EDITOR'S PICK: How to tell if a hepatitis C virus–infected patient will respond to therapy
Hepatitis C virus (HCV) causes hepatitis and increased risk of developing liver cancer. Current treatments are expensive, have severe side effects, and fail in about half the patients treated. However, the Virahep-C Study Group, at Saint Louis University, has now developed an approach that predicted the outcome of therapy, raising the possibility of a test to predict treatment response and reduce treatment failures, something that could save a great deal of pain and expense for HCV-infected patients.
The research team, led by John Tavis and Rajeev Aurora, used a method known as covariation analysis to analyze variation in the genome-wide amino-acid sequence of viruses isolated from HCV-infected patients before they underwent treatment. Using this approach, networks of covariation were found to associate with specific responses of the patients to treatment. The authors suggest that the data has implications for the development of a test to predict how an individual infected with HCV will respond to treatment and might help identify targets for new antiviral drugs. In an accompanying commentary, Thomas Oh and Charles Rice, at Rockefeller University, New York, discuss further the therapeutic implications of these data.
TITLE: Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans
AUTHOR CONTACT:
Rajeev Aurora
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 977-8891; Fax: (314) 977-8717; E-mail: aurorar@slu.edu.
John E. Tavis
Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 977-8893; Fax: (314) 977-8717; E-mail: tavisje@slu.edu
MEDIA CONTACT:
Nancy Solomon
Communications Director
Saint Louis University Medical Center, St. Louis, Missouri, USA.
Phone: (314) 977-8017 (office), (314) 662-6525 (cell); E-mail: solomonn@slu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37085
ACCOMPANYING COMMENTARY
TITLE: Predicting response to hepatitis C therapy
AUTHOR CONTACT:
Charles M. Rice
The Rockefeller University, New York, New York, USA.
Phone: (212) 327-7046; Fax: (212) 327-7048; E-mail: ricec@rockefeller.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38069
EDITOR'S PICK: Hormones increase frequency of inherited form of migraine in women
Familial hemiplegic migraine (FHM) is an inherited form of severe migraine that is accompanied by visual disturbances known as aura. As with other types of migraine, it affects women more frequently than men. Most cases of FHM are caused by mutations in the CACNA1A gene, but whether these lead to spreading depression, the event in the brain that suppresses nerve cell activity and that has been linked to nongenetic forms of migraine with aura, has not been determined. However, Cenk Ayata and colleagues, at Massachusetts General Hospital, have now generated data in mice that address this issue as well as provide insight into the reasons why FHM affects women more frequently than men.
In the study, mice expressing either one of two different CACNA1A mutations that lead to FHM in humans were found to have an increased susceptibility to spreading depression. Interestingly, the mutation linked to more severe FHM caused a greater increase in susceptibility to spreading depression than the mutation linked to a milder form of FHM. As with humans, female mice were more susceptible to spreading depression than male mice. This difference was reversed if the female mice had their ovaries removed, and then partially restored by replacement of the hormone estrogen. The authors therefore conclude that both genetic and hormonal factors modulate an individual's susceptibility to migraines with aura.
In an accompanying commentary, Takahiro Takano and Maiken Nedergaard, at the University of Rochester, Rochester, explain the importance of these data, highlighting the implications for the serious complications that can accompany FHM.
TITLE: Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1
AUTHOR CONTACT:
Cenk Ayata
Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA.
Phone: (617) 726-8021; Fax: (617) 726-2547; E-mail: cayata@partners.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36059
ACCOMPANYING COMMENTARY
TITLE: Deciphering migraine
AUTHOR CONTACT:
Maiken Nedergaard
University of Rochester, Rochester, New York, USA.
Phone: (585) 273-2868; Fax: (585) 275-0550; E-mail: nedergaard@urmc.rochester.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38051
EDITOR'S PICK: Immune cells contribute to the development of Parkinson disease
Parkinson disease is a neurodegenerative disorder that impairs movement, balance, speech, and other functions. It is characterized by the loss of nerves in the brain that produce a substance known as dopamine. Although the loss of dopamine-containing nerves is accompanied by accumulation of immune cells known as T cells, these accumulating T cells were not thought to have a role in the development of disease. However, Stéphane Hunot, Etienne C. Hirsch, and colleagues, at INSERM UMR 679, France, have now shown that CD4+ T cells make a significant contribution to the development of disease in a mouse model of Parkinson disease.
In the study, a substantial number of CD4+ T cells and CD8+ T cells were observed to have accumulated in postmortem brain tissue from individuals with Parkinson disease and mice with a Parkinson-like disease. Importantly, mice lacking all T cells developed substantially less severe disease in the mouse model of Parkinson disease. Further analysis indicated that protection was specifically associated with a lack of CD4+ T cells expressing the protein FasL. The authors therefore suggest that targeting the immune system might provide a new therapeutic approach to treating Parkinson disease. However, in an accompanying commentary, Stanley Appel, at Methodist Neurological Institute, Houston, warns that although these data provide rationale for immune-based strategies, there are a large number of questions that need to be answered before such approaches can be considered in the clinic.
TITLE: Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease
AUTHOR CONTACT:
Stéphane Hunot
INSERM UMR 679, Hôpital de la Salpêtrière, Paris, France.
Phone: 33-14-21-62-172; Fax: 33-14-42-43-658; E-mail: stephane.hunot@upmc.fr.
Etienne C. Hirsch
INSERM UMR 679, Hôpital de la Salpêtrière, Paris, France.
Phone: 33-14-21-62-202; Fax: 33-14-42-43-658; E-mail: etienne.hirsch@upmc.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36470
ACCOMPANYING COMMENTARY
TITLE: CD4+ T cells mediate cytotoxicity in neurodegenerative diseases
AUTHOR CONTACT:
Stanley H. Appel
Methodist Neurological Institute, Houston, Texas, USA.
Phone: (713) 441-3765; Fax: (713) 793-7271; E-mail: sappel@tmhs.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38096
NEUROBIOLOGY: Nerve cell defect contributes to multiple sclerosis
Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord that progresses overtime, with increasing disability. It occurs when the immune system inappropriately attacks both the sheath that insulates and protects the nerve cells and the cells that make this sheath, oligodendrocytes. One question regarding the disease is why precursors of oligodendrocytes are still present in diseased areas of the brain of individuals with MS but do not develop into oligodendrocytes and produce the nerve cell sheath. However, Jin Nakahara and colleagues, at Keio University School of Medicine, Japan, have now provided insight into this issue through analysis of brain tissue from MS patients and rodent cell lines in vitro.
In the study, damaged nerve cells in diseased areas of the brain of individuals with MS were found to express high levels of the protein Contactin, which interacted with the protein Notch1 on precursors of oligodendrocytes. In normal tissues, this triggers a signaling pathway that induces the precursors to develop into oligodendrocytes. However, in the diseased areas of the brain of individuals with MS these signaling events did not occur normally. Specifically, a protein known as TIP30 was abnormally overexpressed, preventing a key signaling component (the Notch1 intracellular domain) from performing its function. The authors therefore conclude that this signaling defect contributes to the development of MS.
In an accompanying commentary, Celia Brosnan and Gareth R. John highlight the key aspects of the study and discuss the implications for our understanding of MS.
TITLE: Abnormal expression of TIP30 and arrested nucleocytoplasmic transport within oligodendrocyte precursor cells in multiple sclerosis
AUTHOR CONTACT:
Jin Nakahara
Keio University School of Medicine, Tokyo, Japan.
Phone: 81-3-3353-1211 ext. 63573; Fax: 81-3-5360-1524; E-mail: nakahara@sc.itc.keio.ac.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35440
ACCOMPANYING COMMENTARY
TITLE: Revisiting Notch in remyelination of multiple sclerosis lesions
AUTHOR CONTACT:
Celia F. Brosnan
Albert Einstein College of Medicine, New York, New York, USA.
Phone: (718) 430-2140; Fax: (718) 430-8541; E-mail: brosnan@aecom.yu.edu.
Gareth R. John
Mount Sinai School of Medicine, New York, New York, USA.
Phone: (212) 241-8142; Fax: (212) 348-1310; E-mail: gareth.john@mssm.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37786
PULMONARY: Alpha-3 integrin, a protein important in idiopathic pulmonary fibrosis
Harold Chapman and colleagues, at the University of California, San Francisco, have provided new insight into the molecular events that occur in the common chronic lung disease idiopathic pulmonary fibrosis (IPF), which has no known cause.
Cells known as fibroblasts have a central role in the disease process, which is thought to be a consequence of aberrant wound healing resulting in progressive scarification. One population of fibroblasts involved in the disease process is thought to be generated by a process known as EMT. In the study, mice lacking the protein alpha-3 integrin in their lung epithelial cells did not develop disease in a model of fibrosis. Further analysis indicated that alpha-3 integrin was required for the formation of the pY654–beta-catenin/pSmad2 signaling complex and the initiation of EMT. Consistent with this mouse data, analysis of lung tissue from patients with IPF revealed the presence of pY654–beta-catenin/pSmad2 signaling complexes. The authors therefore suggest that targeting this pathway may offer therapeutic potential. Zea Borok, at the University of Southern California, Los Angeles, echoes this idea in an accompanying commentary, although she cautions that more work is needed to confirm the utility of such approaches.
TITLE: Epithelial cell alpha-3-beta-1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis
AUTHOR CONTACT:
Harold A. Chapman
University of California, San Francisco, San Francisco, California, USA.
Phone: (415) 514-0896; Fax: (415) 502-4995; E-mail: hal.chapman@ucsf.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36940
ACCOMPANYING COMMENTARY
TITLE: Role for alpha-3 integrin in EMT and pulmonary fibrosis
AUTHOR CONTACT:
Zea Borok
University of Southern California, Los Angeles, California, USA.
Phone: (323) 226-7923; Fax: (323) 442-2611; E-mail: zborok@usc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=38084
Journal
Journal of Clinical Investigation