Hearing loss associated with a lack of cell-cell junctions
Sound waves are filtered through the outer ear to the cochlea, where hair cells convert the sound into the electric impulses that travel through the auditory nerve to the brain. Cochlear hair cells are extremely sensitive to stress and loss of these cells is a common cause of deafness. The formation of tight junctions between cells allows epithelia to form barriers to prevent fluid and other molecules from moving freely throughout the body. In this issue of the Journal of Clinical Investigation, Saima Riazuddin and colleagues at the Cincinnati Children's Hospital, identify a role for the tricellular tight junction protein, TRIC, in cochlear hair cell preservation. A mutation in the TRIC gene had been previously linked to hearing loss in humans; however, the mechanism of hearing loss was unknown. Riazuddin and colleagues introduced the same mutation in mice and found that these mice lost cochlear hair cells. Their data suggests that mutated TRIC creates a toxic environment in the cochlea due to fewer tight cell junctions. In the accompanying commentary, Karen Avraham and colleagues from Tel Aviv University point out that this new mouse model will provide insights into human TRIC-associated deafness and provide insights into how tight junction function can be restored.
TITLE: Tricellulin deficiency affects tight junction architecture and cochlear hair cells
AUTHOR CONTACT:
Saima Riazuddin
Cincinnati Children Hospital Medical Center, Cincinnati, USA
Phone: 513-803-2888; E-mail: saima.riazuddin@cchmc.org
View this article at: http://www.jci.org/articles/view/69031?key=cce6cbae11011a371679
ACCOMPANYING COMMENTARY
TITLE: A "Tric" to tighten cell-cell junctions in the cochlea for hearing
AUTHOR CONTACT:
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/69651?key=acb06cec731ca8eca531
Cancerous cells from donor kidney linked to recipient skin cancer
Patients that receive kidney transplants have an increased risk of an invasive form of skin cancer. It is unclear if donor tissue contributes to cancer formation. In this issue of the Journal of Clinical Investigation, Philippe Ratajczak and colleagues at INSERM demonstrate that donor tissue can lead to caner formation in transplant recipients. They examined tumor cells and transplant tissues from a small sample of kidney transplant patients that had subsequently developed skin squamous cell carcinoma (SCC). In one patient they identified the presence of skin tumor cells that were the same genotype as the donated kidney and contained a mutation in a known cancer-causing gene. Furthermore, cells with this mutation were present in kidney biopsy samples taken at the time of transplant. As Cai-Bin Cui and David Gerber from the University of North Carolina discuss in their accompanying commentary, this case study has important implications for cancer research and clinical care of transplant recipients.
TITLE: Human skin carcinoma arising from kidney transplant–derived tumor cells
AUTHOR CONTACT:
Philippe Ratajczak
View this article at: http://www.jci.org/articles/view/66721?key=6f8e69f0c56dc67b17ec
ACCOMPANYING COMMENTARY
TITLE:
Donor-associated malignancy in kidney transplant patients
AUTHOR CONTACT:
David Gerber
View this article at: http://www.jci.org/articles/view/70438?key=7a4b5b9cbc0b295d0073 A strategy for combating drug-resistant cancers
Many cancer therapies function by activating proteins like Caspase-3 (CASP3) that promote cell death. Several forms of cancer develop resistance to these drugs by down regulating CASP3 through an unknown mechanism. In the absence of CASP3, tumor cells produce another cell death promoting protein CASP7, but it is rendered inactive by the X-linked inhibitor of apoptosis protein (XIAP). In this issue of the Journal of Clinical Investigation, Po-Huang Liang and colleagues at Academia Sinica identify a compound (I-Lys) that disrupts the interaction between CASP7 and XIAP. Release of CASP7 from this complex in drug resistant cancer cells activated cell death and reduced malignancies. Furthermore, no adverse side effects were observed in non-tumor cells treated with the drug. In the accompanying commentary, Gregory Gores from the Mayo Clinic explains that these results are promising for combatting drug resistant cancers, but more work needs to be done to establish if I-Lys will be safe and beneficial for human use.
TITLE:
Targeting the XIAP/caspase-7 complex selectively kills caspase-3–deficient malignancies
AUTHOR CONTACT:
Po-Huang Liang
View this article at: http://www.jci.org/articles/view/67951?key=e86860a6dfda17980263 ACCOMPANYING COMMENTARY
TITLE:
Unshackling caspase-7 for cancer therapy
AUTHOR CONTACT:
Gregory J Gores
View this article at:
http://www.jci.org/articles/view/71440?key=31dca5188081bce3f0ca Protease inhibitor resistance involves multiple stages of the HIV-1 life cycle
HIV-1 protease inhibitors are very effective antiviral drugs. These drugs target HIV-1 proteases, which are required for viral replication. Despite the success of protease inhibitors for suppressing HIV-1, some patients do not respond to protease inhibitor therapy. For most patients, the lack of response is not due to mutation of the HIV-1 protease. In this issue of the Journal of Clinical Investigation, Robert Silcano and colleagues at Johns Hopkins University identify the effects of protease inhibitors on different stages of viral replication. The authors found that protease inhibitors do not prevent virus release from infected cells, but do prevent viral entry into new cells, and have an effect on the reverse transcription and post-transcription stages of the HIV-1 life cycle. Additionally, mutations in the viral envelope protein, which is involved in cell entry, were associated with resistance to protease inhibitor treatment. In the accompanying Attending Physician article, John Bartlett of Duke University discusses how these findings may dictate testing for HIV-1 envelope mutations in patients that have not responded to treatment with protease inhibitors.
TITLE:
Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance
AUTHOR CONTACT:
Robert F. Siliciano
View this article at:
http://www.jci.org/articles/view/67399?key=14be0829c8543f1ce4c5
ACCOMPANYING THE ATTENDING PHYSICIAN
TITLE:
Lack of protease inhibitor resistance following treatment failure — too good to be true?
AUTHOR CONTACT:
John Bartlett
View this article at: http://www.jci.org/articles/view/71784?key=3151ff5b0df4f297747f Origin of a hereditary east Texas bleeding disorder
A severe hereditary bleeding disorder was described in a large family from east Texas in 2001. The affected family members routinely had bruising, nosebleeds, massive blood loss following injury or surgery, and often required blood transfusions. Routine tests for functional components of the blood coagulation pathway did not reveal any obvious defects. Genomic sequencing revealed a mutation in the gene encoding coagulation factor 5 (FV), but it was not considered to contribute to disease, since clotting assays were normal. In this issue of the Journal of Clinical Investigation, Björn Dahlbäck and colleagues at Lund University reveal that this mutation results in a truncated form of FV. This truncated FV was present in plasma from all affected family members. The authors demonstrate that truncated FV forms a complex with tissue factor pathway inhibitor-α (TFPI) that inhibits coagulation pathways. In the accompanying commentary, George Brooze and Thomas Girard at Washington University suggest that treatment of family members with the Texas bleeding disorder with TFPI inhibitors may relieve symptoms of the disorder.
TITLE:
Coagulation factor VA2440G causes east Texas bleeding disorder via TFPIα
AUTHOR CONTACT:
Björn Dahlbäck
View this article at: http://www.jci.org/articles/view/69091?key=c76607c9a8c9cd28d5e8
ACCOMPANYING COMMENTARY
TITLE:
Factor V, tissue factor pathway inhibitor, and east Texas bleeding disorder
AUTHOR CONTACT:
George Broze
View this article at: http://www.jci.org/articles/view/71220?key=808d79bb946446109884 ALSO IN THIS ISSUE
TITLE:
Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions
AUTHOR CONTACT:
Sudhansu Dey
View this article at: http://www.jci.org/articles/view/70098?key=480f4c87ec2244d8a1fe TITLE:
Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis
AUTHOR CONTACT:
Benjamin D. Humphreys
View this article at: http://www.jci.org/articles/view/45361?key=f89f34673b86f8b52fb6
TITLE:
T cell–independent B cell activation induces immunosuppressive sialylated IgG antibodies
AUTHOR CONTACT:
Marc Ehlers
View this article at: http://www.jci.org/articles/view/65938?key=9f5304eb427fc4908b68
TITLE:
A feed-forward spinal cord glycinergic neural circuit gates mechanical allodynia
AUTHOR CONTACT:
Yan Lu
View this article at: http://www.jci.org/articles/view/70026?key=69c47a86c65d4e432860
TITLE:
Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
AUTHOR CONTACT:
James Mulloy
View this article at:
http://www.jci.org/articles/view/68557?key=79befc7fdd53a23fe0cc
Journal of Clinical Investigation
Inserm, Paris, , FRA
b
UNC School of Medicine, Chapel Hill, NC, USA
Phone: 919-966-8008; Fax: 919-966-6308; E-mail: david_gerber@med.unc.edu
Academia Sinica, Taiwan R.O.C., Taipei, , TWN
Phone: +886-2-3366-4069; E-mail: phliang@gate.sinica.edu.tw
Mayo Clinic, Rochester, MN, USA
Phone: 507-284-0686; Fax: 507-284-0762; E-mail: gores.gregory@mayo.edu
Johns Hopkins Univ Schl Of Medicine, Baltimore, MD, USA
Phone: 410/955-2958; Fax: 410-955-0964; E-mail: rsiliciano@jhmi.edu
Duke University School of Medicine, Durham, NC, USA
Phone: (919) 681-8043; E-mail: jab5@duke.edu
Lund University, Malmö, , SWE
Phone: +46 70 6363269; E-mail: bjorn.dahlback@med.lu.se
Washington University Medical Centre, St Louis, MO, USA
Phone: 13143628811; E-mail: gbroze@dom.wustl.edu
Cincinnati Children's Hospital Medical Center, Cincinati, OH, USA
Phone: 513-803-1158; E-mail:sk.dey@cchmc.org
Brigham And Women's Hospital, Boston, MA, USA
Phone: 617-525-5971; Fax: 617-525-5965; E-mail:bhumphreys@partners.org
Institute for Systemic Inflammation Research, Laboratory of Tolerance and A, Luebeck, UNK, DEU
Phone: +49-451-500-3462; Fax: +49-451-500-3069; E-mail: Marc.Ehlers@uk-sh.de
Xijing Hospital, The Fourth Military Medical University, Xian, , CHN
Phone: 86-29-84771249; E-mail: yanlu20008@yahoo.com
Cincinnati Children's Hospital, Cincinnati, OH, USA
Phone: 513-636-1844;E-mail: james.mulloy@cchmc.org
Journal