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Journal of Clinical Investigation

JCI table of contents: August 1, 2007

EDITOR'S PICK: Developing a more effective vaccine for tuberculosis

The microorganism that causes tuberculosis, M. Tuberculosis, infects more than a one third of the world's population. Although the currently used vaccine (M. bovis BCG) provides young children with protection from tuberculosis, it is not effective at preventing the type of tuberculosis that most adolescents and adults suffer from. Therefore, there is an intensive research effort designed to develop new, more efficient vaccines that protect all individuals from tuberculosis.

In a study that appears in the August issue of the Journal of Clinical Investigation, Steven Porcelli and colleagues from the Albert Einstein College of Medicine, New York, show that in mice, immune cells known as CD8+ T cells are more efficiently activated by strains of M. Tuberculosis that lack a protein known as SecA2 than strains of M. Tuberculosis that express SecA2. Efficient CD8+ T cell activation was associated with increased death (by a process known as apoptosis) of another immune cell type, the macrophage. Importantly, vaccination of mice and guinea pigs with M. Tuberculosis lacking SecA2 provided increased protection against infection with M. Tuberculosis than did vaccination with M. bovis BCG. These data led the authors to suggest that this approach, in combination with others currently under development, could be used to generate a new vaccine that protects all individuals from tuberculosis.

The importance of this study for the development of new vaccines to control the tuberculosis pandemic is discussed in more detail in the accompanying commentary by W. Henry Boom from Case Western Reserve University.

TITLE: Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis

AUTHOR CONTACT:
Steven A. Porcelli
Albert Einstein College of Medicine, New York, New York, USA.
Phone: (718) 430-3228; Fax: (718) 430-8711; E-mail: porcelli@aecom.yu.edu.

William R. Jacobs Jr.
Albert Einstein College of Medicine, New York, New York, USA.
Phone: (718) 430-2865; Fax: (718) 518-0366; E-mail: jacobs@aecom.yu.edu.

Karen Gardner
Media Relations Manager
Albert Einstein College of Medicine
Phone: 718-430-3101 ; E-mail: kgardner@aecom.yu.edu

View the PDF of this article at: https://www.the-jci.org/article.php?id=31947

ACCOMPANYING COMMENTARY
TITLE: New TB vaccines: is there a requirement for CD8+ T cells"

AUTHOR CONTACT:
W. Henry Boom
Case Western Reserve University and University Hospitals' Case Medical Center, Cleveland, Ohio, USA.
Phone: (216) 368-4844; Fax: (216) 368-2034; E-mail: whb@case.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32933


EDITOR'S PICK: Identifying the mechanism behind a genetic susceptibility to type 2 diabetes

Type 2 diabetes is reaching epidemic proportions in the developed world. Determining if and how certain genes predispose individuals to type 2 diabetes is likely to lead to the development of new treatment strategies for individuals with the disease.

In a study appearing in the August issue of the Journal of Clinical Investigation Valeriya Lyssenko and colleagues from Lund University in Sweden show that certain variants of the gene TCF7L2 make individuals more susceptible to type 2 diabetes. The susceptibility variants were associated with increased expression of TCF7L2 in pancreatic islet cells and decreased islet cell secretion of insulin. Consistent with this, ectopic overexpression of TCF7L2 in human islet cells decreased insulin secretion in response to exposure to glucose. This study identifies TCF7L2 type 2 diabetes susceptibility variants and provides a mechanism by which these genetic variants might cause susceptibility to the disease. As discussed by the authors and in the accompanying commentary by Andrew Hattersley from Peninsula Medical School in the United Kingdom, future studies are likely to investigate the potential for manipulating the signaling pathways controlled by TCF7L2 for the development of new therapeutics for type 2 diabetes.

TITLE: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes

AUTHOR CONTACT:
Valeriya Lyssenko
Lund University, University Hospital Malma, Malma, Sweden.
Phone: 46-40-391214; Fax: 46-40-391222; E-mail: Valeri.Lyssenko@med.lu.se.

View the PDF of this article at: https://www.the-jci.org/article.php?id=30706

ACCOMPANYING COMMENTARY
TITLE: Prime suspect: the TCF7L2 gene and type 2 diabetes risk

AUTHOR CONTACT:
Andrew T. Hattersley
Institute of Biomedical and Clinical Sciences, Peninsula Medical School, Exeter, United Kingdom.
Phone: 44-1392-406806; Fax: 44-1392-406767; E-mail: Andrew.Hattersley@pms.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33077


GENE THERAPY: Identifying where genes can successfully integrate

Gene therapy -- whereby a retrovirus that integrates into the genome of a treated patient is used to deliver the gene of interest -- has been used to treat some individuals with inherited diseases such as X-linked SCID, a disease that causes widespread immunosuppression and therefore susceptibility to infection. However, a small number of the treated individuals developed leukemia-like diseases because the retrovirus integrated into the genome at a site(s) that caused the cells to divide uncontrollably. Analysis of the sites of retroviral integration in individuals treated with gene therapy is therefore of utmost importance to the further development of such gene therapy approaches and three studies that appear in the August issue of the Journal of Clinical Investigation address this issue.

The three studies -- reported by researchers from the National Center for Tumor Diseases, Heidelberg, Germany; University College London, London, United Kingdom; and the San Raffaele Telethon Institute for Gene Therapy, Milan, Italy -- indicate that the retroviruses used to deliver the genes of interest in these studies, gammaretroviruses, integrated near the 5" ends of genes that are active in the treated cell population. Although the diversity of the detected retroviral integration sites decreased following transplantation into patients because the treated cells differentiated, the sites detected remained at the 5" end of genes active in the cell populations analyzed. Importantly, the retrovirus integration sites observed in cells from successfully treated patients were not significantly different from those observed in cells from patients that went on to develop leukemia-like disease. As discussed in the accompanying commentary by Frederic Bushman from the University of Pennsylvania, Philadelphia, these studies are critical if researchers are to determine whether the dangers of retroviral gene therapy can be predicted and/or eliminated.

TITLE: Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy

AUTHOR CONTACT:
Christof von Kalle
National Center for Tumor Diseases, Heidelberg, Germany.
Phone: 49-6221-56-6990; Fax: 49-6221-56-6967; E-mail: christof.kalle@nct-heidelberg.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31659

RELATED MANUSCRIPTS
TITLE: Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo

AUTHOR CONTACT:
Christof von Kalle
National Center for Tumor Diseases, Heidelberg, Germany.
Phone: 49-6221-56-6990; Fax: 49-6221-56-6967; E-mail: christof.kalle@nct-heidelberg.de.

Adrian J. Thrasher
University College London, London, United Kingdom.
Phone: 44-207-8138490; Fax: 44-207-9052810; E-mail: a.thrasher@ich.ucl.ac.uk

View the PDF of this article at: https://www.the-jci.org/article.php?id=31661

TITLE: Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy

AUTHOR CONTACT:
Allesandro Aiuti
San Raffaele Telethon Institue for Gene Therapy, Milan, Italy.
Phone: 39-022-643-4671; Fax: 39-022-643-4668; E-mail: a.aiuti@hsr.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31666

ACCOMPANYING COMMENTARY
TITLE: Retroviral integration and human gene therapy

AUTHOR CONTACT:
Frederic D. Bushman
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-8372; Fax: (215) 573-4856; E-mail: bushman@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32949


HEMATOLOGY: The protein FoxO3 helps determine when red blood cells die

The accumulation of high levels of oxidants in red blood cells dramatically decreases their lifespan and is associated with anemia. Little was known about the molecular regulation of the response to oxidants in red blood cells, but in a study appearing in the August issue of the Journal of Clinical Investigation the protein FoxO3 is now shown to be required for mouse red blood cells to control their levels of oxidants and it is therefore probable that Foxo3 regulates the lifespan of these cells.

In the study, Saghi Ghaffari and colleagues from the Mount Sinai School of Medicine, New York, show that the induction of high levels of oxidants in mice lacking Foxo3 caused them to die rapidly. Red blood cells from these mice expressed fewer proteins able to scavenge the oxidants and had a shorter lifespan than red blood cells from normal mice. Importantly, treatment of the cells with an antioxidant increased the lifespan of the red blood cells lacking Foxo3. A lack of Foxo3, and therefore high levels of oxidants, also decreased the rate of red blood cell development and led the authors to posit that it might be possible to exploit these functions of Foxo3 to increase the lifespan and rate of development of red blood cells. However, as Harvey Lodish, from the Whitehead Institute for Biomedical Research, notes in his accompanying commentary these data highlight "the importance of determining both the direct targets of Foxo3 and its own regulation in helping us understand how a red blood cell lacking a nucleus knows exactly when to die."

TITLE: FoxO3 is required for the regulation of oxidative stress in erythropoiesis

AUTHOR CONTACT:
Saghi Ghaffari
Mount Sinai School of Medicine, New York, New York, USA.
Phone: (212) 659-8271; Fax: (212) 803-6740; E-mail: saghi.ghaffari@mssm.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31807

ACCOMPANYING COMMENTARY
TITLE: Regulation of erythrocyte lifespan: do reactive oxygen species set the clock"

AUTHOR CONTACT:
Harvey F. Lodish
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.
Phone: (617) 258-5216; Fax: (617) 258-6768; E-mail: lodish@wi.mit.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32559


NEPHROLOGY: Protein leakage from the kidney controlled by dynamin

Many diseases of the kidney are characterized by the presence of protein in the urine (known as proteinuria). Such diseases usually progress to kidney failure and can only be treated by dialysis or transplantation. In a study appearing in the August issue of the Journal of Clinical Investigation, Jochen Reiser and colleagues from Massachusetts General Hospital show that destruction in the kidney of a protein known as dynamin by cathepsin L causes proteinuria in a mouse model of kidney disease. Consistent with this, when mice were engineered to express forms of dynamin that could not be cleaved by cathepsin L they did not develop proteinuria. These data led the authors to suggest that it might be possible to treat human kidney diseases with forms of dynamin that cannot be destroyed by cathepsin L.

The importance of this study for furthering our understanding of proteinuria, as well as its impact on the treatment of proteinuria associated kidney diseases, is discussed in an accompanying commentary by Pierre Ronoco from Tenon Hospital, Paris, France.

TITLE: Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease

AUTHOR CONTACT:
Jochen Reiser
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 726-9363; Fax: (617) 726-5669; E-mail: jreiser@partners.org.

Sanja Sever
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 724-8922; Fax: (617) 726-5669; E-mail: ssever@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32022

ACCOMPANYING COMMENTARY
TITLE: Proteinuria: is it all in the foot"

AUTHOR CONTACT:
Pierre Ronco
University Pierre et Marie Curie, Tenon Hospital, Paris, France.
Phone: 33-1-56-01-66-39; Fax: 33-1-56-01-69-99; E-mail: pierre.ronco@tnn.aphp.fr.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32966


METABOLIC DISEASE: AMPK keeps energy balance steady

The increasing number of individuals with obesity and diabetes has made understanding the regulation of food intake and energy balance a focus of many researchers. One aspect of such research is understanding how the brain controls these processes. Expression of the protein AMPK in neurons in the brain has been suggested to be important for regulating energy balance, but in which neurons its expression is important was not clear.

To address this issue, Dominic Withers and colleagues from University College London, United Kingdom, generated mice lacking AMPK function in either POMC neurons or AgRP neurons. As reported in the August issue of the Journal of Clinical Investigation mice lacking AMPK function in POMC neurons became obese because they reduced their energy expenditure and increased their food intake after fasting. By contrast, mice lacking AMPK function in AgRP neurons showed age-dependent decrease in body weight. Surprisingly, these effects were mediated by an inability of the neurons to respond to changes in glucose levels and not caused by impaired responses to the hormone regulators of energy balance leptin and insulin. These latter observations, that AMPK is only required for the response of POMC and AgRP neurons to some signals that regulate energy balance led the authors to conclude that AMPK is "not a general sensor and integrator of energy homeostasis in the hypothalamus."

The surprising nature of the results is discussed further in an accompanying commentary by Joel Elmquist from the University of Texas Southwestern. Elmquist notes that it is complex studies such as these that uncover unexpected results that are "needed to combat the growing problems that are obesity and diabetes."

TITLE: AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons

AUTHOR CONTACT:
Dominic J. Withers
University College London, London, United Kingdom.
Phone: 44-20-7679-6586; Fax: 44-20-7679-6583; E-mail: d.withers@ucl.ac.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31516

ACCOMPANYING COMMENTARY
TITLE: "AMPing up" our understanding of the hypothalamic control of energy balance

AUTHOR CONTACT:
Joel K. Elmquist,
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-2911; Fax: (214) 648-5612; E-mail: joel.elmquist@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32975


PHYSIOLOGY: EGF helps keep magnesium in

Low levels of magnesium in the blood (known as hypomagnesemia) can be fatal or result in brain damage. Hypomagnesemia can be an inherited disorder and mutations in any one of a number of genes have been shown cause the disorder. A new study in the August issue of the Journal of Clinical Investigation has now added the EGF gene to this list and identified why one mutation in this gene causes hypomagnesemia.

In the study, René Bindels and colleagues from Raboud University Nijmegen Medical Center in The Netherlands, observed that a mutation in the EGF gene was the cause of hypomagnesemia in two individuals with isolated autosomal recessive renal hypomagnesemia. The mutation caused pro-EGF to be inappropriately localized in kidney cells that control how much magnesium is lost in the urine and how much is retained by the body. This inappropriate localization prevents EGF activating its receptor and thereby increasing the expression of a protein know as TRPM6 that enables the cells of the kidney to take up magnesium and prevent it from being lost in the urine. The importance of this process was highlighted by the observation that individuals with colorectal cancer who receive treatment with an antagonist of the receptor for EGF also develop hypomagnesemia. As noted by Shmuel Muallem and Orson W. Moe in an accompanying commentary "This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology."

TITLE: Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia

AUTHOR CONTACT:
Rene J. Bindels
Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Phone: 31-24-3614211; Fax: 31-24-3616413; E-mail: r.bindels@ncmls.ru.nl.

View the PDF of this article at: https://www.the-jci.org/article.php?id=31680

ACCOMPANYING COMMENTARY
TITLE: When EGF is offside, magnesium is wasted

AUTHOR CONTACT:
Shmuel Muallem
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 645-6008; Fax: (214) 645-6049; E-mail: shmuel.muallem@utsouthwestern.edu.

Orson W. Moe
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: (214) 648-7993; Fax: (214) 648-2071; E-mail: orson.moe@utsouthwestern.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=33004

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