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JCI table of contents: Nov. 21, 2007

EDITOR'S PICK: Pregnant women pass on the effects of smoking

Smoking during pregnancy has many adverse effects on fetal development. A new study in mice by Andrea Jurisicova and colleagues at the University of Toronto, Canada, now adds the possibility that smoking before pregnancy or while breast-feeding might substantially decrease the fertility of female offspring to the long list of possible negative outcomes.

The authors found that female mice injected under the skin with polycyclic aromatic hydrocarbons (PAHs) environmental toxins found in cigarette smoke pre-pregancy or while lactating were found to have normal sized litters. However, their female offspring had markedly reduced numbers of resting and early growing follicles cell clusters that each contain a single egg. Further analysis indicated that the effects of PAHs on the number of follicles in female offspring were mediated through the aryl hydrocarbon receptor (Ahr), which upregulated expression of the gene Harakiri that makes a protein that causes cells to die by a process known as apoptosis. The potential importance of these findings for women of child-bearing age was demonstrated by the observation that PAHs triggered similar molecular pathways in human ovarian tissue transplanted into immunocompromised mice.

TITLE: Maternal exposure to polycyclic aromatic hydrocarbons diminishes murine ovarian reserve via induction of Harakiri


Andrea Jurisicova
University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada.
Phone: (416) 586-4800, ext. 2052; Fax: (416) 586-8588; E-mail:


Jodi Salem
Media and Communications Specialist
Mount Sinai Hospital, Toronto, Ontario, Canada.
Phone: (416) 586-4800, ext. 8306; Fax: (416) 586-8544; E-mail:< suggested that something else has to happen if c-Rel is to trigger tumor development. In a new mouse study, Karine Belguise and Gail Sonenshein, from Boston University School of Medicine, have identified one possible mechanism by which aberrantly expressed c-Rel is able to fulfill its tumorigenic potential decreased signaling through the alpha subunit of the receptor for the hormone estrogen (ER-alpha), such as occurs naturally during the menopause, which is when the risk of developing breast cancer increases.

Expression of ER-alpha was observed to be lower in mammary tumors induced by aberrant expression of c-Rel than in normal mammary tissue. Further analysis determined that the protein PKC-theta was responsible for the molecular changes underlying decreased expression of ER-alpha PKC-theta activated Akt, a protein that represses the function of FOXO3a, which in turn induces the expression of ER-alpha. Consistent with the notion that ER-alpha represses the tumorigenic potential of c-Rel, expression of ER-alpha and genes activated by c-Rel were inversely correlated in human breast cancer specimens.

TITLE: PKC-theta promotes c-Reldriven mammary tumorigenesis in mice and humans by repressing estrogen receptoralpha synthesis


Gail E. Sonenshein
Boston University School of Medicine, Boston, Massachusetts, USA.
Phone: (617) 638-4120; Fax: (617) 638-4252; E-mail:

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EDITOR'S PICK: Opposing the (red) devils advocate: carbon monoxide counteracts one side-effect of an anticancer drug

Doxorubicin (DOX) is a red-colored anticancer drug that carries serious side effects for the heart, including cardiac muscle deterioration (cardiomyopathy) and scar tissue accumulation in the heart (fibrosis). These cardio-toxic effects are due to inhibition by DOX of mitochondrial biogenesis, a term used to describe cellular energy generation. In a new study by Claude Piantadosi and his colleagues at Duke University Medical Center, mitochondrial biogenesis was recovered in DOX-treated rodents by either inhalation of carbon monoxide (CO) or overexpression of the protein HO-1.

Mitochondrial biogenesis is known to depend on the presence of CO and HO, which promote energy production and defend the cell from injury. In mice treated with DOX, mitochondrial biogenesis in the heart was suppressed, resulting in heart cell death, thinning and dilation of the heart wall, and fibrosis. However, periodic inhalation of CO by DOX-treated mice restored mitochondrial biogenesis and averted cardiomyopathy. Likewise, overexpression of HO-1 in DOX-treated rat cardiac cells reduced mitochondrial DNA damage and subsequent cell death. The authors therefore suggested that protecting mitochondrial biogenesis in cancer patients treated with DOX might reduce the cardio-toxic side effects of the drug.

TITLE: The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy


Claude A. Piantadosi
Duke University Medical Center, Durham, North Carolina, USA
Phone: (919) 684-6143; Fax: (919) 684-6002; E-mail:

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DEVELOPMENT: Location, location, location: gene determining body organ position identified

Primary ciliary diskinesia (PCD) is an inherited disease caused by mutations in any one of a number of genes, including the gene DNAH5. Individuals with PCD are highly susceptible to chronic recurrent respiratory infections and the left-right positioning of the organs of their body is completely mirror image reversed (i.e., instead of their heart being on the left side of their body it is on the right). Some individuals with PCD exhibit heterotaxy, a condition characterized by randomized left-right organ positioning. It had not been established previously whether the genetic defects that lead to PCD are also responsible for heterotaxy, but new research in mice by Cecelia Lo and colleagues at the National Institutes of Health, Bethesda, has now suggested that this is the case.

In the study, a substantial proportion of fetal mice with a mutation in both copies of their Dnahc5 gene (the mouse equivalent of DNAH5) exhibited heterotaxy and, as observed in human heterotaxy syndromes, these embryos had variable combinations of complex structural heart defects. Further analysis confirmed that these mice were a robust model of PCD, indicating that a Dnahc5 mutation causing PCD-like disease in mice also can cause heterotaxy. These data led the authors to suggest individuals with PCD should be assessed for heterotaxy and associated congenital heart defects, and conversely, patients with heterotaxy should be evaluated for undiagnosed PCD. Such combined diagnoses would dictate very different clinical strategies that may improve outcome.

TITLE: Heterotaxy and complex structural heart defects in a mutant mouse model of primary ciliary dyskinesia


Cecilia W. Lo
National Institutes of Health, Bethesda, Maryland, USA.
Phone: (301) 451-8041, Fax: (301) 480-4581, Email:

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HEMATOLOGY: New role for intestinal protein in blood clotting

An intestinal protein known as BSDL that helps the body breakdown and absorb cholesterol is also found circulating in our bloodstream, where its role has been an enigma. However, in a new study, Laurence Panicot-Dubois and his colleagues at the Universit de la Mditerrane, France, have identified a role for blood-borne BSDL in blood clot formation.

In vitro analysis showed that BSDL enhances the activation of human platelets cells found in the blood that when activated are key to the formation of blood clots. In addition, in normal mice BSDL accumulated at sites of blood clot formation and in BSDL-deficient mice tail injury resulted in increased bleeding time. Further analysis revealed that BSDL mediated its effects on platelets in vitro and in vivo by binding a protein on the surface of platelets known as CXCR4. Indeed, inhibition of CXCR4 prevented BSDL-mediated human platelet activation, and eliminated BSDL accumulation and reduced blot clot size in mice. These data led the authors to conclude that the interaction between BSDL and CXCR4 might be a new target for therapies to treat conditions in which blood clots form inappropriately inside blood vessels, such as occurs in individuals with pancreatic cancer.

TITLE: Bile saltdependent lipase interacts with platelet CXCR4 and modulates thrombus formation in mice and humans


Laurence Panicot-Dubois
Universit de la Mditerrane, Facult de Mdecine Timone, Marseille, France
Phone: 33-491-324-400; Fax: 33-491-830-187; E-mail:

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HEMATOLOGY: Two hits are better than one for causing leukemia

The genetic abnormalities that cause acute myeloid leukemia (AML) are many and varied. Although mice engineered to mimic a single genetic abnormality eventually develop leukemia, it is thought that a second genetic defect occurring as the mice age is required for this to happen. Support for this 2-hit hypothesis has now been generated by Pier Giuseppe Pelicci and colleagues from the European Institute of Oncology, Italy.

In this study, analysis of leukemic cells from individuals with AML indicated that disease associated with aberrant expression of the gene PRDM16 was accompanied by mutations in the gene that makes the p53 protein, which is known to suppress cancer development. Further analysis revealed that when one of the proteins made by the PRDM16 gene, sPRDM16, was overexpressed in the bone marrow of mice it could induce the development of leukemia, but the full extent of its leukemic potential required that the mice lack p53. These data led the authors to conclude that overexpression of sPRDM16 and disruption of the p53 tumor suppressor pathway cooperate in the development of leukemia, both in human patients with AML and in mice, and to suggest that inhibition of sPRDM16 is a potentially relevant antileukemogenic strategy.

TITLE: Overexpression of sPRDM16 coupled with loss of p53 induces myeloid leukemias in mice


Pier Giuseppe Pelicci
European Institute of Oncology, Milan, Italy.
Phone: 39-02-57489868; Fax: 39-02-57489851; E-mail:


Donata Francese

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CARDIOLOGY: Diabetic hearts feel the burn

A normal heart burns both fats and sugars for fuel. In contrast, diabetic hearts rely almost exclusively on fats for energy, leading to heart failure. PPAR-alpha and PPAR-beta/delta are proteins found in heart tissue. In the diabetic heart, enhanced activity of PPAR-alpha drives the use of fats as fuel, but the role of PPAR-beta/delta has been unknown. While seeking to understand the role of these proteins in diabetic heart failure, Daniel Kelly and his colleagues at Washington University School of Medicine, Missouri, have discovered that selective activation of PPAR-beta/delta in the heart improves cardiac function in mice.

The heart of mice in which PPAR-alpha is engineered to be overexpressed only in the heart (MHC-PPAR-alpha mice) has been shown to mimic the diabetic heart with increased fat and decreased sugar fuel usage, and subsequent cardiac arrest. In contrast, in this study, the hearts of mice engineered to overexpress PPAR-beta/delta only in the heart (MHC-PPAR-beta/delta mice) were shown to process sugars for energy and had function normally. Most strikingly, the degree of heart tissue death following heart attack was reduced in MHC-PPAR-beta/delta mice compared with both normal mice and MHC-PPAR-alpha mice. Researchers also uncovered a reason for these observed differences the two proteins have opposite effects on the genes responsible for sugar usage by the heart for fuel. The authors therefore suggested that heart-specific PPAR-beta/delta activation might be a useful therapy for reducing diabetes-induced heart disease in humans.

TITLE: Nuclear receptors PPAR-beta/delta and PPAR-alpha direct distinct metabolic regulatory programs in the mouse heart


Daniel P. Kelly
Washington University School of Medicine, St. Louis, Missouri, USA
Phone: (314) 362-8908; Fax: (314) 362-0186; E-mail:

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OPHTHALMOLOGY: New understanding as to why individuals with an inherited disease dont see clearly

Williams-Beuren syndrome (WBS) is an inherited disease caused by the deletion of a segment of the genome that carries more than 20 genes. Several characteristics identify individuals with WBS, including a distinctive, elfin-like facial appearance; overly friendly personalitites; a love for music; and a lack of motion and depth perception. The latter are thought to be caused by defects in the region of the brain that deals with visual information. However, Miguel Castelo-Branco and colleagues at the IBILI, Portugal, have now determined that individuals with WBS also have a developmental defect in the retina (the thin layer of neural cells that lines the back of the eyeball) and that this causes additional visual deficits.

TITLE: Visual phenotype in Williams-Beuren syndrome challenges magnocellular theories explaining human neurodevelopmental visual cortical disorders


Miguel Castelo-Branco
IBILI, Faculty of Medicine, Coimbra, Portugal.
Phone: 351-239-480286-280; Fax: 351-239-480286-280; E-mail:

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NEPHROLOGY: A breath of fresh air: oxygen deficiency promotes scar tissue formation in the kidneys

A steady loss of kidney function over a period of time is the characteristic symptom of chronic kidney disease (CKD). Kidney biopsy samples from individuals with CKD show the development of scar tissues (also known as fibrotic tissue). New data generated by Volker Haase and colleagues at the University of Pennsylvania, Philadelphia, has indicated a role for oxygen deficiency (hypoxia) in the formation of fibrotic tissue in the kidney.

In the study, elimination of the protein HIF-1-alpha (a key mediator of cellular responses to low oxygen) in kidney cells in mice inhibited the development of fibrotic tissue in a mouse model of kidney fibrosis. In vitro analysis indicated that HIF-1-alpha enhanced a process known as epithelial-to-mesenchymal transition (EMT), a key mechanism underlying the formation of fibrotic tissue, in mouse kidney cells in vitro. The clinical significance of these observations was highlighted by the demonstration that increased expression of HIF-1-alpha in the kidney was associated with tissue fibrosis in individuals with CDK. These data led the authors to suggest that therapies aiming to maintain adequate oxygen levels in the kidney might halt the progression of kidney fibrosis.

TITLE: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition


Volker H. Haase
University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-1846; Fax: (215) 746-5831; E-mail:

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NEPHROLOGY: The coagulation protein tPA wears a new hat

Permanent kidney failure due to any cause is almost always accompanied by significant scarring, a disease state termed renal fibrosis. Protein accumulation in the kidney is responsible for fibrosis, including the deposition of the protein collagen by specialized cells named fibroblasts. In a new study in rodents, Youhua Liu and colleagues at the University of Pittsburgh School of Medicine have identified a new role for the blood clotting protein tPA in the development of renal fibrosis.

Following tPA treatment of rat kidney fibroblasts, collagen was secreted by the cells along with a protein marker of fibroblast activation, alpha-SMA. This protein deposition was independent of the blood clotting effects of tPA, but it did require presence of the protein LRP-1 on the surface of the fibroblasts. These results were confirmed in mice with acute kidney dysfunction. In normal mice, tPA/LRP-1 protein complexes were associated with alpha-SMA in the mouse kidney. However, mice deficient in tPA had reduced levels of both renal proteins. Because tPA is also capable of activating cells outside of the kidneys, the authors concluded from these results that tPA might also be important in the development of lung or liver fibrosis.

TITLE: Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptorrelated protein 1mediated integrin signaling


Youhua Liu
University of Pittsburgh, Pittsburgh, Pennsylvania, USA
Phone: (412) 648-8253; Fax: (412) 648-1916; E-mail:

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ONCOLOGY: The estrogen receptor enables a pre-cancerous mutation to reach its potential

Most cases of primary breast cancer are characterized by aberrant expression of the protein c-Rel. A causal role for c-Rel in the development of breast cancer has been shown in mice. However, the tumors take a long time to develop and it has been

Contact: Karen Honey
Journal of Clinical Investigation

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