Public Release:  JCI early table of contents for June 11, 2012

Journal of Clinical Investigation

ONCOLOGY

Fighting cancer with the immune system | Back to top

The human immune system has a natural ability to identify and attack tumor cells. Natural killer (NK) cells are innate immune cells that are particularly effective at killing tumor cells due to their ability to secrete cytotoxic enzymes. However, mutations have allowed many types of tumors to develop a resistance to NK-mediated killing through ill-defined mechanisms. Dr. Jerome Ritz and colleagues at the Dana-Farber Cancer Institute in Boston sought to pinpoint some of these mechanisms using a library of short hairpin RNAs (shRNA), a type of RNA that binds complementary RNA sequences in the cell and prevents their transcription into proteins. His group used a multiple myeloma cell line to screen for genes whose reduced expression increased susceptibility of the cancer cells to NK-mediated death. They identified dozens of genes that, when shut down by shRNA, allowed increased tumor cell killing by NK cells. The strongest effect was induced by silencing proteins called JAK1 and JAK2, kinases important for integrating signals from many membrane receptor proteins. In addition to targeting these kinases by shRNA, the research team showed that pharmacological inhibition of JAK1 and 2 also increased tumor cell killing. Many kinase inhibitors being used or tested today target genes identified in this screen. The researchers suggest that targeting the JAK1 and 2 pathways in particular may aid in eradicating tumors that have developed mechanisms to escape NK cell killing.

TITLE:

Tyrosine kinase pathways modulate tumor susceptibility to natural killer cells

AUTHOR CONTACT:

Jerome Ritz

Dana Farber Cancer Institute, Boston, MA, USA

Phone: 617/632-3465; Fax: 617-632-5167; E-mail: jerome_ritz@dfci.harvard.edu

View this article at: http://www.jci.org/articles/view/58457?key=e575eea4083aff935b44

ALLERGY AND ASTHMA

Evidence for a new therapeutic target for inflammatory skin diseases | Back to top

Many chronic inflammatory diseases, including atopic dermatitis and asthma, are initially triggered by an allergic reaction. However, the mechanism through which an allergic reaction becomes a chronic condition remains poorly understood. A recent study from Kenji Izuhara and colleagues at the Saga Medical School in Japan investigated the role of periostin, which is a protein involved in tissue development, in a mouse model of allergic inflammation. The team found that following exposure to a known allergen, periostin accumulated in the ear tissue and skin cells of mice and then interacted with a signaling protein called alphav to stimulate chronic inflammation. They also showed that mice lacking periostin or alphav were resistant to allergic skin inflammation compared to control mice. This study reveals that periostin plays an important role in the development of chronic skin inflammation following allergen exposure and identifies periostin as a potential therapeutic target for allergic skin diseases in humans.

TITLE:

Periostin promotes chronic allergic inflammation in response to Th2 cytokines

AUTHOR CONTACT:

Kenji Izuhara

Saga Medical School, Saga, JPN

Phone: +81-952-34-2261; Fax: +81-952-34-2058; E-mail: kizuhara@cc.saga-u.ac.jp

View this article at: http://www.jci.org/articles/view/58978?key=eb83b10be02de645dae0

IMMUNOLOGY

Tolerating transplantation | Back to top

Organ transplantation has saved millions of lives. One of the most critical components to a successful transplant is minimizing the recipient patients immune response to the foreign organ. The use of immunosuppressive drugs has been critical for allowing tolerance of the transplanted organ. Dr. Terry Strom and colleagues at the Harvard Medical School wanted to better understand the specialized immune cells known as regulatory T cells that infiltrate the transplanted organ and play an important role in tolerating the transplant. They identified a population of regulatory T cells in mice that rapidly and robustly infiltrate the transplanted skin grafts. These specialized cells, which express the T cell Immunoglobulin and Mucin domain-3 protein (TIM-3) on their surface, are short-lived and their levels peak at the time of graft rejection. Their results suggest that TIM-3+ regulatory T cells are an important mediator of graft rejection in mice.

TITLE:

Allograft rejection is restrained by short-lived TIM-3+PD-1+Foxp3+ Tregs

AUTHOR CONTACT:

Terry Strom

Beth Israel Deaconess Medical Center, Boston, MA, USA

Phone: 1-617-735-2880; Fax: 1 617 667-0923; E-mail: tstrom@bidmc.harvard.edu

View this article at: http://www.jci.org/articles/view/45138?key=7b4b12decea73b958234

PULMONARY BIOLOGY

Insights into the mechanisms of acute lung injury | Back to top

About 200,000 US citizens develop and 80,000 die every year from acute lung injury. A major cause of acute lung injury is blood transfusion, also known as transfusion-related acute lung injury (TRALI). Acute inflammation and injury in TRALI appear to be dependent on blood platelets sequestered in the lung microcirculation in a process dependent on immune cells known as neutrophils, but the molecular mechanisms are unknown. A research team lead by Mark Looney from the University of California at San Francisco has focused on neutrophil extracellular traps (NETs) to explain the neutrophil and platelet-dependent lung damage observed in TRALI. NETs are extracellular traps to pathogens formed by proteins and DNA filaments released from dead neutrophils. Dr. Looney's team discovered NETs in the lungs and plasma of TRALI patients and in the plasma of patients with acute lung injury. Using a TRALI mouse model, the researchers demonstrated that preventing platelet activation with aspirin reduces NET formation. Moreover, mice were protected from TRALI by targeting NET components by treatment with a blocking antibody or DNaseI, an enzyme that cleaves DNA. This study demonstrates that NETs contribute to lung endothelial injury, and that disrupting NET formation is an attractive target for the treatment of acute lung injury.

TITLE:

Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

AUTHOR CONTACT:

Mark Looney

University of California, San Francisco, San Francisco, CA, USA

Phone: (415) 476-1079; Fax: (415) 502-2126; E-mail: mark.looney@ucsf.edu

View this article at: http://www.jci.org/articles/view/61303?key=350c319e90d4456e2c03

METABOLISM

Thyroid hormone stimulates lipid breakdown | Back to top

For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Dr. Paul Yen and colleagues at the Duke-NUS Medical School in Singapore report that TH stimulation of fatty acid β-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, their results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism.

TITLE:

Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagy

AUTHOR CONTACT:

Paul M Yen

Duke-NUS Graduate Medical School, Singapore, SGP

Phone: 65 6516 7332; Fax: 65 6221 2534; E-mail: pauly1115@gmail.com

View this article at: http://www.jci.org/articles/view/60580?key=edebfef2a8ea5c1cec1a

OPHTHALMOLOGY

Development of vision impairment in central serous chorioretinopathy | Back to top

Central serous chorioretinopathy (CSCR) is a vision-threatening eye disease with no validated treatment and unknown pathogeny. Subretinal fluid accumulation originates from dilation and leakage of choroid vessels underneath the retina. Because glucocorticoids induce and aggravate CSCR and can occupy the mineralocorticoid receptor (MR), CSCR may depend on inappropriate MR activation. Dr. Nicolette Farman and colleagues at INSERM in Paris, France report on the effect of MR activation on rat choroidal vasculature and to transfer results for patients with CSCR. Their results identify MR signaling as a novel pathway controlling choroidal vascular bed relaxation and provide a pathogenic link with human CSCR, leading to proposal of short-term MR blockade to reverse the choroid vasculopathy.

TITLE:

Mineralocorticoid receptor is involved in rat and human ocular chorioretinopathy

AUTHOR CONTACT:

Nicolette Farman

INSERM U872 Centre de Recherche des Cordeliers, Paris, UNK, FRA

Phone: 33144278104; Fax: ; E-mail: nicolette.farman@crc.jussieu.fr

View this article at: http://www.jci.org/articles/view/61427?key=e23d8a1e139de78112dc

ONCOLOGY

New mediator of prostate cancer identified | Back to top

Cell proliferation requires a chain of signaling events that begins with extracellular ligands and ends with alterations in nuclear gene expression. In prostate cancer, these signals change with time, as tumors progress from castration-sensitive (androgen-dominant) to castration-resistant states. While the mechanisms underlying this change remain uncertain, effective prostate cancer treatment will involve characterization of common signaling components that regulate both stages of prostate cancer proliferation. Dr. Stephen Hammes and colleagues at the University of Rochester Medical center report that that paxillin, a known cytoplasmic adaptor protein, regulates both androgen- and epidermal growth factor (EGF)-induced nuclear signaling. Their findings indicated that paxillin is a liaison between extranuclear MAPK signaling and nuclear transcription in response to androgens and growth factors, making it a potential regulator of both castration-sensitive and castration-resistant prostate cancer.

TITLE:

Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation

AUTHOR CONTACT:

Stephen Hammes

University of Rochester Medical Center, Rochester, NY, USA

Phone: 585-275-2901; E-mail: Stephen_Hammes@URMC.Rochester.edu

View this article at: http://www.jci.org/articles/view/62044?key=4cdf336a22dd6b995a80

ONCOLOGY

DNA repair is required for cancer survival in mice with acute inflammation | Back to top

Underlying infections or inflammatory conditions are associated with more than 15% of world-wide cancer deaths. Inflamed tissues are known to harbor elevated DNA damage lesions induced by reactive oxygen and nitrogen species from activated immune system cells such as neutrophils and macrophages. Understanding how inflammation contributes to cancer etiology is important for both cancer prevention and treatment. Using an established mouse model of colon cancer initiation combined with inflammatory stimuli, Leona Samson and colleagues at MIT in Cambridge, Massachusetts show that the DNA repair enzymes ALKBH2 and ALKBH3 provide critical cancer protection.

TITLE:

DNA repair is indispensable for survival after acute inflammation in mice

AUTHOR CONTACT:

Leona Samson

MIT, Cambridge, MA, USA

Phone: 617-258-7813; Fax: 617-253-8099; E-mail: lsamson@mit.edu

View this article at: http://www.jci.org/articles/view/63338?key=ec7af4f54f82816180c5

METABOLISM

Molecular regulators of lipid homeostasis | Back to top

Insulin is the primary stimulator of hepatic lipid production. Dr. Fajun Yang and colleagues at the Albert Einstein College of Medicine in the Bronx, NY identify cyclin-dependent kinase 8 (CDK8) and its regulatory partner Cyclin C (CycC) as negative regulators of the lipogenic pathway in Drosophila, mammalian hepatocytes and mouse livers. Their results demonstrate that CDK8 and CycC function as novel and conserved components of the insulin signaling pathway in regulating lipid homeostasis.

TITLE:

Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1

AUTHOR CONTACT:

Fajun Yang

Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA

Phone: (718) 678-1142; Fax: (718) 678-1020; E-mail: fajun.yang@einstein.yu.edu

View this article at: http://www.jci.org/articles/view/61462?key=8624761da96817b7090c

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