JCI online early table of contents: March 23, 2011

Disorders of the circulatory system- vascular diseases- are common in the developed world, and can lead to heart attacks, strokes and even death. However, treatments for these disorders, such as bypass surgery and angioplasty, themselves induce vascular injury, after which the cells of the blood vessel can over-proliferate in a way that limits blood flow. Nitric oxide (NO) is an important molecule that helps maintain the contractility and health of vascular smooth muscle cells, and multiple studies have linked vascular pathology to a decreased level of NO. Therefore, therapies that increase the availability of NO could help protect vascular health.

NO is synthesized from arginine by an enzyme called nitric oxide synthase (NOS). In new research, Brian Zuckerbraun and colleagues, of the University of Pittsburgh, in Pittsburgh, Pennsylvania, determined that after vessel injury in the rat, the NOS pathway is disrupted, but a secondary pathway that generates NO from nitrate is activated. Furthermore, supplementing rats with nitrate before inducing vessel injury markedly limited the extent of the damage, while a diet low in nitrate exacerbated it. In the accompanying commentary, John Cooke and Yohannes Ghebremariam of Stanford University in Stanford, California point out that high levels of dietary nitrate might in part explain the vascular benefits of diets rich in leafy greens, but warn that high dose supplementation could lead to the generation of carcinogenic molecules.

TITLE:
Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats
AUTHOR CONTACT:
Brian Zuckerbraun
University of Pittsburgh, Pittsburgh, PA, USA
Phone: 412 6470421; Fax: 412 6475959; E-mail: zuckerbraunbs@upmc.edu
View this article at: http://www.jci.org/articles/view/44079?key=1e749dd41ac25c7e8efd

ACCOMPANYING COMMENTARY
TITLE:
Dietary nitrate, nitric oxide, and restenosis
AUTHOR CONTACT:
John Cooke
Stanford Univ, Stanford, CA, USA
Phone: 6507253778; Fax: 6507251599; E-mail: john.cooke@stanford.edu
View this article at: http://www.jci.org/articles/view/57193?key=08699995280948c7eabd

Myocardits is an inflammation of the heart muscles that is a major cause of heart failure in young patients. In some cases, the disease is caused by viral infection, but in other patients it is linked to an autoimmune attack on the heart muscle. There are few effective treatment options for myocarditis, in part because the molecular mechanisms that underlie the defect are poorly defined.

In this paper, researchers led by Myra Lipes, at the Joslin Diabetes Center in Boston, Massachusetts, used a mouse model of spontaneous myocarditis. They found that the disease occurs because the immune system recognizes a protein required for the heart muscle to contract called alpha myosin as a pathogenic molecule, and T cells begin attacking the muscle cells that express it. However, they also demonstrated that they could prevent the disease from occurring in mice if the T cells were exposed to alpha myosin in the thymus as they developed. In the accompanying commentary, Todd Metzger and Mark Anderson at the University of California, San Francisco, suggest that although additional clinical research will be critical, the findings in this paper suggest that measurement of α-myosin might be a useful diagnostic tool for myocarditis, and further that the protein could be a promising therapeutic target.

TITLE:
Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans

AUTHOR CONTACT:
Myra Lipes
Joslin Diabetes Center, Boston, MA, USA
Phone: 617-309-2624; Fax: ; E-mail: myra.lipes@joslin.harvard.edu
View this article at: http://www.jci.org/articles/view/44583?key=ca730049533908ae28b8

ACCOMPANYING COMMENTARY
TITLE:
Myocarditis: a defect in central immune tolerance?
AUTHOR CONTACT:
Mark Anderson
UCSF, San Francisco, CA, USA
Phone: 415-502-8052; Fax: ; E-mail: manderson@diabetes.ucsf.edu
View this article at: http://www.jci.org/articles/view/57211?key=76a2fbb3e84185dfa3d6

Anaphylaxis is a severe, multi-system allergic reaction that can be fatal. Mouse models of the reaction have allowed scientists to discover the cell types and molecules involved, and point to basophils and mast cells, which release histamine, as the primary mediators. However, previous research has also shown that basophils and mast cells are not required for all of the symptoms of acute anaphylaxis, suggesting that another cell type must play an important role in this process.

In new research, Pierre Bruhns and colleagues at the Pasteur Institute in Paris, France, found that another type of white blood cell- neutrophils- were required for acute anaphylaxis in mice. They also showed that human neutrophils made mice sensitive to anaphylaxis, providing strong evidence that this cell type plays a similar role in patients. In the accompanying commentary, Clifford Lowell of the University of California, San Francisco, explains that these findings could have a big impact on the clinical effort to prevent and treat anaphylaxis.

TITLE:
Mouse and human neutrophils induce anaphylaxis
AUTHOR CONTACT:
Pierre Bruhns
Institut Pasteur, Paris, FRA
Phone: +33-1-4568-8629; Fax: ; E-mail: bruhns@pasteur.fr
View this article at: http://www.jci.org/articles/view/45232?key=b2159213ccc9348a0933

Accompanying commentary:
TITLE:
Neutrophils give us a shock
AUTHOR CONTACT:
Clifford Lowell
University of California, San Francisco, San Francisco, CA, USA
Phone: 415-476-2963; Fax: 415-502-9404; E-mail: clifford.lowell@ucsf.edu
View this article at: http://www.jci.org/articles/view/57296?key=b2467dc7a368a068b40c

Each time a cell divides, the ends of the chromosomes (telomeres) shorten slightly, and this process naturally limits the number of times a cell can replicate. The uncontrolled growth of cancer is often characterized by activation of telomerase, which lengthens telomeres and helps cells escape this replication roadblock. How telomerase is activated in cancer cells and controlled in healthy cells is not completely understood.

In this paper, Kun Ping Lu and colleagues, at Beth Israel Deaconess Medical Center in Boston, Massachusetts, demonstrate that a gene that lies in a genomic region frequently deleted in tumors called PinX1 is a negative regulator of telomerase. They found that PinX1 expression was decreased in cancer cell lines and tissues, and mice with reduced levels of PinX1 develop spontaneous tumors. The authors believe that these findings suggest that PinX1 acts as a tumor suppressor, and intuit that inhibition of telomerase might be an effective therapy in patients with PinX1 related cancers. In the accompanying commentary, Brad Johnson, of the University of Pennsylvania in Philadelphia, explains that the findings in current study may also reveal new insights into the interplay of telomere biology, chromosome stability, and cancer initiation.

TITLE:
The telomerase inhibitor PinX1 is a major haploinsufficient tumor suppressor

AUTHOR CONTACT:
Kun Ping Lu
Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA
Phone: 617-735-2016; Fax: 617-735-2050; E-mail: klu@bidmc.harvard.edu
View this article at: http://www.jci.org/articles/view/43452?key=f4922cafd461732a27d4
ACCOMPANYING COMMENTARY

TITLE:
PinX1 the tail on the chromosome
AUTHOR CONTACT:
Brad Johnson
University of Pennsylvania, Philadelphia, PA, USA
Phone: 215 573-5037; Fax: ; E-mail: johnsonb@mail.med.upenn.edu
View this article at: http://www.jci.org/articles/view/57024?key=d9c545bb2db0fdf9d1d4

Tumor growth is supported, in part, by populations of suppressive immune cells which inhibit anti-tumor T cell activation. Identifying the cell populations that promote T cell tolerance could help researchers target this process and improve the efficacy of cancer vaccines. Dendritic cells (DCs) are known to induce T cell tolerance, but the signals and factors that control this process are not completely understood.

In this paper, Arthur Hurwitz and colleagues, at the National Cancer Institute in Frederick, Maryland demonstrate that in human and mouse prostate cancers, the ability of DCs to suppress immune responses requires expression of the transcription factor Foxo3. Furthermore, they found a subpopulation of DCs that could directly convert T cells to a tolerogenic state. In the accompanying commentary, Vincenzo Bronte, of Verona University Hospital in Verona, Italy, suggests that Foxo3 may be a promising target in the design of new cancer therapeutics, but points out that there is likely a network of factors and signaling pathways that all contribute to promoting tolerance, and successful immunotherapy might require simultaneous targeting of multiple molecules.

TITLE:
FOXO3 programs tumor-associated DCs to become tolerogenic in human and murine prostate cancer
AUTHOR CONTACT:
Arthur Hurwitz
Center for Cancer Research, National Cancer Institute, Frederick, MD, USA
Phone: 301-846-5443; Fax: 301-846-7350; E-mail: hurwitza@mail.nih.gov
View this article at: http://www.jci.org/articles/view/44325?key=f9eccc3d3ebe6c7abd01

ACCOMPANYING COMMENTARY
TITLE:
Tolerogenic pDCs: spotlight on Foxo3a
AUTHOR CONTACT:
Vincenzo Bronte
Immunology Section, Verona, ITA
Phone: 0039-045-8124007; Fax: 0039-045-8126455; E-mail: vincenzo.bronte@univr.it
View this article at: http://www.jci.org/articles/view/57190?key=68a31301eebfcb6f4fde

Cancers that form in one part of the body can spread and invade other tissues, a process known as metastasis. Bone is a common site of metastasis for certain types of cancer, however, it is unclear how and why tumor cells re-locate specifically to the bone.

In new research, Russell S. Taichman and colleagues, of the University of Michigan School of Dentistry in Ann Arbor, Michigan, used a mouse model to demonstrate that metastatic prostate cancer cells move to the bone marrow by following the same signals used by hematopoietic stem cells. Indeed, the two populations compete to occupy the stem cell niche, and drugs that mobilize hematopoietic stem cells out of the bone marrow also mobilize metastatic cancer cells. In the accompanying commentary, Laura Schuettpelz and Daniel Link, of Washington University School of Medicine, Saint Louis, Missouri, point out that these findings suggest that the conditions of the niche may be what make metastatic bone cancers resistant to chemotherapy, and that disrupting the cancer cell-niche interaction might improve therapeutic efficacy.

TITLE:
Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow

AUTHOR CONTACT:
Russell Taichman
University of Michigan, Ann Arbor, MI, USA
Phone: 734-764-9952; Fax: ; E-mail: rtaich@umich.edu
View this article at: http://www.jci.org/articles/view/43414?key=4a14368eb66c0035d44b

ACCOMPANYING COMMENTARY
TITLE:
Niche competition and cancer metastasis to bone

AUTHOR CONTACT:
Daniel Link
Washington University, Saint Louis, MO, USA
Phone: 314 362-8771; Fax: ; E-mail: dlink@im.wustl.edu
View this article at: http://www.jci.org/articles/view/57229?key=5716873d300715738120

As tumors grow in size, they require a continuous supply of nutrients and oxygen, supplied by the growth of new blood vessels. Thus, multiple cancer therapeutics that target this pathway (called anti-angiogenics) are currently in use, most of which block signaling through the vascular endothelial growth factor receptor (VEGFR). However, not all patients respond to anti-angiogenic therapy, and even in those that have initial favorable responses, resistance to these drugs inevitably develops. The cellular mechanisms that explain this resistance are not well understood; indeed, it remains unclear whether the resistance occurs due to changes in the tumor cells themselves, or in the surrounding stromal cells.

In this paper, John Heymach and colleagues, at the M. D. Anderson Cancer Center in Houston, Texas, investigated three different models of non small cell lung cancer (NSCLC), and found that resistance to anti-angiogenics developed when stromal cells increased expression of an alternative pro-angiogenic molecule, endothelial growth factor receptor (EGFR). Furthermore, the researchers demonstrated differences in the types of cells that express EGFR depending on whether the model displayed intrinsic or developed resistance to therapy. In the accompanying commentary, Oriol Casanovas of the Catalan Institute of Oncology in Barcelona, Spain, stresses that these findings may be very clinically relevant, and that therapies that combine inhibition of more than one angiogenic pathway might be useful in circumventing resistance.

TITLE:
Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma

AUTHOR CONTACT:
John Heymach
M.D. Anderson Cancer Center, Houston, TX, USA
Phone: 713-792-6363; Fax: 713-792-1220; E-mail: jheymach@mdanderson.org
View this article at: http://www.jci.org/articles/view/42405?key=cd7e028e1b8e99a8f3b5

ACCOMPANYING COMMENTARY
TITLE:
The adaptive stroma joining the antiangiogenic resistance front

AUTHOR CONTACT:
Oriol Casanovas
Catalan Institute of Oncology - IDIBELL, Hospitalet de Llobregat, ESP
Phone: +34-93-2607344; Fax: ; E-mail: ocasanovas@iconcologia.net
View this article at: http://www.jci.org/articles/view/46430?key=bfe316009aee08a81f45

Acute promyelocytic leukemia (APL) is a cancer of the bone marrow that accounts for approximately 1% of pediatric leukemias. APL has been linked to a specific genetic event called a translocation; a fusion between chromosomes 15 and 17 that generates a novel protein thought to be responsible for the cancerous cell growth. However, APL patients are known to have additional chromosomal alterations, and the slow progression of mouse models of the disease suggest that there may be additional mutations that cooperate with the translocation event to promote oncogenesis.

In this paper, Richard Wilson and colleagues, at Washington University in St. Louis, Missouri, describe a new method of sequencing the genome of a mouse model of APL to identify the secondary mutations that allow the cancer to progress. In particular, they identified a mutation in the Jak1 gene, part of an intracellular signaling pathway that regulates growth. In combination with the initiating translocation, this Jak1 mutation led to rapid disease progression in mice. In the accompanying commentary, Raajit Rampal and Ross Levine of Memorial Sloan-Kettering Cancer Center, in New York, New York point out that these data suggest there may be a previously unidentified role for the JAK pathway in the progression of APL that could represent a new therapeutic target. In addition, they believe that this innovative genome sequencing method could be applied to mouse models to uncover the underlying genetic causes of other human diseases.

TITLE:
Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression

AUTHOR CONTACT:
Richard Wilson
The Genome Center, Saint Louis, MO, USA
Phone: 314-286-1804; Fax: 314-286-1810; E-mail: rwilson@wustl.edu
View this article at: http://www.jci.org/articles/view/45284?key=4e885a53dfae35d642d2

ACCOMPANYING COMMENTARY
TITLE:
Finding a needle in a haystack: whole genome sequencing and mutation discovery in murine models

AUTHOR CONTACT:
Ross Levine
Memorial Sloan Kettering, New York, NY, USA
Phone: 646-888-2767; Fax: 646-422-0856; E-mail: leviner@mskcc.org
View this article at: http://www.jci.org/articles/view/57200?key=09eebc45830790c95934