| |
Quickening the pace from bench to
bedside
Study suggests marijuana induces temporary
schizophrenia-like effects
Et cetera
High-fat diet raises cancer risk
High volume not always best
|
|
Quickening the pace from
bench to bedside
A new program speeds laboratory findings into the clinic, cutting years
from the process.
Just eight months after scientists in a lab on Cedar Street devised a
new approach for treating ovarian cancer, clinical trials began in June
at Yale’s gynecologic oncology clinic a block away on Howard Avenue.
The experimental protocol is among four clinical trials under way in the
Discovery to Cure program—an informal collaboration that began in
the late 1990s and took on its new name in June. The program is designed
to speed progress in detecting and treating women’s reproductive
cancers through an unusual alliance of basic researchers, clinical investigators
and nurses. The clinicians report directly back to the laboratory scientists,
who incorporate findings into planning for new research.
The latest study uses the anticancer drug phenoxodiol to sensitize ovarian
cancer cells before chemotherapy. Phenoxodiol, developed in Australia
for possible use as a treatment for cancer and cardiovascular disease
and as an anti-inflammatory, was among about 200 compounds screened for
their anticancer properties by Gil Mor, M.D., Ph.D., an associate professor
of obstetrics, gynecology and reproductive sciences, and his team. Phenoxodiol
attacks a problem common in cancer cells: normal cell death is blocked,
allowing cells to proliferate and form tumors. The drug, which affects
intracellular signaling, helps activate caspases, the enzymes that regulate
cell death. Mor said the intravenous treatment renders the cancer cells
up to 100 times more vulnerable to the chemotherapy drugs cisplatin and
paclitaxel. This sensitization allows doctors to prescribe lower doses
of chemotherapy, reducing the damage to healthy cells that can cause debilitating
side effects.
“Our new approach was not to develop new cytotoxic drugs but to
find something specific that will remove those blockers [to cell death]
in the cancer cell without affecting normal cells,” said Mor.
Mor is encouraged by how quickly discoveries about molecular pathways
are being tested in patient trials. “All these findings are immediately
brought to the clinic,” he said. “This is quite unusual. Findings
in the lab can take years to get to the clinic.”
Once his group developed its therapy, Mor said, it took about eight months
to gain approval from the medical school’s institutional review
board, the Human Investigation Committee, and then recruit 40 patient
volunteers to take part in a combined Phase I/Phase II trial that tests
both safety and effectiveness. Mor said the researchers save time because
lab investigators have immediate access to tissue samples from cancer
patients and a clinical population that allows them to launch a trial
quickly. In one instance in 1999, he noted, a basic science lab without
close ties to a clinic couldn’t get an ovarian cancer drug into
clinical trials until 2003.
“The time cut is years,” said Mor’s clinical colleague,
Thomas J. Rutherford, Ph.D., M.D., FW ’94, associate professor of
obstetrics and gynecology. Rutherford said the researchers learn not only
from each other but also from others on the team, including nurses, who
have insights into man-aging clinical problems. “If you’re
willing to talk and listen—and I’d say listening is most important—there’s
a tremendous amount of information people will give you.”
The Discovery to Cure program sponsors research on four gynecological
cancers: ovarian, cervical, uterine and breast.
Of these cancers, ovarian cancer poses a particularly daunting problem,
because it is rarely discovered in its early stages. When diagnosed in
the advanced stages, the five-year survival rate ranges from 20 to 40
percent. Mor and Rutherford are working to develop a blood test to detect
the cancer early, collaborating with Peter E. Schwartz, M.D., HS ’70,
the John Slade Ely Professor of Obstetrics and Gynecology.
Rutherford is optimistic. “We have identified what we think to be
protein markers for early ovarian cancer,” he said. “If it
proves to be true, it will be a good thing.”
—Cathy Shufro
|
|
|
| |
|
|
Study suggests marijuana
induces temporary schizophrenia-like effects
Anyone who inhaled in the 1960s can recall the effects of cannabis—euphoria,
paranoia, changes in perception, an inability to concentrate and short-term
memory failures. A laboratory-controlled study by Yale scientists published
in the journal Neuropsychopharmacology last summer has found that
delta-9-tetrahydrocannabinol (THC), the active ingredient of cannabis,
transiently induced a range of schizophrenia-like effects in healthy people.
And in the past year, three large epidemiological studies have supported
the long-suggested link between cannabis use and a risk of schizophrenia.
“No one really knew how cannabis worked until about 10 years ago,”
said D. Cyril D’Souza, M.D., associate professor of psychiatry and
lead author of the study. “The discovery of cannabinoid receptors
and several other advances in the basic pharmacology of the cannabinoid
receptor system have renewed interest in that association between cannabis
and psychosis.”
Because animal models of psychosis have significant limitations, scientists
have used drugs to induce transient psychosis in humans. “Perhaps
by studying drug-induced psychosis, that might lead us to a better understanding
of psychoses in general and schizophrenia in particular,” D’Souza
said, adding that this is the first study, to his knowledge, that has
applied measures for schizophrenia to study the effects of THC in healthy
people screened for any vulnerability to schizophrenia.
In the study, THC induced temporary responses similar to the three domains
of schizophrenia: positive symptoms such as paranoia and disorganization
of thinking, negative symptoms such as blunted affect and reduced spontaneity,
and cognitive deficits such as memory lapses. On three test days at least
a week apart, the researchers administered THC to 22 test subjects—including
Yale medical students and undergraduates and other volunteers. All had
used cannabis previously but none had ever been diagnosed with cannabis
abuse disorder or a major psychiatric disorder. On each test day the subjects
received one of three injections, a placebo or a low or medium dose of
THC, before taking a series of behavioral and cognitive tests.
The subjects reported how they felt, using a scale of feeling states associated
with cannabis effects—high, calm, relaxed, tired, anxious and panicked.
Some subjects experienced schizophrenia-like symptoms lasting between
half an hour and an hour. In addition, THC induced euphoria and raised
levels of cortisol and prolactin, biological markers for activity of cannabinoid
receptors.
The tests relied on self-reporting and the observations of trained researchers,
which at times differed from those of the subjects. “We had a subject
who refused to complete some of the cognitive testing because she was
convinced we were trying to trick her,” said D’Souza. “But
when we asked if she felt paranoid, she said ‘no.’ ”
Follow-up months after the study revealed no side effects among participants.
Ultimately, D’Souza said, the research may provide clues about the
pathophysiology of psychotic disorders. “By understanding how cannabis
produces psychosis, that may help us understand what goes wrong in schizophrenia,”
he said.
—John Curtis
|
|
|
| |
|
|
Et Cetera
High-fat diet raises cancer risk
It’s long been a tenet of good nutrition that too much fat and
animal protein can clog the arteries and raise cholesterol. A new study
by Yale researchers found that such a diet also increases the risk of
non-Hodgkin’s lymphoma (NHL), a cancer that attacks the lymphatic
system.
The study reaffirmed another mantra of dieticians and nutritionists—consumption
of high-fiber fruits and vegetables such as broccoli, lettuce, tomatoes
and cauliflower is associated with a lower risk of NHL.
“An association between dietary intake and NHL is biologically plausible
because diets high in protein and fat may lead to altered immunity, resulting
in increased risk of NHL,” said Tongzhang Zheng, Sc.D., associate
professor of epidemiology (environmental health). Zheng was the principal
investigator of the study of Connecticut women, which was published in
the American Journal of Epidemiology earlier this year. “The
antioxidants found in vegetables and fruits may result in a reduced risk
of about 40 percent.”
—J.C.
High volume not always best
The conventional wisdom suggests that only hospitals that perform at
least 400 angioplasties a year should be allowed to offer the procedure.
A higher volume, the reasoning goes, leads to better outcomes.
But researchers at Yale and the University of Pennsylvania challenge that
view in a study published in the Journal of the American College of
Cardiology. The study of 362,748 angioplasties performed between 1998
and 2000 found comparable outcomes in medium- to very-high-volume hospitals.
Yet some low-volume hospitals provided excellent care while some high-volume
hospitals did not, said Saif S. Rathore, M.P.H., a lecturer in cardiovascular
medicine, and one of the study’s authors.
“If you accept volume [as the only standard],” Rathore said,
“you essentially consign all low-volume hospitals to being of poor
quality and you give all high-volume hospitals a pass on quality. What
we ought to be doing is identifying those hospitals or doctors that provide
better quality of care.”
—J.C.
|
|
|
