EDITOR'S PICK: When the smoke clears: molecular link between tobacco carcinogen and cancer
A team of researchers, led by Yi-Ching Wang, at National Cheng Kung University, Taiwan, Republic of China, has uncovered a potential mechanism by which the tobacco-specific carcinogen NNK promotes lung tumor formation and development. Specifically, they suggest that NNK induces the accumulation of a protein known as DNMT1 in the nucleus and that this protein silences genes that suppress tumor formation.
The authors generate several lines of evidence to support their suggested mechanism, one of which is the observation that DNMT1 accumulates in both lung adenomas from NNK-treated mice and tumors from lung cancer patients that were smokers. Of clinical relevance, DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis. These data identify a potential important link between tobacco smoking and lung cancer.
TITLE: The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients
National Cheng Kung University, Taiwan, Republic of China.
Phone: 886-6-2353535 ext. 5502; Fax: 886-6-2749296; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/40706?key=be406da6c2aac829be98
EDITOR'S PICK: New use for statins in children with sickle cell disease?
Statins are used to treat elevated levels of cholesterol and heart disease. They are among the most widely prescribed drugs in the world. A team of researchers, led by Elaine Tuomanen, at St. Jude Children's Research Hospital, Memphis, has now identified a potential new use for statins by studying a mouse model of sickle cell disease, the most common genetic disorder in the world.
Children with sickle cell disease have a much greater risk of developing an invasive infection with pneumococcal bacteria, something that is often lethal, that those that do not have the disease. In the study, when sickle cell–disease mice were treated with a statin before being infected with pneumococcal bacteria they lived for much longer than did infected, untreated sickle cell–disease mice. Further analysis identified two mechanisms underlying the protective effect of statins in this context: they reduced bacterial invasion into the blood system and they prevented cells being killed by the bacterial toxins. These data therefore suggest that prophylactic treatment with statins might reduce the susceptibility of children with sickle cell disease to invasive pneumococcal infection.
TITLE: Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease
Elaine I. Tuomanen
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Phone: (901) 595-3114; Fax: (901) 595-3099; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/39843?key=4703d86cb370ef068f28
ONCOLOGY: Nlp: all new tumor-forming protein
Proteins that when expressed out of context cause a cell to become cancerous are known as oncogenic proteins. Qimin Zhan and colleagues, at the Chinese Academy of Medical Sciences and Peking Union Medical College, People's Republic of China, have now identified in mice a new oncogenic protein that is also expressed at elevated levels in human breast cancers and lung carcinomas.
In the study, Nlp was found to be expressed at elevated levels in the majority of human breast and lung cancers analyzed. In the lung cancers analyzed, these high protein levels were a result of NLP gene amplification. In vitro analysis of the function of Nlp indicated that it conferred on cells tumorigenic properties, suggesting that it was an oncogenic protein. Consistent with this, mice engineered to overexpress Nlp spontaneously developed tumorigenesis in the breast, ovary, and testicle. The authors therefore suggest that Nlp abnormalities might lead to tumor formation and development.
TITLE: Centrosomal Nlp is an oncogenic protein that is gene-amplified in human tumors and causes spontaneous tumorigenesis in transgenic mice
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Phone: 86-10-67762694; Fax: 86-10-67715058; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/39447?key=a475f34512aaf559304f
IMMUNOLOGY: TLR proteins can provide security from tissue destruction
TLRs are best known for their role in triggering an inflammatory response upon recognition of microbial products. However, they also initiate inflammatory responses, thereby amplifying tissue destruction, upon binding damage-associated molecular patterns (DAMPs), molecules released by cells damaged under sterile conditions. A team of researchers at Memorial Sloan-Kettering Cancer Center, New York, has now determined in mice that TLR recognition of DAMPs also triggers a response that protects from excessive tissue damage.
The team, led by Ronald DeMatteo studied a mouse model of sterile inflammation in which liver damage was caused by temporarily restricting blood flow to the liver. Liver damage was increased in this model of sterile inflammation by prior depletion of immune cells known as conventional DCs (cDCs). Further in vitro and in vivo analysis indicated that cDCs produced the antiinflammatory molecule IL-10 in response to TLR9 recognition of liver cell DNA and that this was crucial to their ability to reduce liver damage in the model of sterile inflammation. The authors therefore suggest that it might be possible to reduce tissue damage caused by temporary restriction of blood flow (something that occurs often in surgery) by harnessing the antiinflammatory potential of cDCs via TLR9.
TITLE: Conventional DCs reduce liver ischemia/reperfusion injury in mice via IL-10 secretion
Ronald P. DeMatteo
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (212) 639-3976; Fax: (212) 639-4031; E-mail: email@example.com.
View this article at: http://www.jci.org/articles/view/40008?key=03dffeb8c31903d0d00a
TUMOR IMMUNOLOGY: How anticancer immune responses are suppressed
Immune cells known as myeloid-derived suppressor cells (MDSCs) keep other immune cells in check. They have been found to accumulate in individuals with cancer, where they are thought to contribute to tumor development. François Ghiringhelli and colleagues, at INSERM U866, Dijon, France, have now identified a molecular pathway that enhances the immunosuppressive functions of tumor-associated mouse and human MDSCs.
In the study, tiny vesicles known as exosomes released by human and mouse tumor cells were found to have the molecule Hsp72 on their surface. This bound the protein TLR2 on human and mouse MDSCs, triggering a signaling pathway that resulted in enhanced MDSC suppressive function. Importantly, decreasing tumor exosome release pharmacologically in vivo enhanced the antitumor effects of the chemotherapeutic drug cyclophosphamide in three different mouse models of cancer. The authors therefore suggest that drugs that prevent tumor exosome release might be beneficial to cancer patients being treated with conventional chemotherapeutic drugs.
TITLE: Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells
INSERM U866, University of Burgundy, Dijon, France.
Phone: 33-3-80-39-33-53; Fax: 33-3-80-39-34-34; E-mail: firstname.lastname@example.org or email@example.com.
View this article at: http://www.jci.org/articles/view/40483?key=1bffd0554df56a3041a4
HEMATOLOGY: A role for the protein c-Myb in leukemia
Our genes are arranged on 23 pairs of chromosomes. Chromosomal abnormalities that occur when nonmatching pairs of chromosomes swap genetic information are known as chromosomal translocations. Chromosomal translocations are the cause of several forms of leukemia, as they can result in dysregulation of genes that cause cancer. The gene MLL is often inappropriately regulated in acute leukemias caused by chromosomal translocation, and Alan Gewirtz and colleagues, at the University of Pennsylvania School of Medicine, Philadelphia, have now identified a molecular pathway that is important for inducing MLL-associated leukemia formation.
In the study, the authors find that in human leukemia cells the protein c-myb binds to MLL via the protein menin and that this is important for MLL to drive mouse blood cells to become leukemic. Further analysis indicated that the c-myb/menin/MLL complex induced changes to genomic structure, leading to changes in gene expression. The authors suggest that deeper understanding of the gene networks regulated by the c-myb/menin/MLL complex might provide new drug targets for treatments for acute leukemia.
TITLE: c-Myb binds MLL through menin in human leukemia cells and is an important driver of MLL-associated leukemogenesis
Alan M. Gewirtz
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-4499; Fax: (215) 573-2078; E-mail: firstname.lastname@example.org.
View this article at: http://www.jci.org/articles/view/38030?key=ceab507951a5ab84b038
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