A pedagogical strategy addressing an unmet need: Making the biology of aging an accessible part of interdisciplinary gerontology education.

In an age of specialization, obstacles to interdisciplinary training and integrated intellectual growth are expected. One such obstacle to graduate-level training in gerontology is the challenge of making the biology of aging accessible to nonbiologists. In this article, the authors' aim is to share 15 years of experience developing a pedagogical strategy that situates the biology of aging as an accessible part of interdisciplinary gerontology education for nonbiologists and biologists alike. The approach hinges on a four-pronged learning opportunity-four course offerings-that places high priority on exactitude with language and sees development of an attitude of precision with language as essential to intellectual growth. By inspiring students to master language in the key of B-Biology of Aging-we unleash a versatile method for developing cross-disciplinary discoverers prepared for a lifetime of seeing and reporting.

Correlates of estimated lifetime cruciate ligament survival inform potential rupture risk reduction strategies: findings from the Exceptional Aging in Rottweilers Study.

Cranial cruciate ligament (CCL) rupture is one of the most commonly diagnosed orthopedic conditions of pet dogs, making estimated lifetime cruciate ligament survival an attractive endpoint for studies attempting to define clinical and genetic correlates of rupture risk reduction. Early life experiences contribute significantly to the origins of adult health outcomes, yet our current understanding of modifiable susceptibility factors that drive the high frequency of CCL rupture remains limited. We reasoned that combining lifetime medical history with standardized late-life assessment of lifetime cruciate ligament survival and detailed phenotyping of each dog for selected risk variables would provide a sensitive approach to identify factors that would differentiate between lifelong avoidance versus susceptibility to ligament rupture. Here, we report results of Kaplan-Meier analysis of estimated lifetime cruciate ligament survival and Cox proportional hazards modeling to assess risk variables in a lifetime cohort study of 123 purebred Rottweilers, a breed at high risk for veterinarian-diagnosed CCL rupture. We show that gonad removal during the 24-month developmental period is adversely associated with three measures of susceptibility-increased incidence of CCL rupture, multiplicity (bilateral rupture), and accelerated time to initial CCL failure. Our analysis reveals two other phenotypes-short adult height and the production of offspring (in females)-are associated with significant CCL rupture risk reduction. Together, the results provide clues to an early endocrine influence on lifetime cruciate ligament survival. Further, we identify two distinct clinical syndromes of CCL failure, providing a disease subtyping framework to advance future progress in genetic epidemiology, pathogenesis, and prediction. By conducting an evaluation of estimated lifetime CCL survival in dogs, we show that cruciate ligament survival may be jeopardized by gonad removal during the developmental period. Avoidance of such early environmental adversity may represent an actionable method for the control of canine CCL disease in certain breeds.

Differential responses to selenomethionine supplementation by sex and genotype in healthy adults.

A year-long intervention trial was conducted to characterise the responses of multiple biomarkers of Se status in healthy American adults to supplemental selenomethionine (SeMet) and to identify factors affecting those responses. A total of 261 men and women were randomised to four doses of Se (0, 50, 100 or 200 µg/d as L-SeMet) for 12 months. Responses of several biomarkers of Se status (plasma Se, serum selenoprotein P (SEPP1), plasma glutathione peroxidase activity (GPX3), buccal cell Se, urinary Se) were determined relative to genotype of four selenoproteins (GPX1, GPX3, SEPP1, selenoprotein 15), dietary Se intake and parameters of single-carbon metabolism. Results showed that supplemental SeMet did not affect GPX3 activity or SEPP1 concentration, but produced significant, dose-dependent increases in the Se contents of plasma, urine and buccal cells, each of which plateaued by 9-12 months and was linearly related to effective Se dose (µg/d per kg0·75). The increase in urinary Se excretion was greater for women than men, and for individuals of the GPX1 679 T/T genotype than for those of the GPX1 679 C/C genotype. It is concluded that the most responsive Se-biomarkers in this non-deficient cohort were those related to body Se pools: plasma, buccal cell and urinary Se concentrations. Changes in plasma Se resulted from increases in its non-specific component and were affected by both sex and GPX1 genotype. In a cohort of relatively high Se status, the Se intake (as SeMet) required to support plasma Se concentration at a target level (Se(pl-target)) is: Se(in) = [(Se(pl - target) - Se(pl))/(18.2ng d kg°.75/ml per mu g)] .

A modern pulse of ultrafast exhumation and diachronous crustal melting in the Nanga Parbat Massif.

We combine monazite petrochronology with thermal modeling to evaluate the relative roles of crustal melting, surface denudation, and tectonics in facilitating ultrafast exhumation of the Nanga Parbat Massif in the western Himalayan syntaxis. Our results reveal diachronous melting histories between samples and a pulse of ultrafast exhumation (9 to 13 mm/year) that began ~1 Ma and was preceded by several million years of slower, but still rapid, exhumation (2 to 5 mm/year). Recent studies show that an exhumation pulse of similar timing and magnitude occurred in the eastern Himalayan syntaxis. A synchronous exhumation pulse in both Himalayan syntaxes suggests that neither erosion by rivers and/or glaciers nor a pulse of crustal melting was a primary trigger for accelerated exhumation. Rather, our results, combined with those of recent studies in the eastern syntaxis, imply that larger-scale tectonic processes impose the dominant control on the current tempo of rapid exhumation in the Himalayan syntaxes.

On the self-renewal of teachers.

In previous issues of the Journal of Veterinary Medical Education, wide-ranging insights on how to achieve excellence in the classroom have been framed by award-winning teachers. These recipes for educational success, however, invariably lack a key ingredient-the teacher's process of self-renewal. What skills and attitudes prime the teacher for continued high performance? To stay out of the ruts of expertise, where does the teacher turn? Teachers and administrators alike recognize its great importance, yet few opportunities for the renewal of teachers are built into the educational system. In this article, we challenge teachers to see their own self-renewal as an underutilized approach to innovate education. We propose a schema for sustained self-renewal: each educator developing her own personalized, hand-picked gallery of intellectual heroes who in turn serve as the educator's life-long teachers. To illustrate the value of this activity, we introduce our own collection of 10 gifted thinkers, providing a brief encounter with each sage as a way of stimulating new thinking on the skills and attitudes that promote personal growth and transformative teaching. We conclude that the veterinary profession should work to create better opportunities for the self-renewal of teachers. By envisioning even our best teachers as unfinished and under construction, we open up a new dialogue situating the self-renewal of teachers at the very core of educational excellence.

Devising a new dialogue for nutrition science: how life course perspective, U-shaped thinking, whole organism thinking, and language precision contribute to our understanding of biological heterogeneity and forge a fresh advance toward precision medicine.

The process of designing and implementing individualized health-promoting interventions, nutritional or otherwise, is fraught with great difficulty owing to the heterogeneity inherent in factors that influence healthy longevity. This article proposes that careful attention to three principles-life course perspective, U-shaped thinking, and whole organism thinking-creates an attitudinal framework that can be used to reframe biological heterogeneity into the clinically relevant question: Who will benefit? The search for tools to cope with the complexity of this heterogeneity has been dominated by technological advances, including state-of-the-art "-omics" approaches and machine-based handling of "big data." Here, it is proposed that language precision and nuanced category usage could provide critical tools for coping with heterogeneity, thereby enabling interventionalists to design and implement strategies to promote healthy longevity with greater precision. The lack of a clear understanding of "Who will benefit?" stands as a major obstacle to the design and implementation of nutritional strategies to optimize healthy longevity. This article opens a new dialogue situating the principles of life course perspective, U-shaped thinking, and whole organism thinking, along with cultivating an attitude of language precision at the very core of accelerating creative discovery and refining practical advance in the field of nutrition science.

Supplemental dietary racemic equol has modest benefits to bone but has mild uterotropic activity in ovariectomized rats.

Soy isoflavones and their metabolites, with estrogenic activity, have been considered candidates for reducing postmenopausal bone loss. In this study, we examined the effect of dietary equol, a bioactive metabolite of the soy isoflavone daidzein, on equol tissue distribution, bone parameters, and reproductive tissue activity using an adult ovariectomized (OVX) rat model. An 8-wk feeding study was conducted to compare 4 dietary treatments of equol (0, 50, 100, 200 mg/kg diet) in 6-mo-old OVX female Sprague-Dawley rats. A dose response increase in tissue equol concentrations was observed for serum, liver, kidney, and heart, and a plateau occurred at 100 mg equol/kg diet for intestine. In OVX rats receiving 200 mg equol/kg diet, femoral calcium concentration was greater than those receiving lower doses but was still less than SHAM (P < 0.05), and other bone measures were not improved. Tibia calcium concentrations were lower in OVX rats receiving 100 and 200 mg equol/kg diet compared with the OVX control rats. Trabecular bone mineral density of tibia was also lower in equol-fed OVX rats. At this dietary equol intake, uterine weight was higher (P < 0.05) than in other OVX groups but lower than the SHAM-operated intact rats. The 200 mg/kg diet dose of dietary equol significantly increased proliferative index in the uterine epithelium. Dietary equol had no stimulatory effect on mammary gland epithelium. We conclude that in OVX rats, a dietary equol dose that had modest effect on bone also exerts mild uterotropic effects.

Reevaluation of predictive factors for complete recovery in dogs with nonambulatory tetraparesis secondary to cervical disk herniation.

The vast majority of dogs with cervical disk herniation experience cervical pain and only mild motor deficits; therefore, not much is known about the factors that predict recovery in dogs with nonambulatory tetraparesis (NAT) secondary to cervical disk herniation. In this retrospective study, we tested the hypothesis that two previously reported prognostic factors, site of disk herniation and severity of neurological deficits, are useful predictors of complete recovery. Overall, 20 (62%) of 32 dogs with cervical disk herniation-associated NAT had complete recovery. Site of disk herniation was not a significant predictor of complete recovery; dogs with high cervical lesions (C2 to C3, C3 to C4) did not have a higher likelihood of complete recovery than other dogs. Likewise, severity of neurological deficits (i.e., intact voluntary motor function versus absent voluntary motor function) was not a significant predictor of complete recovery. Using stepwise logistic regression, two significant predictors of complete recovery were identified. Small dogs (delta15 kg body weight) were six times more likely to achieve complete recovery than larger dogs. Dogs that regained the ability to walk within 96 hours after surgery were seven times more likely to completely recover than dogs not walking 96 hours after surgery. We conclude that neither the site of disk herniation nor severity of neurological deficits assists the clinician in predicting postoperative outcome in dogs with cervical disk herniation-associated NAT. Reliable preoperative predictors of complete recovery are needed to advance current diagnostic and treatment protocols to improve overall prognosis.

Five threads: How U-shaped thinking weaves together dogs, men, selenium, and prostate cancer risk.

Prostate cancer is one of the leading causes of cancer-related mortality among men living in developed countries, making the development of safe, practical approaches to prostate cancer risk reduction a high research priority. The relationship between prostate cancer risk and selenium, an essential nutrient required for a number of metabolically important enzymes including glutathione peroxidases, has been investigated, but a satisfactory integration of results has proven elusive. Dogs, like men, naturally develop prostate cancer during aging, providing an appropriate context to study the effects of selenium supplementation on the dysregulation of homeostasis that drives cancer development within the aging prostate. In this paper, we summarize the translational significance of research results gained from dog studies on selenium and prostate cancer risk. Our discovery of a U-shaped dose-response between toenail selenium concentration and prostatic DNA damage in dogs remarkably parallels data on the relationship between selenium status and prostate cancer risk in men. Notably, the dog U-curve provides a plausible explanation for the unanticipated increase in prostate cancer incidence among men with highest baseline selenium who received selenium supplementation in the largest-ever prostate cancer prevention trial (SELECT). Moreover, the dog U-curve guided the discovery of a non-antioxidant, anti-carcinogenic mechanism of organic selenium - the preferential triggering of apoptosis in DNA damaged cells, which we have termed "homeostatic housecleaning". Taken together, the data from dogs and men indicate that increasing selenium status will not necessarily be associated with prostate cancer risk reduction. Landing in the trough of the U - achieving mid-range selenium status - is better than being too low or too high. Personalizing health promotion in a more-is-not-necessarily-better world poses distinctive challenges. Dog studies can be relied upon to contribute important insights into dose-dependent and form-dependent effects - two critical aspects of selenium biology that will have to be disentangled if the burgeoning science of selenium is to be translated into effective strategies for human disease prevention. Beyond contributing to understanding the role of selenium in biology, our work situates the concept of U-shaped thinking at the core of personalized medicine and precision nutrition.

Noninvasive prediction of prostatic DNA damage by oxidative stress challenge of peripheral blood lymphocytes.

To move closer to the goal of individualized risk prediction for prostate cancer, we used an in vivo canine model to evaluate whether the susceptibility of peripheral blood lymphocytes (PBLs) to oxidative stress-induced DNA damage could identify those individuals with the highest prostatic DNA damage. This hypothesis was tested in a population of 69 elderly male beagle dogs after they had completed a 7-month randomized feeding trial to achieve the broad range of dietary selenium status observed in U.S. men. The alkaline Comet assay was used to directly compare the extent of DNA damage in PBLs with prostatic DNA damage in each dog. Using stepwise logistic regression, the sensitivity of PBLs to oxidative stress challenge with hydrogen peroxide (H(2)O(2)) predicted dogs in the highest tertile of prostatic DNA damage. Dogs with PBLs highly sensitive to H(2)O(2) were 7.6 times [95% confidence interval (95% CI), 1.5-38.3] more likely to have high prostatic DNA damage than those in the H(2)O(2)-resistant group. This risk stratification was observed in multivariate analysis that considered other factors that might influence DNA damage, such as age, toenail selenium concentration, and serum testosterone concentration. Our data show that the sensitivity of PBLs to oxidative stress challenge, but not endogenous DNA damage in PBLs, provides a noninvasive surrogate marker for prostatic DNA damage. These findings lend support to the concept that oxidative stress contributes to genotoxic damage, and that oxidative stress challenge may stratify men for prostate cancer risk.

Cyclooxygenase inhibitors in urinary bladder cancer: in vitro and in vivo effects.

More than 14,000 people die from invasive transitional cell carcinoma (TCC) of the urinary bladder yearly in the United States. Cyclooxygenase (COX)-inhibiting drugs are emerging as potential antitumor agents in TCC. The optimal in vitro or in vivo systems to investigate COX inhibitor antitumor effects have not been defined. The purpose of this study was to determine COX-1 and COX-2 expression and antitumor effects of COX inhibitors in human TCC cell lines (HT1376, RT4, and UMUC3 cells) and xenografts derived from those cell lines. COX-2 expression (Western blot, immunocytochemistry) was high in HT1376, modest in RT4, and absent in UMUC3 cells in vitro. Similarly, COX-2 expression was noted in RT4 but not UMUC3 xenografts. COX-2 expression in HT1376 xenografts was slightly lower than that observed in vitro. None of four COX inhibitors evaluated (celecoxib, piroxicam, valeryl salicylate, and NS398) reduced TCC growth in standard in vitro proliferation assays at concentrations that could be safely achieved in vivo (< or =5 micromol/L). Higher celecoxib concentrations (> or =50 micromol/L) inhibited proliferation and induced apoptosis in all three cell lines. Celecoxib or piroxicam treatment in athymic mice significantly delayed progression of HT1376 xenografts, which express COX-2, but not UMUC3 xenografts that lack COX-2 expression. In conclusion, standard in vitro assays were not useful in predicting COX inhibitor antitumor effects observed in vivo. Athymic mice bearing TCC xenografts provide a useful in vivo system for COX inhibitor studies. Results of this study provide justification for further evaluation of COX inhibitors as antitumor agents against TCC.

Nuclear imaging of Met-expressing human and canine cancer xenografts with radiolabeled monoclonal antibodies (MetSeek).

PURPOSE: Met, an oncogene product and receptor tyrosine kinase, is a keystone molecule for malignant progression in solid human tumors. We are developing Met-directed imaging and therapeutic agents, including anti-Met monoclonal antibodies (MetSeek). In this study, we compared two antibodies, Met5 and Met3, for nuclear imaging of human and canine Met-expressing tumor xenografts in nude mice. EXPERIMENTAL DESIGN: Xenografts representing cancers of three different human tissue origins and metastatic canine prostate cancer were raised s.c. in host athymic nude mice. Animals were injected i.v. with I-125-Met5 or I-125-Met3, posterior total body gamma camera images were acquired for several days postinjection, and quantitative region-of-interest activity analysis was done. RESULTS: PC-3, SK-LMS-1/HGF, and CNE-2 xenografts imaged with I-125-Met5 were compared with PC-3, SK-LMS-1/HGF, and DU145 xenografts imaged with I-125-Met3. Nuclear imaging contrast was qualitatively similar for I-125-Met5 and I-125-Met3 in PC-3 and SK-LMS-1/HGF host mice. However, by region-of-interest analysis, the set of human tumors imaged with I-125-Met3 exhibited a pattern of rapid initial tumor uptake followed by a continuous decline in activity, whereas the set of human tumors imaged with I-125-Met5 showed slow initial uptake, peak tumor-associated activity at 1 day postinjection, and persistence of activity in xenografts for at least 5 days. GN4 canine prostate cancer xenografts were readily imaged with I-125-Met5. CONCLUSIONS: We conclude that radioiodinated Met3 and Met5 offer qualitatively similar nuclear images in xenograft-bearing mice, but quantitative considerations indicate that Met5 might be more useful for radioimmunotherapy. Moreover, canine prostate cancer seems to be a suitable model for second-stage preclinical evaluation of Met5.

Effects of dietary selenium supplementation on DNA damage and apoptosis in canine prostate.

The trace mineral selenium inhibits cancer development in a variety of experimental animal models. We used an in vivo canine model to evaluate the effects of dietary selenium supplementation on DNA damage in prostate tissue and on apoptosis in prostate epithelial cells. Sexually intact elderly male beagle dogs were randomly assigned to receive an unsupplemented diet (control group) or diets that were supplemented with selenium (treatment group), either as selenomethionine or as high-selenium yeast at 3 micro g/kg or 6 micro g/kg body weight per day for 7 months. The extent of DNA damage in prostate cells and in peripheral blood lymphocytes, as determined by the alkaline comet assay, was lower among the selenium-supplemented dogs than among the control dogs (prostate P<.001; peripheral blood lymphocytes P =.003; analysis of variance) but was not associated with the activity of the antioxidant enzyme glutathione peroxidase in plasma. The median number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling-positive (i.e., apoptotic) prostate epithelial cells was 3.7 (interquartile range = 1.1-7.6) for the selenium-supplemented dogs and 1.7 (interquartile range = 0.2-2.8) for the control dogs ( P =.04, Mann-Whitney U test). These data suggest that dietary selenium supplementation decreases DNA damage and increases epithelial cell apoptosis within the aging canine prostate.

RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival.

Hepatocyte growth factor/scatter factor-Met signaling has been implicated in tumor growth, invasion, and metastasis. Suppression of this signaling pathway by targeting the Met protein tyrosine kinase may be an ideal strategy for suppressing malignant tumor growth. Using RNA interference technology and adenovirus vectors carrying small-interfering RNA constructs (Ad Met small-interfering RNA) directed against mouse, canine, and human Met, we can knock down c-met mRNA. We show a dramatic dependence on Met in both ligand-dependent and ligand-independent mouse, canine, and human tumor cell lines. Mouse mammary tumor (DA3) cells and Met-transformed NIH3T3 (M114) cells, as well as both human and canine prostate cancer (PC-3 and TR6LM, human sarcoma (SK-LMS-1), glioblastoma (DBTRG), and gastric cancer (MKN45) cells, all display a dramatic reduction of Met expression after infection with Ad Met small-interfering RNA. In these cells, we observe suppression of tumor cell growth and viability in vitro as well as inhibition of hepatocyte growth factor/scatter factor-mediated scattering and invasion in vitro, whether Met activation was ligand dependent or not. Importantly, Ad Met small-interfering RNA led to apoptotic cell death in many of the tumor cell lines, especially DA3 and MKN45, but did not adversely affect MDCK canine kidney cells. Met small-interfering RNA also abrogated downstream Met signaling to molecules such as Akt and p44/42 mitogen-activated protein kinase. We further show that intratumoral infection with c-met small-interfering RNA adenovirus results in a substantial reduction in tumor growth. Thus, Met small-interfering RNA adenoviruses are reliable tools for studying Met function and raise the possibility of their application for cancer therapy.

Epidemiology and statistical methods in prediction of patient outcome.

Substantial gaps exist in the data of the assessment of risk and prognosis that limit our understanding of the complex mechanisms that contribute to the greatest cancer epidemic, prostate cancer, of our time. This report was prepared by an international multidisciplinary committee of the World Health Organization to address contemporary issues of epidemiology and statistical methods in prostate cancer, including a summary of current risk assessment methods and prognostic factors. Emphasis was placed on the relative merits of each of the statistical methods available. We concluded that: 1. An international committee should be created to guide the assessment and validation of molecular biomarkers. The goal is to achieve more precise identification of those who would benefit from treatment. 2. Prostate cancer is a predictable disease despite its biologic heterogeneity. However, the accuracy of predicting it must be improved. We expect that more precise statistical methods will supplant the current staging system. The simplicity and intuitive ease of using the current staging system must be balanced against the serious compromise in accuracy for the individual patient. 3. The most useful new statistical approaches will integrate molecular biomarkers with existing prognostic factors to predict conditional life expectancy (i.e. the expected remaining years of a patient's life) and take into account all-cause mortality.

Endogenous gonadal hormone exposure and bone sarcoma risk.

Although experimental and clinical evidence suggest that endogenous sex hormones influence bone sarcoma genesis, the hypothesis has not been adequately tested in an appropriate animal model. We conducted a historical cohort study of Rottweiler dogs because they frequently undergo elective gonadectomy and spontaneously develop appendicular bone sarcomas, which mimic the biological behavior of the osteosarcomas that affect children and adolescents. Data were collected by questionnaire from owners of 683 Rottweiler dogs living in North America. To determine whether there was an association between endogenous sex hormones and risk of bone sarcoma, relative risk (RR) of incidence rates and hazard ratios for bone sarcoma were calculated for dogs subdivided on the basis of lifetime gonadal hormone exposure. Bone sarcoma was diagnosed in 12.6% of dogs in this cohort during 71,004 dog-months follow-up. Risk for bone sarcoma was significantly influenced by age at gonadectomy. Male and female dogs that underwent gonadectomy before 1 year of age had an approximate one in four lifetime risk for bone sarcoma and were significantly more likely to develop bone sarcoma than dogs that were sexually intact [RR +/-95% CI = 3.8 (1.5-9.2) for males; RR +/-95% CI = 3.1 (1.1-8.3) for females]. Chi(2) test for trend showed a highly significant inverse dose-response relationship between duration of lifetime gonadal exposure and incidence rate of bone sarcoma (P = 0.008 for males, P = 0.006 for females). This association was independent of adult height or body weight. We conclude that the subset of Rottweiler dogs that undergo early gonadectomy represent a unique, highly accessible target population to further study the gene:environment interactions that determine bone sarcoma risk and to test whether interventions can inhibit the spontaneous development of bone sarcoma.

Folate-conjugated liposomes preferentially target macrophages associated with ovarian carcinoma.

The folate receptor (FR) is overexpressed on many epithelial cancers and has been exploited for targeted delivery of folate-linked liposomes to cancer cells in vitro. The present studies investigate the distribution of folate-targeted liposomes in a FR(+) mouse model of ovarian cancer. According to flow cytometric analysis, folate-conjugation of liposomes significantly enhanced their uptake into ovarian cancer cells and tumor-associated macrophages within tumor ascites fluid. Compared to ovarian cancer cells, macrophages acquired tenfold more liposomes, and approximately 50% of this uptake was FR-dependent. These results demonstrate that, in addition to their cancer cell-targeting properties, folate-liposomes may be useful for targeting drugs to tumor-associated macrophages in vivo.

Molecular pathology of non-invasive urothelial carcinomas (part I).

An international consultation on the diagnosis of non-invasive urothelial neoplasms was held in Ancona, Italy in May 2001. Besides histology and problems of classification, one group of experts (Committee no. 3) discussed the molecular pathology and cytometry of non-invasive urothelial carcinomas. In the following first part, special immunohistochemical and molecular markers for stratifications in bladder cancer were discussed including different cytokeratins (clone 34betaE12, CK 20), cell proliferation markers (Ki67/MIB-1, PCNA, AgNOR, DNA-cytometry), tumor suppressor genes and oncogenes (p53, p21, erb-B2, bcl-2), different receptor expressions of epidermal growth factor and vascular endothelial growth factor and others. These molecular markers were analyzed in diagnosis of urothelial carcinomas, recurrences, progression and response to treatment.

Exceptional longevity in pet dogs is accompanied by cancer resistance and delayed onset of major diseases.

To characterize extreme aged pet dogs as a first step in developing an animal model of exceptional longevity, we constructed lifetime medical histories for 345 Rottweiler dogs using information collected from owners and veterinarians. Extreme aged dogs (alive at the 95th percentile age at death for the study population, > or =13.3 years) were compared with a usual longevity group (9-10 years). Exceptional longevity in Rottweiler dogs was accompanied by a significant delay in the onset of major life-threatening diseases; 76% of extreme aged dogs remained free of all major diseases during the first 9 years of life. Only 19% of extreme aged dogs died of cancer versus 82% of dogs with usual longevity (p <.0001). The reduction in cancer mortality in oldest-old pet dogs mimics that seen in human centenarians and provides strong rationale for using this animal model to study comparative mechanisms of cancer resistance in the extreme aged.

Preparation of 66Ga- and 68Ga-labeled Ga(III)-deferoxamine-folate as potential folate-receptor-targeted PET radiopharmaceuticals.

A folate-receptor-targeting radiopharmaceutical, Ga(III)-deferoxamine-folate (Ga-DF-Folate), was radiolabeled with two positron-emitting isotopes of gallium, cyclotron-produced (66)Ga (9.5 hour half-life) and generator-produced (68)Ga (68 minute half-life). The [(66)Ga]Ga-DF-Folate was administered to athymic mice with folate-receptor-positive human KB cell tumor xenografts to demonstrate that microPET mouse tumor imaging is feasible with (66)Ga, despite the relatively high positron energy of this radionuclide. Using the athymic mouse KB tumor xenograft model, dual-isotope autoradiography was also performed following i.v. co-administration of [(18)F]-FDG, a marker of regional metabolic activity, and folate-receptor-targeted [(111)In]In-DTPA-Folate. The autoradiographic images of 1 mm tumor sections demonstrate the gross heterogeneity of the KB cell tumor xenograft, as well as subtle disparity in the regional accumulation of the two radiotracers.