JCI table of contents: June 20, 2008

June 20, 2008

EDITOR'S PICK: Smoking out the mediators of airway damage caused by pollutants

New insight into how pollution and cigarette smoke damage airways has been provided by Pierangelo Geppetti and colleagues, at the University of Florence, Italy, who studied the effects of such chemicals on guinea pig airways. As discussed, in an accompanying commentary, by Sidney Simon and Wolfgang Liedtke, at Duke University Medical Center, it is hoped that this information will help in the development of therapeutics to combat the effects of pollutants and perhaps help individuals with smoke-related diseases such as chronic obstructive pulmonary disease and chronic asthma.

In the study, chemicals found in cigarette smoke were shown to activate signaling in nerves that ended in the airways of guinea pigs. These effects were abolished using a molecule that inhibited a protein known as TRPA1. Consistent with a central role for TRPA1 in sensing chemicals in cigarette smoke, no signaling in nerves that end in the airways was observed in mice lacking TRPA1 after exposure to the chemicals in cigarette smoke. Further analysis showed that alpha,beta-unsaturated aldehydes were the chemicals that activated TRPA1, suggesting that they might contribute to the airway damage that occurs in smoke-related diseases.

TITLE: Cigarette smoke-induced neurogenic inflammation is mediated by alpha,beta-unsaturated aldehydes and the TRPA1 receptor in rodents

AUTHOR CONTACT:
Pierangelo Geppetti
University of Florence, Florence, Italy.
Phone: 39-055-427-1329; Fax: 39-055-427-1280; E-mail: pierangelo.geppetti@unifi.it.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34886

ACCOMPANYING COMMENTARY

TITLE: How irritating: the role of TRPA1 in sensing cigarette smoke and aerogenic oxidants in the airways

AUTHOR CONTACT:
Sidney A. Simon
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 684-4178; Fax: (919) 684-4431; Email: sas@neuro.duke.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36111




EDITOR'S PICK: Battle of the bulge: low leptin levels undermine successful weight loss

Individuals who are obese are at increased risk of many diseases, including type 2 diabetes and heart disease. As 75%-95% of previously obese individuals regain their lost weight, many researchers are interested in developing treatments to help individuals maintain their weight loss. A new study, by Michael Rosenbaum and colleagues, at Columbia University Medical Center, New York, has provided new insight into the critical interaction between the hormone leptin and the brain's response to weight loss.

Leptin levels fall as obese individuals lose weight. So, the authors set out to see whether changes in leptin levels altered activity in the regions of the brain known to have a role in regulating food intake. They observed that activity in these regions of the brain in response to visual food-related cues changed after an obese individual successfully lost weight. However, these changes in brain activity were not observed if the obese individual who had successfully lost weight was treated with leptin. These data are consistent with the idea that the decrease in leptin levels that occurs when an individual loses weight serves to protect the body against the loss of body fat. Further, both the authors and, in an accompanying commentary, Rexford Ahima, at the University of Pennsylvania School of Medicine, Philadelphia, suggest that leptin therapy after weight loss might improve weight maintenance by overriding this fat-loss defense.

TITLE: Leptin reverses weight loss-induced changes in regional neural activity responses to visual food stimuli

AUTHOR CONTACT:
Michael Rosenbaum
Columbia University Medical College, New York, New York, USA.
Phone: (212) 305-9949; Fax: (212) 851-5306; E-mail: mr475@columbia.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35055

ACCOMPANYING COMMENTARY

TITLE: Revisiting leptin's role in obesity and weight loss

AUTHOR CONTACT:
Rexford S. Ahima
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-1872; Fax: (215) 573-5809; E-mail: ahima@mail.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36284




ONCOLOGY: Overcoming resistance to a cancer drug

Drugs that target members of the EGFR family of proteins have proven effective for the treatment of certain types of cancer, including breast cancer. However, in a large number of patients for whom the treatment initially works well, the tumor recurs and is resistant to the effects of the drug. New insight into the mechanisms of tumor resistance to a drug known as gefitinib, which targets EGFR, has now been provided by a team of researchers at Vanderbilt University Medical Center, Nashville, and Massachusetts General Hospital Cancer Center, Charlestown. As discussed by both the authors and, in an accompanying commentary, Mark Greene and Qiang Wang, at the University of Pennsylvania Medical Center, Philadelphia, these observations help us understand why tumors become resistant to the effects of EGFR-targeted drugs, information that is essential if more effective therapies are to be developed.

The team, led by Carlos Arteaga and Jeffrey Engelman, generated cancer cells resistant to the effects of gefitinib and found that these cells were constantly sending signals from a protein on their surface known as IGF1R. This meant that two proteins known as IRS-1 and PI3K were always associated. If this association was disrupted then the cells once again became susceptible to the effects of gefitinib. Further analysis showed that if mice with a human tumor were treated with gefitinib and a drug inhibiting IGF1R their tumors did not recur, whereas neither drug alone could prevent tumor recurrence. The authors therefore suggest that drug combinations that target both EGFR and IGF1R might be of benefit to individuals with cancers that are responsive to EGFR-targeted therapies.

TITLE: Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins

AUTHOR CONTACT:
Carlos L. Arteaga
Vanderbilt University Medical Center, Nashville, Tennessee, USA
Phone: (615) 936-3524; Fax: (615) 936-1790; E-mail: carlos.arteaga@vanderbilt.edu.

Jeffrey A. Engelman
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts, USA.
Phone: (617) 724-7298; Fax: (617) 724-9648; E-mail: jengelman@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34588

ACCOMPANYING COMMENTARY

TITLE: Mechanisms of resistance to ErbB-targeted cancer therapeutics

AUTHOR CONTACT:
Mark I. Greene
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 898-2870; Fax: (215) 898-2401; Email: greene@reo.med.upenn.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36260




IMMUNOLOGY: How an anticancer drug dampens the immune system

Drugs known as HDAC inhibitors, which have antitumor activity and can be used to treat some forms of skin cancer and some types of leukemia, are also known to have anti-inflammatory properties, but the mechanisms by which they modulate the immune system have not been determined. New data, generated by Pavan Reddy and colleagues, at the University of Michigan Cancer Center, Ann Arbor, have now indicated one mechanism by which HDAC inhibitors modulate the mouse and human immune system and the information gained has been used to develop an approach to protect mice from graft-versus-host disease after bone marrow transplantation.

In the study, two different HDAC inhibitors were shown to prevent mouse and human immune cells known as dendritic cells (DCs) from initiating proinflammatory immune responses in vitro. Further, if DCs treated ex vivo with HDAC inhibitors were injected into mice after they had received a bone marrow transplant, the incidence and severity of graft-versus-host disease was dramatically reduced. Detailed analysis revealed that the HDAC inhibitors mediated their effects by inducing DCs to express more of a molecule known as IDO, which is a suppressor of DC function. The authors therefore hope that their data provide support for studies to determine whether HDAC inhibitors might be of benefit to individuals receiving bone marrow transplants and to those with other immune-mediated diseases.

TITLE: Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase-dependent DC functions and regulates experimental graft-versus-host disease in mice

AUTHOR CONTACT:
Pavan Reddy
University of Michigan Cancer Center, Ann Arbor, Michigan, USA.
Phone: (734) 647-5954; Fax: (734) 647-9271; E-mail: reddypr@umich.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34712




VASCULAR BIOLOGY: A prickly problem: hedgehog signaling in the blood vessels of the heart

New data, generated by David Ornitz and colleagues, at Washington University School of Medicine, St. Louis, have indicated a crucial role for signaling pathways that involve the protein sonic hedgehog in maintaining the blood vessels that supply the mouse heart and keep it beating. These data have implications for drug development as they suggest that antagonists of hedgehog signaling pathways, such as those being developed as anticancer therapeutics, might have unwanted side effects.

In the study, mice lacking the ability to mediate hedgehog signaling in cells that form part of the blood vessels that supply the heart were found to die of heart failure. This was because in the absence of hedgehog signaling the blood vessels of the heart were lost, meaning that the heart cells were no longer supplied with enough oxygen and died. Although these data indicate a need for caution when developing clinical antagonists of hedgehog signaling, it is possible that the degree of inhibition needed to have a clinical effect on tumor development might not have the effect on blood vessels of the heart that completely eliminating expression of the protein does.

TITLE: Hedgehog signaling is critical for maintenance of the adult coronary vasculature in mice

AUTHOR CONTACT:
David M. Ornitz
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-3908; Fax: (314) 362-7058; E-mail: dornitz@wustl.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34561




VIROLOGY: How a measles virus infection gets going

New data, generated by Roberto Cattaneo and colleagues, have raised doubts about the current model of the initial events that lead to infection with measles virus.

Individuals inhale measles virus particles in aerosols and it is currently thought that these particles infect the cells that line the airways (respiratory epithelial cells) before being passed to immune cells that carry the virus particles to other parts of the body and then back to the airways, which again become infected and shed virus into exhaled aerosols. In the study, a measles virus unable to bind to and infect epithelial cells was found to cause symptoms of measles virus infection in monkeys even though it did not infect respiratory epithelial cells and was not being shed into exhaled aerosols. These data suggest that, in fact, inhaled measles virus particles first infect lymphocytes and are only passed to respiratory epithelial cells from the lymphocytes in the tissues. Further, they indicate that the protein that measles virus particles bind to on respiratory epithelial cells, which has yet to be identified, is likely to be found on the surface of the cells that faces the tissues rather than the surface that faces the airways, as previously assumed. As discussed in an accompanying commentary by Makoto Takeda, at Kyushu University, Japan, the results of this study should help researchers identify this protein.

TITLE: Measles virus blind to its epithelial cell receptor remains virulent in rhesus monkeys but cannot cross the airway epithelium and is not shed

AUTHOR CONTACT:
Roberto Cattaneo
Mayo Clinic, Rochester, Minnesota, USA.
Phone: (507) 538-1188; Fax: (507) 266-2122; E-mail: cattaneo.roberto@mayo.edu.

MEDIA CONTACT:
Robert J Nellis
Mayo Clinic, Rochester, Minnesota, USA.
Phone: (507) 284-5005; E-mail: Nellis.Robert@mayo.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35454

ACCOMPANYING COMMENTARY

TITLE: Measles virus breaks through epithelial cell barriers to achieve transmission

AUTHOR CONTACT:
Makoto Takeda
Kyushu University, Fukuoka, Japan.
Phone: 81-92-642-6138; Fax: 81-92-642-6140; Email: mtakeda@virology.med.kyushu-u.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36251




INFLAMMATION: Immune cells cause inflammation by destroying an anti-inflammatory protein

Among the first cells of the immune system to respond to microorganisms that invade our body are neutrophils. Although neutrophils are considered the "good guys" in such circumstances, they also contribute to the noninfectious chronic inflammation that underlies various diseases, including autoimmune diseases such as rheumatoid arthritis. One mechanism by which neutrophils protect us is to internalize microorganisms and destroy them using proteins known as neutrophil serine proteases (NSPs), but whether NSPs have a role in noninfectious chronic inflammation has not been clearly determined. However, using mice lacking two very similar NSPs, PR3 and NE, a team of researchers at the Max-Planck-Institute of Neurobiology, Germany, have now shown that these two NSPs have a crucial role in one form of noninfectious chronic inflammation. Detailed analysis revealed that PR3 and NE destroy an anti-inflammatory molecule known as PGRN and in this way help to promote inflammation in the absence of invading microorganisms. The authors therefore suggest that these data provide rationale for considering inhibitors of NSPs as anti-inflammatory drugs.

TITLE: Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin

AUTHOR CONTACT:
Kai Kessenbrock
Max-Planck-Institute of Neurobiology, Martinsried, Germany.
Phone: 49-89-8578-3588; Fax: 49-89-8578-3790; E-mail: kessenbrock@neuro.mpg.de.

Dieter E. Jenne
Max-Planck-Institute of Neurobiology, Martinsried, Germany.
Phone: 49-89-8578-3589; Fax: 49-89-8578-3790; E-mail: djenne@neuro.mpg.de.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34694
-end-


JCI Journals

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.