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JCI early table of contents for July 16, 2012

2012-07-17
(Press-News.org) ONCOLOGY A new target in acute myeloid leukemia | Back to top Acute myeloid leukemia, a common leukemia in adults, is characterized by aberrant proliferation of cancerous bone marrow cells. Activating mutations in a protein receptor known as FLT3 receptor are among the most prevalent mutations observed in acute myeloid leukemias. FLT3 mutants are thought to activate several signaling pathways that contribute to cancer development. Dr. Daniel Tenen and colleagues from Harvard University in Boston discovered a new pathway activated by FLT3 mutation. Their results show that cyclin dependent kinase 1 (CDK1), a critical regulator of cell division is activated in FLT3 mutated leukemias, leading to the activation of downstream gene transcription. Most importantly, they demonstrate that inhibiting CDK1 activity promotes differentiation of cells from patient-derived peripheral blood samples. As clinical trials with CDK1 inhibitors are ongoing, their data strongly suggest that therapies targeting the CDK1 pathway may be efficacious for acute myeloid leukemias with FLT3 mutation, especially in patients resistant to FLT3 inhibitor therapies.

TITLE:

Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα

AUTHOR CONTACT:

Daniel Tenen

Beth Israel Deaconess Medical Center, Boston, MA, USA

Phone: 617-735-2235; Fax: 617-735-2222; E-mail: dtenen@bidmc.harvard.edu

View this article at: http://www.jci.org/articles/view/43354?key=65aa2f71faac98dd69ed

ONCOLOGY A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers | Back to top Cancer is principally considered a genetic disease, and numerous mutations are thought essential to drive its growth. However, the existence of genomically stable cancers raises the possibility that changes in few genes that regulate chromatin structure and gene expression are capable of driving cancer formation. Dr. Charles Roberts and colleauges at the Dana-Farber Cancer Institute in Boston sequenced the expressed genes of rhabdoid tumors, highly aggressive cancers of early childhood. These tumors typically exhibit loss of a protein known as SMARCB1, a subunit of the chromatin remodeling complex that is important in controlling gene transcription. The Roberts group identified an extremely low rate of mutations, with loss of SMARCB1 as the only recurrent event. Their results demonstrate that high mutation rates are typically associated with cancer development is not required in all tumors, particularly for cancers driven by mutation of a chromatin remodeling complex. Thus, remarkably simple genetic changes can underlie cancer development.

TITLE:

A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers

AUTHOR CONTACT:

Charles Roberts

Dana-Farber Cancer Institute, Boston, MA, USA

Phone: 617-632-6497; Fax: 617-582-8096; E-mail: charles_roberts@dfci.harvard.edu

View this article at: http://www.jci.org/articles/view/64400?key=226866e0e308ef85783e

ONCOLOGY PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response | Back to top The DNA damage response (DDR) is a complex regulatory network that is critical for maintaining genome integrity. Posttranslational modifications are widely used to ensure strict spatiotemporal control of signal flow, but how the DDR responds to environmental cues, such as changes in ambient oxygen tension, remains poorly understood. Cam Patterson and colleagues at the University of North Carolina found that an essential component of the ATR/CHK1 signaling pathway, known as HCLK2, associated with and was hydroxylated by prolyl hydroxylase domain protein 3 (PHD3). HCLK2 hydroxylation was necessary for its interaction with ATR and the subsequent activation of the DDR. Inhibiting PHD3 prevented activation of the ATR/CHK1/p53 pathway and decreased cell death induced by DNA damage. Consistent with these observations, they found that mice lacking PHD3 were resistant to the effects of ionizing radiation and had decreased thymic apoptosis, a biomarker of genomic integrity.

TITLE:

PHD3-dependent hydroxylation of HCLK2 promotes the DNA damage response

AUTHOR CONTACT:

Cam Patterson

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Phone: 919-843-6477; Fax: 9198434585; E-mail: cpatters@med.unc.edu

View this article at: http://www.jci.org/articles/view/62374?key=2f34187c2dec70f6cd0e

OPHTHALMOLOGY Inflammation and age−related retinal degeneration | Back to top Disruption of cellular processes affected by multiple genes and accumulation of numerous insults throughout life dictate the progression of age−related disorders, but their complex etiology is poorly understood. Post−mitotic neurons, such as photoreceptor cells in the retina, and the adjacent retinal pigmented epithelium that together maintain vision, are especially susceptible to age−related retinal degeneration (ARD). The multi-genic etiology of ARD in humans is reflected by the relative paucity of effective compounds for its early prevention and treatment. To understand the background genetic differences that drive the phenotypic progression of ARD, Dr. Krzysztof Palczewski and colleagues at Case Western University in Cleveland, OH studied a strain of mice that develop more pronounced ARD than other inbred mouse models. Using state-of-the-art genetic analysis, they identified several genetic changes that cause an increased predisposition to ARD in mice. These insights may further improve our understanding of susceptible genetic loci that drive disease involved in age−associated disorders, including several human blinding diseases.

TITLE:

Inflammatory priming predisposes to age−related retinal degeneration in mice

AUTHOR CONTACT:

Krzysztof Palczewski

Case Western Reserve University, Cleveland, OH, USA

Phone: 216-368-4631; E-mail: kxp65@case.edu

View this article at: http://www.jci.org/articles/view/64427?key=226400a103c96592270a

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ELSE PRESS RELEASES FROM THIS DATE:

A new target in acute myeloid leukemia

2012-07-17
Acute myeloid leukemia, a common leukemia in adults, is characterized by aberrant proliferation of cancerous bone marrow cells. Activating mutations in a protein receptor known as FLT3 receptor are among the most prevalent mutations observed in acute myeloid leukemias. FLT3 mutants are thought to activate several signaling pathways that contribute to cancer development. Dr. Daniel Tenen and colleagues from Harvard University in Boston discovered a new pathway activated by FLT3 mutation. Their results show that cyclin dependent kinase 1 (CDK1), a critical regulator of cell ...

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2012-07-17
An innovative, high-tech "smart village" built in Malaysia provides a potential global template for addressing rural poverty in a sustainable environment, say international experts meeting in California's Silicon Valley. Rimbunan Kaseh, a model community built north-east of Kuala Lumpur, consists of 100 affordable homes, high-tech educational, training and recreational facilities, and a creative, closed-loop agricultural system designed to provide both food and supplementary income for villagers. Malaysian Dato' Tan Say Jim detailed the project Monday at a special meeting ...

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2012-07-17
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Study suggests racial disparities may exist in larynx preservation therapy for cancer

2012-07-17
CHICAGO – A study of laryngeal (voice box) cancers suggests that racial disparities may exist with black patients less likely to undergo larynx preservation than white patients, according to a report published by Archives of Otolaryngology – Head & Neck Surgery, a JAMA Network publication. Annually about 12,000 cases of laryngeal cancer are diagnosed in the United States, and the standard of care historically has been total laryngectomy (removal of the voice box) followed by radiation for locally advanced cancer. However, studies have now resulted in widespread acceptance ...

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New study reveals racial disparities in voice box-preserving cancer treatment

2012-07-17
(SACRAMENTO, Calif.) —A new epidemiological study led by UC Davis researchers reveals significant racial disparities in the use of non-surgical larynx-preservation therapy for locally advanced laryngeal cancer. A review of medical records between 1991 and 2008 from across the country reveals that over 80 percent of white patients received radiation treatment combined with chemotherapy that preserves the larynx, or voice box. Only 74.5 percent of African American patients received this same treatment, with the remainder undergoing surgery that removed the larynx altogether, ...

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[Press-News.org] JCI early table of contents for July 16, 2012