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JCI early table of contents for March 26, 2012
Date:3/20/2012

EDITOR'S PICK
New evidence links Alzheimer's disease and diabetes

An emerging body of research suggests that Alzheimer's disease may be linked to insulin resistance, constituting a third type of diabetes. This model is based on several observations including an increased risk of developing Alzheimer's disease for diabetic patients, and reduced insulin levels in the brain tissue of Alzheimer's disease patients. Though intriguing, the existing evidence does not reveal if defective insulin signaling is causative of Alzheimer's or how insulin resistance impacts cognitive function. Two back-to-back research articles in the Journal of Clinical Investigation led by Konrad Talbot, Steve Arnold and colleagues at the University of Pennsylvania and by Fernanda De Felice, Sergio Ferreiria and colleagues at the University of Rio de Janeiro - address the connection between insulin resistance and Alzheimer's disease. The University of Pennsylvania team examined insulin signaling in human brain tissue postmortem, and concluded that the activation state of many insulin signaling molecules were highly related to memory and cognitive function. They further suggest that insulin resistance is a common and early feature of Alzheimer's disease. The De Felice group also observed impaired insulin signaling in Alzheimer's brain tissue in rodent and non-human primate model systems as well as from tissue from human patients. They went on to show in a mouse model system of Alzheimer's disease that treatment with a new anti-diabetic drug normalized insulin signaling and remarkably improved cognitive function. Cumulatively, these two new studies strongly support a connection between insulin resistance and Alzheimer's disease and provide hope for new therapeutics in Alzheimer's disease treatment.

TITLE:

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's diseaseassociated Aβ oligomers

AUTHOR CONTACT:

Fernanda De Felice

Federal University of Rio de Janeiro, Rio de Janeiro, , BRA

Phone: +552125626790 or +552125626515; E-mail: felice@bioqmed.ufrj.br

View this article at: http://www.jci.org/articles/view/57256?key=de0efc001f2106f5edc4

ACCOMPANYING ARTICLE

TITLE:

Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline

AUTHOR CONTACT:

Konrad Talbot

University of Pennsylvania, Philadelphia, PA, USA

Phone: (215) 589-2483; E-mail: talbotk2@mail.med.upenn.edu

View this article at: http://www.jci.org/articles/view/59903?key=f9a078d273792af09d60


ONCOLOGY
Promise of new treatment options for chemotherapy-resistant breast cancers

p53 is lost or functionally impaired in many human cancers, and its absence is often associated with a poor response to conventional chemotherapy. Thus, much effort is currently devoted to developing novel treatments for p53-deficient malignancies. One approach is to target pathways that are selectively required for the survival of p53-deficient cancer cells, in effect exploiting a synthetic lethal interaction. Previous studies have demonstrated that inhibition of the ATR/CHK1 pathway in p53-deficient cells can induce such a synthetic lethal outcome. In this issue of the JCI, Ma et al. take these findings a step closer to the clinic by demonstrating that highly specific inhibitors of CHK1 synergize with chemotherapy to stem progression of p53-deficient triple-negative breast cancers in a xenotransplant model of this disease. Together with other recent studies, this report highlights the promise of ATR and CHK1 inhibitors in targeted cancer treatment.

COMMENTARY TITLE:

CHK'ing p53-deficient breast cancers

COMMENTARY AUTHOR CONTACT:

Eric Brown

Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA, USA

Phone: (215) 746-2805; Fax: (215) 573-2486; E-mail: brownej@mail.med.upenn.edu

View this article at: http://www.jci.org/articles/view/63205?key=f40f5596cbb82d7ecffa

RESEARCH ARTICLE TITLE:

Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models

CORRESPONDING AUTHOR CONTACT:

Helen Piwnica-Worms

Washington University School of Medicine St. Louis, St Louis, MO, USA

Phone: 314 362-6812; E-mail: hpiwnica@wustl.edu

View this article at: http://www.jci.org/articles/view/58765?key=5f216a8dcd8a0d88872f


NEUROLOGICAL DISEASE
Parkinson Disease: Don't Mess with Calcium

The hallmark of the movement disorder Parkinson disease (PD) is progressive degeneration of dopaminergic neurons. Mitochondrial dysfunction, impaired ubiquitin-mediated proteolysis of α-synuclein, and endoplasmic reticulum (ER) stress are each implicated in the complex and poorly understood sequence of events leading to dopaminergic neuron demise. In this issue of the JCI, Selvaraj et al. report that in a mouse neurotoxin-based model of PD, reduced Ca2+ influx through transient receptor potential C1 (TRPC1) channels in the plasma membrane of dopaminergic neurons triggers a cell deathinducing ER stress response. These new findings suggest that TRPC1 channels normally function in Ca2+-mediated signaling pathways that couple adaptive/neurotrophic responses to metabolic and oxidative stress, and suggest that disruption of these pathways may contribute to PD.

COMMENTARY TITLE:

Parkinson Disease: Don't Mess with Calcium

COMMENTARY AUTHOR CONTACT:

Mark Mattson

National Institute on Aging, Baltimore, MD, USA

Phone: 410 558 8463; E-mail: mattsonm@grc.nia.nih.gov

View this article at: http://www.jci.org/articles/view/62835?key=24384dcabf70f47d05f3

RESEARCH ARTICLE TITLE

Neurotoxin-induced ER stress in mouse dopaminergic neurons involves downregulation of TRPC1 and inhibition of AKT/mTOR signaling

CORRESPONDING AUTHOR CONTACT:

Brij Singh

School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, USA

Phone: 701-777-0834; Fax: 701-777-2382; E-mail: brij.singh@med.und.edu

View this article at: http://www.jci.org/articles/view/61332?key=256b328425acdd810dd2


HEMATOLOGY
Unintended consequences: how transfusions of aged blood impact recipients

Blood transfusion represents the first and most prescribed cell-based therapy, however, clinical safety and efficacy trials are lacking. Clinical cohort studies have suggested that massive transfusion and/or transfusion of aged stored blood may contribute to multi-organ dysfunction in susceptible patients. In this issue of the JCI, Baek and colleagues report that aged stored blood hemolyzes after massive transfusion in a guinea pig model. Hemolysis led to vascular and kidney injury that was mediated by cell-free plasma hemoglobin and prevented by co-infusion of the specific hemoglobin scavenger protein, haptoglobin. These studies support an expanding body of research indicating that intravascular hemolysis is a pathological mechanism in several human diseases, including multi-organ dysfunction following either massive red blood cell transfusion or hemoglobin-based blood substitute therapy, the hemoglobinopathies, malaria, and other acquired and genetic hemolytic conditions.

COMMENTARY TITLE:

Hemolysis and cell-free hemoglobin drives an intrinsic mechanism for human disease

COMMENTARY AUTHOR CONTACT:

Mark Gladwin

University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Phone: 412-692-2117; E-mail: gladwinmt@upmc.edu

View this article at: http://www.jci.org/articles/view/62972?key=5505af9c496ee6d7eaae

RESEARCH ARTICLE TITLE:

Hemoglobin-driven pathophysiology is an in vivo consequence of the red blood cell storage lesion that can be attenuated in guinea pigs by haptoglobin therapy

CORRESPONDING AUTHOR CONTACT:

Paul Buehler

Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA

Phone: 301-451-3953; E-mail: paul.buehler@fda.hhs.gov

View this article at: http://www.jci.org/articles/view/59770?key=19eae2af01a0c12f3198


CELL BIOLOGY
Uncovering cilia protein interactions

Cilia are unique cellular organelles found in nearly all cell types. In recent years, the importance of these organelles has been highlighted by the discovery that mutations in genes encoding proteins related to cilia biogenesis and function cause a class of complex syndromes termed ciliopathies. Emerging evidence suggests interactions between the various ciliopathy-associated proteins, but the precise mechanisms by which these interactions generate functional networks have remained elusive. In this issue of the JCI, Rachel and colleagues have now clearly linked two ciliopathy-associated proteins (CEP290 and MKKS). Surprisingly, the effects of a hypomorphic disease-causing Cep290 allele were rescued by loss of MKKS function, suggesting that it might be possible to treat some ciliopathies by fine tuning interactions within the expanding ciliary network.

COMMENTARY TITLE:

A so cilia network : cilia proteins start social networking

COMMENTARY AUTHOR CONTACT:

Frederic SAUDOU

Institut Curie, ORSAY, , FRA

Phone: +33169863024; E-mail: frederic.saudou@curie.fr

View this article at: http://www.jci.org/articles/view/62971?key=13cefd837237be0f9d06

RESEARCH ARTICLE TITLE

Combining Cep290 and Mkks ciliopathy alleles in mice rescues sensory defects and restores ciliogenesis

AUTHOR CONTACT:

Anand Swaroop

National Eye Institute, Bethesda, MD, USA

Phone: (301) 435-5754; E-mail: swaroopa@nei.nih.gov

View this article at: http://www.jci.org/articles/view/60981?key=b4a507d9065027e4f078


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Contact: Sarah Jackson
press_releases@the-jci.org
Journal of Clinical Investigation
Source:Eurekalert

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