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LOVELACE RESPIRATORY RESEARCH INSTITUTE(LRRI)An independent,
nonprofit, research institute serving humanity through research on
the prevention, treatment, and cure of respiratory disease.LRRI is
the only private, basic-science biomedical research organization
totally dedicated to the study of respiratory diseases and
reduction of their public health burden
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IT ALL STARTED WITH A BOY BORN IN A LOG CABIN, TUBERCULOSIS, AND
A RAILROADBelle, MOSt. Louis, MOStrong City, KS,Stone
quarries,Lantry Construction& the AmarilloCut-offSunnyside,
NM,And the Belen cut-offAlbuquerque,NMBNSF Route Map
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WHO WAS LOVELACE (William Randolph Lovelace I) ? William
Randolph Lovelace born in log cabin in Belle, MO WRL goes to
medical school in St. Louis1905WRL graduates from St. Louis
University Med. School & begins internship at St. Marys
Hospital (Sisters of Charity) Fatigue & Pulmonary hemorrhage
reveal tuberculosis. WRL contacts Lantry & Sharp Co. about a
job as company surgeon on the new Santa Fe RR construction in
NM1906WRL arrives in Sunnyside (Ft. Sumner) in late April
1908Entire family moved to NM (including brother Edgar, his wife,
and 6 month old son WRLII)1913Moved to Albuquerque, opened office
above Kistler Collister on Central, got contract for Santa Fe RR
health operations, became heavily involved with St. Joseph
Hospital1915Began visits to Mayo Clinic & friendship with Will
& Charlie1919Dr. Edgar Lassiter marries WRLs sister Lora (&
became partner)1922 Lovelace Clinic began1946Uncle Doc recruits
nephew Randy to head organization
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YOUNG DOC LOVELACES FIRST CLINIC
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WHO WAS LOVELACE (William Randolph Lovelace I) ? William
Randolph Lovelace born in log cabin in Belle, MO WRL goes to
medical school in St. Louis1905WRL graduates from St. Louis
University Med. School & begins internship at St. Marys
Hospital (Sisters of Charity) Fatigue & Pulmonary hemorrhage
reveal tuberculosis. WRL contacts Lantry & Sharp Co. about a
job as company surgeon on the new Santa Fe RR construction in
NM1906WRL arrives in Sunnyside (Ft. Sumner) in late April
1908Entire family moved to NM (including brother Edgar, his wife,
and 6 month old son WRLII)1913Moved to Albuquerque, opened office
above Kistler Collister on Central, got contract for Santa Fe RR
health operations, became heavily involved with St. Joseph
Hospital1915Began visits to Mayo Clinic & friendship with Will
& Charlie1919Dr. Edgar Lassiter marries WRLs sister Lora (&
became partner)1922 Lovelace Clinic began1946Uncle Doc recruits
nephew Randy to head organization
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DOC LOVELACES SPORTY TRANSPORTATION FOR MAKING HOUSE CALLS
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WHO WAS LOVELACE (William Randolph Lovelace I) ? William
Randolph Lovelace born in log cabin in Belle, MO WRL goes to
medical school in St. Louis1905WRL graduates from St. Louis
University Med. School & begins internship at St. Marys
Hospital (Sisters of Charity) Fatigue & Pulmonary hemorrhage
reveal tuberculosis. WRL contacts Lantry & Sharp Co. about a
job as company surgeon on the new Santa Fe RR construction in
NM1906WRL arrives in Sunnyside (Ft. Sumner) in late April
1908Entire family moved to NM (including brother Edgar, his wife,
and 6 month old son WRLII)1913Moved to Albuquerque, opened office
above Kistler Collister on Central, got contract for Santa Fe RR
health operations, became heavily involved with St. Joseph
Hospital1915Began visits to Mayo Clinic & friendship with Will
& Charlie1919Dr. Edgar Lassiter marries WRLs sister Lora (&
became partner)1922 Lovelace Clinic began1946Uncle Doc recruits
nephew Randy to head organization
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THE ORIGINAL LOVELACE FAMILY HOME
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WHO WAS LOVELACE (William Randolph Lovelace II) ?1908Randy came
to NM as 6 mo child of WRL Is brother Edgar, raised on fathers
ranch and in Uncle Docs home1925Graduated Albuquerque HS (voted
least likely to succeed!)1928Became pilot in Navy ROTC1930BS from
Washington Univ. , St. Louis1934MD from Harvard1936Fellowship in
surgery at Mayo, member of Mayo Aero Medical Unit, Surgical Chief
in 19411940Collier Trophy for BLB oxygen mask1943Chief of military
Aero Medical Laboratory, Wright Field, OH1943Distinguished Flying
Cross for parachute jump from 40,200 ft. to test oxygen equipment
(his first jump!)1946Lost two sons to polio, returned to
NM1947Joined Uncle Doc in organizing and managing Lovelace
Foundation for Medical Education & Research1965Died in airplane
accident returning from Aspen, CO
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Col. Randy et. al. invented the oxygen masks and G-suits that
became standard for military pilots.
He believed his science to the extent that he laid his life on
the line by making his first parachute jump (against Uncle Docs
strong advice).
Jumping at 40,000 ft, and sky-diving to a lower altitude, he
lost a glove and nearly froze a hand but the mask worked fine!
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WHO WAS LOVELACE (William Randolph Lovelace II) ?1908Randy came
to NM as 6 mo child of WRL Is brother Edgar, raised on fathers
ranch and in Uncle Docs home1925Graduated Albuquerque HS (voted
least likely to succeed!)1928Became pilot in Navy ROTC1930BS from
Washington Univ. , St. Louis1934MD from Harvard1936Fellowship in
surgery at Mayo, member of Mayo Aero Medical Unit, Surgical Chief
in 19411940Collier Trophy for BLB oxygen mask1943Chief of military
Aero Medical Laboratory, Wright Field, OH1943Distinguished Flying
Cross for parachute jump from 40,200 ft. to test oxygen equipment
(his first jump!)1946Lost two sons to polio, returned to
NM1947Joined Uncle Doc in organizing and managing Lovelace
Foundation for Medical Education & Research1965Died in airplane
accident returning from Aspen, CO
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UNCLE DOC AND RANDYAT THE BIRTH OF THE FOUNDATION
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WHO WAS LOVELACE (William Randolph Lovelace II) ?1908Randy came
to NM as 6 mo child of WRL Is brother Edgar, raised on fathers
ranch and in Uncle Docs home1925Graduated Albuquerque HS (voted
least likely to succeed!)1928Became pilot in Navy ROTC1930BS from
Washington Univ. , St. Louis1934MD from Harvard1936Fellowship in
surgery at Mayo, member of Mayo Aero Medical Unit, Surgical Chief
in 19411940Collier Trophy for BLB oxygen mask1943Chief of military
Aero Medical Laboratory, Wright Field, OH1943Distinguished Flying
Cross for parachute jump from 40,200 ft. to test oxygen equipment
(his first jump!)1946Lost two sons to polio, returned to
NM1947Joined Uncle Doc in organizing and managing Lovelace
Foundation for Medical Education & Research1965Died in airplane
accident returning from Aspen, CO
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FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys
dreamTakes shapeWork on radiationand blast injurybeginsA contract
is received from AEC to build a program on inhaled
aircontaminantsResearch on altitude physiology, airline pilots and
astronauts
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THE FPIL FACILITY IN 1969
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FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys
dreamTakes shapeWork on radiationand blast injurybeginsA contract
is received from AEC to build a program on inhaled
aircontaminantsLBERI is createdto operate ITRIseparately from the
parent corporationResearch on altitude physiology, airline pilots
and astronauts
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LBERI/ITRI EXECUTIVE MANAGEMENT
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FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys
dreamTakes shapeWork on radiationand blast injurybeginsA contract
is received from AEC to build a program on inhaled
aircontaminantsThe Board of DirectorsDecides that it doesnt want to
be in the HMO business (and the endowment is born)After a 7-year
effort,DOE agrees to privatizethe ITRI facilityLBERI is createdto
operate ITRIseparately from the parent corporationResearch on
altitude physiology, airline pilots and astronauts
LSR is created to conduct clinical trialsBob Rubin rides into
town and operations are merged into a single entity structured
around a lung health mission
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FROM UNCLE DOC TO PRESIDENT BOBUncle Docs dream comestrue!Randys
dreamTakes shapeWork on radiationand blast injurybeginsA contract
is received from AEC to build a program on inhaled
aircontaminantsThe Board of DirectorsDecides that it doesnt want to
be in the HMO business (and the endowment is born)After a 7-year
effort,DOE agrees to privatizethe ITRI facilityLBERI is createdto
operate ITRIseparately from the parent corporationResearch on
altitude physiology, airline pilots and astronauts
LSR is created to conduct clinical trialsBob Rubin rides into
town and operations are merged into a single entity structured
around a lung health mission
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HOW IS LRRI ORGANIZED TODAY?
Lovelace Respiratory Research Institute (LRRI):Parent
corporationNot-for-profit 501(c)(3)Non-federal research,
philanthropy, endowment
Lovelace Biomedical and Environmental Research Institute
(LBERI):Wholly-owned not-for-profit subsidiaryFederally-funded
research
Lovelace Scientific Resources (LSR):Wholly-owned for-profit
subsidiaryClinical trials, other for-profit research
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LRRI EXECUTIVE STRUCTURE
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Bob RubinPresident & Chief Executive Officer
Jacqueline Lovelace-JohnsonChairman, Board of Directors
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Pat MarxVice President, LRRIChief Operating Officer, LRRI
Joe MauderlyVice President, LRRIPresident, LBERI
Chuck HobbsVice President, LBERI
Tess BurlesonPresident, LSRChief Financial Officer, LRRI
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LRRI ORGANIZATION CHART
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LRRI SCIENTIFIC ORGANIZATIONAL CHART
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LSR ORGANIZATION
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LRRI Headquarters and Research Facility North (125,000 sq.
ft.)Inhalation Toxicology Research Institute Facility South
(325,000 sq. ft.)
LRRI FACILITIES
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WHAT DOES LRRI DO?
Research on Causes, Mechanisms, Prevention & Treatment of
Respiratory Diseases
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WHO PAYS FOR IT?Sources of FY-2003 Non-LSR Research Funding
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HOW IS LRRI DOING?
$M Total FederalWeve grown slightly despite the close-out of
major DOE fundingWeve been investing heavily in people, working
structure, facilities, and new major programs since the 1996
privatization
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NIH REVENUE IS GROWING STEADILY
$M(est.)This was one of Dr. Rubins major goals for the past
several years
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OUR FUNDING SUCCESS RATE IS GREAT!FY-03 Non-Clinical Research
Proposals(As of 2/20/04, Does Not Include LSR or NERC)Funded Not
Funded PendingTotal
FederalNo.25 (39%)39 (61%)16 80$M 10.9 (27%) 29.5 (73%)24.1
64.5
Non-FederalNo.39 (53%)35 (47%)11 85$M 4.1 (34%) 7.8 (66%) 3.2
15.1
TotalNo.64 (46%)74 (54%)27 165*$M15.0 (29%)37.3 (71%)27.3
79.6______________* A proposal was sent out every 1.5 working
days!
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WHAT ARE OUR PRINCIPAL RESEARCH ACTIVITIES? MECHANISMS,
DETECTION, AND TREATMENT OF DISEASEInflammation (triggers,
mediators, cell damage & repair, control of mucous cells)Lung
Cancer (responsible genes, early detection)Asthma and immunology
(determinants of allergic asthma, immunosuppresion)Infectious
disease (defenses, impairment of resistance to viruses &
bacteria)Emphysema (mechanisms, animal models, tobacco and
environmental causes)Preclinical studies of new drugs (efficacy,
safety, FDA compliance)Inhalation drug delivery (aerosolization,
regional deposition, pharmacokinetics)Clinical trials (phases II
IV, multiple centers)Pharmacoeconomics (burden of illness, costs,
medication compliance, outcomes)
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Principal Research Activities Contd. RESPIRATORY HEALTH
RISKSInhalation toxicology (toxic mechanisms, dosimetry &
metabolism, dose-response, interspecies comparisons)Inhalation
hazard assessment (commercial and defense-related chemical and
biological agents, product safety testing, Regulatory compliance,
workplace hazards)Environmental air pollution (source emissions,
particles, multi-pollutant mixtures, bio-toxins)Radiation (inhaled
radionuclides, external radiation, risk modeling)AEROSOL TECHNOLOGY
Instrumentation (development, testing, & demonstration,
chambers & wind tunnels, field studies, verification of
detection efficiency)Aerosol generation & dispersion
(generation technologies, surrogate & tracer aerosols, room
& site dispersion, on-site measurements)
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WHAT DOES LSR DO?Clinical Trials contracting with pharmaceutical
companies to test new drugs and therapies in humans Primarily phase
II-IV trialsI Initial in-bed toxicity testsII Efficacy/toxicity
trials in small groupsIII Efficacy trials in larger populationsIV
New uses for approved drugs Expecting $4 million in revenues this
yearLSR has done over 750 trials and now has multiple
centersAlbuquerque1987Phoenix1994Las Vegas1997Miami2002Santa
Anna/Beverly Hills2003Santa Fe2003Austin2004Sarasota2004
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OUR NON-RESEARCH ACTIVITIES SUPPORT THE RESEARCH
MISSIONPhilanthropic fundraisingDonations solicited from
individuals, companies, and foundationsTax deductable gifts (money,
goods)Facilities rentalLeasing/subleasing office, laboratory, and
storage spaceEndowmentInvestment income from principal created by
sale of healthcare systemLovelace-Anderson Endowment
FoundationLovelace endowmentNon-respiratory research activities
capitalizing on facilities & capabilitiesPrimate
housingResearch on non-respiratory issuesEducational activities
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WHAT ARE OUR DISTINGUISHING RESEARCH ASSETS?Core capabilities
(not the only ones of course, but the ones we are best known
for)Aerosol science Animal models of human responses &
diseaseInhalation exposuresRespiratory molecular & cellular
biologyHazardous materialsCore facilitatorsFlexible,
entrepreneurial, management structureCollaborative,
cross-disciplinary teamworkTranslational, gene-to-disease
expression perspectiveExtensive, specialized
facilitiesMulti-species animal resourcesDedicated grants, quality
assurance, and communications support
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HOW ARE WE DOING WITH PUBLICATIONS OUR PRIMARY PRODUCT?In CY
2003, LRRI scientists authored or co-authored 79 submitted
articles, chapters, books, and published reports
In addition to several published and unpublished technical
reports to sponsors
The publications reflect a high level of collaboration within
LRRI and with external scientists
Only 3 submissions had only one author
LRRI staff were the lead authors of 54 publications (research
done entirely or primarily at LRRI)
External scientists were lead authors of 25 publications
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HOW DOES THIS BUSINESS WORK? Example: Dr. Ted Barrett et al. -
Progress on Asthma PreventionEvolved from longstanding research on
pulmonary immunityLRRI internal funds invested in venture science
1. Proved that allergic parents produce allergy-prone babiesMated
dogs sensitized to ragweed (& non-sensitized dogs)Exposed all
pups to airborne ragweed pollen beginning at 6 daysResults: Pups
from allergic parents developed ragweed allergy by 6 mo! Pups from
non-allergic parents did not Pups from allergic parents +
ragweed
Pups from allergic parents ragweed Pups from non-allergic
parents + ragweed
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Example Contd Outcomes Published the study in a top journalE.G.
Barrett, K. Rudolph, L.E. Bowen & D. E. Bice, Prenatal Allergic
Status Influences the Risk of Developing Allergic Sensitization and
an Asthmatic-Like Phenotype in Canine Offspring, Immunology 110:
493-500, 2003
Journal commissioned a special commentary on the studyB. Zemann
& A. Rot, What Dogs may Teach Humans About the Vertical
Transmission of Allergy Predisposition, Immunology, 110: 427-429,
2003Well-controlled mechanistic experimental models, such as the
canine model established by Barrett et al. may provide invaluable
clues to the molecular mechanisms of vertical transfer of allergy
predisposition -----. In the long term, to asthmatic parents and
children, the dog may truly turn out to be mans best friend.
Began capitalizing on the model to explore prevention by immune
priming
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Example Contd the Second Study2. Proved that single treatment
with a certain bacterial DNA sequence (CpG) prevented
allergyRepeated first experiment with allergic parentsGave some
pups single inhalation dose of CpG at 6 daysResult: Pups receiving
CpG did not develop ragweed allergy! Pups not receiving CpG
didRagweed without CpG
No Ragweed or CpG Ragweed with CpG
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Example Contd Current Status Ted & colleagues have an NIH
grant pendingMaternal Influence in the Development of Asthma5 years
for total of $3.1M ($592K first year) Currently under review
We propose to test the hypothesis that elevated levels of
maternal allergen-specific factors and/or a skewed cytokine
environment during pregnancy and/or early childhood are risk
factors for the development of allergic sensitization and asthma in
offspring from allergic mothers.
Ted & colleagues are working with a pharmaceutical company
to develop the preventive therapy (aka asthma vaccine)Yield on
investment:Substantial scientific and public health return
Substantial likely financial return
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IT TAKES QUITE A TEAM TO MAKE LRRI WORK!
This is a small, dedicated, personal organization where everyone
can, and should, feel like part of a teamI think Uncle Doc and
Randy would like what we are doing today!et. al. is ourmost
valuableemployee!
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MOTHERS SMOKING DURING PREGNANCY MAY CAUSE ASTHMA IN
ADOLESCENTSMice exposed to cigarette smoke or clean air during
pregnancyYoung exposed to either cigarette smoke or clean air after
birthAirway reactivity to Aspergillus protein tested at 8 weeks of
age 4 groups: no smoke, smoke before, both before and after, or
only after birthResult:Exposure before birth or both before and
after birth nearly doubled airway reactivity in adolescent rats,
but exposure only after birth had little effect Implication:Mothers
smoking during pregnancy may contribute to airway reactivity of
adolescents, but exposure to second-hand smoke after birth may
not.Dr. Mohan Sopori, et. al.New Study Points Finger Toward Smoking
Before Birth! Of course, exposure of children to tobacco smoke is
known to increase other respiratory illnesses
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% of Normal AirwayReactivity
None After Before Before Birth + After Birth Birth Exposure to
Tobacco Smoke
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TREATMENT IMPROVES SURVIVAL OF PATIENTS WITH CRONIC LUNG
DISEASENew Evidence Overturns Conventional Wisdom! Question: Do
inhaled corticosteroids (ICS) and/or long-acting beta agonists
(LABA) prolong survival of patients with serious chronic
obstructive pulmonary disease (COPD)? (Most clinicians thought not)
Data from Lovelace Health Plan (Albuquerque) and Kaiser Health Plan
(Atlanta) Groups: ICS only = 786, LABA only = 170, ICS + LABA =
332, Other treatments = 397Dr. Floyd Frost, et. al.Results:Both ICS
and LABA increased survival during 1100-day follow-upCombination
even more beneficialImplications:These findings refute the
conventional wisdom that inhaled corticosteroids have little
benefit for survival, and indicate that the 2-drug combination
yields benefits that outweigh side effectsGathering more data to
confirm results and better define treatment-survival
relationships
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1400
1600
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0.4
0.5
0.6
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Days of Observation
Other Treatments
ICS
LABA
ICS + LABA
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NEW MEXICO LAB EMERGES AS NEW PLAYER ON THE PHARMACEUTICAL
RESEARCH SCENE Group Shifts Efforts Toward Preclinical Drug
Research Beginning in 1996, LRRI began turning its respiratory
research expertise and the newly-privatized Inhalation Toxicology
Research Institute facility into a center for preclinical studies
of new pharmaceuticalsDr. Chuck Hobbs, et. al. By FY-1999, annual
revenue had surpassed $1 million By 2002, the preclinical business
was boomingAnipryl (L-deprenylHCl): on the market because of LRRI
research Targets cognitive function and behavioral problems in aged
dogs (e.g.,Alzheimers) Deprenyl Animal Health Inc. came to LRRI
because of old dogs in colony Partnered with U. California, Irvine
to study learning and memory function FDA approved claims of
efficacy based on our results Promotion and distribution now
managed by Pfizer LRRI will be a silent partner behind new
respiratory drugs appearing on the shelf in coming years
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Fiscal Year
Revenue in $ M
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NEW EVIDENCE INCREASES URGENCY OF GETTING SMOKING VEHICLES OFF
THE ROADHigh Polluters Even More Dangerous than Expected! Samples
collected from normal and smoking gasoline and diesel cars &
pickups Lung inflammation measured in rats 24 hrs after dosing into
lung Five different measures of inflammation gave consistent
potency ranking Result:At same dose, emissions from smokers were
more toxic than emissions from normal vehiclesImplication:High
polluters not only emit more pollution, but their emissions are
also more toxic all the more reason to get them off the road!It was
known that 20% of vehicles cause 80% of pollutionThese results show
that high polluters cause an even greater portion of the lung
irritation from vehicle emissionsDr. JeanClare Seagrave. et.
al.
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RelativeInflammatoryPotency (Average of 5 different measures of
inflammation)
White Black Smoking Normal NormalSmoker Smoker Diesel Diesel
GasolineGasoline Gasoline
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2-DRUG COMBINATION MAY BE KNOCK-OUT PUNCH FOR REPEAT LUNG TUMORS
IN SMOKERSAnti-cancer genes are silenced two ways: Changing gene
structure (methylation) Cloaking with protein (histone
formation)Drug combo targets both effects : deoxyazacytidine (DAC)
sodium phenyl butyrate (SPB) Mice given tobacco carcinogen known to
cause multiple lung tumors Treated with 2-drug combination for 4
weeksResult:Treatment for only 4 weeks reduced the tumor response
by two-thirdsImplication:Proof of concept for preventing recurrence
using 2-drug combination Toxic DAC can only be used for
chemotherapy, not prevention Now testing selenium, which has same
action (selenium/SPB combo would be safe) Human chemoprevention
trial with selenium is underwayDr. Steve Belinsky, et.
al.Breakthrough in Preventing Second Tumors After Surgery?
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Tumor Response
Average Number of TumorsPer Mouse
Untreated Treated
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LRRI MODEL POINTS TOWARD PROTECTIVE EFFECT OF LOW DOSES OF
RADIATIONThe Hormesis Crowd May Have it Right After All!Dr. Bobby
Scot, et. al.tRegulations assume even the smallest doses cause
excess cancer risk Termed linear, no-threshold (LNT)
assumptionEvidence from humans, animals, and cells suggesting that
very low doses may actually reduce risk has not been incorporated
into predictive modelsLRRI developed revolutionary mathematical
model showing protective effect, using recent data from animal and
human cells in other labsResult:Model fitting the recent data shows
the magnitude of protective effect at doses below those causing
adverse effectsImplications:Reduces estimates of health impact from
low dosesSupports using low-dose anti-cancer therapy
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No. of TransformedCells per 105
Gamma Radiation Dose (millisievert)
Model For Low-Dose Protection From Neoplastic Transformation
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CLINICAL TRIALS LAB HELPS BRING NEW DRUGS TO MARKET Lovelace
Scientific Resources (LSR) operates clinical trials in multiple
centers Over 100 studies in Albuquerque, 30 in Phoenix, and 30 in
Las Vegas last year Many drugs now on the market were tested by
LSRActos Detrol-LA NeurontinAdvair inhaler Diovan SingularAvandia
Fosamax ViagraCelebrex Lantus VioxxCozaar Lipitor Zocor
Darlene Harbour, RN, CCRC, et. al.