EDITOR'S PICK: Predicting liver cancer spread
Patients with cancer usually do not die as a result of their originally diagnosed tumor. However, many do so as a result of metastatic disease — tumors that arise at distant sites after spreading from the original tumor. Identifying biomarkers of tumor metastasis would therefore be of immense clinical benefit. In this context, a team of researchers — led by Peng Loh, at the National Institutes of Health, Bethesda; and Ronnie Poon, at the The University of Hong Kong, China — has now identified a potential biomarker for predicting future metastasis in patients with the most common form of liver cancer (hepatocellular carcinoma [HCC]). Specifically, the team found that quantification of the mRNA template for a truncated version of the protein carboxypeptidase E (CPE) in HCC patient samples predicted intrahepatic metastasis with high sensitivity and specificity. They therefore suggest that this truncated protein could be a powerful biomarker for predicting future metastasis in patients with HCC and thereby be of use to clinicians, helping guide therapeutic decisions.
TITLE: An N-terminal truncated carboxypeptidase E splice isoform induces tumor growth and is a biomarker for predicting future metastasis in human cancers
AUTHOR CONTACT:
Y. Peng Loh
National Institutes of Health, Bethesda, Maryland, USA.
Phone: 301.496.3239; Fax: 301.496.9938; E-mail: lohp@mail.nih.gov.
Ronnie T. Poon
The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Phone: 852.2855.3641; Fax: 852.2817.5475, E-mail: poontp@hkucc.hku.hk.
View this article at: http://www.jci.org/articles/view/40433?key=4a1a18f6169983df9588
ONCOLOGY: Overcoming cancerous genetic mutation
Genetic mutation of the P53 gene is seen in approximately half of all human cancers. These mutations lead to the generation of a mutant p53 protein lacking normal p53 function. This has led to the suggestion that restoring p53 expression might be a promising anticancer therapy. However, in the majority of cases, the mutant p53 protein expressed by the cancer cells has gained new functions, and it is not known whether restoring p53 expression will be of benefit in these cases. By analyzing this question in mice expressing a mutant gain-of-function form of p53 equivalent to that found in about 6% of human cancers, Guillermina Lozano and colleagues, at The University of Texas MD Anderson Cancer Center, Houston, have generated data that support the use of p53 restoration as a strategy to treat human cancers with P53 mutations that generate gain-of-function mutant p53 proteins. However, it is important to note that although restoring normal p53 expression suppressed the growth of tumors expressing the gain-of-function mutant p53, it did not cause tumor regression.
TITLE: Restoring expression of wild-type p53 suppresses tumor growth but does not cause tumor regression in mice with a p53 missense mutation
AUTHOR CONTACT:
Guillermina Lozano
The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Phone: 713.834.6386; Fax: 713.834.6380; E-mail: gglozano@mdanderson.org.
View this article at: http://www.jci.org/articles/view/44504?key=65b5ecaa6ac46a0799a3
ALLERGY AND ASTHMA: Why air pollution exacerbates allergic asthma
Many individuals with allergic asthma suffer heightened symptoms when exposed to increased levels of air pollutants. This is because inhalable particles from air pollutants efficiently deliver airborne allergens deep into the airways. However, the cellular mechanisms underlying this remain unknown, in part because most studies of allergic asthma use soluble allergens (sAgs) rather than inhalable particulate allergens (pAgs). Now, Soman Abraham and colleagues, at Duke University Medical Center, Durham, have shed light on this matter by comparing the ability of sAgs and pAgs to induce disease in allergen-sensitized mice. They found that pAgs triggered markedly heightened disease and that this was a result of the ability of pAgs to provoke a response from immune cells known as mast cells. If the same mast cell response pathway is triggered by pAgs in humans, it could provide new therapeutic targets for the treatment of allergic asthma.
TITLE: Particulate allergens potentiate allergic asthma in mice through sustained IgE-mediated mast cell activation
AUTHOR CONTACT:
Soman N. Abraham
Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919.684.3630; Fax: 919.684.2021; E-mail: soman.abraham@duke.edu.
View this article at: http://www.jci.org/articles/view/43584?key=d316aa486d248db097e5
MUSCLE BIOLOGY: New gene therapy approach for muscular dystrophy?
A team of researchers, led by Jeffery Molkentin, at Cincinnati Children's Hospital Medical Center, Cincinnati, has identified, though work using mice, a potential new therapeutic approach to treating the underlying cause of most forms of muscular dystrophy.
Muscular dystrophy is the term given to a diverse group of genetic disorders that result in progressive muscle wasting and premature death. In the majority of patients, the underlying genetic mutation in some way disrupts the DGC protein complex. This ultimately leads to altered levels of calcium (Ca2+) inside affected muscle cells and their subsequent death. Molkentin and colleagues were able to abrogate altered intracellular levels of Ca2+ in both a mouse model of Duchenne muscular dystrophy and a mouse model of limb-girdle muscular dystrophy by overexpressing the protein SERCA1 in skeletal muscle cells. This, in turn, mitigated the dystrophic muscle disease in the mice, leading them to suggest that a gene therapy approach to expressing SERCA1 might help alleviate most forms of muscular dystrophy.
TITLE: Mitigation of muscular dystrophy in mice by SERCA overexpression in skeletal muscle
AUTHOR CONTACT
Jeffery D. Molkentin
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513.636.3557; Fax: 513.636.5958; E-mail: jeff.molkentin@cchmc.org.
View this article at: http://www.jci.org/articles/view/43844?key=d858fb0146c6734d4c99
DEVELOPMENT: New developmental disorder caused by SC4MOL genetic mutation
Cholesterol is often thought of as bad for our bodies due to links between high cholesterol levels and type 2 diabetes and its associated conditions. However, cholesterol is in fact a key structural component of cells and an immediate precursor of steroids, vitamin D, and bile acids. Inherited defects in the pathway that leads to the generation of cholesterol can result in a range of outcomes, from neonatal lethality to the developmental delay and distinctive facial features of individuals with Smith-Lemli-Opitz syndrome. A team of researchers, led by Jerry Vockley, at Children's Hospital of Pittsburgh, has now determined that yet another combination of clinical symptoms is caused by an inherited defect in the cholesterol generation pathway, specifically an inherited defect in the protein templated by the SC4MOL gene. Deficiency of this protein led to the accumulation of intermediates in the cholesterol generation pathway that caused cell overproliferation in both skin and blood and altered immune cell phenotype. Thus, reduced cholesterol generation and the accumulation of pathway intermediates lead to a new clinical syndrome.
TITLE: Mutations in the human SC4MOL gene encoding a methyl sterol oxidase cause psoriasiform dermatitis, microcephaly, and developmental delay
AUTHOR CONTACT:
Jerry Vockley
Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Phone: 412.692.7746; Fax: 412.692.7816; E-mail: gerard.vockley@chp.edu.
View this article at: http://www.jci.org/articles/view/42650?key=ba8f2adf27c588a8916d
HEMATOLOGY: To self-renew or differentiate: a decision for Notch2
All our different blood cell types arise from cells known as hematopoietic stem cells (HSCs). When these cells divide, they have the choice to either form more HSCs (i.e., to self-renew) or to differentiate to give rise to more specialized cell types. Surprisingly, little is known about the molecular control of the decision by HSCs to self-renew or differentiate. However, a team of researchers, led by Irwin Bernstein, at the Fred Hutchinson Cancer Research Center, Seattle, has now determined in mice that signaling via the protein Notch2 has a key role in inhibiting the differentiation of blood cells of the myeloid lineage and in enhancing the formation of HSCs and multipotent progenitor cells. Importantly, Notch2 only played this role when the bone marrow and blood cell compartments were recovering from injury induced by chemotherapy or radiation. As such, these data have clinical implications for reconstituting bone marrow in patients undergoing HSC transplantation following chemo- or radiotherapy.
TITLE: Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells
AUTHOR CONTACT:
Irwin D. Bernstein
Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Phone: 206.667.4886; Fax: 206.667.6084; E-mail: ibernste@fhcrc.org.
View this article at: http://www.jci.org/articles/view/43868?key=ee814ff0ce53032af33f
PULMONARY BIOLOGY: Structural determinants of lung cell death
Acute lung injury is a life-threatening condition in critically ill patients. It is characterized by injury to the lining of the airways and lungs as a result of the death of the cells that constitute the lining. Recent data indicate that signals triggered by the protein FasL are linked to the cell death associated with acute lung injury. A team of researchers, led by Thomas Martin, at the VA Puget Sound Medical Center, Seattle, has now characterized the structural determinants of soluble FasL from the lungs of patients with acute lung injury that are critical to its ability to trigger cell death. The data lead the authors to conclude that the lung/airway microenvironment of patients with acute lung injury contains factors that modulate the structure of soluble FasL and enhance its bioactivity.
TITLE: The biological activity of FasL in human and mouse lungs is determined by the structure of its stalk region
AUTHOR CONTACT:
Thomas R. Martin
VA Puget Sound Medical Center, Seattle, Washington, USA.
Phone: 206.764.2219; Fax: 206.768.5289; E-mail: trmartin@u.washington.edu.
View this article at: http://www.jci.org/articles/view/43004?key=f6ffdaea79e231753598
Journal
Journal of Clinical Investigation