JCI early table of contents for Dec. 20, 2013

December 20th, 2013
Fungal surface protein promotes host cell

Opportunistic infection of individuals on immunosuppressive therapy are a major problem for patient outcome, despite current prophylactic strategies. While the ability to prevent infection with well-characterized pathogens has improved, infection by less-known microbes have been on the rise. One such example is the increasing occurrence of mucormycosis, a life-threatening infection caused by Mucorales fungi. A defining characteristic of Mucorales is the ability to invade host cells via interaction with glucose-regulated protein 78 (GRP78) on the surface of endothelial cell. In this issue of the Journal of Clinical Investigation, Ashraf Ibrahim and colleagues at the University of California, Los Angeles identified spore coat protein homologues (CotH) on the surface of Mucorales fungi as the ligand for GRP78 and that gene encoding these proteins are unique to Mucorales. Furthermore, loss of CotH in the Mucorales fungi Rhizopus oryzae decreased invasion and virulence. In a companion commentary, J. Andrew Alspaugh of Duke University discusses the potential of targeting CotH proteins for prevention and treatment of mucormycosis.

TITLE: CotH3 mediates fungal invasion of host cells during mucormycosis

AUTHOR CONTACT: Ashraf Ibrahim

Geffen School of Medicine at UCLA, Torrance, CA, USA

Phone: 310 222-6424; Fax: 310782-2016; E-mail: ibrahim@labiomed.org

View this article at: http://www.jci.org/articles/view/71349?key=631ba0139a19415df26f

ACCOMPANYING COMMENTARY

TITLE: Hostile takeover: fungal protein promotes host cell invasion

AUTHOR CONTACT: J. Andrew Alspaugh

Duke University Medical Center, Durham, NC, USA

Phone: (919) 684-0045; Fax: (919) 684-8902; E-mail: andrew.alspaugh@duke.edu

View this article at: http://www.jci.org/articles/view/73585?key=a7047734ecfbac9ec645


Angiogenic factor secretion by melanocytes associated with pigmentation level

The decreased vision loss that accompanies age-related macular degeneration (AMD) is associated with abnormal blood vessel growth in the eye. Frequencies of AMD development are different among racial backgrounds, with occurrence of AMD highest among individuals of mixed European decent. Furthermore, other diseases associated with dysfunctional neovascularization occur at different frequencies depending on racial background, suggesting a connection between pigmentation and susceptibility to angiogenic disease. In this issue of the Journal of Clinical Investigation, Irit Adini and colleagues at the Harvard Medical School determined that melanocytes from light-skinned humans and albino mice secrete high levels of fibromodulin and that fibromodulin promotes angiogenesis. In a companion commentary, Christopher Kontos of Duke University discusses the potential for fibromodulin to be both a useful biomarker and a therapeutic target for diseases associated with increased vascularization.

TITLE: Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment

AUTHOR CONTACT: Irit Adini

Boston Children's Hospital, Harvard Medical School, Boston, , USA

Phone: 6179192256; E-mail: irit.adini@childrens.harvard.edu

View this article at: http://www.jci.org/articles/view/69404?key=7a4fd104c01f1ae48717

ACCOMPANYING COMMENTARY

TITLE: More than skin deep: connecting melanocyte pigmentation and angiogenic diseases

AUTHOR CONTACT: Christopher D. Kontos

Duke University Medical Center, Durham, NC, USA

Phone: 919-684-2119; Fax: 919-684-8591; E-mail: cdkontos@duke.edu

View this article at: http://www.jci.org/articles/view/73559?key=7e215c2de07cacbcdc96


Nonsense suppression drug restores function in a mouse model of aniridia

Congenital aniridia is a progressive disease that is associated with improper development of eye structures as well as abnormalities in the brain and pancreas. A variety of nonsense mutations in the PAX6 gene are linked with aniridia; however, despite understanding the genetic basis of the disease, few treatment and prevention strategies are available. In this issue of the Journal of Clinical Investigation, Cheryl Gregory-Evans and colleagues at the University of British Columbia evaluated a small molecule nonsense suppression strategy for relief of aniridia-associated defects in a mouse model of the disease. The authors developed a formulation of the nonsense suppression drug ataluren that could be given topically to postnatal aniridia mice. Administration of their ataluren-based formulation inhibited disease progression, reversed eye deformations, and restored eye function in aniridia mice. In an accompanying commentary, José-Alain Sahel and Katia Marazova of the Institut de la Vision suggest that ataluren administration should be further explored as a therapeutic option for treatment of congenital eye defects associated with nonsense mutations

TITLE: Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

AUTHOR CONTACT: Cheryl Gregory-Evans

University of British Columbia, Vancouver, BC, CAN

Phone: 604-875-5529; Fax: 604-875-4663; E-mail: cge30@mail.ubc.ca

View this article at: http://www.jci.org/articles/view/70462?key=f3d20cd7e7397c048ea0

ACCOMPANYING COMMENTARY TITLE:

Toward postnatal reversal of ocular congenital malformations

AUTHOR CONTACT: Jose-Alain Sahel

The French National Center, Paris Cedex 12, UNK, FRA

Phone: +33608643841 (cell); Fax: +33140021499; E-mail: j-sahel@quinze-vingts.fr

View this article at: http://www.jci.org/articles/view/73560?key=e350629cb164faec9c64


Dysfunctional TGF-β signaling contributes to Loeys-Dietz syndrome-associated aortic aneurysm

Patients with the connective tissue disorder Loeys-Dietz syndrome (LDS) are at high risk for aortic aneurysm. LDS results in the presence of missense mutations within either of the genes encoding receptors for TGF-β. LDS-associated mutations are predicted to reduce TGF-β signaling; however, aortic tissue samples from LDS patients indicate that TGF-β signaling may be enhanced. In this issue of the Journal of Clinical Investigation, Harry Dietz and colleagues at Johns Hopkins School of Medicine developed a mouse model of LDS, in which transgenic animals expressing Tgfbr1 or Tgfbr2 with LDS-associated mutations recapitulated human phenotypes. Using this model, the authors determined that even though the mutated TGF-β receptors were functionally defective, there was evidence of increased TGF-β signaling as indicated by elevated Smad2 phosphorylation. Furthermore, development of aortic aneurysms in these mice was ameliorated by treatment with an Angiotensin II type 1 (AT1) receptor antagonist. In a companion commentary, Alan Daughtery and colleagues at the University of Kentucky discuss the therapeutic implications of this study on the use of AT1 receptor agonists to treat LDS-associated aneurism.

TITLE: Angiotensin II–dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis

AUTHOR CONTACT: Elena Gallo MacFarlane

Johns Hopkins University School of Medicine, Baltimore, MD, USA

Phone: 4106148876; Fax: 4106142256; E-mail: galloem@gmail.com

View this article athttp://www.jci.org/articles/view/69666?key=f036d148e02247c5f5d6

ACCOMPANYING COMMENTARY

TITLE: Aortic aneurysms in Loeys-Dietz syndrome—a tale of two pathways?

AUTHOR CONTACT: Alan Daugherty

University of Kentucky, Lexington, KY, USA

Phone: 8593233512; E-mail: alan.daugherty@uky.edu

View this article at: http://www.jci.org/articles/view/73906?key=fe840c2f4387dc7d0d58


Evaluation of mangafodipir treatment for oxaliplatin-associated neuropathy

An unfortunate side effect of the platinum-chemotherapy drug oxaliplatin is the development of neurotoxicity, which can adversely affect a patient's quality of life; therefore, the benefit of oxaliplatin-based therapy must be balanced with prevention of neuropathies. Currently, there are no therapeutic interventions available to relieve oxaliplatin-associated neurological symptoms, which are thought to be a result of reactive oxygen species-associated damage. In this issue of the Journal of Clinical Investigation, Frédéric Batteux and colleagues at the Laboratoire d'Immunologie evaluated use of the MRI contrast agent mangafodipir, which has antioxidant properties, for relief of oxaliplatin-associated neuropathies. In a mouse model of oxaliplatin-induced neurologic damage, administration of mangafodipir reduced neurotoxicity and the presence of oxidized protein products. Furthermore, in a cohort of 22 patients with oxaliplatin-associated neuropathy, mangafodipir treatment appeared to decrease neurological symptoms. In their accompanying commentary, Charles Loprinzi and colleagues at the May Clinic caution that even though these results seem promising, larger clinical trails have not been able to confirm similar results from other agents that have shown promise for treating chemotherapy-induced neuropathy in animal models and small phase II small.

TITLE: Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

AUTHOR CONTACT: Frederic Batteux

Faculté de médecine, Université Paris-Descartes, Sorbonne Paris-Cité, Paris, , FRA

Phone: 00 33 1 58 41 20 07; Fax: 00 33 1 58 41 20 08; E-mail: frederic.batteux@cch.aphp.fr

View this article at: http://www.jci.org/articles/view/68730?key=6064e89c86534c430e19

ACCOMPANYING COMMENTARY

TITLE: The search for treatments to reduce chemotherapy-induced peripheral neuropathy

AUTHOR CONTACT: Charles Loprinzi

Mayo Clinic, Rochester, , USA

Phone: 507-284-4849; Fax: 507-284-1803; E-mail: cloprinzi@mayo.edu

View this article at: http://www.jci.org/articles/view/73908?key=e458bafc63766b2f6665


ALSO IN THIS ISSUE

TITLE: Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice

AUTHOR CONTACT: Brett Monia

Isis Pharmaceuticals, Carlsbad, CA, USA

Phone: 7606032350; E-mail: BMonia@isisph.com

View this article at: http://www.jci.org/articles/view/67968?key=cceab5ab5e0dfdb1e2bd

TITLE: Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

AUTHOR CONTACT: Xiao-Jiang Li

Emory University, Atlanta, GA, USA

Phone: 404-727-3290; E-mail: mailto:xiaoli@genetics.emory.edu

View this article at: http://www.jci.org/articles/view/69206?key=259955ca604c34094c8f

TITLE: Heparan sulfate deficiency disrupts developmental angiogenesis and causes congenital diaphragmatic hernia

AUTHOR CONTACT: Lianchun Wang

University of Georgia, Athens, GA, USA

Phone: 706-542-6445; E-mail: lwang@ccrc.uga.edu

View this article at: http://www.jci.org/articles/view/71090?key=9109e3c2edefb2191a54

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