JCI table of contents: Oct. 25, 2010

October 25, 2010

EDITOR'S PICK: Pregnancy outcome affected by immune system genes

A team of researchers, led by Ashley Moffett, at the University of Cambridge, United Kingdom, has shed new light on genetic factors that increase susceptibility to and provide protection from common disorders of pregnancy, specifically recurrent miscarriage, preeclampsia, and fetal growth restriction.

A key step in the initiation of a successful pregnancy is the invasion of the lining of the uterus by fetal cells known as trophoblasts, which become the main cell type of the placenta. Recurrent miscarriage, preeclampsia, and fetal growth restriction are thought to result from inadequate trophoblast invasion of the uterus lining. Interactions between maternal cells known as uterine NK cells and fetal trophoblasts -- specifically interactions between HLA-C molecules on the fetal trophoblasts and KIRs on the maternal uterine NK cells -- are key to determining the extent of trophoblast invasion. Previous data from Moffett's lab indicated that a particular combination of fetal HLA-C and maternal KIR was associated with increased risk of preeclampsia. In this study, the team has extended this correlation to recurrent miscarriage and fetal growth restriction. Furthermore, they have determined that the presence of other maternal KIRs that combine with the same HLA-C molecule provides protection against the same common disorders of pregnancy.

In an accompanying commentary, Peter Parham and Lisbeth Guethlein, at Stanford University, discuss the importance of these data and how they might explain distinct immune system gene expression patterns in different populations.

TITLE: Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2

AUTHOR CONTACT:
Ashley Moffett
University of Cambridge, Cambridge, United Kingdom.
Phone: 44.1223.333729; Fax: 44.1223.765065; E-mail: am485@cam.ac.uk.

View this article at: http://www.jci.org/articles/view/43998?key=cfb4e33703c44a22516f

ACCOMPANYING COMMENTARY
TITLE: Pregnancy immunogenetics: NK cell education in the womb?

AUTHOR CONTACT:
Peter Parham
Stanford University, Stanford, California, USA.
Phone: 650.723.7456; Fax: 650.723.8464; E-mail: peropa@stanford.edu.

View this article at: http://www.jci.org/articles/view/44559?key=a12c31691937fa2e1d6b




EDITOR'S PICK: Stop the bleeding: new way to restore numbers of key blood clotting cells

Platelets are cells in the blood that have a key role in stopping bleeding. Thrombocytopenia is the medical term used to describe the presence of abnormally low numbers of platelets in the blood. Platelet transfusion is used to treat several causes of thrombocytopenia, but there is a shortage of donors. Mortimer Poncz and colleagues, at Children's Hospital of Philadelphia, working with mice, have now identified a potential new approach to platelet replacement therapy that circumvents the problem of donor shortage.

Platelets in the blood arise from cells known as megakaryocytes. In the study, Poncz and colleagues found that mature megakaryocytes that were infused into mice could generate platelets of normal size and function. They therefore are hopeful that it might be possible to treat individuals with thrombocytopenia through mature megakaryocyte infusion, although they estimate that 10^9 mature megakaryocytes might be needed for an average 70-kg patient. Although Andrew Leavitt, at the University of California, San Francisco, notes in an accompanying commentary, that this might be a low estimate, he discuses why the new data generated by Poncz and colleagues are an important step forward in identifying new approaches to platelet replacement therapy.

TITLE: Infusion of mature megakaryocytes into mice yields functional platelets

AUTHOR CONTACT:
Mortimer Poncz
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Phone: 215.590.3574; Fax: 215.267.5476; E-mail: poncz@email.chop.edu.

View this article at: http://www.jci.org/articles/view/43326?key=70d31a6f7d6d4fe7c13f

ACCOMPANYING COMMENTARY
TITLE: Are there more tricks in the bag for treating thrombocytopenia?

AUTHOR CONTACT:
Andrew D. Leavitt
University of California at San Francisco, San Francisco, California, USA.
Phone: 415.514.3432; Fax: 415.514.3433; E-mail: leavitta@labmed2.ucsf.edu.

View this article at: http://www.jci.org/articles/view/45179?key=aed7bfaf9544a904a1d9




VIROLOGY: The need to curtail speed: predicting rapid progression to AIDS in monkeys

The rate at which individuals infected with HIV-1 progress to AIDS differs dramatically: rapid progressors develop AIDS within 2𔃃 years of infection, while it takes approximately 10 years in typical progressors. Although the number of rapid progressors has been dramatically reduced in developed countries through the use of antiretroviral therapy, it remains a significant problem in the developing world. A team of researchers, led by Rama Amara, at Emory University, Atlanta, has now identified an immune system correlate of rapid disease progression in monkeys infected with SIV (the monkey equivalent of HIV-1) that they hope might point to an early predictor for rapid disease progression in individuals infected with HIV-1.

In the study, rapid, sustained depletion of immune cells known as activated memory B (mBAct) cells was associated with rapid disease progression. Interestingly, blocking the PD-1 protein on mBAct cells enhanced their survival and improved the ability of treated monkeys to mount B cell immune responses. In an accompanying commentary, Francesca Chiodi, at the Karolinska Institutet, Sweden, suggests that therapies based on PD-1 blockade might help enhance immune responsiveness in individuals infected with HIV-1.

TITLE: Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques

AUTHOR CONTACT:
Rama R. Amara
Emory University, Atlanta, Georgia, USA.
Phone: 404.727.8765; Fax: 404.727.7768; E-mail: ramara@emory.edu.

View this article at: http://www.jci.org/articles/view/43271?key=b83a6c441af1aa49477c

ACCOMPANYING COMMENTARY
TITLE: New therapy to revert dysfunctional antibody responses during HIV-1 infection

AUTHOR CONTACT:
Francesca Chiodi
Karolinska Institutet, Stockholm, Sweden.
Phone: 46.8.52486315; Fax: 46.8.330498; E-mail: francesca.chiodi@ki.se.

View this article at: http://www.jci.org/articles/view/44872?key=d219fc94dba73976b212




ONCOLOGY: Tumors driven by KRAS mutations depend on the protein WT1

In human tumors, one of the most commonly mutated genes is KRAS. This should, in theory, make the proteins these mutated genes generate ideal targets for anti-cancer drugs. However, developing drugs to target KRAS proteins has proven extremely difficult. A team of researchers, led by Alejandro Sweet-Cordero, at Stanford University School of Medicine, Stanford, has now identified a potential approach to indirectly combat tumors caused by KRAS mutations.

In the study, screening in mouse cell lines revealed that the protein WT1 was required by cells expressing KRAS mutations for their growth. This requirement for WT1 was confirmed in primary mouse cells, a mouse model of KRAS-driven lung cancer, and human cell lines. Importantly, a genetic signature characteristic of loss of the WT1 gene identified those patients with improved survival among a group of lung cancer patients whose disease was associated with KRAS mutations. These data identify a link between cancer-causing KRAS signaling and expression of WT1. Both the authors and, in an accompanying commentary, Joseph Kissil and Silvia Licciulli, at the Wistar Institute, Philadelphia, suggest that further studies of this link could provide new therapeutic targets for the treatment of KRAS-driven cancers.

TITLE: Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models

AUTHOR CONTACT:
E. Alejandro Sweet-Cordero
Stanford University School of Medicine, Stanford, California, USA.
Phone: 650.725.5901; Fax: 650.736.0195; E-mail: ascor@stanford.edu.

View this article at: http://www.jci.org/articles/view/44165?key=a613ddb99b5ac4a1ce9e

ACCOMPANYING COMMENTARY
TITLE: WT1: a weak spot in KRAS-induced transformation

AUTHOR CONTACT:
Joseph L. Kissil
The Wistar Institute, Philadelphia, Pennsylvania, USA.
Phone: 215.898.3874; Fax: 215.898.3572; E-mail: jkissil@wistar.org.

View this article at: http://www.jci.org/articles/view/44901?key=01be8afb76e5b9a60dda




ONCOLOGY: Processing the facts: protein-template processing linked to lung cancer

A team of researchers, led by Charles Chalfant, at Virginia Commonwealth University, Richmond, has determined that dysregulation of a mechanism controlling protein expression contributes to the cancerous characteristics of non-small cell lung cancer (NSCLC) tumors.

A protein in a cell is made from a template known as an mRNA molecule, which in turn is a copy of the information contained in a gene. mRNA molecules undergo numerous processing events, each of which can affect protein expression. In this study, Chalfant and colleagues found that an mRNA processing event known as alternative splicing was modulated in human NSCLC cells. Specifically, the ratio of caspase-9a/caspase-9b mRNA molecules, which are generated from the same caspase-9 mRNA by alternative splicing, was dramatically reduced in human NSCLC cells. This reduction has implications for tumor development because caspase-9a generates a protein that promotes cell death while caspase-9b generates a protein that inhibits cell death. Further analysis revealed that increased activity of the protein hnRNP L, which promotes production of caspase-9b mRNA, was behind the change in alternative splicing in human NSCLC cells. Importantly, downregulation of hnRNP L in NSCLC cells rendered them incapable of forming a tumor when transplanted into mice due to the changes in alternative splicing of caspase-9 mRNA.

In an accompanying commentary, Kristen Lynch, at the University of Pennsylvania, Philadelphia, discusses the importance of these data for understanding the mechanisms driving NSCLC and for their therapeutic implications.

TITLE: hnRNP L regulates the tumorigenic capacity of lung cancer xenografts in mice via caspase-9 pre-mRNA processing

AUTHOR CONTACT:
Charles E. Chalfant
Virginia Commonwealth University, Richmond, Virginia, USA.
Phone: 804.828.9526; Fax: 804.828.1473; E-mail: cechalfant@vcu.edu.

View this article at: http://www.jci.org/articles/view/43552?key=68ebdf2c321605b15458

ACCOMPANYING COMMENTARY
TITLE: Living or dying by RNA processing: caspase expression in NSCLC

AUTHOR CONTACT:
Kristen W. Lynch
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215.573.7749; Fax: 215.573.8899; E-mail: klync@mail.med.upenn.edu.

View this article at: http://www.jci.org/articles/view/45037?key=efe5b1de65901d70cc63




INFLAMMATION: White blood cell numbers rescued with the drug rapamycin

Individuals with conditions associated with sustained immune system activity, e.g., those with chronic infections, chronic inflammation, or autoimmune diseases, often have decreased numbers of white blood cells and platelets (cells in the blood that are key to stopping bleeding). Pan Zheng, Yang Liu, and colleagues, at the University of Michigan, Ann Arbor, have now shown that the decreased blood cell numbers observed in both a mouse model of autoimmune disease and a mouse model of inflammation are a result of excessive activation of the mTOR signaling pathway in hematopoietic stem cells -- the cells in the bone marrow that give rise to all cell types in the blood. Importantly, treatment of the mice with rapamycin (a drug that inhibits mTOR signaling and is used in the clinic to prevent transplanted organs from being rejected) substantially improved the low white blood cell numbers. As noted by the authors, and, in an accompanying commentary, Stephen Emerson and Russell Garrett, at Haverford College, these data have important implications for patient care.

TITLE: Mammalian target of rapamycin activation underlies HSC defects in autoimmune disease and inflammation in mice

AUTHOR CONTACT:
Pan Zheng
University of Michigan, School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Phone: 734.615.3158; Fax: 734.763.2162; E-mail: panz@umich.edu

Yang Liu
University of Michigan, School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Phone: 734.615.3158; Fax: 734.763.2162; E-mail: yangl@umich.edu.

View this article at: http://www.jci.org/articles/view/43873?key=b3c470174c32138da90c

ACCOMPANYING COMMENTARY
TITLE: Pharmacologic eigenvalues: beating the rap on bone marrow failure

AUTHOR CONTACT:
Stephen G. Emerson
Haverford College, Haverford, Pennsylvania, USA.
Phone: 610.896.1021; Fax: 610.896.2402; E-mail: semerson@haverford.edu.

View this article at: http://www.jci.org/articles/view/45060?key=0b1d96d981ca575606dd




VASCULAR BIOLOGY: Gasping for oxygen: how blood vessel-lining cells respond

The amount of oxygen available to a tissue becomes reduced in many natural settings, such as wound healing and exercise, and in many disease settings, such as heart attack, stroke, and cancer. Cells have therefore developed a complex response to reduced oxygen levels in order to survive. Key to this response is decreased degradation of the protein HIF-1-alpha, which promotes the growth of new blood vessels from pre-existing vessels (a process known as angiogenesis). Sundaram Ramakrishnan and colleagues, at the University of Minnesota, Minneapolis, have now identified in human endothelial cells (the cells that line blood vessels) a new mechanism by which HIF-1-alpha levels are stabilized.

MicroRNAs are small RNA molecules with a potent ability to regulate protein expression. In the study, Ramakrishnan and colleagues found that hypoxia increased levels of microRNA-424 in isolated human endothelial cells. Further analysis characterized a molecular mechanism by which this microRNA stabilized HIF-1-alpha and demonstrated that it promoted angiogenesis in vitro and in mice. In an accompanying commentary, Joseph Loscalzo, at Harvard Medical School, Boston, describes how this new pathway provides an elegant control system for modulating the endothelial cell response to reduce oxygen levels.

TITLE: Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-alpha isoforms and promotes angiogenesis

AUTHOR CONTACT:
Sundaram Ramakrishnan
University of Minnesota, Minneapolis, Minnesota, USA.
Phone: 612.626.6461; Fax: 612.625.8408; E-mail: sunda001@umn.edu.

View this article at: http://www.jci.org/articles/view/42980?key=7c0e6bfab9bbeaca94dd

ACCOMPANYING COMMENTARY
TITLE: The cellular response to hypoxia: tuning the system with microRNAs

AUTHOR CONTACT:
Joseph Loscalzo
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617.732.6340; Fax: 617.732.6439; E-mail: jloscalzo@partners.org.

View this article at: http://www.jci.org/articles/view/45105?key=da96cf07965800364e10
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