[ Back to EurekAlert! ] Public release date: 25-Jan-2013
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Contact: Jillian Hurst
Journal of Clinical Investigation

JCI early table of contents for Jan. 25, 2013

Prostate cancer cells thrive on stress

Prostate cancer patients have increased levels of stress and anxiety; however, several recent studies have found that men who take drugs that interfere with the stress hormone adrenaline have a lower incidence of prostate cancer. In this issue of the Journal of Clinical Investigation George Kulik and colleagues at Wake Forest University examined the relationship between stress and cancer progression in a mouse model of prostate cancer. Kulik and colleagues found that mice that had been subjected to stress (exposed to the scent of a predator) exhibited a significantly reduced response to a drug that induces cancer cell death compared to their unstressed counterparts. Administration of adrenaline also blocked cancer cell death. Conversely, drugs that inhibited adrenaline signaling ablated the effect of stress on prostate cancer. These findings suggest that beta-blockers, which are used for the treatment of high blood pressure and block the effects of adrenaline, could increase the efficacy of anti-cancer therapies. In a companion commentary, Anil Sood and colleagues at MD Anderson Cancer Center discuss additional studies that will be required to move these findings from bench to bedside.

Behavioral stress accelerates prostate cancer development in mice

George Kulik
Wake Forest University Health Sciences, Winston-Salem, NC, USA
Phone: 336-713-6750; E-mail: gkulik@wakehealth.edu

View this article at: http://www.jci.org/articles/view/63324?key=6ae78db845f6f7d9379b


Why stress is BAD for cancer patients

Anil Sood
M. D. Anderson Cancer Center, Houston, TX, USA
Phone: 713-745-5266; Fax: 713-792-7586; E-mail: asood@mdanderson.org

View this article at: http://www.jci.org/articles/view/67887?key=741bcde7c39c877f58de

An important LINC in human hearing

In this issue of the Journal of Clinical Investigation, Karen Avraham and colleagues at Tel Aviv University identified a genetic mutation in two families with hereditary high frequency hearing loss. The mutated gene, which has not previously been linked to hearing loss, encodes NESP4, a protein that is expressed in the outer nuclear membrane (ONM) of the hair cells of the ear. Avraham and colleagues found that mutated NESP4 was mislocalized, disrupting a cellular complex known as the "linker of nucleoskeleton and cytoskeleton" or LINC, which maintains the position of the nucleus within the cell. Hair cells in mice lacking NESP4 or another component of the LINC complex, SUN1, developed normally, but the mice developed hearing loss as they matured. These results demonstrate that the LINC complex is essential for hearing and indicate that nuclear positioning is important for the maintenance of normal hearing. In a companion commentary, Howard Worman of Columbia University discusses the role of the LINC complex in physiology and disease.

The LINC complex is essential for hearing

Karen B. Avraham
Tel Aviv University, Tel Aviv, UNK, ISR
Phone: 972-3-640-6642; Fax: 972-3-640-9360; E-mail: karena@post.tau.ac.il

View this article at: http://www.jci.org/articles/view/66911?key=408541c0a7d6a28c221c


Nucleocytoplasmic connections and deafness

Howard Worman
Columbia University College of Physcians and Surgeons, New York, NY, USA
Phone: 212 305-1306; Fax: 212 305-6443; E-mail: hjw14@columbia.edu

View this article at: http://www.jci.org/articles/view/67454?key=9e95d8d9835bfa8639b5

Green tea and Vardenafil: a killer chemotherapy combo

Several recent studies have demonstrated that EGCG, a major constituent of green tea, has anti-cancer properties, but the molecular mechanisms underlying its effects are unknown. In this issue of the Journal of Clinical Investigation, Hirofumi Tachibana and colleagues at Kyushu University in Fukuoka, Japan, demonstrate that EGCG activates the 67-kDa laminin receptor, which elevates intracellular levels of the molecule cGMP to induce cell death. Tachibana and colleagues combined EGCG with vardenafil, a drug used to treat erectile dysfunction, which blocks the activity of PDE5, a protein that degrades cGMP. In a mouse model of multiple myeloma, vardenafil potentiated the effects of EGCG to mediate cancer cell death. Chung Yan and Hong Wang of Rutgers University discuss these findings in a companion commentary.

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis

Hirofumi Tachibana
Kyushu University, Fukuoka, JPN
Phone: +81-92-642-3008; E-mail: tatibana@agr.kyushu-u.ac.jp

View this article at: http://www.jci.org/articles/view/64768?key=230ac8bcfd7fc9e49bd2


Cancer therapy combination: Green tea and a phosphodiesterase 5 inhibitor?

Chung S Yang
Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey, Piscataway, , USA
Phone: (732) 445 3400 x244; E-mail: csyang@pharmacy.rutgers.edu

View this article at: http://www.jci.org/articles/view/67589?key=f3fc8081773f164f2bda

Researchers explain how coal tar treats eczema

Coal tar soap is one of the oldest remedies for atopic dermatitis (aka eczema), but it is unclear exactly why this treatment is effective. In this issue of the Journal of Clinical Investigation, Ellen van den Bogaard and colleagues at Radboud University in Nijmegen, the Netherlands, identified the aryl hydrocarbon receptor (AHR) as the molecular target of coal tar. Using a skin model of atopic dermatitis, van den Bogaard and colleagues demonstrated that coal tar activates AHR to diminish cell death, expression of inflammatory proteins, and skin cell swelling (spongiosis), and restored barrier proteins that maintain skin integrity. In a companion commentary, Irwin McClean and Alan Irvine of the University of Dundee, detail the history of coal tar as a therapeutic and discuss how these findings could be used to identify new therapies for atopic dermatitis.

Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis

Ellen H. van den Bogaard
Radboud University Nijmegen Medical Centre, Nijmegen, , NLD
Phone: 0031243614903; E-mail: e.vandenbogaard@derma.umcn.nl

View this article at: http://www.jci.org/articles/view/65642?key=b7cee98bcfeb630f5430


Old King Coal molecular mechanisms underlying an ancient treatment for atopic eczema

W.H. Irwin McLean
Univ. of Dundee, Dundee, GBR
E-mail: w.h.i.mclean@dundee.ac.uk

View this article at: http://www.jci.org/articles/view/67438?key=d82918f652b44fc17c6f

iRHOM2: the newest gadget in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory joint disorder that gradually destroys cartilage, causing loss of joint function and mobility. TNF is a protein that mediates inflammation in RA. TNF is generated when an enzyme known as TACE release TNF from immune cells. Therapeutic targeting of TACE could reduce TNF, but TACE is also important to other physiological processes, making it a poor drug target. In this issue of the Journal of Clinical Investigation, Carl Blobel and colleagues at Weill Cornell University demonstrated that the protein iRHOM2 in immune cells. Blobel and colleagues found that inhibition of iRHOM2 selectively blocked TACE activity in immune cells without disrupting other functions. Additionally, mice lacking iRHOM2 were protected from inflammatory arthritis. In a companion commentary, Stefan Lichtenthaler of the German Center for Neurodegenerative Diseases in Munich Germany discusses iRHOM2's potential as a therapeutic target in RA.

iRHOM2 is a critical pathogenic mediator of inflammatory arthritis

Carl Blobel
Weill Medical College of Cornell University, New York, NY, USA
Phone: 212-606-1429; Fax: 212-774-2560; E-mail: blobelc@hss.edu

View this article at: http://www.jci.org/articles/view/66168?key=fe267ffb4e5319ded04e


iRhom2 takes control of rheumatoid arthritis

Stefan Lichtenthaler
German Center for Neurodegenerative Diseases (DZNE) & TUM, Munich, UNK, DEU
Phone: +498970958416; E-mail: stefan.lichtenthaler@dzne.lmu.de

View this article at: http://www.jci.org/articles/view/67548?key=1a92eca12fdd73f8da76

Rooting out hormone refractory prostate cancer

Prostate cancer is one of the most common malignancies in men. It is highly treatable in early stages; however, once the cancer becomes metastatic, it cannot be cured. In this issue of the Journal of Clinical Investigation, Fillippo Giancotti and colleagues at Memorial Sloan-Kettering Cancer Center in New York, demonstrate that a significant fraction of advanced, hormone refractory prostate cancers express high levels of the protein β4 integrin. Using a mouse model of prostate cancer, Giancotti and colleagues found that loss of the β4 integrin gene significantly inhibited prostate tumor growth and progression by blocking activation of the oncogenic proteins ErbB2 and c-Met, which are responsible for sustaining prostate cancer stem cells. In a companion commentary Max Wicha of the University of Michigan discusses how targeting of these proteins could be a useful therapeutic strategy for the treatment of advanced prostate cancer.

β4 Integrin signaling induces expansion of prostate tumor progenitors

Filippo Giancotti
MSKCC, New York, NY, USA
Phone: 212-639-6998; Fax: 212-794-6236; E-mail: f-giancotti@ski.mskcc.org

View this article at: http://www.jci.org/articles/view/60720?key=5d9712f139a9b198e261


B4 Androgen ablation: Attacking the prostate cancer stem cell

Max S. Wicha
University of Michigan, Ann Arbor, MI, USA
Phone: 1-734-618-7324; E-mail: mwicha@med.umich.edu

View this article at: http://www.jci.org/articles/view/67460?key=37db186328102ebb8897

Researchers identify key mediators of sepsis-induced lung injury

Sepsis is an illness in which the body has a severe reaction to a bacterial infection. Bacterial toxins activate the immune system, causing widespread inflammation and increased blood calcium levels, oxidative stress, and inflammatory factors. This increased inflammation and immune activation can cause fatal organ damage, particularly in the lungs. The molecular mechanisms underlying this damage are unknown. In this issue of the Journal of Clinical Investigation, Madesh Muniswamy and colleagues at Temple University identified a signaling pathway that mediates lung injury during sepsis. Using a mouse model of sepsis-induced lung injury, Muniswamy and colleagues demonstrated that the proteins STIM1 and NOX2 drive the body's response to bacterial toxins, as mice lacking these proteins were not susceptible to lung injury. Additionally, treatment with a calcium channel blocker known as BTP2 halted sepsis-induced lung injury. These findings identify therapeutic targets that could be used to limit sepsis-induced lung injury.

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Madesh Muniswamy
Temple University, Philadelphia, PA, USA
Phone: 2157075465; Fax: 2157077536; E-mail: madeshm@temple.edu

View this article at: http://www.jci.org/articles/view/65647?key=a0fec1e2ea29b7adbf2a

New insight into Liddle syndrome

Liddle syndrome is a form of early onset, severe hypertension that is caused by mutations in the NEDD4 gene. NEDD4 is a ubiquitin ligase, which mediates the destruction of target proteins. Liddle's syndrome is hypothesized to be caused by the inability of mutant NEDD4 to induce destruction of the kidney sodium channel ENaC, perturbing sodium homeostasis to induce hypertension. In this issue of the Journal of Clinical Investigation, Olivier Staub and colleagues at the University of Lausanne investigated the effects of mutant NEDD4 in the kidney. Staub and colleagues engineered a mouse that only expressed mutant NEDD4 in the renal tubules. Mutant mice exhibited increased ENaC but did not have higher blood sodium levels. These results demonstrate that the current model of Liddle's syndrome is incorrect. Interestingly, expression of mutant NEDD4 led to an increase in NCC, a sodium/chloride transporter, which could contribute to the elevated sodium and hypertension associated with Liddle's syndrome. These results indicate that NEDD4 could be a therapeutic target for the treatment of hypertension. In a companion commentary, David Ellison of Oregon Health and Science University discusses how these findings will affect our understanding of hypertension.

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Olivier Staub
University of Lausanne, Lausanne, UNK, CHE
Phone: 41 21 692 54 07; Fax: +4121 692-5355; E-mail: olivier.staub@unil.ch

View this article at: http://www.jci.org/articles/view/61110?key=6546ac09cd62f90bc4b8


Ubiquitylation and the pathogenesis of hypertension

David H. Ellison
Oregon Health Sciences University, Portland, OR, USA
Phone: 5034948490; Fax: 5034945330; E-mail: ellisond@ohsu.edu

View this article at: http://www.jci.org/articles/view/66882?key=eea1260ee7700d4b31f5

Researchers identify ITAM as an important regulator of vascular integrity

Platelets survey blood vessels, searching for blood vessel damage. When damage is detected, the platelets form a clump and release factors that prevent blood loss and promote repair. Atherotrhombosis is the inappropriate clumping of platelets within blood vessels that occludes blood flow and many anti-platelet drugs are under development for the treatment of atherothrombosis. In addition to injury, inflammation caused by infection or stroke can also induce leaky blood vessels. In this issue of the Journal of Clinical Investigation, researchers led by Wolfgang Bergmeier at the University of North Carolina at Chapel Hill identified the protein ITAM as a critical modulator of blood vessel integrity during inflammation. Using a mouse model, Bergmeier and colleagues demonstrated that platelets that lack ITAM could not prevent inflammation-induced hemorrhages. This study highlights potential complications of anti-platelet drugs that target ITAM for the treatment of atherothrombosis.

Platelet ITAM signaling is critical for vascular integrity in inflammation

Yacine Boulaftali
The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Phone: 9199627332; Fax: 919.966.7639; E-mail: boulafta@email.unc.edu

View this article at: http://www.jci.org/articles/view/65154?key=050725186512d9ae3bf7


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