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Pulmonary Fibrosis |
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Biomarkers identified for idiopathic
pulmonary fibrosis
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The first evidence of a distinctive protein
signature that could help to transform the diagnosis
and improve the monitoring of the devastating lung
disease idiopathic pulmonary fibrosis (IPF) is being
reported by University of Pittsburgh School of
Medicine researchers in this month’s edition of
PLoS Medicine, an open-access journal of the
Public Library of Science.
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In the paper, Naftali Kaminski, M.D.,
director of the Dorothy P. & Richard P. Simmons
Center for Interstitial Lung Disease in the Division
of Pulmonary, Allergy and Critical Medicine at the
University of Pittsburgh School of Medicine, and his
colleagues describe a unique combination of blood
proteins that appears to distinguish IPF patients
from normal controls with extraordinary sensitivity
and precision.
“Our findings suggest that we may be able to monitor
what is happening in the lungs by measuring certain
proteins in the peripheral blood,” explains senior
author Dr. Kaminski, who also is associate professor
of medicine. “More study is needed to confirm
whether these biomarkers might be useful as a
clinical blood test to detect lung fibrosis. But
right now, there is no straightforward test for IPF.
The lung is not highly accessible; biopsy procedures
carry risk, and while imaging is good, it can’t
follow the disease biologically.”
IPF is a degenerative illness distinguished by
progressive lung scarring and diminished breathing
capacity, typically leading to death within about
five years of diagnosis. It is estimated that 5
million people worldwide and 130,000 in the United
States are affected by pulmonary fibrosis and about
30,000 people die of the disease every year. For
this study, researchers analyzed the concentrations
of 49 proteins in the plasma of 74 patients with IPF
and 53 normal controls. A combination of five
proteins related to normal tissue breakdown and
remodeling and certain disease processes, including
arthritis and cancer, was found to be highly
indicative of IPF.
Increases in two of the five, matrix
metalloproteinases (MMP) 7 and 1, also were observed
in tissue and fluid taken from the lungs of IPF
patients. Other proteins in the IPF signature are
matrix metalloproteinase 8, insulin-like growth
factor binding protein 1 and tumor necrosis factor
receptor superfamily member 1A. “These proteins were
increased in IPF patients, but not in patients with
lung illnesses such as chronic obstructive pulmonary
disease,” says Ivan O. Rosas, M.D., first author on
the study and assistant professor of medicine,
University of Pittsburgh School of Medicine.
Elevated MMP1 and MMP7 also distinguished IPF when
compared to levels associated with another disease
that closely mimics IPF, called subacute/chronic
hypersensitivity pneumonia. In particular, increased
concentrations of MMP7 “may be indicative of
asymptomatic lung disease and perhaps reflect
disease progression,” Dr. Rosas says.
“One of the challenges is to know whether a blood
protein actually reflects the situation in the
lung,” notes Thomas J. Richards, Ph.D., study
co-first author and research assistant professor in
the Division of Pulmonary, Allergy and Critical Care
Medicine, University of Pittsburgh School of
Medicine. The team evaluated all the genes expressed
in IPF-affected lung tissue to determine the
proteins in the peripheral blood on which they
should focus. Based on their detailed analysis, the
team believes that increased levels of these five
proteins probably are reflective of the disease.
“IPF can have a slow progression, so drug companies
may wait a long time to see whether a particular
drug is having any effect,” says Dr. Kaminski. “But
a blood biomarker could indicate whether a drug is
working earlier. The biomarkers also might be used
for risk assessment and for evaluation of disease
progression.”
Some known causes of pulmonary fibrosis include
occupational and environmental exposure to asbestos,
metal dust, farming chemicals and mold, an
inflammatory disease called sarcoidosis, radiation,
drug reactions, autoimmune disorders and possibly a
genetic predisposition, according to the American
Lung Association. Most cases are considered to be
idiopathic, or of unknown origin. There is no proven
effective therapy for IPF, and most drug
interventions are considered experimental. Long-term
benefit may be possible with lung transplantation, a
radical approach dependent upon a limited number of
donated organs.
Source: University of Pittsburgh,
April 29, 2008
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Former
InterMune CEO W. Scott Harkonen Indicted for
Wire Fraud and FDA Violations
SAN FRANCISCO, March 18 /PRNewswire-USNewswire/
-- W. Scott Harkonen, M.D., the
former CEO of InterMune Inc., was
indicted on wire fraud and felony
Food, Drug and Cosmetic Act charges
for his role in the creation and
dissemination of false and
misleading information about the
efficacy of InterMunes drug
Actimmune (Interferon gamma-1b) as a
treatment for idiopathic pulmonary
fibrosis (IPF), the Justice
Department announced today.
The indictment alleges that
Harkonen, a medical doctor, was the
chief executive officer of InterMune
from February 1998 through June 30,
2003, and a member of InterMunes
board of directors from February
1998 through September 2003. Under
Harkonen's direction, InterMune
marketed and sold Actimmune to treat
IPF, a fatal disease, despite the
fact that the drug was not approved
by the Food and Drug Administration
(FDA) as a safe and effective
treatment.
According to the indictment,
Harkonen promoted and caused the
promotion by InterMune of Actimmune
as a safe and effective treatment
for IPF, despite the lack of FDA
approval, in order to sell more
Actimmune and to generate revenues
and profits from sales of the
pharmaceutical for InterMune. The
cost of Actimmune for one IPF
patient for one year was
approximately $50,000 and the vast
majority of the companys sales of
Actimmune were for the unapproved,
off-label use of treating IPF.
The indictment further states
that Harkonen devised a scheme to
induce doctors to prescribe, and
patients to take, Actimmune to treat
IPF. As part of that scheme to
defraud, on Aug. 28, 2002, InterMune
issued a press release publicly
announcing the results of a clinical
trial of Actimmune for the treatment
of IPF. Although the clinical trial
in fact failed, Harkonen caused the
issuance and distribution of a false
and misleading press release to
portray that the results of the
trial established that Actimmune
helped IPF patients live longer.
Specifically, the press release's
headline falsely stated that,
InterMune Announces Phase III Data
Demonstrating Survival Benefit of
Actimmune in IPF, with the
subheading Reduces Mortality by 70%
in Patients With Mild to Moderate
Disease.
According to the indictment, it
was part of the scheme to defraud
that the information in the press
release be conveyed to pharmacies
that sold Actimmune and to patients
and doctors. In furtherance of this
scheme, defendant Harkonen caused a
specialty pharmacy to distribute the
misleading information in the press
release to more than 2,000
pulmonologists and to patients
taking Actimmune.
In October 2006, InterMune agreed
to enter into a deferred prosecution
agreement and to pay nearly $37
million to resolve criminal charges
and civil liability in connection
with the illegal promotion and
marketing of its drug Actimmune.
InterMune also entered into a 5-year
Corporate Integrity Agreement with
the Office of Inspector General for
the Department of Health and Human
Services.
When corporate executives provide
false and misleading information
about pharmaceuticals, they
jeopardize the public health and
welfare, said Jeffrey S. Bucholtz,
acting Assistant Attorney General
for the Civil Division. The
Department of Justice is committed
to ensuring that patients and their
doctors receive truthful information
about medical products and will hold
accountable those individuals who
are responsible for sending the
public deceptive information.
The U.S. Attorney's Office for
the Northern District of California
is committed to protecting the
public against health care fraud,
said Brian J. Stretch, acting U.S.
Attorney. Those who unlawfully
violate the trust that exists among
the biotechnology industry, the FDA,
doctors and patients will be
prosecuted.
The maximum statutory penalty for
wire fraud is 20 years in prison, a
$250,000 fine, three years
supervised release, and $100
mandatory special assessment. The
maximum statutory penalty for acting
with intent to defraud and mislead,
resulting in drugs being misbranded
while held for sale after shipment
in interstate commerce, is three
years in prison, a $250,000 fine,
one year supervised release, and
$100 mandatory special assessment.
However, any sentence following
conviction would be imposed by the
court after consideration of the
U.S. Sentencing Guidelines and the
federal statute governing the
imposition of a sentence. Harkonen
is scheduled to be arraigned on
Friday, March 28, 2008, at 9:30 a.m.
before the Hon. Magistrate Judge
Joseph C. Spero.
Pharmaceutical executives who
promote drugs using false and
misleading information should not be
allowed to hide behind a corporate
shield, said Kim Rice, Special Agent
in Charge of FDA's Office of
Criminal Investigations, Washington
Field Office. Pharmaceutical
companies do not run themselves, and
those who engage in criminal conduct
will be held personally accountable.
We have an obligation to pursue
and bring to justice those who prey
on the vulnerable and place profits
before public health, said FBI
Special Agent in Charge Charlene B.
Thornton. This four-year
investigation reflects the
seriousness with which the FBI takes
violations of the law by those
entrusted to safeguard the health of
the public.
The results of this criminal
investigation show our commitment to
protect the Veteran Administrations
healthcare system from deceptive and
fraudulent practices by
pharmaceutical companies, said
Special Agent in Charge Douglas J.
Carver of the U.S. Department of
Veterans Affairs, Office of
Inspector General. These charges are
the result of a multi-year
investigation by the Federal Bureau
of Investigation; the Food and Drug
Administration's Office of Criminal
Investigations; the Department of
Veterans Affairs' Office of
Investigations; and the Office of
Personnel Management's Office of
Investigations.
This case is being prosecuted by
Assistant U.S. Attorney Ioana Petrou
of the Northern District of
California and trial Attorneys
Sondra Mills and Allan Gordus of the
Office of Consumer Litigation in the
Civil Division in Washington with
the assistance of Associate Chief
Counsel Anne Walsh of the FDA Office
of General Counsel, Paralegal
Specialists Maryam Beros and Matthew
McCrobie, and Legal Technician Ana
Guerra.
An indictment contains only
allegations against an individual
and, as with all defendants, the
defendant in this case must be
presumed innocent unless and until
proven guilty.
SOURCE U.S. Department of Justice
Contact: U.S. Department of
Justice Office of Public Affairs,
+1-202-514-2007, TDD,
+1-202-514-1888
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How Can We Develop New Treatments
For
Idiopathic Pulmonary Fibrosis?
04 Mar 2008
Idiopathic pulmonary fibrosis (IPF)
is a devastating lung disorder of
unknown cause that leads to death in
a relatively short time because of
the lack of any effective treatment.
In an article in this week's PLoS
Medicine, a team of researchers
from Mexico and the US discusses how
a better understanding of the
molecular pathways involved in
causing IPF may lead to the
development
of new therapies.
Moisés Selman (Instituto Nacional de
Enfermedades Respiratorias, Mexico
City, Mexico) and colleagues say
that the lungs of patients with IPF
are enriched with genes associated
with lung development in the embryo.
In healthy adults, these genes are
switched off but they appear to
be abnormally switched on in IPF.
"Dysfunctional activation of
embryological pathways regularly
repressed in the adult life may
explain the persistent nature of the
disease," say the authors.
"Designing and implementing
interventions that target these
embryological pathways may be
required to develop novel anti-IPF
therapies and to significantly
improve the outcome of IPF
patients."
Citation: Selman M, Pardo A,
Kaminski N (2008) Idiopathic
pulmonary fibrosis: Aberrant
recapitulation of developmental
programs? PLoS Medicine 5(3):
e62.
Link to the published article.
CONTACT:
Moisés Selman
Instituto Nacional de Enfermedades
Respiratorias
Tlalpan 4502
Mexico City, DF 14080
Mexico
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New organ-transplant method
could eliminate rejection drugs
Jan. 24, 2008: LOS ANGELES - In what is being called a major
advance in organ transplants, doctors say they have
developed a technique that could free many patients from
having to take anti-rejection drugs for the rest of their
lives.
The treatment involved weakening the patient's immune
system, then giving the recipient bone marrow from the
person who donated the organ. In one experiment, four of
five kidney recipients were off immune-suppressing medicines
up to five years later.
"There's reason to hope these patients will be off drugs for
the rest of their lives," said Dr. David Sachs of
Massachusetts General Hospital in Boston, who led the
research published in today's New England Journal of
Medicine.
Since the world's first transplant more than 50 years ago,
scientists have searched for ways to trick the body to
accept a foreign organ as its own. Immune-suppressing drugs
that prevent organ rejection came into wide use in the
1980s. But they raise the risk of cancer and kidney failure.
And they have side effects such as excessive hair growth,
bloating and tremors.
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Acid
Reflux Study Looks At Lifespan Of
Sufferers
Jan. 4th, 2008: Gastroesophageal reflux
disease (GERD), often known as acid
reflux, is a common problem that has
been associated with cancers, asthma,
recurrent aspiration and pulmonary
fibrosis. A new study published in
The American Journal of Gastroenterology
examines whether GERD sufferers may have
shorter lifespans than those without the
disease.
Drawing on over 50,000 person-years of
data, the study provides reassuring
evidence that people with acid reflux
symptoms do not have an increased risk
of death, finding no difference in
survival rates between sufferers and
non-sufferers.
In fact, the study finds that people
with infrequent acid reflux may actually
have better survival rates than those
with either daily symptoms, or none at
all. "It may be that occasional reflux
symptoms are a reflection of potential
protective behaviors that are associated
with reflux, such as regular exercise or
modest amounts of alcohol ingestion,"
suggest Nicholas J. Talley and G.
Richard Locke, III, co-authors of the
study.
The study adds perspective to the risk
of acid reflux symptoms. While there are
a large number of acid reflux sufferers
in the U.S., incidences of related
cancer are extremely rare. "Although
extraesophageal manifestations occur in
some people with reflux disease, our
results suggest that this disease is a
benign condition in the vast majority of
sufferers," say the authors.
This
study is published in The American
Journal of Gastroenterology.
Nicholas J. Talley, M.D.,
Ph.D., is Editor-in-Chief of The
American Journal of Gastroenterology; a
Professor of Medicine and Epidemiology
at the Mayo Clinic College of Medicine;
and Chair of the Department of Internal
Medicine at the Mayo Clinic,
Jacksonville.
G. Richard Locke, III, M.D., is a
Professor of Medicine at the Mayo Clinic
College of Medicine; Consultant,
Division of Gastroenterology and
Hepatology, Department of Internal
Medicine; and Consultant, Division of
Health Care Policy & Research,
Department of Health Sciences Research
at the Mayo Clinic. |
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Translational
research patented first experimental treatment against
idiopathic pulmonary fibrosis
Innovative pneumocytes
transplantation has reverted the disease for the first time in
rats
21-Dec-2007 Barcelona, Spain:
Idiopathic pulmonary fibrosis is a disease with
unknown cause with a very severe prognosis; when detected, it is
already in an advanced stage. Patients suffering from it cannot
develop with normality pulmonary gas exchange, and have a very
reduced quality of life. Because of lack of an effective
treatment, they rarely survive 5 years after being diagnosed.
Idiopathic pulmonary fibrosis affects 13 out of 100,000 men and
7 out of 100,000 women, normally over 40 years of age.
Researchers from the Biomedical Research Institute of Barcelona
CSIC (IIBB-CSIC), a centre developing research in the framework
of the Institut d’Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), have discovered and patented a method to stop and
revert this disease in an animal model. A clinical study will be
soon conducted in humans in the Hospital Clínic de Barcelona.
Results of their research work are published in the last
issue of the American Journal of Respiratory and Critical
Care Medicine (176(12):1261-8).
This study has had the collaboration of basic researchers, such
as Dr. Anna Serrano-Mollar, and Dr. Oriol Bulbena,
first and last signatories of the study; and researchers with a
clinical background, such as Dr. Antoni Xaubet, from the
Unit of Pneumology of the Hospital Clínic de Barcelona. This
turns this work into a paradigm of translational research
promoted in IDIBAPS and through other initiatives such as the
Network of Centres of Biomedical Research (CIBERs). This
research work has been financed through a contribution from the
Fondo de Investigaciones Sanitarias (FIS) from the Instituto de
Salud Carlos III.
Gas exchange is developed in lungs thanks to type 1
pneumocytes in alveoli, cells recovering the inner walls of the
alveolar cavity. Occupying the same spaces, there are also type
II pneumocytes, precursor cells that repair the damaged alveolar
tissue. When idiopathic pulmonary fibrosis appears, this
regeneration process cannot be developed correctly and fibrosis
advances until respiration is impossible. The technique
developed by researchers from the IIBB-CSIC-IDIBAPS consists in
a transplantation of type II pneumocytes via intratracheal. In
order to monitor correctly the transplanted cells with genetic
and fluorescence techniques, sexual chromosomal differences were
used. Thus, the disease was induced in female rats, and cells
from male rats were transplanted. This is a lowly invasive
technique which has permitted to regenerate, for the first time,
rat fibrotic alveoli where idiopathic pulmonary fibrosis was
induced.
CSIC has patented as a treatment the cell suspension
transplanted with this innovative strategy. The world patent
will be proved in humans with a clinical study, soon conducted
in the Hospital Clínic de Barcelona thanks to the financing of
the Fundación Genoma España and CSIC This study will have the
participation of 6 recently diagnosed patients who will receive
a suspension of type II pneumocytes coming from a dead donor,
since these cells cannot be cultured in the laboratory. All this
events throw new and hopeful light into basic and clinical
research lines. One of the following steps of researchers will
be to try to obtain type II pneumocytes from adult stem cells.
Further information:
Communication Area IDIBAPS
Marc de Semir, Head of Communication (mdesemir@clinic.ub.es)
Àlex Argemí, scientific editor (aargemi@clinic.ub.es)
Tel.: 00 34 93 227 57 00
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Fibrosis
can be Stopped,
Cured and
Reversed
| Tue 18-Dec-2007,
University of California, San Diego
researchers have proven in animal
studies that fibrosis in the liver can
be not only stopped, but reversed. Their
discovery, to be published in PLoS
Online on December 26, opens the door to
treating and curing conditions that lead
to excessive tissue scarring such as
viral hepatitis, fatty liver disease,
cirrhosis, pulmonary fibrosis,
scleroderma and burns.
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University of California, San Diego
researchers have proven in animal studies that
fibrosis in the liver can be not only stopped,
but reversed. Their discovery, to be published
in PLoS Online on December 26, opens the
door to treating and curing conditions that lead
to excessive tissue scarring such as viral
hepatitis, fatty liver disease, cirrhosis,
pulmonary fibrosis, scleroderma and burns.
Six years ago, the UC San Diego School of
Medicine research team discovered the cause of
the excess fibrous tissue growth that leads to
liver fibrosis and cirrhosis, and developed a
way to block excess scar tissue in mice. At that
time, the best hope seemed to be future
development of a therapy that would prevent or
stop damage in patients suffering from the
excessive scarring related to liver or lung
disease or severe burns.
In their current study, Martina Buck, Ph.D.,
assistant professor of medicine at UCSD and the
Veterans Affairs San Diego Healthcare System,
and Mario Chojkier, M.D., UCSD professor of
medicine and liver specialist at the VA, show
that by blocking a protein linked to
overproduction of scar tissue, they can not only
stop the progression of fibrosis in mice, but
reverse some of the cell damage that already
occurred.In response to liver injury – for
example, cirrhosis caused by alcohol – hepatic
stellate cell (HSC) activated by oxidative
stress results in large amounts of collagen.
Collagen is necessary to heal wounds, but
excessive collagen causes scars in tissues. In
this paper, the researchers showed that
activation of a protein called RSK results in
HSC activation and is critical for the
progression of liver fibrosis. They theorized
that the RSK pathway would be a potential
therapeutic target, and developed an RSK
inhibitory peptide to block activation of RSK.
The scientists used mice with severe liver
fibrosis – similar to the condition in humans
with cirrhosis of the liver – that was induced
by chronic treatment with a liver toxin known to
cause liver damage. The animals, which continued
on the liver toxin, were given the RSK-inhibitory
peptide. The peptide inhibited RSK activation,
which stopped the HSC from proliferating. The
peptide also directly activated the caspase or
“executioner" protein, which killed the cells
producing liver cirrhosis but not the normal
cells.“All control mice had severe liver
fibrosis, while all mice that received the RSK-inhibitory
peptide had minimal or no liver fibrosis,” said
Buck. Buck explained that the excessive collagen
response is blocked by the RSK-inhibitory
peptide, but isn’t harmful to the liver. “The
cells continue to do their normal, healing work
but their excess proliferation is controlled,”
Buck said. “Remarkably, the death of HSC may
also allow recovery from liver injury and
reversal of liver fibrosis.”
The researchers found a similar activation of
RSK in activated HSC in humans with severe liver
fibrosis but not in control livers, suggesting
that this pathway is also relevant in human
liver fibrosis. Liver biopsies from patients
with liver fibrosis also showed activated RSK.
The study expands on work reported in 2001 in
the journal Molecular Cell announcing that a
team led by Buck had found that a small piece of
an important regulatory protein called C/EBP
beta was responsible for fibrous tissue growth,
or excessive scar tissue following injury or
illness. When normal scarring goes awry,
excessive build-up of fibrous tissue can produce
disfiguring scars or clog vital internal organs
and lead to serious complications. Buck and
colleagues developed a mutated protein that
stopped this excessive fibrous tissue growth.
“Six years ago, we showed a way to prevent or
stop the excessive scarring in animal models,”
said Buck. “Our latest finding proves that we
can actually reverse the damage.” Worldwide,
almost 800,000 people die from liver cirrhosis
each year, and there is currently no treatment
for it. Excessive tissue repair in chronic liver
disease induced by viral, toxic, immunologic and
metabolic disorders all result in excessive scar
tissue, and could benefit from therapy developed
from the UCSD researchers’ findings.The research
was supported by grants from the National
Institutes of Health, the Department of Veterans
Affairs and UCSD’s Medical Research Foundation.
Buck is the recipient of a Howard Temin Award
from the National Cancer Institute.
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Molecular pathway
appears crucial in development of pulmonary fibrosis
Discovery may
provide new therapeutic target for dangerous lung
disease
Massachusetts
General Hospital
12-Dec-2007
A study led by Massachusetts General
Hospital (MGH) researchers may have found a key
mechanism underlying idiopathic pulmonary fibrosis (IPF),
a usually fatal lung disease for which
transplantation is the only successful treatment.
The investigators found that a specific molecular
pathway appears responsible for key aspects of the
scarring of lung tissue that characterizes IPF, the
cause of which is currently unknown. The results
will appear in the January issue of Nature Medicine
and have received early online release.
“Identifying the key role of this pathway in the
development of fibrosis gives us an exciting new
target for devising treatments,” says Andrew Tager,
MD, of the MGH Pulmonary and Critical Care Unit, who
led the study. “An agent that blocks this pathway is
already being developed as a potential cancer
treatment, and we’re hoping to be able to test it in
our animal model of IPF to determine whether it
might be a candidate for trials in patients.”
About 50,000 new cases of IPF are diagnosed in
the U.S. each year, primarily in people aged 50 to
75. While some patients may survive for extended
periods, in others the diseases progresses rapidly,
leading to death in an average of 3 to 5 years.
Theories about the cause of IPF previously focused
on chronic inflammation of the lungs, but recent
evidence has suggested that an abnormal healing
response to some sort of lung injury may be
responsible.
The primary characteristic of IPF is scarring
(fibrosis) of the lung surface, rendering it unable
to transmit oxygen into the bloodstream. In any part
of the body, scarring occurs when cells called
fibroblasts, an important part of normal wound
healing, make collagen to reinforce the healing
matrix that forms over damaged tissue. Normally
scarring is limited, but if too many fibroblasts
travel to the site of an injury, large amounts of
collagen can be deposited, producing excessive,
fibrotic scarring. Fibroblasts are known to be
present in affected lung tissue in IPF, and previous
studies showed that the activity of factors that
attract fibroblasts to the site of an injury rises
with the severity of the disease. The current study
was designed to determine which specific
“chemoattractants” were associated with IPF,
something not previously known.
Analysis of fluid from the lung surfaces of a
mouse model of pulmonary fibrosis suggested that the
activity of lysoposphatidic acid (LPA), acting
through its receptor LPA1, was responsible for
attracting fibroblasts in the disorder. This
association was supported by the fact that a strain
of mice lacking the gene for LPA1 did not develop
pulmonary fibrosis when treated with a compound that
usually causes the disease in the animals. Lung
fluid samples from human IPF patients not only had
significantly higher levels of LPA than control
samples, laboratory tests showed that patient
samples attracted fibroblasts while fluid from
controls did not. In addition, an agent that blocks
the LPA1 receptor eliminated the ability of fluid
from IPF patients to attract fibroblasts.
“These results indicate that the LPA-LPA1 pathway
is responsible for the abnormal migration of
fibroblasts into the lungs in IPF, an absolutely
crucial step in the development of fibrosis,” says
Andrew Luster, MD, PhD, senior author of the study.
“This pathway appears to be involved in several
steps in the development of fibrosis, including the
leaking of blood vessels, which is why the LPA1
knockout mice are so dramatically protected. If
we’re right, then targeting this pathway should be a
very exciting new therapeutic strategy for IPF.”
Luster is director of the MGH Center for Immunology
and Inflammatory Disease (CIID) and a professor of
Medicine at Harvard Medical School (HMS). Tager is
also associated with the MGH CIID and has opened a
clinic focused on pulmonary fibrosis and related
lung diseases. He is an assistant professor of
Medicine at HMS.
Additional co-authors of the study are Peter
LaCamera, Barry Shea, Gabriele Campanella, John Wain,
Banu Karimi-Shah, Nancy Kim, and William Hart, of
the MGH; Moises Selman, National Institute for
Respiratory Disorders, Mexico; Zhenwen Zhao, and Yan
Xu, Indiana University School of Medicine; Vasiliy
Polosukhin, and Timothy Blackwell, Vanderbilt
University School of Medicine; Annie Pardo, National
Autonomous University of Mexico; and Jerold Chun,
Scripps Research Institute. The study was supported
by grants from the Pulmonary
Fibrosis Foundation, the American Lung
Association, the Nirenberg Center for Advanced Lung
Disease, the National Autonomous University of
Mexico, and the U.S. National Institutes of Health.
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Breakthrough
brings hope to Seattle scientists
UW to get cells early next year
Seattle
Wednesday, November 21, 2007
Tuesday's announcement that scientists have
created the equivalent of embryonic stem cells without
using an embryo has Seattle researchers cautiously
optimistic about the future of stem cell research in the
area. The research was published online by two journals,
Cell and Science. The Cell paper is from a team at Kyoto
University in Japan; the team published by Science was
from the University of Wisconsin-Madison.
Dr. Chuck Murry, a pathology professor at the
University of Washington, said he wrote to both groups
asking for cells to be sent to the university. The
Wisconsin scientists agreed to send them, probably by
the first of the year, he said. Murry's protocol for
regenerating damaged hearts in rats using embryonic stem
cells was used by the Japanese scientists whose work was
reported in Cell, he said.
"My intention is to get these cells in Seattle and do
what we want to do with them," Murray said. "I'm
cautiously enthusiastic ... things have been wrong
before and if it's not reproducible it's not science ...
but two very good labs have published (the same
findings) in two very good journals." Dr. Beverly
Torok-Storb, a stem cell scientist at the Fred
Hutchinson Cancer Research Center, said she and many
other scientists have been expecting this announcement
for some time. She pointed out that scientists still
must prove the cells are as good as embryonic stem cells
over the long haul. She cautioned against the public
expecting immediate cures and said the next step will be
to try to make certain the cells are safe for humans.
"Will they really be as good and as long-lived as an
embryonic stem cell? We don't know that yet," she said.
Seattle was home many years ago to the first
successful medical use of stem cells, a kind of master
cell that can grow into any one of the body's more than
200 cell types. This allows them to replace cells that
have died and they have been used to replace defective
cells and tissues in patients who have certain diseases
or defects. Scientists at the Hutch are conducting
similar research using canine cells, Torok-Storb said.
Virginia Mason Medical Center also is involved in stem
cell research. Torok-Storb said the findings, which used
human skin cells, eliminate the ethical and moral
dilemma of using human embryonic stem cells for research
and makes every patient his or her own donor with no
worries of rejection. The findings also could mean that
someday two separate lab designs would no longer be
needed at the University of Washington's Institute for
Stem Cell and Regenerative Medicine, Murray said.
Scheduled to open in July 2008, one side would be used
to work only on the federally approved, non-embryonic,
stem cells; the other side for any kind of stem cells.
The findings also increase the potential for more
federal funding, which now is restricted for embryonic
stem cell research, Murray said. "If these cells are the
real deal, which I think they are, there's no reason why
anyone could object to them," he said. "We'll see how
this plays out." |
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Eli
Lilly Issues post marketing warning that
cancer drug Gemzar may result in
Pulmonary Fibrosis
May
31, 2007
The
following adverse events have been
identified during post-approval use of
Gemzar. These events have occurred after
Gemzar single-agent use and Gemzar in
combination with other cytotoxic agents.
Decisions to include these events are
based on the seriousness of the event,
frequency of reporting, or potential
causal connection to Gemzar.
Cardiovascular —
Congestive heart failure and myocardial
infarction have been reported very
rarely with the use of Gemzar.
Arrhythmias, predominantly
supraventricular in nature, have been
reported very rarely.
Vascular Disorders —
Clinical signs of peripheral vasculitis
and gangrene have been reported very
rarely.
Skin — Cellulitis
and non-serious injection site reactions
in the absence of extravasation have
been rarely reported. Severe skin
reactions, including desquamation and
bullous skin eruptions, have been
reported very rarely.
Hepatic — Increased
liver function tests including
elevations in aspartate aminotransferase
(AST), alanine aminotransferase (ALT),
gamma-glutamyl transferase (GGT),
alkaline phosphatase, and bilirubin
levels have been reported rarely.
Serious hepatotoxicity including liver
failure and death has been reported very
rarely in patients receiving Gemzar
alone or in combination with other
potentially hepatotoxic drugs.
Pulmonary
— Parenchymal toxicity, including
interstitial pneumonitis, pulmonary
fibrosis, pulmonary edema, and adult
respiratory distress syndrome (ARDS),
has been reported rarely following one
or more doses of Gemzar administered to
patients with various malignancies. Some
patients experienced the onset of
pulmonary symptoms up to 2 weeks after
the last Gemzar dose. Respiratory
failure and death occurred very rarely
in some patients despite discontinuation
of therapy.
Renal — Hemolytic-Uremic
Syndrome (HUS) and/or renal failure have
been reported following one or more
doses of Gemzar. Renal failure leading
to death or requiring dialysis, despite
discontinuation of therapy, has been
rarely reported. The majority of the
cases of renal failure leading to death
were due to HUS. |
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Rapid Progressors Speed to End-Stage
Pulmonary Fibrosis
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MEXICO CITY, May 31 -- A difference in genetic
patterns may explain why some idiopathic pulmonary
fibrosis patients, especially men who smoke, die
more quickly after diagnosis than others do. These
rapid progressors were 6.5-fold more likely to be
men and seven-fold more likely to have been smokers
than slow progressors, found Moisés Selman, M.D., of
the Instituto Nacional de Enfermedades Respiratorias
here, and colleagues. In the retrospective study,
gene expression patterns differed between fast and
slow progressors, implying biologically-distinct
phenotypes of the disease, they wrote online in the
journal Public Library of Science ONE. The
findings suggest that physicians should pay more
attention to the time of onset of symptoms to
identify these patients who are at greater risk,
they said. Most idiopathic pulmonary fibrosis
patients have symptoms long before diagnosis, then
slowly progress, with death coming within five years
of diagnosis, they noted. But, they said, distinct
patterns of disease progression have become
increasingly clear clinically.
To characterize these patterns,
the researchers reviewed the charts of 167
consecutive patients with the disease who were
evaluated at a single center between 1995 and 2004.
Seven healthy volunteers as well as lung samples
from autopsies were also studied as controls for
immunohistochemistry, cellular and genetic
profiling. Rapid progressors were defined as those
with no more than six months of symptoms before
seeking medical attention. From symptom onset, these
26 patients had a median follow-up of 13.5 months
and median survival of 27 months. From diagnosis,
median follow-up was 10 months and survival was 25
months. Slow progressors were defined as those with
at least 24 months of symptoms before presentation.
From symptom onset, these 88 patients had a median
follow-up of 60.5 months and median survival of 93
months. From diagnosis, median follow-up was 17
months and median survival was 32 months. In a
multivariate analysis, significant factors in
survival among the overall cohort included time from
symptom onset to first consult, smoking, male
gender, and lung function as measured by forced
vital capacity.
Among the 80% to 85% of patients
with known vital status, rapid progressors had
significantly lower survival rates than slow
progressors (hazard ratio 9.0, 95% confidence
interval 4.48 to 18.3, P<0.001) or
intermediate progressors (P=0.045).
Mortality determined from the time of diagnosis also
tended to be higher in the rapid progressors (HR
1.5, 95% CI 0.81 to 2.87, P=0.18). Among
rapid progressors, significantly more patients were:
- Male (odds ratio 6.5, 95% CI
1.4 to 29.5, P=0.006).
- Ever smokers (OR 3.04, 95% CI
1.1 to 8.3, P=0.04).
- Current smokers (OR 7.1, 95%
CI 1.2 to 40.9, P=0.02)
These rapid progressors, though,
were not simply patients presenting at a different
stage of disease or an acute exacerbation, the
researchers said. Their physiologic, radiologic, and
histopathologic parameters were similar to those of
slow progressors. Socioeconomic and educational
background -- which can influence when patients seek
treatment -- as well as initial treatment were
similar between groups, they said. And there were no
differences between rapid and slow progressors in
pack-years smoked. Nor were there baseline
differences in age, lung function alterations,
oxygen saturation, extent of changes seen on high
resolution computed tomography, or bronchoalveolar
lavage cellular profile, the researchers noted.
Lung biopsies done on 31% of
patients showed no differences in baseline
morphology for interstitial inflammation, pulmonary
hypertension changes, smooth muscle hyperplasia,
type 2 cell hyperplasia, or extent of fibrosis or
honeycombing. However, Dr. Selman wrote, there were
important differences showing that "rapid
progressors appear to represent a distinct
biological phenotype among patients with idiopathic
pulmonary fibrosis." In a global gene expression
analysis in a subset of patients, the researchers
found that 437 genes were expressed differently
between groups. Rapid progressors overexpressed
genes involved in morphogenesis, oxidative stress,
migration and proliferation, and fibroblast and
smooth muscle cell function. This upregulation was
seen on immunohistochemistry for the adenosine-2B
receptor, which is involved in a key process of
fibrotic remodeling, and prominin-1/CD133, which is
found in hematopoietic stem cells and embryonic
epithelium. Furthermore, bronchoalveolar lavage
showed that rapid progressors had more than a
twofold increase in active matrix
metalloproteinase-9, which may contribute to
abnormal tissue repair and remodeling, compared with
slow progressors.
Rapid progressors also had higher
fibroblast migration than slow progressors (238%
versus 123%, P<0.05) or controls (238%
versus 30%, P<0.01). While these subgroup
studies were of limited size, "the relatively
stringent selection of genes, the protein
verification by immunohistochemistry on additional
samples, and the biological relevance of the genes
suggest that our results are biologically
meaningful," the investigators wrote. They also
noted, however, that their study was preliminary and
limited by retrospective data collection and
dependence on patient recall of symptom duration.
However, "taken together with reports of the impact
of acute exacerbations of idiopathic pulmonary
fibrosis on morbidity and mortality, our results
further highlight the variability in the progression
and outcome of [the disease]," they concluded.
"These findings may explain, in part, the difficulty
in obtaining significant and reproducible results in
studies of therapeutic interventions in patients
with idiopathic pulmonary fibrosis," they added.
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The study was partially supported by a grant
from the Universidad Nacional Autónoma de
México. One of the researchers was supported
by grants from the National Institutes of
Health and by a donation from the Simmons
family. The researchers reported no
conflicts of interest. |
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Extra-aggressive Form
Of Idiopathic Pulmonary Fibrosis
Identified
Science Daily —May 29, 2007
- Idiopathic pulmonary fibrosis (IPF) is
a chronic and progressive lung disorder
from which most patients die within 5
years after diagnosis. The disease is
characterized by the insidious onset of
dyspnea or cough and usually evolves
slowly.
Now, Selman and coworkers present strong
evidence indicating that a subset of IPF
patients has a short duration of
symptoms before diagnosis and display an
accelerated clinical course to end-stage
disease. The authors postulate that
these "rapid progressor" patients,
predominantly smoking males, represent a
distinct clinical phenotype compared
with the usual "slow progressors"
patients.
"These findings highlight the
variability in the progression and
outcome of IPF, and may explain, in
part, the difficulty in obtaining
significant and reproducible results in
studies of therapeutic interventions in
patients with IPF," said Dr Selman, who
is the Director of Research at the
National Institute of Respiratory
Research in Mexico City and the lead
author on this publication. "They also
suggest that physicians should pay more
attention to the time of onset of
symptoms, and to look for other signs
that allow the identification of these
rapid progressor patients." In this
study the authors performed global gene
expression analysis and other molecular
studies in a subset of patients and
identified a number of genes that were
differentially expressed in both groups,
suggesting that rapid progressors are
biologically distinct from slow
progressors.
"While preliminary, these results may
allow investigators to identify
biomarkers of disease progression," said
Dr King, who is the Chief of Medicine at
San Francisco General Hospital and an
internationally renowned expert in
research and management of pulmonary
fibrosis. The senior author on this
paper, Dr Naftali Kaminski, who is the
Director of the Simmons Center for
Interstitial Lung Disease at the
University of Pittsburgh, added that
this research highlighted the need to
collect as much information on patients
with IPF as possible. "We are only now
starting to really understand the
disease and characterize it," he said,
"therefore, it is critical for patients
with the disease to be seen in centers
that are actively involved in IPF
research."Better identification and
understanding of these differences may
provide insights into the pathogenesis
of IPF and assist in the development of
therapeutic interventions for this
devastating lung disease.
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Cold War,
hellish consequences
Ex-nuke
weapons workers caught in medical crossfire
By Laura Frank, Rocky
Mountain News - April
7, 2007
Harold Hinton is dying.
He is slowly suffocating from incurable lung
disease that the government acknowledges is linked
to his work making nuclear bomb fuel during the Cold
War. Harold Hinton, 76, gets
an insulin shot from his full-time nurse at his
Cortez home. Hinton - as a young man he ground up
uranium ore that became the feedstock for atomic
bombs at a plant in Utah - fears he may lose his
around- the-clock health care because the Department
of Labor wants to reduce it. Hinton, of
Cortez, is eligible for medical care through a
federal program designed to compensate ill nuclear
weapons workers who weren't fully warned by the
government of the dangers they faced. His physician
said Hinton needed around-the-clock nursing care at
his home in southwestern Colorado, but a government
worker reduced the doctor's orders to eight hours a
day. Hinton is not alone, says the president of a
Denver-based company that provides nursing care to
Hinton and about 60 other former nuclear weapons
workers across the country.
The U.S. Department of Labor is disregarding
doctors' orders and approving less care than doctors
say is medically necessary, said Greg Austin,
president of Professional Case Management.
Department officials have also called family members
and doctors, pressuring both to agree to lower
levels of care, he said. Labor Department officials
said they are simply trying to be good stewards of
public funds while getting ill workers the help they
need. Assistant Deputy Labor Secretary Shelby
Hallmark, who oversees the program, said
Professional Case Management is pressuring doctors
to prescribe 24-hour home nursing care when less
costly care would do. " I think what's going on here
is (PCM) wants to maximize cash flow," Hallmark
said, adding that he has referred PCM's cases to the
Labor Department's Office of Inspector General for
review. Austin says the Labor Department's decisions
are dangerous. "If we do what the Department of
Labor says instead of what the doctors say,
literally, lives could be put at risk," he said.
Crying himself to
sleep
Verna Keaton, of Ohio, said her husband, Addison,
cried himself to sleep Wednesday night after
learning that the Labor Department was trying to
take away the nursing care that keeps him home with
his wife of 44 years. Addison Keaton is dying of
cancer that the government says was caused by
exposure to radioactive uranium at the Portsmouth
Gaseous Diffusion Plant in Portsmouth, Ohio. His
colon cancer has spread to his lungs, heart and
esophagus.
PCM has served more than 100 ill weapons workers
in 11 states during the past five years. The total
bill for those five years has approached $30
million, Hallmark said. Austin said Labor Department
officials have created such an "adversarial culture"
toward ill workers that it is affecting workers'
already fragile health. The company is considering
assisting some patients with a class-action lawsuit
against the Labor Department. The suit would ask a
judge to stop officials from ignoring medical
directives. On Wednesday, a Labor Department doctor
called Addison Keaton's doctor to question his home
health-care order, Verna Keaton said. Unbeknownst to
the Keatons, the government doctor had already
contacted a hospice-care company, which would be
less expensive than full-time nursing care, to open
a case on Addison Keaton. "I think they want him to
hurry up and die because it's costing them too much
money," said Verna Keaton. "How can a doctor in
Washington, D.C., determine what kind of help my
husband needs?" She said the Labor Department
doctor was relying on reports from case managers
without medical degrees. "I don't know what's going
to happen next because I haven't gotten hold of DOL
to answer my questions," she said. "They won't
return my calls."
The Labor Department runs the program that
Congress created in 2001 to compensate nuclear
weapons workers whose toxic exposures made them ill,
including those from the now-defunct Rocky Flats
weapons plant northwest of Denver. The program
includes coverage of medical bills for illnesses
linked to those exposures. The Labor Department and
the White House have come under fire recently from
the ill, their advocates and several federal
lawmakers. The critics say recently released
internal communications show the Bush administration
has been more concerned about containing costs than
helping the ill workers, whom they call Cold War
veterans. "These brave Americans are suffering, and
in some cases, dying, because of the hazardous
service they performed for their country," said U.S.
Rep. Zoe Lofgren, D-Calif., who heads the
congressional committee with oversight of the Labor
Department program. "These people deserve better,
and I will work with my colleagues in Congress to
ensure that they receive the benefits that they were
promised."
Producing yellowcake
As a young man during the Cold War, Harold Hinton
ground up uranium ore and moved it from one chemical
solution to another until it was a fine yellow
powder that became the feedstock for atomic bombs.
His bosses at the mill just over the Colorado border
in Utah told him the radioactive ore was safe. His
only protective gear was a hard hat, as he toiled at
the mill, coming home covered in yellow uranium
dust. The product of the mill - uranium 308, or
yellowcake as it was known for its appearance - was
shipped to nuclear facilities at Oak Ridge, Tenn.,
and later to Portsmouth. Hinton knew that Portsmouth
workers such as Addison Keaton were turning the
yellowcake into fuel for atomic bombs. But he and
his fellow workers didn't know the yellowcake itself
was radioactive. "We were never warned," he said.
Oak Ridge workers recalled being told in the 1950s
that yellowcake was safe enough to eat. "Remember,
at that time, they were trying real hard to get the
warheads on the missiles," Hinton said. "They needed
it real bad to protect the nation."
In 1986, two decades after he left the mill,
Hinton began having trouble breathing. The
radioactive uranium dust had scarred his lungs. He
developed pulmonary fibrosis, a disease with no cure
and no effective treatment. "I have anywhere from
six months to two or three years (to live)," Hinton
said. "To me, believe me, (the home health care) is
a godsend. I have thanked God for it many times." On
the last Friday of February, Hinton's doctor was
ready to discharge him from the hospital after a
particularly severe episode of breathing difficulty.
But there was no one to care for Hinton once he got
home. His wife is on oxygen and struggles to care
for their son's children, a teenager and a disabled
21-year-old. The Hintons' son is in a Tulsa, Okla.,
hospital fighting lung cancer. Harold Hinton
believes his wife's and son's lung problems resulted
from contamination he brought home from the uranium
mill. At the request of Professional Case
Management, Hinton's doctor delayed his discharge
until the next Monday in hopes of getting quick
approval for Hinton's home care. But the Department
of Labor took two weeks to approve the care and
reduced the order to eight hours a day instead of
the 24 hours ordered by the doctor.
E-mail and voice-mail messages provided by PCM
indicate a case manager in Denver made the decision
to offer less care without consulting Hinton's
doctor.
Dr. Leonard Cain, Hinton's doctor in Cortez, said
ordering 24-hour nursing care is not an easy
decision. "It's complicated," Cain said. "If I put a
home-health aide (instead of a nurse) in the home
and the patient has a medical need during the night,
that can't be handled by a home-health aide." Such
aides, known as certified nursing assistants, are
qualified to help patients bathe or move from a bed
to a chair, PCM's Austin said. But they legally
cannot administer medications, draw blood, change
oxygen levels or do many other things that these
patients might require at any time. "Yes, this
program covers more than Medicare or some other
social safety net," Austin said. "But this isn't a
social program - it's a compensation program. These
workers' illnesses were caused by their work for
this country. They can never get their health back,
but they can get some relief and be with their
families until they pass away."
Caught in the middle
As a doctor, Cain said he feels caught between
Professional Case Management advocating for patient
care and the Labor Department trying to save money.
"I'm going to err on the side of providing the most
care for the patient," Cain said. "This level of
care is not provided to anyone else in our
health-care system. But (the law creating the
workers' compensation program) says we're going to
provide this level of care for these people who need
it." Cain said he resents being put in the
middle. "There should be negotiation and
communication on this," he said. PCM's Austin
agreed, saying his company has requested that the
Labor Department participate in discussing patients'
care with health professionals. "They have said they
are not interested," Austin said. Hallmark said he
was not aware that PCM had asked the Labor
Department to participate in patient case
conferences. However, he said, PCM complained when
the department talked directly with the physicians.
Austin said PCM nurses should always be involved in
decisions because they see the patients more than
their doctors do. Meanwhile, PCM has been providing
full-time nursing care to Hinton since Feb. 26 with
no guarantee of payment. "There would be a huge
liability for us if we didn't do what the doctor
ordered," Austin said. "But we can't afford to do
that forever."
How it happened
At the height of the Cold War, thousands of
Americans were busy at urgent work they couldn't
discuss with their neighbors: building atomic bombs
for the arms race with the Soviet Union. At the
Rocky Flats plant northwest of Denver - and at
scores of other sites across the nation - workers
were exposed daily to myriad poisons. Radiation.
Exotic heavy metals. Chemicals in uncommon variety
and quantity. The government routinely withheld
information about the risk workers faced. Records of
exposures were often incomplete; others were later
destroyed. Today, more than 60,000 former nuclear
weapons workers are ill and believe that their
ailments are linked to their Cold War work. The
government denied almost all such links until 2000.
The next year, Congress created a compensation
program to give lump-sum payments and medical
coverage to workers whose illnesses were likely
caused by workplace exposures.
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Commentary
A Paradigm Shift For Medical
Research
Michael J. Fox
05.07.07, 6:00 AM ET
The U.S. was founded on the radical notion that by
independently pursuing our dreams we can build a future
that's better for everyone. That's why it's always been home
to great thinkers and doers, risk-takers and
entrepreneurs--people who insist on questioning the status
quo and finding a better path forward. That insistence,
individual and collective, has made this country a world
leader in many fields, including science and technology.
Yet when it comes to the vast enterprise of biomedical
research, there's room to question how well the system we've
created serves our needs. Do we put enough emphasis on
producing new therapies and cures for disease? Are we making
progress fast enough in the eyes of the millions touched by
illness or injury?
Over $100 billion is spent on biomedical research each
year. Roughly a third of that money goes toward expanding
our understanding of the basic mechanisms of life. That
seems reasonable: Basic research is vital to advancement
over the long haul. The other two-thirds goes to the
business end of things, where venture capitalists and the
pharmaceutical industry are mostly concerned with making a
profit for their shareholders. To patients observing from the sidelines, it can feel--on
our cynical days--as if the lion's share of today's
commercial investment focuses on tweaking innovations from a
decade ago.
So we burn through this pile of cash, yet we're left with
a major problem: Who's investing in innovation right now?
Only a minuscule fraction of our current efforts are
strategically allocated to converting basic discoveries into
truly new therapies. This is a higher-risk and higher-reward
investment arena--for my money, a classic challenge for
American ingenuity. Bold action today will pay off for years
to come in the form of improved, practical treatments with a
chance to benefit people living with disease now.
I'm certain we can achieve tangible results faster. In
fact, that's the premise on which I set up my foundation,
where we come to work every day to accelerate the best ideas
on their path from the labs to the patients. Our goal is to
improve the daily lives of people with Parkinson's disease
today and find a cure within the decade. But this
is a complex problem that requires a better strategy than
throwing billions more dollars at biomedical research and
hoping for the best.
It's time for a broad-based paradigm shift, one that
reflects what America is all about: rapid innovation toward
practical results that we can feel in our everyday lives.
The good news: This actually isn't a question of throwing
more money at the problem. (Not hitting up the taxpayers for
more money--how's that for a radical notion?) It is
a question of deploying our financial, scientific and
intellectual capital differently, creatively and urgently
and designing new solutions to complex challenges. Where we
go from here is up to all of us.
Through our experience at the foundation, we know
firsthand that America is home not only to many of the most
talented and innovative people in the world, but also to
some of its most generous. We must figure out how to hold
onto the best of what we have--infrastructure and resources
that attract the best and brightest scientists; the benefits
that accrue from basic research--while pushing ourselves to
go still further. Let's think big about new ways to
stimulate innovation and seed the drug development pipeline
with the next generation of therapies assuring investors of
transformative results--high returns on financial capital,
yes, but also on human health.
It may be a tall order, but I'm optimistic. When we work
together and use our talents and resources for the
collective good, everything is possible. To me, that's the
core of the American Dream.
Michael J. Fox |
Gene Mutations Linked To
Hereditary Lung Disease
Article Date: 01 Apr 2007 - 5:00 PDT
Scientists at Johns Hopkins have identified the
genetic culprits that trigger a hereditary form of a
fatal lung disease. The findings, published in the
March 29, 2007 issue of the New England Journal
of Medicine, may provide new directions in
diagnosis and treatment for families that inherit
genes for the disease, as well as for those that
develop non-inherited forms of the illness. A
progressive scarring of the lungs with no effective
treatment, idiopathic pulmonary fibrosis (IPF)
affects approximately 50,000 Americans annually, and
like some cancers often is fatal within three years.
As many as 20 percent of IPF sufferers are thought
to have inherited genetic mistakes that predispose
them to the disease; and until now, these gene flaws
remained unknown.
To locate the genetic problem, Hopkins investigators
screened DNA from blood samples of 73 people with
inherited IPF and discovered that six of them (eight
percent) had mutations in two genes that produce an
enzyme which helps lengthen the fragile ends of
chromosomes. Chromosome ends, or telomeres, contain
repetitive bits of DNA code that wear down each time
a cell divides. The mutations were spotted in two
genes that regulate the enzyme telomerase, which
keeps telomere length extended just beyond the
borders of needed genes. With mutations in
telomerase, however, chromosome ends fray and wear
down far more quickly, which can trigger cell death.
The scientists' first hint that telomerase plays a
role in IPF came from studying the genetic traits of
a family with a rare, premature-aging disorder
caused by short telomeres. Many of the family
members were suffering from the disorder's
second-leading cause of death -- pulmonary fibrosis.
"We thought that perhaps there might be a link
between telomerase mutations and IPF," says Mary
Armanios, M.D., assistant professor of oncology at
the Johns Hopkins Kimmel Cancer Center.
In the current study, mutation carriers had
telomeres about one-third the length of those in
family members with no gene mistakes. Short
telomeres also were found in seven younger relatives
who had gene mutations but not IPF. Gene tests are
currently not available for IPF, but scientists are
evaluating ways to assess risk of disease by
screening telomere length. "If we follow the genetic
threads of families that inherit IPF, it may lead us
to understand the genetic properties causing more
common forms of the disease," says Armanios.
Patients with non-inherited IPF also may have short
telomeres, so, says Armanios, "there may be other
causes for short telomeres, such as older age and
smoking, which also happen to be the main risk
factors for IPF."
To determine the link between short telomeres and
non-inherited IPF, investigators will need to study
a larger group of these patients. If studies reveal
a solid link between the two, Armanios says that it
may change the way IPF is treated. "For many years,
we've thought that IPF is caused by an immune attack
against the lungs, even though current therapies
aimed at dampening the immune system don't work,"
she explains. "If we're not so tied to immune
suppression therapies, we could eventually tailor
drugs to a different target."
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| Government makes investment to
improve respiratory health of Canadians
OTTAWA - April 26, 2007 - Federal Health
Minister Tony Clement today joined the Canadian Lung
Association to announce the development of a national action
plan to improve the respiratory health of Canadians.
The National Lung Health Framework represents a coordinated
approach to prevent and manage respiratory diseases in
Canada. The framework will lead to better policy,
leadership, research, innovation and education on lung
health. Over the next two days, 175 stakeholders
representing a wide range of interests will discuss an
outline for the
action plan and establish priorities and goals for going
forward.
Canada’s New Government is investing more than $1 million
in financial and technical support to enable the development
of the framework, including $350,000 to the Canadian Lung
Association for consultations across Canada, including
meetings with provincial and territorial government
representatives.
“Respiratory diseases affect more than 3.5 million
Canadians, some of whom end up in Canadian emergency rooms,”
said Minister Clement. “Today, Canada’s New Government
is taking action with the Canadian Lung Association to
improve the lung health of all Canadians.”
“Through partnership with the Government of Canada and
stakeholders nationwide, we are building an Action Plan on
Lung Health that will make a significant improvement to the
health of Canadians and their families,” said Nora Sobolov,
Chair of the Interim Steering Committee for the National
Lung Health Framework. “It is simply not acceptable that one
Canadian dies every 20 minutes from lung disease, or that
rates of lung disease continue to grow at a staggering rate.
The time for action is now: and that is exactly what this is
all about.”
Serious lung diseases include asthma, chronic obstructive
pulmonary disease, lung cancer, influenza and pneumonia,
bronchiolitis, tuberculosis, pulmonary fibrosis, and
respiratory distress syndrome. According to the World
Health Organization, lung disease will be the third leading
cause of death in the world by 2020.
The Public Health Agency of Canada works to prevent and
control the health effects of chronic respiratory diseases.
For more information, visit
www.phac-aspc.gc.ca. |
Gene Mutations Linked To
Hereditary Lung Disease
01 Apr 2007:
Scientists at Johns Hopkins have identified the
genetic culprits that trigger a hereditary form of a
fatal lung disease. The findings, published in the
March 29, 2007 issue of the New England Journal
of Medicine, may provide new directions in
diagnosis and treatment for families that inherit
genes for the disease, as well as for those that
develop non-inherited forms of the illness. A
progressive scarring of the lungs with no effective
treatment, idiopathic pulmonary fibrosis (IPF)
affects approximately 50,000 Americans annually, and
like some cancers often is fatal within three years.
As many as 20 percent of IPF sufferers are thought
to have inherited genetic mistakes that predispose
them to the disease; and until now, these gene flaws
remained unknown.
To locate the genetic problem, Hopkins investigators
screened DNA from blood samples of 73 people with
inherited IPF and discovered that six of them (eight
percent) had mutations in two genes that produce an
enzyme which helps lengthen the fragile ends of
chromosomes. Chromosome ends, or telomeres, contain
repetitive bits of DNA code that wear down each time
a cell divides. The mutations were spotted in two
genes that regulate the enzyme telomerase, which
keeps telomere length extended just beyond the
borders of needed genes. With mutations in
telomerase, however, chromosome ends fray and wear
down far more quickly, which can trigger cell death.
The scientists' first hint that telomerase plays a
role in IPF came from studying the genetic traits of
a family with a rare, premature-aging disorder
caused by short telomeres. Many of the family
members were suffering from the disorder's
second-leading cause of death -- pulmonary fibrosis.
"We thought that perhaps there might be a link
between telomerase mutations and IPF," says Mary
Armanios, M.D., assistant professor of oncology at
the Johns Hopkins Kimmel Cancer Center.
In the current study, mutation carriers had
telomeres about one-third the length of those in
family members with no gene mistakes. Short
telomeres also were found in seven younger relatives
who had gene mutations but not IPF. Gene tests are
currently not available for IPF, but scientists are
evaluating ways to assess risk of disease by
screening telomere length. "If we follow the genetic
threads of families that inherit IPF, it may lead us
to understand the genetic properties causing more
common forms of the disease," says Armanios.
Patients with non-inherited IPF also may have short
telomeres, so, says Armanios, "there may be other
causes for short telomeres, such as older age and
smoking, which also happen to be the main risk
factors for IPF."
To determine the link between short telomeres and
non-inherited IPF, investigators will need to study
a larger group of these patients. If studies reveal
a solid link between the two, Armanios says that it
may change the way IPF is treated. "For many years,
we've thought that IPF is caused by an immune attack
against the lungs, even though current therapies
aimed at dampening the immune system don't work,"
she explains. "If we're not so tied to immune
suppression therapies, we could eventually tailor
drugs to a different target."
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| Viagra May
Help Improve Exercise Capacity in Pulmonary Fibrosis Patients
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Monday, March 12, 2007
University of California Los Angeles
UCLA researchers have found that Viagra may help patients with
idiopathic pulmonary fibrosis, an incurable disease
characterized by progressive scarring in the lungs, which often
leads to a lung transplant. Published in the March issue of the
journal Chest, the research shows that more than half of the
patients treated with Viagra, also known medically as Sildenafil,
improved their walking distance by at least 20 percent during a
standard test to measure lung function.
"Over five million worldwide suffer from this devastating
disease, so we are hopeful that this drug may prove an effective
therapy for pulmonary fibrosis," said the study's principal
investigator, Dr. David A. Zisman, medical director of UCLA's
Interstitial Lung Disease Program and assistant professor of
pulmonary and critical care medicine at the David Geffen School
of Medicine at UCLA. Many patients with pulmonary fibrosis also
have pulmonary hypertension, which constricts arteries and
lessens blood flow to the lungs, resulting in diminished lung
capacity and breathing difficulties. According to Zisman,
Sildenafil may help breathing by opening or dilating blood
vessels to allow more blood flow to the lungs.
In this pilot study, 14 idiopathic pulmonary fibrosis
patients initially took a standard six-minute walking test. All
patients were then given oral Sildenafil therapy for three
months, followed by a second walking test to gauge performance
changes. Researchers noted that 57 percent of the patients
improved their walking distance by 20 percent or more. The
average improvement in walking distance was 49 meters (161
feet).
Eleven patients completed the study. Only two patients
experienced side effects and had to stop the medication - one
due to diarrhea and the other due to abnormally low blood
pressure. "In this small pilot study, the drug was
well-tolerated," said Zisman. "The next step is to confirm this
finding in a large, randomized clinical trial." The study was
funded by the National Institutes of Health.
Other authors include: Dr. Harold R. Collard, department of
medicine, San Francisco General Hospital, University of
California, San Francisco; Kevin J. Anstrom, Ph.D., Duke
Clinical Research Institute, Duke University; and Dr. Marvin I.
Schwarz, department of medicine, University of Colorado Health
Sciences
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InterMune
Discontinues Phase 3 INSPIRE Trial of Actimmune
in Idiopathic Pulmonary Fibrosis
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BRISBANE, Calif., March 5, 2007 /PRNewswire-FirstCall
via COMTEX News Network/ --
InterMune, Inc. today announced that
it has discontinued the Phase 3
INSPIRE clinical trial evaluating
Actimmune(R) (interferon gamma-1b)
in patients with idiopathic
pulmonary fibrosis (IPF) based upon
the recommendation of the study's
independent data monitoring
committee (DMC). In a planned
interim analysis that included a
total of 115 deaths, the DMC found
the overall survival result crossed
a predefined stopping boundary for
lack of benefit of Actimmune(R)
relative to placebo. Among the 826
randomized patients, there was not a
statistically significant difference
between treatment groups in overall
mortality (14.5% in the Actimmune
group as compared to 12.7% in the
placebo group). Based on a
preliminary review of the interim
safety data, the adverse events
associated with Actimmune(R) therapy
appear generally consistent with
prior clinical experience, including
constitutional symptoms, neutropenia
and possibly pneumonia.
INSPIRE was a randomized,
double-blind, placebo-controlled
Phase 3 study designed to evaluate
the safety and efficacy of
Actimmune(R) in IPF patients with
mild to moderate impairment in lung
function. The primary endpoint was
survival time. The lack of benefit
stopping boundary was developed to
allow for early study termination in
the event interim data were
statistically inconsistent with a
clinically meaningful treatment
effect of Actimmune(R). InterMune
plans to submit the data from the
Phase 3 INSPIRE trial for
presentation at an appropriate
medical meeting and for publication
in a peer-reviewed journal.
"The interim results of the INSPIRE
trial and our decision to
discontinue the trial are
disappointing," said Steve Porter,
M.D., Ph.D., Chief Medical Officer
at InterMune. "We are extremely
grateful for the strong support we
received from physicians, healthcare
providers and especially the
patients who participated in the
clinical evaluation of Actimmune(R).
The overall conduct of the study by
investigators and the participation
by patients were exemplary."
Dan Welch, President and Chief
Executive Officer of InterMune,
said, "Although we are disappointed
by this result with Actimmune(R), we
remain committed to addressing the
significant unmet medical need in
IPF with pirfenidone through our
Phase 3 CAPACITY program. A positive
treatment effect of pirfenidone on
lung function has been supported in
several Phase 2 studies and in a
Phase 3 study as recently reported
by Shionogi & Co., Ltd. We also are
focused on advancing our novel
hepatitis C virus drug candidate,
ITMN-191. In collaboration with our
partner Roche, our Phase 1a study of
ITMN-191 is proceeding as planned."
Mr. Welch continued, "We will
promptly evaluate the implications
of the INSPIRE study termination on
our corporate strategy and our
infrastructure. We expect to provide
an update on this evaluation,
including revised financial
guidance, in the near future."
Actimmune(R) is a synthesized
version of interferon gamma, a
naturally occurring protein believed
to stimulate the immune system.
InterMune markets Actimmune(R) for
the treatment of two
life-threatening congenital
diseases: chronic granulomatous
disease and severe, malignant
osteopetrosis. The most common side
effects are flu-like symptoms,
including headache, fatigue, fever,
chills and rash. Physicians and
patients can obtain additional
prescribing information regarding
Actimmune(R) including the product's
safety profile, by visiting
www.actimmune.com. |
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FivePrime Enters Osteoarthritis and Pulmonary
Fibrosis Collaboration With Centocor
Wednesday January 3, 2007 SAN
FRANCISCO--(BUSINESS WIRE)--Five Prime
Therapeutics, Inc. today announced a worldwide
collaborative research and license agreement
with Centocor Research and Development Inc. The
collaboration will focus on novel therapeutic
products to treat osteoarthritis and pulmonary
fibrosis. Under the collaboration, FivePrime
will screen its comprehensive protein library
against cell-based assays directed to
osteoarthritis and fibrosis and Centocor will
have exclusive rights to the proteins and
targets identified in these screens.
FivePrime will receive an upfront payment of
$15 million, comprised of cash and an equity
investment by Johnson and Johnson Development
Corporation (JJDC), and two years research
funding from Centocor. Centocor will have
exclusive worldwide rights to develop and
commercialize products and targets discovered
during the research term in exchange for future
milestones and royalties. Further details of the
agreement have not been disclosed. "With
Centocor as a partner in these disease areas, we
should be able to move the products of our
discovery platform into clinical trials faster
and more effectively," commented Lewis T.
"Rusty" Williams, FivePrime's founder and
Executive Chairman.
"Centocor has a long-standing commitment to
innovative biotherapeutics," added Gail Maderis,
President and CEO of FivePrime. "We are
extremely pleased to be working with a group
that shares our enthusiasm for the tremendous
potential of novel biologic therapies.
Additionally, we welcome JJDC to our premier
group of investors." A key component of the
collaboration is FivePrime's comprehensive,
rapid protein discovery system. FivePrime's
protein screening library contains essentially
all human secreted proteins and their receptors,
including many that are unavailable in public
collections. FivePrime screens its protein
library in complex, primary cell assays with a
level of precision, speed and thoroughness
previously achievable only in small molecule
screening. Using technologies for rapid in vivo
validation of hits from its screens, FivePrime
aims to reduce time from idea to an
Investigational New Drug to less than three
years.
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KIN SUING CITY OVER 'WTC TOXIN' DEATH
By CARL CAMPANILE
New York: January 29, 2007 -- The wife of a utility
repairman who restored essential cellphone service at Ground Zero - and
died last year of a rare lung disease - has filed a $20 million
wrongful-death claim against the city, The Post has learned. Mark
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