone or stress stimulation in a process involving mammalian target of rapamycin complex 1, and this interaction is a prerequisite for epigenetic reprogramming and induction of genes involved in hypertrophy. Inhibition of Chaer expression in the heart before, but not after, the onset of pressure overload substantially attenuates cardiac hypertrophy and dysfunction. Our study reveals that stress-induced pathological gene activation in the heart requires a previously uncharacterized lncRNA-dependent epigenetic checkpoint.

Nat Med: 11 Sep 2016; epub ahead of print
Wang Z, Zhang XJ, Ji YX, Zhang P, ... Li H, Wang Y
Nat Med: 11 Sep 2016; epub ahead of print | PMID: 27618650
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease.

Dreier JP
The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.

Nat Med: 08 Apr 2011; 17:439-47
Dreier JP
Nat Med: 08 Apr 2011; 17:439-47 | PMID: 21475241
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

RGB marking facilitates multicolor clonal cell tracking.

Weber K, Thomaschewski M, Warlich M, Volz T, ... Benten D, Fehse B
We simultaneously transduced cells with three lentiviral gene ontology (LeGO) vectors encoding red, green or blue fluorescent proteins. Individual cells were thereby marked by different combinations of inserted vectors, resulting in the generation of numerous mixed colors, a principle we named red-green-blue (RGB) marking. We show that lentiviral vector-mediated RGB marking remained stable after cell division, thus facilitating the analysis of clonal cell fates in vitro and in vivo. Particularly, we provide evidence that RGB marking allows assessment of clonality after regeneration of injured livers by transplanted primary hepatocytes. We also used RGB vectors to mark hematopoietic stem/progenitor cells that generated colored spleen colonies. Finally, based on limiting-dilution and serial transplantation assays with tumor cells, we found that clonal tumor cells retained their specific color-code over extensive periods of time. We conclude that RGB marking represents a useful tool for cell clonality studies in tissue regeneration and pathology.

Nat Med: 28 Mar 2011; epub ahead of print
Weber K, Thomaschewski M, Warlich M, Volz T, ... Benten D, Fehse B
Nat Med: 28 Mar 2011; epub ahead of print | PMID: 21441917
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...Seth Berkley.

Khamsi R
On 13 June, donors to the GAVI Alliance will gather in London to affirm their commitment to fund immunizations in the developing world. At the meeting, participants will address the estimated $3.7 billion financing gap needed over the next four years to scale up childhood vaccination efforts to meet the demand forecasts for those countries that receive assistance from the Geneva-based organization. But attendees of the pledging conference will also be discussing something not on the formal agenda: the announcement last month that Seth Berkley, who founded and heads the International AIDS Vaccine Initiative (IAVI), will take over the helm of the alliance in August. Berkley will lead a unique chapter in GAVI\'s development as the organization narrows in on the looming deadline set by Millennium Development Goal 4, which aims to reduce child mortality by two thirds by 2015. Yet, in a sense, these efforts will be a continuation of the work Berkley has fostered at IAVI since he formally launched the New York-based nonprofit in 1996. Berkley, an epidemiologist who previously held jobs with the Rockefeller Foundation, the Carter Center and the US Centers for Disease Control and Prevention, has witnessed ups and downs in the vaccination field, from the disappointing STEP trial in 2007 to the more recent good news from the 2009 Thai study, which reported as much as 31% protection against HIV. Roxanne Khamsi spoke with Berkley about what he has learned in his quest for a preventative shot against AIDS.

Nat Med: 08 Apr 2011; 17:404
Khamsi R
Nat Med: 08 Apr 2011; 17:404 | PMID: 21475222
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation.

Panizzi P, Nahrendorf M, Figueiredo JL, Panizzi J, ... Bock PE, Weissleder R
Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.

Nat Med: 22 Aug 2011; epub ahead of print
Panizzi P, Nahrendorf M, Figueiredo JL, Panizzi J, ... Bock PE, Weissleder R
Nat Med: 22 Aug 2011; epub ahead of print | PMID: 21857652
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Learning from bacterial competition in the host to develop antimicrobials.

Raffatellu M
In recent years, the alarming increase of antibiotic resistance, compounded by the simultaneous decrease in development of new antibiotics, has created serious concerns for public health. Moreover, current antibiotics also target the beneficial commensal microbes (microbiota) that inhabit our body, sometimes with significant health consequences. The answer to the antibiotic crisis thus involves broad, creative efforts to develop new treatments for infectious agents. Here I discuss what can be learned from investigating microbial competition in vivo and how this knowledge can be utilized to devise new narrow-spectrum therapeutics that target bacterial pathogens while minimizing deleterious effects to the microbiota.

Nat Med: 05 Aug 2018; epub ahead of print
Raffatellu M
Nat Med: 05 Aug 2018; epub ahead of print | PMID: 30082869
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The cellular and signaling networks linking the immune system and metabolism in disease.

Osborn O, Olefsky JM
It is now recognized that obesity is driving the type 2 diabetes epidemic in Western countries. Obesity-associated chronic tissue inflammation is a key contributing factor to type 2 diabetes and cardiovascular disease, and a number of studies have clearly demonstrated that the immune system and metabolism are highly integrated. Recent advances in deciphering the various cellular and signaling networks that participate in linking the immune and metabolic systems together have contributed to understanding of the pathogenesis of metabolic diseases and may also inform new therapeutic strategies based on immunomodulation. Here we discuss how these various networks underlie the etiology of the inflammatory component of insulin resistance, with a particular focus on the central roles of macrophages in adipose tissue and liver.

Nat Med: 06 Mar 2012; 18:363-74
Osborn O, Olefsky JM
Nat Med: 06 Mar 2012; 18:363-74 | PMID: 22395709
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice.

Wang Y, Zhao Z, Rege SV, Wang M, ... Goldman SA, Zlokovic BV
Activated protein C (APC) is a blood protease with anticoagulant activity and cell-signaling activities mediated by the activation of protease-activated receptor 1 (F2R, also known as PAR1) and F2RL1 (also known as PAR3) via noncanonical cleavage. Recombinant variants of APC, such as the 3K3A-APC (Lys191-193Ala) mutant in which three Lys residues (KKK191-193) were replaced with alanine, and/or its other mutants with reduced (>90%) anticoagulant activity, engineered to reduce APC-associated bleeding risk while retaining normal cell-signaling activity, have shown benefits in preclinical models of ischemic stroke, brain trauma, multiple sclerosis, amyotrophic lateral sclerosis, sepsis, ischemic and reperfusion injury of heart, kidney and liver, pulmonary, kidney and gastrointestinal inflammation, diabetes and lethal body radiation. On the basis of proof-of-concept studies and an excellent safety profile in humans, 3K3A-APC has advanced to clinical trials as a neuroprotectant in ischemic stroke. Recently, 3K3A-APC has been shown to stimulate neuronal production by human neural stem and progenitor cells (NSCs) in vitro via a PAR1-PAR3-sphingosine-1-phosphate-receptor 1-Akt pathway, which suggests the potential for APC-based treatment as a strategy for structural repair in the human central nervous (CNS) system. Here we report that late postischemic treatment of mice with 3K3A-APC stimulates neuronal production by transplanted human NSCs, promotes circuit restoration and improves functional recovery. Thus, 3K3A-APC-potentiated neuronal recruitment from engrafted NSCs might offer a new approach to the treatment of stroke and related neurological disorders.

Nat Med: 21 Aug 2016; epub ahead of print
Wang Y, Zhao Z, Rege SV, Wang M, ... Goldman SA, Zlokovic BV
Nat Med: 21 Aug 2016; epub ahead of print | PMID: 27548576
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53.

Wu H, Pomeroy SL, Ferreira M, Teider N, ... Spyracopoulos L, Leng RP
The TP53 gene (encoding the p53 tumor suppressor) is rarely mutated, although frequently inactivated, in medulloblastoma and ependymoma. Recent work in mouse models showed that the loss of p53 accelerated the development of medulloblastoma. The mechanism underlying p53 inactivation in human brain tumors is not completely understood. We show that ubiquitination factor E4B (UBE4B), an E3 and E4 ubiquitin ligase, physically interacts with p53 and Hdm2 (also known as Mdm2 in mice). UBE4B promotes p53 polyubiquitination and degradation and inhibits p53-dependent transactivation and apoptosis. Notably, silencing UBE4B expression impairs xenotransplanted tumor growth in a p53-dependent manner and overexpression of UBE4B correlates with decreased expression of p53 in these tumors. We also show that UBE4B overexpression is often associated with amplification of its gene in human brain tumors. Our data indicate that amplification and overexpression of UBE4B represent previously undescribed molecular mechanisms of inactivation of p53 in brain tumors.

Nat Med: 14 Feb 2011; epub ahead of print
Wu H, Pomeroy SL, Ferreira M, Teider N, ... Spyracopoulos L, Leng RP
Nat Med: 14 Feb 2011; epub ahead of print | PMID: 21317885
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...George Radda.

Cyranoski D
Singapore, the fastest growing economy in Asia last year, has enjoyed a decade of free-flowing research funding. Money is still pouring in, but the question remains whether money can buy international-class science, especially after the sudden attachment of strings to grant money starting last fall. Perhaps the best person to answer this question is Sir George Radda (he received his knighthood in 2000). Radda was the chief executive of the UK\'s Medical Research Council (MRC) from 1996 to 2003. In his final year at the helm of the MRC, he had his first interaction with Singapore\'s budding biomedical program as a member of the A*STAR Biomedical Sciences International Advisory Council. Shortly thereafter, Radda was asked to help with the next five years\' science and technology plan. A pioneer in nuclear magnetic resonance imaging, he became the founding chairman of the Singapore Bioimaging Consortium, traveling to Asia nearly once a month before he moved to Singapore three years ago. In April 2009, he was appointed chairman of the city-state\'s Biomedical Research Council (BMRC), which coordinates the country\'s biomedical activities and oversees institutes that comprise the Biopolis, a hub of more than 2,000 researchers and staff. Here he talks with David Cyranoski about what\'s ahead for Singapore.

Nat Med: 06 May 2011; 17:525
Cyranoski D
Nat Med: 06 May 2011; 17:525 | PMID: 21546958
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Vascular anastomosis using controlled phase transitions in poloxamer gels.

Chang EI, Galvez MG, Glotzbach JP, Hamou CD, ... Longaker MT, Gurtner GC
Vascular anastomosis is the cornerstone of vascular, cardiovascular and transplant surgery. Most anastomoses are performed with sutures, which are technically challenging and can lead to failure from intimal hyperplasia and foreign body reaction. Numerous alternatives to sutures have been proposed, but none has proven superior, particularly in small or atherosclerotic vessels. We have developed a new method of sutureless and atraumatic vascular anastomosis that uses US Food and Drug Administration (FDA)-approved thermoreversible tri-block polymers to temporarily maintain an open lumen for precise approximation with commercially available glues. We performed end-to-end anastomoses five times more rapidly than we performed hand-sewn controls, and vessels that were too small (<1.0 mm) to sew were successfully reconstructed with this sutureless approach. Imaging of reconstructed rat aorta confirmed equivalent patency, flow and burst strength, and histological analysis demonstrated decreased inflammation and fibrosis at up to 2 years after the procedure. This new technology has potential for improving efficiency and outcomes in the surgical treatment of cardiovascular disease.

Nat Med: 29 Aug 2011; epub ahead of print
Chang EI, Galvez MG, Glotzbach JP, Hamou CD, ... Longaker MT, Gurtner GC
Nat Med: 29 Aug 2011; epub ahead of print | PMID: 21873986
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...Joel Kupersmith.

Dolgin E
The US Department of Veteran Affairs (VA) last month announced plans to expand its Million Veteran Program, a massive data collection effort launched earlier this year, to all 109 of the agency\'s research-equipped medical centers across the country. Over the next five to seven years, investigators plan to collect DNA samples from former service personnel who volunteer for the program and link the genetic data to the VA\'s nationwide electronic medical record. With the goal of a million participants, the VA hopes to create the world\'s largest research database of genetic, military exposure and health information. Leading the charge is Joel Kupersmith, the Veterans Health Administration\'s chief research and development officer. A cardiology researcher, former medical school administrator and Navy veteran from the Vietnam era, Kupersmith joined the VA in 2005 with a mission: to improve the way clinical research is done. To that end, Kupersmith has helped create a central institutional review board (IRB), overseen an increase in research related to the Iraq and Afghanistan conflicts, cut bureaucratic red tape at the agency and launched a major genomics initiative that includes the Million Veteran Program. As the effort ramps up, Elie Dolgin spoke to Kupersmith to learn what sets VA medical and prosthetic research apart from other biomedical research in the country.

Nat Med: 07 Jun 2011; 17:654
Dolgin E
Nat Med: 07 Jun 2011; 17:654 | PMID: 21647137
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca(2+) release.

Zhou Q, Xiao J, Jiang D, Wang R, ... Back TG, Chen SR
Carvedilol is one of the most effective beta blockers for preventing ventricular tachyarrhythmias in heart failure, but the mechanisms underlying its favorable antiarrhythmic benefits remain unclear. Spontaneous Ca(2+) waves, also called store overload-induced Ca(2+) release (SOICR), evoke ventricular tachyarrhythmias in individuals with heart failure. Here we show that carvedilol is the only beta blocker tested that effectively suppresses SOICR by directly reducing the open duration of the cardiac ryanodine receptor (RyR2). This unique anti-SOICR activity of carvedilol, combined with its beta-blocking activity, probably contributes to its favorable antiarrhythmic effect. To enable optimal titration of carvedilol\'s actions as a beta blocker and as a suppressor of SOICR separately, we developed a new SOICR-inhibiting, minimally beta-blocking carvedilol analog, VK-II-86. VK-II-86 prevented stress-induced ventricular tachyarrhythmias in RyR2-mutant mice and did so more effectively when combined with either of the selective beta blockers metoprolol or bisoprolol. Combining SOICR inhibition with optimal beta blockade has the potential to provide antiarrhythmic therapy that can be tailored to individual patients.

Nat Med: 11 Jul 2011; epub ahead of print
Zhou Q, Xiao J, Jiang D, Wang R, ... Back TG, Chen SR
Nat Med: 11 Jul 2011; epub ahead of print | PMID: 21743453
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice.

Kempf T, Zarbock A, Widera C, Butz S, ... Vestweber D, Wollert KC
Inflammatory cell recruitment after myocardial infarction needs to be tightly controlled to permit infarct healing while avoiding fatal complications such as cardiac rupture. Growth differentiation factor-15 (GDF-15), a transforming growth factor-β (TGF-β)-related cytokine, is induced in the infarcted heart of mice and humans. We show that coronary artery ligation in Gdf15-deficient mice led to enhanced recruitment of polymorphonuclear leukocytes (PMNs) into the infarcted myocardium and an increased incidence of cardiac rupture. Conversely, infusion of recombinant GDF-15 repressed PMN recruitment after myocardial infarction. In vitro, GDF-15 inhibited PMN adhesion, arrest under flow and transendothelial migration. Mechanistically, GDF-15 counteracted chemokine-triggered conformational activation and clustering of β(2) integrins on PMNs by activating the small GTPase Cdc42 and inhibiting activation of the small GTPase Rap1. Intravital microscopy in vivo in Gdf15-deficient mice showed that Gdf-15 is required to prevent excessive chemokine-activated leukocyte arrest on the endothelium. Genetic ablation of β(2) integrins in myeloid cells rescued the mortality of Gdf15-deficient mice after myocardial infarction. To our knowledge, GDF-15 is the first cytokine identified as an inhibitor of PMN recruitment by direct interference with chemokine signaling and integrin activation. Loss of this anti-inflammatory mechanism leads to fatal cardiac rupture after myocardial infarction.

Nat Med: 25 Apr 2011; epub ahead of print
Kempf T, Zarbock A, Widera C, Butz S, ... Vestweber D, Wollert KC
Nat Med: 25 Apr 2011; epub ahead of print | PMID: 21516086
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

RGMa modulates T cell responses and is involved in autoimmune encephalomyelitis.

Muramatsu R, Kubo T, Mori M, Nakamura Y, ... Kuwabara S, Yamashita T
In multiple sclerosis, activated CD4(+) T cells initiate an immune response in the brain and spinal cord, resulting in demyelination, degeneration and progressive paralysis. Repulsive guidance molecule-a (RGMa) is an axon guidance molecule that has a role in the visual system and in neural tube closure. Our study shows that RGMa is expressed in bone marrow-derived dendritic cells (BMDCs) and that CD4(+) T cells express neogenin, a receptor for RGMa. Binding of RGMa to CD4(+) T cells led to activation of the small GTPase Rap1 and increased adhesion of T cells to intracellular adhesion molecule-1 (ICAM-1). Neutralizing antibodies to RGMa attenuated clinical symptoms of mouse myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) and reduced invasion of inflammatory cells into the CNS. Silencing of RGMa in MOG-pulsed BMDCs reduced their capacity to induce EAE following adoptive transfer to naive C57BL/6 mice. CD4(+) T cells isolated from mice treated with an RGMa-specific antibody showed diminished proliferative responses and reduced interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4 and IL-17 secretion. Incubation of PBMCs from patients with multiple sclerosis with an RGMa-specific antibody reduced proliferative responses and pro-inflammatory cytokine expression. These results demonstrate that an RGMa-specific antibody suppresses T cell responses, and suggest that RGMa could be a promising molecular target for the treatment of multiple sclerosis.

Nat Med: 22 Mar 2011; epub ahead of print
Muramatsu R, Kubo T, Mori M, Nakamura Y, ... Kuwabara S, Yamashita T
Nat Med: 22 Mar 2011; epub ahead of print | PMID: 21423182
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Schizophrenia susceptibility pathway neuregulin 1-ErbB4 suppresses Src upregulation of NMDA receptors.

Pitcher GM, Kalia LV, Ng D, Goodfellow NM, ... Lambe EK, Salter MW
Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.

Nat Med: 28 Mar 2011; epub ahead of print
Pitcher GM, Kalia LV, Ng D, Goodfellow NM, ... Lambe EK, Salter MW
Nat Med: 28 Mar 2011; epub ahead of print | PMID: 21441918
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses.

Moynihan KD, Opel CF, Szeto GL, Tzeng A, ... Wittrup KD, Irvine DJ
Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte-associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8(+) T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.

Nat Med: 23 Oct 2016; epub ahead of print
Moynihan KD, Opel CF, Szeto GL, Tzeng A, ... Wittrup KD, Irvine DJ
Nat Med: 23 Oct 2016; epub ahead of print | PMID: 27775706
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Developmental timing and critical windows for the treatment of psychiatric disorders.

Marín O
There is a growing understanding that pathological genetic variation and environmental insults during sensitive periods in brain development have long-term consequences on brain function, which range from learning disabilities to complex psychiatric disorders such as schizophrenia. Furthermore, recent experiments in animal models suggest that therapeutic interventions during sensitive periods, typically before the onset of clear neurological and behavioral symptoms, might prevent or ameliorate the development of specific pathologies. These studies suggest that understanding the dynamic nature of the pathophysiological mechanisms underlying psychiatric disorders is crucial for the development of effective therapies. In this Perspective, I explore the emerging concept of developmental windows in psychiatric disorders, their relevance for understanding disease progression and their potential for the design of new therapies. The limitations and caveats of early interventions in psychiatric disorders are also discussed in this context.

Nat Med: 25 Oct 2016; epub ahead of print
Marín O
Nat Med: 25 Oct 2016; epub ahead of print | PMID: 27783067
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...Phil Willis.

Mullard A
When Phil Willis, a former school headmaster turned politician, landed a seat on the UK government\'s Science and Technology Committee in 2005, he found a way to make his mark as a nonscientist by obsessively asking for evidence from researchers. Now in the House of Lords, he continues to advise the government on biomedicine, among other topics. Willis recently found a new cause to champion as well, the Association of Medical Research Charities (AMRC). The AMRC represents 124 UK nonprofits that collectively spend £1 billion ($1.6 billion) a year on biomedical research, around one third of the total amount of money put toward health research in the country. As Willis stepped into his role as chairman of the association in November, he spoke with Asher Mullard about his plans to drive the sector forward through tough economic times.

Nat Med: 10 Jan 2011; 17:11
Mullard A
Nat Med: 10 Jan 2011; 17:11 | PMID: 21217661
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

PU.1-mediated upregulation of CSF1R is crucial for leukemia stem cell potential induced by MOZ-TIF2.

Aikawa Y, Katsumoto T, Zhang P, Shima H, ... Tenen DG, Kitabayashi I
Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. Cancer stem cell eradication is thought to be crucial for successful anticancer therapy. Using an acute myeloid leukemia (AML) model induced by the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. The MOZ fusion proteins MOZ-TIF2 and MOZ-CBP interacted with the transcription factor PU.1 to stimulate the expression of macrophage colony-stimulating factor receptor (CSF1R, also known as M-CSFR, c-FMS or CD115). Studies using PU.1-deficient mice showed that PU.1 is essential for the ability of MOZ-TIF2 to establish and maintain AML stem cells. Cells expressing high amounts of CSF1R (CSF1R(high) cells), but not those expressing low amounts of CSF1R (CSF1R(low) cells), showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the CSF1R promoter, we cured AML by ablation of CSF1R(high) cells. Moreover, induction of AML was suppressed in CSF1R-deficient mice and CSF1R inhibitors slowed the progression of MOZ-TIF2-induced leukemia. Thus, in this subtype of AML, leukemia stem cells are contained within the CSF1R(high) cell population, and we suggest that targeting of PU.1-mediated upregulation of CSF1R expression might be a useful therapeutic approach.

Nat Med: 26 Apr 2010; epub ahead of print
Aikawa Y, Katsumoto T, Zhang P, Shima H, ... Tenen DG, Kitabayashi I
Nat Med: 26 Apr 2010; epub ahead of print | PMID: 20418886
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A role for interleukin-2 trans-presentation in dendritic cell-mediated T cell activation in humans, as revealed by daclizumab therapy.

Wuest SC, Edwan JH, Martin JF, Han S, ... Waldmann TA, Bielekova B
Although previous studies have described CD25 expression and production of interleukin-2 (IL-2) by mature dendritic cells (mDCs), it remains unclear how these molecules participate in the activation of T cells. In search of the mechanisms by which daclizumab, a humanized monoclonal antibody against CD25, inhibits brain inflammation in multiple sclerosis, we observed that although the drug has limited effects on polyclonal T cell activation, it potently inhibits activation of antigen-specific T cells by mDCs. We show that mDCs (and antigen-experienced T cells) secrete IL-2 toward the mDC-T cell interface in an antigen-specific manner, and mDCs \'lend\' their CD25 to primed T cells in trans to facilitate early high-affinity IL-2 signaling, which is crucial for subsequent T cell expansion and development of antigen-specific effectors. Our data reveal a previously unknown mechanism for the IL-2 receptor system in DC-mediated activation of T cells.

Nat Med: 02 May 2011; epub ahead of print
Wuest SC, Edwan JH, Martin JF, Han S, ... Waldmann TA, Bielekova B
Nat Med: 02 May 2011; epub ahead of print | PMID: 21532597
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Caspase-2 cleavage of tau reversibly impairs memory.

Zhao X, Kotilinek LA, Smith B, Hlynialuk C, ... Cleary J, Ashe KH
In Alzheimer\'s disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Nat Med: 09 Oct 2016; epub ahead of print
Zhao X, Kotilinek LA, Smith B, Hlynialuk C, ... Cleary J, Ashe KH
Nat Med: 09 Oct 2016; epub ahead of print | PMID: 27723722
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Re-evaluating the link between neuropsychiatric disorders and dysregulated adult neurogenesis.

Yun S, Reynolds RP, Masiulis I, Eisch AJ
People diagnosed with neuropsychiatric disorders such as depression, anxiety, addiction or schizophrenia often have dysregulated memory, mood, pattern separation and/or reward processing. These symptoms are indicative of a disrupted function of the dentate gyrus (DG) subregion of the brain, and they improve with treatment and remission. The dysfunction of the DG is accompanied by structural maladaptations, including dysregulation of adult-generated neurons. An increasing number of studies using modern inducible approaches to manipulate new neurons show that the behavioral symptoms in animal models of neuropsychiatric disorders can be produced or exacerbated by the inhibition of DG neurogenesis. Thus, here we posit that the connection between neuropsychiatric disorders and dysregulated DG neurogenesis is beyond correlation or epiphenomenon, and that the regulation of adult-generated DG neurogenesis merits continued and focused attention in the ongoing effort to develop novel treatments for neuropsychiatric disorders.

Nat Med: 25 Oct 2016; epub ahead of print
Yun S, Reynolds RP, Masiulis I, Eisch AJ
Nat Med: 25 Oct 2016; epub ahead of print | PMID: 27783068
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Determinants of HIV-1 broadly neutralizing antibody induction.

Rusert P, Kouyos RD, Kadelka C, Ebner H, ... Trkola A, Swiss HIV Cohort Study
Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10(-5)). Thus, key host, disease and viral determinants, including subtype-specific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.

Nat Med: 25 Sep 2016; epub ahead of print
Rusert P, Kouyos RD, Kadelka C, Ebner H, ... Trkola A, Swiss HIV Cohort Study
Nat Med: 25 Sep 2016; epub ahead of print | PMID: 27668936
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning.

Guo W, Allan AM, Zong R, Zhang L, ... Jin P, Zhao X
Deficiency in fragile X mental retardation protein (FMRP) results in fragile X syndrome (FXS), an inherited form of intellectual disability. Despite extensive research, it is unclear how FMRP deficiency contributes to the cognitive deficits in FXS. Fmrp-null mice show reduced adult hippocampal neurogenesis. As Fmrp is also enriched in mature neurons, we investigated the function of Fmrp expression in neural stem and progenitor cells (aNSCs) and its role in adult neurogenesis. Here we show that ablation of Fmrp in aNSCs by inducible gene recombination leads to reduced hippocampal neurogenesis in vitro and in vivo, as well as markedly impairing hippocampus-dependent learning in mice. Conversely, restoration of Fmrp expression specifically in aNSCs rescues these learning deficits in Fmrp-deficient mice. These data suggest that defective adult neurogenesis may contribute to the learning impairment seen in FXS, and these learning deficits can be rectified by delayed restoration of Fmrp specifically in aNSCs.

Nat Med: 25 Apr 2011; epub ahead of print
Guo W, Allan AM, Zong R, Zhang L, ... Jin P, Zhao X
Nat Med: 25 Apr 2011; epub ahead of print | PMID: 21516088
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

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

Harmon GS, Dumlao DS, Ng DT, Barrett KE, ... 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.

Nat Med: 15 Feb 2010; epub ahead of print
Harmon GS, Dumlao DS, Ng DT, Barrett KE, ... Dong H, Glass CK
Nat Med: 15 Feb 2010; epub ahead of print | PMID: 20154695
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mechanisms of NAFLD development and therapeutic strategies.

Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ
There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.

Nat Med: 01 Jul 2018; epub ahead of print
Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ
Nat Med: 01 Jul 2018; epub ahead of print | PMID: 29967350
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK-β and NF-κB.

Purkayastha S, Zhang G, Cai D
Obesity-related hypertension has become an epidemic health problem and a major risk factor for the development of cardiovascular disease (CVD). Recent research on the pathophysiology of obesity has implicated a role for the hypothalamus in the pathogenesis of this condition. However, it remains unknown whether the often-seen coupling of hypertension with obesity can also be explained by hypothalamic dysfunction, despite the emerging appreciation that many forms of hypertension are neurogenic in origin. Our studies here revealed that acute activation of the proinflammatory protein nuclear factor κB (NF-κB) and its upstream activator IκB kinase-β (IKK-β, encoded by Ikbkb) in the mediobasal hypothalamus rapidly elevated blood pressure in mice independently of obesity. This form of hypothalamic inflammation-induced hypertension involved the sympathetic upregulation of hemodynamics and was reversed by sympathetic suppression. Loss-of-function studies further showed that NF-κB inhibition in the mediobasal hypothalamus counteracted obesity-related hypertension in a manner that was dissociable from changes in body weight. In addition, we found that pro-opiomelanocortin (POMC) neurons were crucial for the hypertensive effects of the activation of hypothalamic IKK-β and NF-κB, which underlie obesity-related hypertension. In conclusion, obesity-associated activation of IKK-β and NF-κB in the mediobasal hypothalamus-particularly in the hypothalamic POMC neurons-is a primary pathogenic link between obesity and hypertension. Breaking this pathogenic link may represent an avenue for controlling obesity-related hypertension and CVD without requiring obesity control.

Nat Med: 06 Jun 2011; epub ahead of print
Purkayastha S, Zhang G, Cai D
Nat Med: 06 Jun 2011; epub ahead of print | PMID: 21642978
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

CIB1 is a regulator of pathological cardiac hypertrophy.

Heineke J, Auger-Messier M, Correll RN, Xu J, ... 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.

Nat Med: 19 Jul 2010; epub ahead of print
Heineke J, Auger-Messier M, Correll RN, Xu J, ... Parise LV, Molkentin JD
Nat Med: 19 Jul 2010; epub ahead of print | PMID: 20639889
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Dominant TNF-α(+) Mycobacterium tuberculosis-specific CD4(+) T cell responses discriminate between latent infection and active disease.

Harari A, Rozot V, Enders FB, Perreau M, ... Bart PA, Pantaleo G
Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4(+) T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4(+) T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4(+) T cells is a new tool for the rapid diagnosis of active tuberculosis disease.

Nat Med: 21 Feb 2011; epub ahead of print
Harari A, Rozot V, Enders FB, Perreau M, ... Bart PA, Pantaleo G
Nat Med: 21 Feb 2011; epub ahead of print | PMID: 21336285
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The search for imaging biomarkers in psychiatric disorders.

Abi-Dargham A, Horga G
The field of medicine is moving toward the use of biomarkers for the optimization of individualized care. This is a particular challenge for the field of psychiatry, in which diagnosis is based on a descriptive collection of behaviors without the availability of any objective test to stratify patients. Neuroimaging techniques such as molecular imaging with positron-emission tomography (PET) or structural and functional magnetic resonance imaging (MRI) provide an opportunity to bring psychiatry from an era of subjective descriptive classification into objective and tangible brain-based measures. Here we provide steps toward the development of robust, reliable and valid biomarkers. The success of such development is crucial because it will enable the field of psychiatry to move forward into the era of modern medicine.

Nat Med: 25 Oct 2016; epub ahead of print
Abi-Dargham A, Horga G
Nat Med: 25 Oct 2016; epub ahead of print | PMID: 27783066
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression.

Horiuchi D, Camarda R, Zhou AY, Yau C, ... Werb Z, Goga A
Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC-an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes-is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine-threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.

Nat Med: 23 Oct 2016; epub ahead of print
Horiuchi D, Camarda R, Zhou AY, Yau C, ... Werb Z, Goga A
Nat Med: 23 Oct 2016; epub ahead of print | PMID: 27775705
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

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

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.

Nat Med: 18 Jan 2010; epub ahead of print
Clarke TB, Davis KM, Lysenko ES, Zhou AY, Yu Y, Weiser JN
Nat Med: 18 Jan 2010; epub ahead of print | PMID: 20081863
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Dietary zinc alters the microbiota and decreases resistance to Clostridium difficile infection.

Zackular JP, Moore JL, Jordan AT, Juttukonda LJ, ... Caprioli RM, Skaar EP
Clostridium difficile is the most commonly reported nosocomial pathogen in the United States and is an urgent public health concern worldwide. Over the past decade, incidence, severity and costs associated with C. difficile infection (CDI) have increased dramatically. CDI is most commonly initiated by antibiotic-mediated disruption of the gut microbiota; however, non-antibiotic-associated CDI cases are well documented and on the rise. This suggests that unexplored environmental, nutrient and host factors probably influence CDI. Here we show that excess dietary zinc (Zn) substantially alters the gut microbiota and, in turn, reduces the minimum amount of antibiotics needed to confer susceptibility to CDI. In mice colonized with C. difficile, excess dietary Zn severely exacerbated C. difficile-associated disease by increasing toxin activity and altering the host immune response. In addition, we show that the Zn-binding S100 protein calprotectin has antimicrobial effects against C. difficile and is an essential component of the innate immune response to CDI. Taken together, these data suggest that nutrient Zn levels have a key role in determining susceptibility to CDI and severity of disease, and that calprotectin-mediated metal limitation is an important factor in the host immune response to C. difficile.

Nat Med: 25 Sep 2016; epub ahead of print
Zackular JP, Moore JL, Jordan AT, Juttukonda LJ, ... Caprioli RM, Skaar EP
Nat Med: 25 Sep 2016; epub ahead of print | PMID: 27668938
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Single atom substitution in mouse protein kinase G eliminates oxidant sensing to cause hypertension.

Prysyazhna O, Rudyk O, Eaton P
Blood pressure regulation is crucial for the maintenance of health, and hypertension is a risk factor for myocardial infarction, heart failure, stroke and renal disease. Nitric oxide (NO) and prostacyclin trigger well-defined vasodilator pathways; however, substantial vasorelaxation in response to agents such as acetylcholine persists when the synthesis of these molecules is prevented. This remaining vasorelaxation activity, termed endothelium-derived hyperpolarizing factor (EDHF), is more prevalent in resistance than in conduit blood vessels and is considered a major mechanism for blood pressure control. Hydrogen peroxide (H(2)O(2)) has been shown to be a major component of EDHF in several vascular beds in multiple species, including in humans. H(2)O(2) causes the formation of a disulfide bond between the two α subunits of protein kinase G I-α (PKGI-α), which activates the kinase independently of the NO-cyclic guanosine monophosphate (cGMP) pathway and is coupled to vasodilation. To test the importance of PKGI-α oxidation in the EDHF mechanism and blood pressure control in vivo, we generated a knock-in mouse expressing only a C42S \'redox-dead\' version of PKGI-α. This amino acid substitution, a single-atom change (an oxygen atom replacing a sulfur atom), blocked the vasodilatory action of H(2)O(2) on resistance vessels and resulted in hypertension in vivo.

Nat Med: 16 Jan 2012; epub ahead of print
Prysyazhna O, Rudyk O, Eaton P
Nat Med: 16 Jan 2012; epub ahead of print | PMID: 22245782
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi.

Li Y, Oosting M, Deelen P, Ricaño-Ponce I, ... Kumar V, Netea MG
Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals. To systematically describe cytokine responses elicited by distinct pathogens and to determine the effect of genetic variation on cytokine production, we profiled cytokines produced by peripheral blood mononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG) cohort in the Human Functional Genomics Project (http://www.humanfunctionalgenomics.org), obtained over three different years. We compared bacteria- and fungi-induced cytokine profiles and found that most cytokine responses were organized around a physiological response to specific pathogens, rather than around a particular immune pathway or cytokine. We then correlated genome-wide single-nucleotide polymorphism (SNP) genotypes with cytokine abundance and identified six cytokine quantitative trait loci (QTLs). Among them, a cytokine QTL at the NAA35-GOLM1 locus markedly modulated interleukin (IL)-6 production in response to multiple pathogens and was associated with susceptibility to candidemia. Furthermore, the cytokine QTLs that we identified were enriched among SNPs previously associated with infectious diseases and heart diseases. These data reveal and begin to explain the variability in cytokine production by human immune cells in response to pathogens.

Nat Med: 03 Jul 2016; epub ahead of print
Li Y, Oosting M, Deelen P, Ricaño-Ponce I, ... Kumar V, Netea MG
Nat Med: 03 Jul 2016; epub ahead of print | PMID: 27376574
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.

Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, ... Grigoriadis A, Tutt AN
Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.

Nat Med: 23 Oct 2016; epub ahead of print
Brasó-Maristany F, Filosto S, Catchpole S, Marlow R, ... Grigoriadis A, Tutt AN
Nat Med: 23 Oct 2016; epub ahead of print | PMID: 27775704
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Platelets contribute to postnatal occlusion of the ductus arteriosus.

Echtler K, Stark K, Lorenz M, Kerstan S, ... Shivdasani RA, Massberg S
The ductus arteriosus (DA) is a fetal shunt vessel between the pulmonary artery and the aorta that closes promptly after birth. Failure of postnatal DA closure is a major cause of morbidity and mortality particularly in preterm neonates. The events leading to DA closure are incompletely understood. Here we show that platelets have an essential role in DA closure. Using intravital microscopy of neonatal mice, we observed that platelets are recruited to the luminal aspect of the DA during closure. DA closure is impaired in neonates with malfunctioning platelet adhesion or aggregation or with defective platelet biogenesis. Defective DA closure resulted in a left-to-right shunt with increased pulmonary perfusion, pulmonary vascular remodeling and right ventricular hypertrophy. Our findings indicate that platelets are crucial for DA closure by promoting thrombotic sealing of the constricted DA and by supporting luminal remodeling. A retrospective clinical study revealed that thrombocytopenia is an independent predictor for failure of DA closure in preterm human newborns, indicating that platelets are likely to contribute to DA closure in humans.

Nat Med: 07 Dec 2009; epub ahead of print
Echtler K, Stark K, Lorenz M, Kerstan S, ... Shivdasani RA, Massberg S
Nat Med: 07 Dec 2009; epub ahead of print | PMID: 19966813
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

TCF1 links GIPR signaling to the control of beta cell function and survival.

Campbell JE, Ussher JR, Mulvihill EE, Kolic J, ... MacDonald PE, Drucker DJ
The glucagon-like peptide-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor transduce nutrient-stimulated signals to control beta cell function. Although the GLP-1 receptor (GLP-1R) is a validated drug target for diabetes, the importance of the GIP receptor (GIPR) for the function of beta cells remains uncertain. We demonstrate that mice with selective ablation of GIPR in beta cells (MIP-Cre:Gipr(Flox/Flox); Gipr(-/-βCell)) exhibit lower levels of meal-stimulated insulin secretion, decreased expansion of adipose tissue mass and preservation of insulin sensitivity when compared to MIP-Cre controls. Beta cells from Gipr(-/-βCell) mice display greater sensitivity to apoptosis and markedly lower islet expression of T cell-specific transcription factor-1 (TCF1, encoded by Tcf7), a protein not previously characterized in beta cells. GIP, but not GLP-1, promotes beta cell Tcf7 expression via a cyclic adenosine monophosphate (cAMP)-independent and extracellular signal-regulated kinase (ERK)-dependent pathway. Tcf7 (in mice) or TCF7 (in humans) levels are lower in islets taken from diabetic mice and in humans with type 2 diabetes; knockdown of TCF7 in human and mouse islets impairs the cytoprotective responsiveness to GIP and enhances the magnitude of apoptotic injury, whereas restoring TCF1 levels in beta cells from Gipr(-/-βCell) mice lowers the number of apoptotic cells compared to that seen in MIP-Cre controls. Tcf7(-/-) mice show impaired insulin secretion, deterioration of glucose tolerance with either aging and/or high-fat feeding and increased sensitivity to beta cell injury relative to wild-type (WT) controls. Hence the GIPR-TCF1 axis represents a potential therapeutic target for preserving both the function and survival of vulnerable, diabetic beta cells.

Nat Med: 06 Dec 2015; epub ahead of print
Campbell JE, Ussher JR, Mulvihill EE, Kolic J, ... MacDonald PE, Drucker DJ
Nat Med: 06 Dec 2015; epub ahead of print | PMID: 26642437
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Imaging the subcellular structure of human coronary atherosclerosis using micro-optical coherence tomography.

Liu L, Gardecki JA, Nadkarni SK, Toussaint JD, ... Bouma BE, Tearney GJ
Progress in understanding, diagnosis, and treatment of coronary artery disease (CAD) has been hindered by our inability to observe cells and extracellular components associated with human coronary atherosclerosis in situ. The current standards for microstructural investigation, histology and electron microscopy are destructive and prone to artifacts. The highest-resolution intracoronary imaging modality, optical coherence tomography (OCT), has a resolution of ∼10 μm, which is too coarse for visualizing most cells. Here we report a new form of OCT, termed micro-optical coherence tomography (μOCT), whose resolution is improved by an order of magnitude. We show that μOCT images of cadaver coronary arteries provide clear pictures of cellular and subcellular features associated with atherogenesis, thrombosis and responses to interventional therapy. These results suggest that μOCT can complement existing diagnostic techniques for investigating atherosclerotic specimens, and that μOCT may eventually become a useful tool for cellular and subcellular characterization of the human coronary wall in vivo.

Nat Med: 11 Jul 2011; epub ahead of print
Liu L, Gardecki JA, Nadkarni SK, Toussaint JD, ... Bouma BE, Tearney GJ
Nat Med: 11 Jul 2011; epub ahead of print | PMID: 21743452
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Efficient derivation of microglia-like cells from human pluripotent stem cells.

Muffat J, Li Y, Yuan B, Mitalipova M, ... Ransohoff RM, Jaenisch R
Microglia, the only lifelong resident immune cells of the central nervous system (CNS), are highly specialized macrophages that have been recognized to have a crucial role in neurodegenerative diseases such as Alzheimer\'s, Parkinson\'s and adrenoleukodystrophy (ALD). However, in contrast to other cell types of the human CNS, bona fide microglia have not yet been derived from cultured human pluripotent stem cells. Here we establish a robust and efficient protocol for the rapid production of microglia-like cells from human (h) embryonic stem (ES) and induced pluripotent stem (iPS) cells that uses defined serum-free culture conditions. These in vitro pluripotent stem cell-derived microglia-like cells (termed pMGLs) faithfully recapitulate the expected ontogeny and characteristics of their in vivo counterparts, and they resemble primary fetal human and mouse microglia. We generated these cells from multiple disease-specific cell lines and find that pMGLs derived from an hES model of Rett syndrome are smaller than their isogenic controls. We further describe a platform to study the integration and live behavior of pMGLs in organotypic 3D cultures. This modular differentiation system allows for the study of microglia in highly defined conditions as they mature in response to developmentally relevant cues, and it provides a framework in which to study the long-term interactions of microglia residing in a tissue-like environment.

Nat Med: 25 Sep 2016; epub ahead of print
Muffat J, Li Y, Yuan B, Mitalipova M, ... Ransohoff RM, Jaenisch R
Nat Med: 25 Sep 2016; epub ahead of print | PMID: 27668937
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Regulation of glucose homeostasis through a XBP-1-FoxO1 interaction.

Zhou Y, Lee J, Reno CM, Sun C, ... Biddinger SB, Ozcan U
To date, the only known role of the spliced form of X-box-binding protein-1 (XBP-1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding-defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes.

Nat Med: 14 Feb 2011; epub ahead of print
Zhou Y, Lee J, Reno CM, Sun C, ... Biddinger SB, Ozcan U
Nat Med: 14 Feb 2011; epub ahead of print | PMID: 21317886
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1.

Lu M, Wan M, Leavens KF, Chu Q, ... Kahn CR, Birnbaum MJ
Considerable data support the idea that forkhead box O1 (Foxo1) drives the liver transcriptional program during fasting and is then inhibited by thymoma viral proto-oncogene 1 (Akt) after feeding. Here we show that mice with hepatic deletion of Akt1 and Akt2 were glucose intolerant, insulin resistant and defective in their transcriptional response to feeding in the liver. These defects were normalized with concomitant liver-specific deletion of Foxo1. Notably, in the absence of both Akt and Foxo1, mice adapted appropriately to both the fasted and fed state, and insulin suppressed hepatic glucose production normally. A gene expression analysis revealed that deletion of Akt in liver led to the constitutive activation of Foxo1-dependent gene expression, but again, concomitant ablation of Foxo1 restored postprandial regulation, preventing the inhibition of the metabolic response to nutrient intake caused by deletion of Akt. These results are inconsistent with the canonical model of hepatic metabolism in which Akt is an obligate intermediate for proper insulin signaling. Rather, they show that a major role of hepatic Akt is to restrain the activity of Foxo1 and that in the absence of Foxo1, Akt is largely dispensable for insulin- and nutrient-mediated hepatic metabolic regulation in vivo.

Nat Med: 19 Feb 2012; epub ahead of print
Lu M, Wan M, Leavens KF, Chu Q, ... Kahn CR, Birnbaum MJ
Nat Med: 19 Feb 2012; epub ahead of print | PMID: 22344295
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta.

Oga T, Matsuoka T, Yao C, Nonomura K, ... Shimizu T, Narumiya S
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.

Nat Med: 07 Dec 2009; 15:1426-30
Oga T, Matsuoka T, Yao C, Nonomura K, ... Shimizu T, Narumiya S
Nat Med: 07 Dec 2009; 15:1426-30 | PMID: 19966781
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury.

Choi YK, Maki T, Mandeville ET, Koh SH, ... Kim KW, Lo EH
At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator. Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2\'-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.

Nat Med: 25 Sep 2016; epub ahead of print
Choi YK, Maki T, Mandeville ET, Koh SH, ... Kim KW, Lo EH
Nat Med: 25 Sep 2016; epub ahead of print | PMID: 27668935
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1.

Haemmerle G, Moustafa T, Woelkart G, Büttner S, ... Mayer B, Zechner R
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-α agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.

Nat Med: 22 Aug 2011; epub ahead of print
Haemmerle G, Moustafa T, Woelkart G, Büttner S, ... Mayer B, Zechner R
Nat Med: 22 Aug 2011; epub ahead of print | PMID: 21857651
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Microenvironment-dependent growth of preneoplastic and malignant plasma cells in humanized mice.

Das R, Strowig T, Verma R, Koduru S, ... Flavell RA, Dhodapkar MV
Most human cancers, including myeloma, are preceded by a precursor state. There is an unmet need for in vivo models to study the interaction of human preneoplastic cells in the bone marrow microenvironment with non-malignant cells. Here, we genetically humanized mice to permit the growth of primary human preneoplastic and malignant plasma cells together with non-malignant cells in vivo. Growth was largely restricted to the bone marrow, mirroring the pattern in patients with myeloma. Xenografts captured the genomic complexity of parental tumors and revealed additional somatic changes. Moreover, xenografts from patients with preneoplastic gammopathy showed progressive growth, suggesting that the clinical stability of these lesions may in part be due to growth controls extrinsic to tumor cells. These data demonstrate a new approach to investigate the entire spectrum of human plasma cell neoplasia and illustrate the utility of humanized models for understanding the functional diversity of human tumors.

Nat Med: 09 Oct 2016; epub ahead of print
Das R, Strowig T, Verma R, Koduru S, ... Flavell RA, Dhodapkar MV
Nat Med: 09 Oct 2016; epub ahead of print | PMID: 27723723
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Lrp5 functions in bone to regulate bone mass.

Cui Y, Niziolek PJ, Macdonald BT, Zylstra CR, ... Warman ML, Robling AG
The human skeleton is affected by mutations in low-density lipoprotein receptor-related protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with osteocyte-specific expression of inducible Lrp5 mutations that cause high and low bone mass phenotypes in humans. We found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also induced an Lrp5 mutation in cells that form the appendicular skeleton but not in cells that form the axial skeleton; we observed that bone properties were altered in the limb but not in the spine. These data indicate that Lrp5 signaling functions locally, and they suggest that increasing LRP5 signaling in mature bone cells may be a strategy for treating human disorders associated with low bone mass, such as osteoporosis.

Nat Med: 23 May 2011; epub ahead of print
Cui Y, Niziolek PJ, Macdonald BT, Zylstra CR, ... Warman ML, Robling AG
Nat Med: 23 May 2011; epub ahead of print | PMID: 21602802
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Iduna protects the brain from glutamate excitotoxicity and stroke by interfering with poly(ADP-ribose) polymer-induced cell death.

Andrabi SA, Kang HC, Haince JF, Lee YI, ... Dawson TM, Dawson VL
Glutamate acting on N-methyl-D-aspartate (NMDA) receptors induces neuronal injury following stroke, through activation of poly(ADP-ribose) polymerase-1 (PARP-1) and generation of the death molecule poly(ADP-ribose) (PAR) polymer. Here we identify Iduna, a previously undescribed NMDA receptor-induced survival protein that is neuroprotective against glutamate NMDA receptor-mediated excitotoxicity both in vitro and in vivo and against stroke through interfering with PAR polymer-induced cell death (parthanatos). Iduna\'s protective effects are independent and downstream of PARP-1 activity. Iduna is a PAR polymer-binding protein, and mutation at the PAR polymer binding site abolishes the PAR binding activity of Iduna and attenuates its protective actions. Iduna is protective in vivo against NMDA-induced excitotoxicity and middle cerebral artery occlusion-induced stroke in mice. To our knowledge, these results define Iduna as the first known endogenous inhibitor of parthanatos. Interfering with PAR polymer signaling could be a new therapeutic strategy for the treatment of neurologic disorders.

Nat Med: 23 May 2011; epub ahead of print
Andrabi SA, Kang HC, Haince JF, Lee YI, ... Dawson TM, Dawson VL
Nat Med: 23 May 2011; epub ahead of print | PMID: 21602803
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models.

Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, ... Metallo CM, Shaw RJ
Continuous de novo fatty acid synthesis is a common feature of cancer that is required to meet the biosynthetic demands of a growing tumor. This process is controlled by the rate-limiting enzyme acetyl-CoA carboxylase (ACC), an attractive but traditionally intractable drug target. Here we provide genetic and pharmacological evidence that in preclinical models ACC is required to maintain the de novo fatty acid synthesis needed for growth and viability of non-small-cell lung cancer (NSCLC) cells. We describe the ability of ND-646-an allosteric inhibitor of the ACC enzymes ACC1 and ACC2 that prevents ACC subunit dimerization-to suppress fatty acid synthesis in vitro and in vivo. Chronic ND-646 treatment of xenograft and genetically engineered mouse models of NSCLC inhibited tumor growth. When administered as a single agent or in combination with the standard-of-care drug carboplatin, ND-646 markedly suppressed lung tumor growth in the Kras;Trp53(-/-) (also known as KRAS p53) and Kras;Stk11(-/-) (also known as KRAS Lkb1) mouse models of NSCLC. These findings demonstrate that ACC mediates a metabolic liability of NSCLC and that ACC inhibition by ND-646 is detrimental to NSCLC growth, supporting further examination of the use of ACC inhibitors in oncology.

Nat Med: 18 Sep 2016; epub ahead of print
Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, ... Metallo CM, Shaw RJ
Nat Med: 18 Sep 2016; epub ahead of print | PMID: 27643638
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...Valery Danilenko.

Peach G
Russian medicine is-at long last-undergoing a renaissance. The country\'s rocky economic ride following the collapse of the Soviet Union disrupted its research rubric and impoverished its healthcare system. Now, however, the nation\'s leadership is spearheading various initiatives to reverse the situation. One of them, the US-Russian Scientific Forum, established two years ago by a bilateral presidential commission, hopes to bring improvements by facilitating public-private research in biomedicine and innovative drugs. The Forum, which on the Russian side is represented by the country\'s Ministry of Health and Social Development and the Russian Academy of Sciences, among others, held its inaugural planning meeting in late April in Moscow. Valery Danilenko, who is helping to spearhead the effort and also leads the biotechnology division at the Vavilov Institute of General Genetics in Moscow, told Nature Medicine about the meeting and Russia\'s hopes for the Forum. The interview was conducted in Russian and translated by the interviewer, Gary Peach.

Nat Med: 08 Jul 2011; 17:764
Peach G
Nat Med: 08 Jul 2011; 17:764 | PMID: 21738143
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Signals from the gut microbiota to distant organs in physiology and disease.

Schroeder BO, Bäckhed F
The ecosystem of the human gut consists of trillions of bacteria forming a bioreactor that is fueled by dietary macronutrients to produce bioactive compounds. These microbiota-derived metabolites signal to distant organs in the body, which enables the gut bacteria to connect to the immune and hormone system, to the brain (the gut-brain axis) and to host metabolism, as well as other functions of the host. This microbe-host communication is essential to maintain vital functions of the healthy host. Recently, however, the gut microbiota has been associated with a number of diseases, ranging from obesity and inflammatory diseases to behavioral and physiological abnormalities associated with neurodevelopmental disorders. In this Review, we will discuss microbiota-host cross-talk and intestinal microbiome signaling to extraintestinal organs. We will review mechanisms of how this communication might contribute to host physiology and discuss how misconfigured signaling might contribute to different diseases.

Nat Med: 05 Oct 2016; 22:1079-1089
Schroeder BO, Bäckhed F
Nat Med: 05 Oct 2016; 22:1079-1089 | PMID: 27711063
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Therapeutic targeting of splicing in cancer.

Lee SC, Abdel-Wahab O
Recent studies have highlighted that splicing patterns are frequently altered in cancer and that mutations in genes encoding spliceosomal proteins, as well as mutations affecting the splicing of key cancer-associated genes, are enriched in cancer. In parallel, there is also accumulating evidence that several molecular subtypes of cancer are highly dependent on splicing function for cell survival. These findings have resulted in a growing interest in targeting splicing catalysis, splicing regulatory proteins, and/or specific key altered splicing events in the treatment of cancer. Here we present strategies that exist and that are in development to target altered dependency on the spliceosome, as well as aberrant splicing, in cancer. These include drugs to target global splicing in cancer subtypes that are preferentially dependent on wild-type splicing for survival, methods to alter post-translational modifications of splicing-regulating proteins, and strategies to modulate pathologic splicing events and protein-RNA interactions in cancer.

Nat Med: 06 Sep 2016; 22:976-986
Lee SC, Abdel-Wahab O
Nat Med: 06 Sep 2016; 22:976-986 | PMID: 27603132
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation.

Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, ... Zeiher AM, Dimmeler S
Adenosine-to-inosine (A-to-I) RNA editing, which is catalyzed by a family of adenosine deaminase acting on RNA (ADAR) enzymes, is important in the epitranscriptomic regulation of RNA metabolism. However, the role of A-to-I RNA editing in vascular disease is unknown. Here we show that cathepsin S mRNA (CTSS), which encodes a cysteine protease associated with angiogenesis and atherosclerosis, is highly edited in human endothelial cells. The 3\' untranslated region (3\' UTR) of the CTSS transcript contains two inverted repeats, the AluJo and AluSx(+) regions, which form a long stem-loop structure that is recognized by ADAR1 as a substrate for editing. RNA editing enables the recruitment of the stabilizing RNA-binding protein human antigen R (HuR; encoded by ELAVL1) to the 3\' UTR of the CTSS transcript, thereby controlling CTSS mRNA stability and expression. In endothelial cells, ADAR1 overexpression or treatment of cells with hypoxia or with the inflammatory cytokines interferon-γ and tumor-necrosis-factor-α induces CTSS RNA editing and consequently increases cathepsin S expression. ADAR1 levels and the extent of CTSS RNA editing are associated with changes in cathepsin S levels in patients with atherosclerotic vascular diseases, including subclinical atherosclerosis, coronary artery disease, aortic aneurysms and advanced carotid atherosclerotic disease. These results reveal a previously unrecognized role of RNA editing in gene expression in human atherosclerotic vascular diseases.

Nat Med: 04 Sep 2016; epub ahead of print
Stellos K, Gatsiou A, Stamatelopoulos K, Perisic Matic L, ... Zeiher AM, Dimmeler S
Nat Med: 04 Sep 2016; epub ahead of print | PMID: 27595325
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure.

Malherbe ST, Shenai S, Ronacher K, Loxton AG, ... Vorster M, Griffith-Richards S
The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET-CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET-CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.

Nat Med: 04 Sep 2016; epub ahead of print
Malherbe ST, Shenai S, Ronacher K, Loxton AG, ... Vorster M, Griffith-Richards S
Nat Med: 04 Sep 2016; epub ahead of print | PMID: 27595324
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection.

Alves-Filho JC, Sônego F, Souto FO, Freitas A, ... Cunha FQ, Liew FY
Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33-treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (T(H)1) to T(H)2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.

Nat Med: 17 May 2010; epub ahead of print
Alves-Filho JC, Sônego F, Souto FO, Freitas A, ... Cunha FQ, Liew FY
Nat Med: 17 May 2010; epub ahead of print | PMID: 20473304
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

HAUSP deubiquitinates and stabilizes N-Myc in neuroblastoma.

Tavana O, Li D, Dai C, Lopez G, ... Sun H, Gu W
The MYCN proto-oncogene is amplified in a number of advanced-stage human tumors, such as neuroblastomas. Similar to other members of the MYC family of oncoproteins, MYCN (also known as N-Myc) is a transcription factor, and its stability and activity are tightly controlled by ubiquitination-dependent proteasome degradation. Although numerous studies have demonstrated that N-Myc is a driver of neuroblastoma tumorigenesis, therapies that directly suppress N-Myc activity in human tumors are limited. Here we have identified ubiquitin-specific protease 7 (USP7; also known as HAUSP) as a regulator of N-Myc function in neuroblastoma. HAUSP interacts with N-Myc, and HAUSP expression induces deubiquitination and subsequent stabilization of N-Myc. Conversely, RNA interference (RNAi)-mediated knockdown of USP7 in neuroblastoma cancer cell lines, or genetic ablation of Usp7 in the mouse brain, destabilizes N-Myc, which leads to inhibition of N-Myc function. Notably, HAUSP is more abundant in patients with neuroblastoma who have poorer prognosis, and HAUSP expression substantially correlates with N-Myc transcriptional activity. Furthermore, small-molecule inhibitors of HAUSP\'s deubiquitinase activity markedly suppress the growth of MYCN-amplified human neuroblastoma cell lines in xenograft mouse models. Taken together, our findings demonstrate a crucial role of HAUSP in regulating N-Myc function in vivo and suggest that HAUSP inhibition is a potential therapy for MYCN-amplified tumors.

Nat Med: 11 Sep 2016; epub ahead of print
Tavana O, Li D, Dai C, Lopez G, ... Sun H, Gu W
Nat Med: 11 Sep 2016; epub ahead of print | PMID: 27618649
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Neonatal gut microbiota associates with childhood multisensitized atopy and T cell differentiation.

Fujimura KE, Sitarik AR, Havstad S, Lin DL, ... Johnson CC, Lynch SV
Gut microbiota bacterial depletions and altered metabolic activity at 3 months are implicated in childhood atopy and asthma. We hypothesized that compositionally distinct human neonatal gut microbiota (NGM) exist, and are differentially related to relative risk (RR) of childhood atopy and asthma. Using stool samples (n = 298; aged 1-11 months) from a US birth cohort and 16S rRNA sequencing, neonates (median age, 35 d) were divisible into three microbiota composition states (NGM1-3). Each incurred a substantially different RR for multisensitized atopy at age 2 years and doctor-diagnosed asthma at age 4 years. The highest risk group, labeled NGM3, showed lower relative abundance of certain bacteria (for example, Bifidobacterium, Akkermansia and Faecalibacterium), higher relative abundance of particular fungi (Candida and Rhodotorula) and a distinct fecal metabolome enriched for pro-inflammatory metabolites. Ex vivo culture of human adult peripheral T cells with sterile fecal water from NGM3 subjects increased the proportion of CD4(+) cells producing interleukin (IL)-4 and reduced the relative abundance of CD4(+)CD25(+)FOXP3(+) cells. 12,13-DiHOME, enriched in NGM3 versus lower-risk NGM states, recapitulated the effect of NGM3 fecal water on relative CD4(+)CD25(+)FOXP3(+) cell abundance. These findings suggest that neonatal gut microbiome dysbiosis might promote CD4(+) T cell dysfunction associated with childhood atopy.

Nat Med: 11 Sep 2016; epub ahead of print
Fujimura KE, Sitarik AR, Havstad S, Lin DL, ... Johnson CC, Lynch SV
Nat Med: 11 Sep 2016; epub ahead of print | PMID: 27618652
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trial.

Rolland M, Tovanabutra S, Decamp AC, Frahm N, ... McCutchan FE, Mullins JI
We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell pressure on breakthrough viruses, we identified potential T cell epitopes in the founder sequences and compared them to epitopes in the vaccine. We found greater distances to the vaccine sequence for sequences from vaccine recipients than from placebo recipients. The most significant signature site distinguishing vaccine from placebo recipients was Gag amino acid 84, a site encompassed by several epitopes contained in the vaccine and restricted by human leukocyte antigen (HLA) alleles common in the study cohort. Moreover, the extended divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol and Nef) and not found in other HIV-1 proteins. These results represent what is to our knowledge the first evidence of selective pressure from vaccine-induced T cell responses on HIV-1 infection in humans.

Nat Med: 01 Mar 2011; epub ahead of print
Rolland M, Tovanabutra S, Decamp AC, Frahm N, ... McCutchan FE, Mullins JI
Nat Med: 01 Mar 2011; epub ahead of print | PMID: 21358627
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

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

Akahata W, Yang ZY, Andersen H, Sun S, ... 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.

Nat Med: 29 Jan 2010; epub ahead of print
Akahata W, Yang ZY, Andersen H, Sun S, ... Rao S, Nabel GJ
Nat Med: 29 Jan 2010; epub ahead of print | PMID: 20111039
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Recurrent MET fusion genes represent a drug target in pediatric glioblastoma.

International Cancer Genome Consortium PedBrain Tumor Project
Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ∼10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.

Nat Med: 16 Oct 2016; epub ahead of print
International Cancer Genome Consortium PedBrain Tumor Project
Nat Med: 16 Oct 2016; epub ahead of print | PMID: 27748748
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Purinergic receptors in the carotid body as a new drug target for controlling hypertension.

Pijacka W, Moraes DJ, Ratcliffe LE, Nightingale AK, ... Ford AP, Paton JF
In view of the high proportion of individuals with resistance to antihypertensive medication and/or poor compliance or tolerance of this medication, new drugs to treat hypertension are urgently needed. Here we show that peripheral chemoreceptors generate aberrant signaling that contributes to high blood pressure in hypertension. We discovered that purinergic receptor P2X3 (P2rx3, also known as P2x3) mRNA expression is upregulated substantially in chemoreceptive petrosal sensory neurons in rats with hypertension. These neurons generate both tonic drive and hyperreflexia in hypertensive (but not normotensive) rats, and both phenomena are normalized by the blockade of P2X3 receptors. Antagonism of P2X3 receptors also reduces arterial pressure and basal sympathetic activity and normalizes carotid body hyperreflexia in conscious rats with hypertension; no effect was observed in rats without hypertension. We verified P2X3 receptor expression in human carotid bodies and observed hyperactivity of carotid bodies in individuals with hypertension. These data support the identification of the P2X3 receptor as a potential new target for the control of human hypertension.

Nat Med: 04 Sep 2016; epub ahead of print
Pijacka W, Moraes DJ, Ratcliffe LE, Nightingale AK, ... Ford AP, Paton JF
Nat Med: 04 Sep 2016; epub ahead of print | PMID: 27595323
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen.

Xu M, Lee EM, Wen Z, Cheng Y, ... Song H, Tang H
In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.

Nat Med: 28 Aug 2016; epub ahead of print
Xu M, Lee EM, Wen Z, Cheng Y, ... Song H, Tang H
Nat Med: 28 Aug 2016; epub ahead of print | PMID: 27571349
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo.

Yoo H, Kim JW, Shishkov M, Namati E, ... Jaffer FA, Tearney GJ
Advancing understanding of human coronary artery disease requires new methods that can be used in patients for studying atherosclerotic plaque microstructure in relation to the molecular mechanisms that underlie its initiation, progression and clinical complications, including myocardial infarction and sudden cardiac death. Here we report a dual-modality intra-arterial catheter for simultaneous microstructural and molecular imaging in vivo using a combination of optical frequency domain imaging (OFDI) and near-infrared fluorescence (NIRF) imaging. By providing simultaneous molecular information in the context of the surrounding tissue microstructure, this new catheter could provide new opportunities for investigating coronary atherosclerosis and stent healing and for identifying high-risk biological and structural coronary arterial plaques in vivo.

Nat Med: 07 Nov 2011; epub ahead of print
Yoo H, Kim JW, Shishkov M, Namati E, ... Jaffer FA, Tearney GJ
Nat Med: 07 Nov 2011; epub ahead of print | PMID: 22057345
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.

Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, ... Metrakos P, Reynolds AR
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy.

Nat Med: 16 Oct 2016; epub ahead of print
Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, ... Metrakos P, Reynolds AR
Nat Med: 16 Oct 2016; epub ahead of print | PMID: 27748747
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.

Rohm M, Schäfer M, Laurent V, Üstünel BE, ... Berriel Diaz M, Herzig S
Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.

Nat Med: 28 Aug 2016; epub ahead of print
Rohm M, Schäfer M, Laurent V, Üstünel BE, ... Berriel Diaz M, Herzig S
Nat Med: 28 Aug 2016; epub ahead of print | PMID: 27571348
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Zika viral dynamics and shedding in rhesus and cynomolgus macaques.

Osuna CE, Lim SY, Deleage C, Griffin BD, ... Lewis MG, Whitney JB
Infection with Zika virus has been associated with serious neurological complications and fetal abnormalities. However, the dynamics of viral infection, replication and shedding are poorly understood. Here we show that both rhesus and cynomolgus macaques are highly susceptible to infection by lineages of Zika virus that are closely related to, or are currently circulating in, the Americas. After subcutaneous viral inoculation, viral RNA was detected in blood plasma as early as 1 d after infection. Viral RNA was also detected in saliva, urine, cerebrospinal fluid (CSF) and semen, but transiently in vaginal secretions. Although viral RNA during primary infection was cleared from blood plasma and urine within 10 d, viral RNA was detectable in saliva and seminal fluids until the end of the study, 3 weeks after the resolution of viremia in the blood. The control of primary Zika virus infection in the blood was correlated with rapid innate and adaptive immune responses. We also identified Zika RNA in tissues, including the brain and male and female reproductive tissues, during early and late stages of infection. Re-infection of six animals 45 d after primary infection with a heterologous strain resulted in complete protection, which suggests that primary Zika virus infection elicits protective immunity. Early invasion of Zika virus into the nervous system of healthy animals and the extent and duration of shedding in saliva and semen underscore possible concern for additional neurologic complications and nonarthropod-mediated transmission in humans.

Nat Med: 02 Oct 2016; epub ahead of print
Osuna CE, Lim SY, Deleage C, Griffin BD, ... Lewis MG, Whitney JB
Nat Med: 02 Oct 2016; epub ahead of print | PMID: 27694931
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Classification and characterization of microsatellite instability across 18 cancer types.

Hause RJ, Pritchard CC, Shendure J, Salipante SJ
Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, and colorectal tumors, yet the landscape of instability events across a wider variety of cancer types remains poorly understood. To explore MSI across malignancies, we examined 5,930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci and constructed a genomic classifier for MSI. We identified MSI-positive tumors in 14 of the 18 cancer types. We also identified loci that were more likely to be unstable in particular cancer types, resulting in specific instability signatures that involved cancer-associated genes, suggesting that instability patterns reflect selective pressures and can potentially identify novel cancer drivers. We also observed a correlation between survival outcomes and the overall burden of unstable microsatellites, suggesting that MSI may be a continuous, rather than discrete, phenotype that is informative across cancer types. These analyses offer insight into conserved and cancer-specific properties of MSI and reveal opportunities for improved methods of clinical MSI diagnosis and cancer gene discovery.

Nat Med: 02 Oct 2016; epub ahead of print
Hause RJ, Pritchard CC, Shendure J, Salipante SJ
Nat Med: 02 Oct 2016; epub ahead of print | PMID: 27694933
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice.

Liang J, Zhang Y, Xie T, Liu N, ... Jiang D, Noble PW
Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure.

Nat Med: 02 Oct 2016; epub ahead of print
Liang J, Zhang Y, Xie T, Liu N, ... Jiang D, Noble PW
Nat Med: 02 Oct 2016; epub ahead of print | PMID: 27694932
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Serotonin-reuptake inhibitors act centrally to cause bone loss in mice by counteracting a local anti-resorptive effect.

Ortuño MJ, Robinson ST, Subramanyam P, Paone R, ... Mann JJ, Ducy P
The use of selective serotonin-reuptake inhibitors (SSRIs) has been associated with an increased risk of bone fracture, raising concerns about their increasingly broader usage. This deleterious effect is poorly understood, and thus strategies to avoid this side effect remain elusive. We show here that fluoxetine (Flx), one of the most-prescribed SSRIs, acts on bone remodeling through two distinct mechanisms. Peripherally, Flx has anti-resorptive properties, directly impairing osteoclast differentiation and function through a serotonin-reuptake-independent mechanism that is dependent on intracellular Ca(2+) levels and the transcription factor Nfatc1. With time, however, Flx also triggers a brain-serotonin-dependent rise in sympathetic output that increases bone resorption sufficiently to counteract its local anti-resorptive effect, thus leading to a net effect of impaired bone formation and bone loss. Accordingly, neutralizing this second mode of action through co-treatment with the β-blocker propranolol, while leaving the peripheral effect intact, prevents Flx-induced bone loss in mice. Hence, this study identifies a dual mode of action of SSRIs on bone remodeling and suggests a therapeutic strategy to block the deleterious effect on bone homeostasis from their chronic use.

Nat Med: 04 Sep 2016; epub ahead of print
Ortuño MJ, Robinson ST, Subramanyam P, Paone R, ... Mann JJ, Ducy P
Nat Med: 04 Sep 2016; epub ahead of print | PMID: 27595322
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Straight talk with...Alexander von Gabain.

Waters H
Although many of the world\'s best known drugmakers hail from Europe, historically the continent\'s academic institutions haven\'t been as adept as their US counterparts at spinning off companies. So, in 2008, the European Commission founded the European Institute of Innovation and Technology (EIT) to bring technology and ideas developed at universities to market. The EIT was modeled after the Massachusetts Institute of Technology in Cambridge-but it doesn\'t bring its students and researchers to a common location. Instead, EIT-funded projects are based within virtual Knowledge and Innovation Communities (KICs) spread across the continent. So far, the institute has established three subject-specific KICs focused on climate change, sustainable energy and information technology, with a total of 75 collaborating universities, companies and other investors. On 15 September, microbiologist Alexander von Gabain will take over from physicist and founding chairman Martin Schuurmans as head of the EIT. A professor at the Max Perutz Laboratories in Vienna and a cofounder of the Austrian biotech Intercell, von Gabain brings with him a new focus on advancing biomedical innovations at the institute. Hannah Waters spoke with him about how he plans to move the EIT into the biomedical arena.

Nat Med: 08 Sep 2011; 17:1029
Waters H
Nat Med: 08 Sep 2011; 17:1029 | PMID: 21900907
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Paraoxonase-1 is a major determinant of clopidogrel efficacy.

Bouman HJ, Schömig E, van Werkum JW, Velder J, ... Ten Berg JM, Taubert D
Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

Nat Med: 20 Dec 2010; epub ahead of print
Bouman HJ, Schömig E, van Werkum JW, Velder J, ... Ten Berg JM, Taubert D
Nat Med: 20 Dec 2010; epub ahead of print | PMID: 21170047
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin.

Holland WL, Miller RA, Wang ZV, Sun K, ... Summers SA, Scherer PE
The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite-sphingosine-1-phosphate (S1P)-independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

Nat Med: 27 Dec 2010; epub ahead of print
Holland WL, Miller RA, Wang ZV, Sun K, ... Summers SA, Scherer PE
Nat Med: 27 Dec 2010; epub ahead of print | PMID: 21186369
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Translocation and dissemination of commensal bacteria in post-stroke infection.

Stanley D, Mason LJ, Mackin KE, Srikhanta YN, ... Moore RJ, Wong CH
Bacterial infection is highly prevalent in patients who have had a stroke. Despite the potential contribution of micro-aspiration in post-stroke pneumonia, we found that the majority of the microorganisms detected in the patients who developed infections after having a stroke were common commensal bacteria that normally reside in the intestinal tracts. In a mouse model of ischemic stroke, post-stroke infection was only observed in mice that were born and raised in specific-pathogen-free facilities; this was not seen in mice that were born and raised in germ-free facilities. Using high-throughput 16S rRNA gene amplicon sequencing and bioinformatics analyses, we provide evidence demonstrating that the source of the bacteria forming the microbial community in the lungs of post-stroke mice was indeed the host small intestine. Additionally, stroke-induced gut barrier permeability and dysfunction preceded the dissemination of orally inoculated bacteria to peripheral tissues. This study identifies a novel pathway in which stroke promotes the translocation and dissemination of selective strains of bacteria that originated from the host gut microbiota.

Nat Med: 02 Oct 2016; epub ahead of print
Stanley D, Mason LJ, Mackin KE, Srikhanta YN, ... Moore RJ, Wong CH
Nat Med: 02 Oct 2016; epub ahead of print | PMID: 27694934
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A rapid pro-hemostatic approach to overcome direct oral anticoagulants.

Thalji NK, Ivanciu L, Davidson R, Gimotty PA, Krishnaswamy S, Camire RM
Direct inhibitors of coagulation factor Xa (FXa) or thrombin are promising oral anticoagulants that are becoming widely adopted. The ability to reverse their anticoagulant effects is important when serious bleeding occurs or urgent medical procedures are needed. Here, using experimental mouse models of hemostasis, we show that a variant coagulation factor, FXa(I16L), rapidly restores hemostasis in the presence of the anticoagulant effects of these inhibitors. The ability of FXa(I16L) to reverse the anticoagulant effects of FXa inhibitor depends, at least in part, on the ability of the active site inhibitor to hinder antithrombin-dependent FXa inactivation, paradoxically allowing uninhibited FXa to persist in plasma. Because of its inherent catalytic activity, FXa(I16L) is more potent (by >50-fold) in the hemostasis models tested than a noncatalytic antidote that is currently in clinical development. FXa(I16L) also reduces the anticoagulant-associated bleeding in vivo that is induced by the thrombin inhibitor dabigatran. FXa(I16L) may be able to fill an important unmet clinical need for a rapid, pro-hemostatic agent to reverse the effects of several new anticoagulants.

Nat Med: 24 Jul 2016; epub ahead of print
Thalji NK, Ivanciu L, Davidson R, Gimotty PA, Krishnaswamy S, Camire RM
Nat Med: 24 Jul 2016; epub ahead of print | PMID: 27455511
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs.

Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, ... Brogi E, Massagué J
We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSI1-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche.

Nat Med: 27 Jun 2011; epub ahead of print
Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, ... Brogi E, Massagué J
Nat Med: 27 Jun 2011; epub ahead of print | PMID: 21706029
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance.

Jang C, Oh SF, Wada S, Rowe GC, ... Kasper DL, Arany Z
Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes.

Nat Med: 06 Mar 2016; epub ahead of print
Jang C, Oh SF, Wada S, Rowe GC, ... Kasper DL, Arany Z
Nat Med: 06 Mar 2016; epub ahead of print | PMID: 26950361
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction.

Yang S, Kim J, Ryu JH, Oh H, ... Min BH, Chun JS
Osteoarthritic cartilage destruction is caused by an imbalance between anabolic and catabolic factors. Here, we show that hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by EPAS1) is a catabolic transcription factor in the osteoarthritic process. HIF-2alpha directly induces the expression in chondrocytes of genes encoding catabolic factors, including matrix metalloproteinases (MMP1, MMP3, MMP9, MMP12 and MMP13), aggrecanase-1 (ADAMTS4), nitric oxide synthase-2 (NOS2) and prostaglandin-endoperoxide synthase-2 (PTGS2). HIF-2alpha expression was markedly increased in human and mouse osteoarthritic cartilage, and its ectopic expression triggered articular cartilage destruction in mice and rabbits. Moreover, mice transgenic for Epas1 only in chondrocytes showed spontaneous cartilage destruction, whereas heterozygous genetic deletion of Epas1 in mice suppressed cartilage destruction caused by destabilization of the medial meniscus (DMM) or collagenase injection, with concomitant modulation of catabolic factors. Our results collectively demonstrate that HIF-2alpha causes cartilage destruction by regulating crucial catabolic genes.

Nat Med: 24 May 2010; epub ahead of print
Yang S, Kim J, Ryu JH, Oh H, ... Min BH, Chun JS
Nat Med: 24 May 2010; epub ahead of print | PMID: 20495569
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Simultaneous two-photon imaging of oxygen and blood flow in deep cerebral vessels.

Lecoq J, Parpaleix A, Roussakis E, Ducros M, ... Vinogradov SA, Charpak S
Uncovering principles that regulate energy metabolism in the brain requires mapping of partial pressure of oxygen (PO(2)) and blood flow with high spatial and temporal resolution. Using two-photon phosphorescence lifetime microscopy (2PLM) and the oxygen probe PtP-C343, we show that PO(2) can be accurately measured in the brain at depths up to 300 μm with micron-scale resolution. In addition, 2PLM allowed simultaneous measurements of blood flow and of PO(2) in capillaries with less than one-second temporal resolution. Using this approach, we detected erythrocyte-associated transients (EATs) in oxygen in the rat olfactory bulb and showed the existence of diffusion-based arterio-venous shunts. Sensory stimulation evoked functional hyperemia, accompanied by an increase in PO(2) in capillaries and by a biphasic PO(2) response in the neuropil, consisting of an \'initial dip\' and a rebound. 2PLM of PO(2) opens new avenues for studies of brain metabolism and blood flow regulation.

Nat Med: 06 Jun 2011; epub ahead of print
Lecoq J, Parpaleix A, Roussakis E, Ducros M, ... Vinogradov SA, Charpak S
Nat Med: 06 Jun 2011; epub ahead of print | PMID: 21642977
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats.

Zhang Y, Xu J, Ruan YC, Yu MK, ... Zheng Y, Qin L
Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. Here we show the formation of abundant new bone at peripheral cortical sites after intramedullary implantation of a pin containing ultrapure magnesium into the intact distal femur in rats. This response was accompanied by substantial increases of neuronal calcitonin gene-related polypeptide-α (CGRP) in both the peripheral cortex of the femur and the ipsilateral dorsal root ganglia (DRG). Surgical removal of the periosteum, capsaicin denervation of sensory nerves or knockdown in vivo of the CGRP-receptor-encoding genes Calcrl or Ramp1 substantially reversed the magnesium-induced osteogenesis that we observed in this model. Overexpression of these genes, however, enhanced magnesium-induced osteogenesis. We further found that an elevation of extracellular magnesium induces magnesium transporter 1 (MAGT1)-dependent and transient receptor potential cation channel, subfamily M, member 7 (TRPM7)-dependent magnesium entry, as well as an increase in intracellular adenosine triphosphate (ATP) and the accumulation of terminal synaptic vesicles in isolated rat DRG neurons. In isolated rat periosteum-derived stem cells, CGRP induces CALCRL- and RAMP1-dependent activation of cAMP-responsive element binding protein 1 (CREB1) and SP7 (also known as osterix), and thus enhances osteogenic differentiation of these stem cells. Furthermore, we have developed an innovative, magnesium-containing intramedullary nail that facilitates femur fracture repair in rats with ovariectomy-induced osteoporosis. Taken together, these findings reveal a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.

Nat Med: 28 Aug 2016; epub ahead of print
Zhang Y, Xu J, Ruan YC, Yu MK, ... Zheng Y, Qin L
Nat Med: 28 Aug 2016; epub ahead of print | PMID: 27571347
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Endothelial exocytosis of angiopoietin-2 resulting from CCM3 deficiency contributes to cerebral cavernous malformation.

Zhou HJ, Qin L, Zhang H, Tang W, ... Wu D, Min W
Cerebral cavernous malformations (CCMs) are vascular malformations that affect the central nervous system and result in cerebral hemorrhage, seizure and stroke. CCMs arise from loss-of-function mutations in one of three genes: KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3). PDCD10 mutations in humans often result in a more severe form of the disease relative to mutations in the other two CCM genes, and PDCD10-knockout mice show severe defects, the mechanistic basis for which is unclear. We have recently reported that CCM3 regulates exocytosis mediated by the UNC13 family of exocytic regulatory proteins. Here, in investigating the role of endothelial cell exocytosis in CCM disease progression, we found that CCM3 suppresses UNC13B- and vesicle-associated membrane protein 3 (VAMP3)-dependent exocytosis of angiopoietin 2 (ANGPT2) in brain endothelial cells. CCM3 deficiency in endothelial cells augments the exocytosis and secretion of ANGPT2, which is associated with destabilized endothelial cell junctions, enlarged lumen formation and endothelial cell-pericyte dissociation. UNC13B deficiency, which blunts ANGPT2 secretion from endothelial cells, or treatment with an ANGPT2-neutralizing antibody normalizes the defects in the brain and retina caused by endothelial-cell-specific CCM3 deficiency, including the disruption of endothelial cell junctions, vessel dilation and pericyte dissociation. Thus, enhanced secretion of ANGPT2 in endothelial cells contributes to the progression of CCM disease, providing a new therapeutic approach for treating this devastating pathology.

Nat Med: 21 Aug 2016; epub ahead of print
Zhou HJ, Qin L, Zhang H, Tang W, ... Wu D, Min W
Nat Med: 21 Aug 2016; epub ahead of print | PMID: 27548575
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.