The OncoSim model: development and use for better decision-making in Canadian cancer control.

The Canadian Partnership Against Cancer was created in 2007 by the federal government to accelerate cancer control across Canada. Its OncoSim microsimulation model platform, which consists of a suite of specific cancer models, was conceived as a tool to augment conventional resources for population-level policy- and decision-making. The Canadian Partnership Against Cancer manages the OncoSim program, with funding from Health Canada and model development by Statistics Canada. Microsimulation modelling allows for the detailed capture of population heterogeneity and health and demographic history over time. Extensive data from multiple Canadian sources were used as inputs or to validate the model. OncoSim has been validated through expert consultation; assessments of face validity, internal validity, and external validity; and model fit against observed data. The platform comprises three in-depth cancer models (lung, colorectal, cervical), with another in-depth model (breast) and a generalized model (25 cancers) being in development. Unique among models of its class, OncoSim is available online for public sector use free of charge. Users can customize input values and output display, and extensive user support is provided. OncoSim has been used to support decision-making at the national and jurisdictional levels. Although simulation studies are generally not included in hierarchies of evidence, they are integral to informing cancer control policy when clinical studies are not feasible. OncoSim can evaluate complex intervention scenarios for multiple cancers. Canadian decision-makers thus have a powerful tool to assess the costs, benefits, cost-effectiveness, and budgetary effects of cancer control interventions when faced with difficult choices for improvements in population health and resource allocation.

Using the Cancer Risk Management Model to evaluate the health and economic impacts of cytology compared with human papillomavirus DNA testing for primary cervical cancer screening in Canada.

BACKGROUND: In Canada, discussion about changing from cytology to human papillomavirus (hpv) dna testing for primary screening in cervical cancer is ongoing. However, the Canadian Task Force on Preventive Health Care has not yet made a recommendation, concluding that the evidence is insufficient. METHODS: We used the cervical cancer and hpv transmission models of the Cancer Risk Management Model to study the health and economic outcomes of primary cytology compared with hpv dna testing in 14 screening scenarios with varying screening modalities and intervals. Projected cervical cancer cases, deaths, colposcopies, screens, costs, and incremental cost-effectiveness were evaluated. We performed sensitivity analyses for hpv dna test costs. RESULTS: Compared with triennial cytology from age 25, 5-yearly hpv dna screening alone from age 30 resulted in equivalent incident cases and deaths, but 55% (82,000) fewer colposcopies and 43% (1,195,000) fewer screens. At hpv dna screening intervals of 3 years, whether alone or in an age-based sequence with cytology, screening costs are greater, but at intervals of more than 5 years, they are lower. Scenarios on the cost-effectiveness frontier were hpv dna testing alone every 10, 7.5, 5, or 3 years, and triennial cytology starting at age 21 or 25 when combined with hpv dna testing every 3 years. CONCLUSIONS: Changing from cytology to hpv dna testing as the primary screening test for cervical cancer would be an acceptable strategy in Canada with respect to incidence, mortality, screening and diagnostic test volumes.

Micron scale directional coupler as a transducer for biochemical sensing.

A microfabricated directional coupler (DC) was used for the detection of DNA conjugated with quantum dots. Output optical signals from DCs of a wide range of device lengths correspond well to theoretical and simulation results. Even 20 µm-long DC devices could detect changes in the output optical intensity by monitoring the near-field pattern using a CCD camera. The signal was enhanced 60 × using a 1500 µm-long DC device. For large cladding refractive-index changes between air and water, the normalized signal changed cyclically several times between 0 and 1. The results suggest that the DC can be the basis for miniaturized two-dimensionally integrated biochemical sensors.

The effect of higher-order dispersion on slow light propagation in photonic crystal waveguides.

We have studied the dispersion of ultrafast pulses in a photonic crystal waveguide as a function of optical frequency, in both experiment and theory. With phase-sensitive and time-resolved near-field microscopy, the light was probed inside the waveguide in a non-invasive manner. The effect of dispersion on the shape of the pulses was determined. As the optical frequency decreased, the group velocity decreased. Simultaneously, the measured pulses were broadened during propagation, due to an increase in group velocity dispersion. On top of that, the pulses exhibited a strong asymmetric distortion as the propagation distance increased. The asymmetry increased as the group velocity decreased. The asymmetry of the pulses is caused by a strong increase of higher order dispersion. As the group velocity was reduced to 0.116(9) .c, we found group velocity dispersion of -1.1(3) .10(6) ps(2)/km and third order dispersion of up to 1.1(4) .10(5) ps(3)/km. We have modelled our interferometric measurements and included the full dispersion of the photonic crystal waveguide. Our mathematical model and the experimental findings showed a good correspondence. Our findings show that if the most commonly used slow light regime in photonic crystals is to be exploited, great care has to be taken about higher-order dispersion.

Tol2-mediated transgenesis, gene trapping, enhancer trapping, and Gal4-UAS system.

The Tol2 element is an active transposon that was found from the genome of the Japanese medaka fish. Since the Tol2 transposition system is active in all vertebrate cells tested so far, it has been applied to germ line transgenesis in various model animals including fish, frog, chicken, and mouse, and to gene transfer in culture cells. In zebrafish, the Tol2 system consists of the transposase mRNA and a Tol2 transposon-donor plasmid, and is introduced into fertilized eggs by microinjection. Thus genomic integrations of the Tol2 construct are generated in the germ lineage and transmitted to the offspring very efficiently. By using the Tol2 transposition system, we have developed important genetic methods, such as transgenesis, gene trapping, enhancer trapping, and the Gal4-UAS system in zebrafish and applied to many aspects of biological studies. In this chapter, we describe how these methods are performed.

Gal4 Driver Transgenic Zebrafish: Powerful Tools to Study Developmental Biology, Organogenesis, and Neuroscience.

Targeted expression by the Gal4-UAS system is a powerful genetic method to analyze the functions of genes and cells in vivo. Although the Gal4-UAS system has been extensively used in genetic studies in Drosophila, it had not been applied to genetic studies in vertebrates until the mid-2000s. This was mainly due to the lack of an efficient transgenesis tool in model vertebrates, such as the P-transposable element of Drosophila, that can create hundreds or thousands of transgene insertions in different loci on the genome and thereby enables the generation of transgenic lines expressing Gal4 in various tissues and cells via enhancer trapping. This situation was revolutionized when a highly efficient transgenesis method using the Tol2 transposable element was developed in the model vertebrate zebrafish. By using the Tol2 transposon system, we and other labs successfully performed gene trap and enhancer trap screens in combination with the Gal4-UAS system. To date, numerous transgenic fish lines that express engineered versions of Gal4 in specific cells, organs, and tissues have been generated and used for various aspects of biological studies. By constructing transgenic fish lines harboring genes of interest downstream of UAS, the Gal4-expressing cells and tissues in those transgenic fish have been visualized and manipulated via the Gal4-UAS system. In this review, we describe how the Gal4-UAS system works in zebrafish and how transgenic zebrafish that express Gal4 in specific cells, tissues, and organs have been used for the study of developmental biology, organogenesis, and neuroscience.

Polypeptide hormone receptor phosphorylation: is there a role in receptor-mediated endocytosis of human growth hormone?

To determine whether receptor phosphorylation is a critical step in the internalization of polypeptide hormones and their receptors, we have studied a model system wherein insulin stimulates phosphorylation of its receptor and is also internalized. Using insulin as a positive control, we found that it stimulated a partially purified plasma membrane preparation of IM-9 lymphocytes to autophosphorylate its receptor and to catalyze the phosphorylation of a tyrosine-containing substrate. The human GH (hGH) receptor of the IM-9 lymphocytes, when coupled to [125I]iodo-hGH, migrated as a 140,000-dalton protein on polyacrylamide gel electrophoresis. This protein, in contrast to the insulin receptor, was not phosphorylated by the addition of hGH, nor did hGH stimulate this preparation to phosphorylate the tyrosine-containing substrate poly-(GluNa,Tyr)4:1, casein, or histone f2b under a variety of conditions. We conclude that receptor phosphorylation is not a critical intermediate in the receptor-mediated endocytosis of hGH and probably other polypeptide hormones and growth factors.

Demonstration of insulin-like growth factor I in human urine.

Immunoreactive and receptor-reactive insulin-like growth factor I (IGF-I) was demonstrated in human urine. Thirty percent of the IGF-I immunoreactivity in urine was free, and the remainder was a high mol wt form (approximately 43K). Urinary IGF-I was quantitated by RIA after extraction with octadecylsilyl silica cartridges (Sep-Pak C18 cartridge), a method that measures only free IGF-I. The mean urinary immunoreactive IGF-I levels in normal adults (n = 8) and patients with acromegaly (n = 10) or hypopituitarism (n = 9) were 72 +/- 7 (+/- SEM), 225 +/- 34, and 19 +/- 4 pg/mg creatinine, respectively; these mean values were significantly different from one another. The results indicate that IGF-I is present in human urine and that the quantity in urine is altered in patients with GH excess and deficiency.

Plasma clearance of intravenously administered pituitary human growth hormone: gel filtration studies of heterogeneous components.

Both pituitary and plasma human GH (hGH) comprise heterogeneous components, exhibiting similar patterns when gel filtered on Sephadex G-100. To determine at what rate the components are cleared from the circulation, blood was obtained at specific intervals following a bolus injection of pituitary hGH in hypopituitary patients. Each sample was gel filtered to determine its component profile of RIA values, which, when plotted vs. the time interval it represented, yielded a means of monitoring its disappearance from the plasma. Total hGH was cleared with a t 1/2 of 21.5 min, the little component was cleared at 19.0 min, the big component was cleared at 26.5 min, and the pre-big component was cleared at 45 min. These data indicate that the larger the hGH component, the longer it takes to be cleared from the plasma.

Urinary growth hormone (GH) measurements are useful for evaluating endogenous GH secretion.

Daily (24-h) urinary GH excretion was measured using a highly sensitive sandwich enzyme immunoassay in 10 normal adults, 6 patients with hypopituitarism, 25 normal but short children who had normal plasma GH responses (peak plasma GH level, greater than 10 micrograms/L) to provocative tests, and 8 patients with acromegaly. The mean urinary GH values in the normal adults, patients with acromegaly, and patients with hypopituitarism were 13.8 +/- 4.0 (+/- SE) and 431.1 +/- 149.1 ng/g creatinine (Cr) (1.56 +/- 0.45 and 48.77 +/- 16.87 ng/mmol Cr) and undetectable, respectively; these mean values were significantly different from each other. In the normal but short children the urinary values ranged from undetectable to 55.8 ng/g Cr (6.31 ng/mmol Cr). All of the normal but short children and 4 patients with hypopituitarism participated in a 24-h endogenous GH secretion study. The urinary GH values correlated significantly with the mean 24-h plasma GH concentrations as an index of endogenous GH secretion (r = 0.81; P less than 0.001) and plasma somatomedin-C levels (r = 0.67; P less than 0.001), respectively. In 6 patients with acromegaly whose plasma GH levels were constant throughout a 4-h period, the urinary GH values also significantly correlated with the mean plasma GH levels (r = 0.95; P less than 0.01). These data indicate that urinary GH measurements reflect endogenous GH secretion and that measurement of urinary GH excretion is a useful, simple, and practical method for evaluating endogenous GH secretion.

Plasma growth hormone (GH) response to GH-releasing factor in normal children with short stature and patients with pituitary dwarfism.

Synthetic human pancreatic GRF (hpGRF-44) was administered as an iv bolus to 28 normal children with short stature and 27 patients with GH deficiency. After a dose of 1 or 2 micrograms hpGRF-44/kg BW, mean plasma GH levels peaked at 15 and 30 min, respectively, with corresponding values of 30.1 +/- 4.7 and 33.2 +/- 3.7 ( +/- SE) ng/ml in normal but short children. The overall plasma GH response was greater than that of other GH stimulation tests such as insulin-induced hypoglycemia, glucagon-propranolol or L-dopa administration. Plasma LH, FSH, TSH, PRL, and cortisol levels were not altered by hpGRF-44 injection. Sixteen of 27 patients with GH deficiency did not respond to a 2 micrograms/kg BW hpGRF-44. However, plasma GH increases to greater than 5 ng/ml occurred in the remaining 11 patients. Their GH levels reached peaks between 15 and 90 min, with values ranging between 5.8 and 17.8 ng/ml. Two of these responding patients were infused iv with hpGRF-44 at 2.5 micrograms/min for 90 min after receiving an iv bolus injection of 2 micrograms/kg BW. Their plasma GH levels increased and remained near peak values throughout the infusion period. However, no increase in plasma GH levels occurred after a second bolus injection of hpGRF-44 given at the end of the infusion. These results suggest that hpGRF-44 is useful for the diagnosis of GH deficiency in individuals with short stature and that some patients with GH deficiency, diagnosed on the basis of established tests, have GH responses to hpGRF-44.

Growth hormone and insulin-like growth factor I stimulate Leydig cell steroidogenesis.

Leydig cells from 40 days old rats were incubated with or without human growth hormone (hGH) or insulin-like growth factor I (IGF-I) in the presence or absence of human chorionic gonadotropin (hCG), and testosterone and cyclic AMP (cAMP) levels in the medium were measured. Neither hGH nor IGF-I increased testosterone production in the absence of hCG in concentrations up to 1000 and 100 ng/ml, respectively. However, both peptides increased hCG-induced testosterone production in a dose-dependent manner. The maximal stimulatory concentrations of hGH and IGF-I were 100 and 50 ng/ml, respectively. Human GH did not further enhance the IGF-I-stimulated steroidogenesis. The hGH-augmented steroidogenesis was inhibited by anti-hGH IgG and anti-IGF-I IgG. hGH also enhanced hCG-stimulated cAMP production time dependently, suggesting that the stimulatory effect of hGH on steroidogenesis was due to an increased cAMP production. These data suggest that the effect of hGH might be mediated by locally produced IGF-I, which may act as a modulator on gonadal development in the presence of gonadotropin.

Insulin-like growth factor I stimulates growth in normal growing rats.

The scarcity of purified somatomedin/insulin-like growth factor (SM/IGF) has prevented investigation of the mechanisms of SM/IGF action. Recently insulin-like growth factor I (IGF-I) has been synthesized by recombinant DNA technology. The availability of large quantities of the biosynthetic IGF-I made it possible to study its effects by administering 120 micrograms/day via s.c. implanted minipump to rats for 7 days. After this 7 day administration of IGF-I, the body weight increased to 197.6 +/- 3.5% of initial values; the value was significantly greater than that of the control (179.4 +/- 3.7% of initial values, P less than 0.01). The body length and tibial epiphyseal width in IGF-I-treated rats were also significantly increased over those of control rats. The weights of kidneys, liver, testes and pituitary in IGF-I-treated rats were greater than those in control rats as well. These results provide a first demonstration that IGF-I stimulates growth in normal rats in vivo, and suggest that IGF-I might be useful in the treatment of growth retardation.

Cultural variations in optimistic and pessimistic bias: do Easterners really expect the worst and Westerners really expect the best when predicting future life events?

The authors compared levels of optimistic and pessimistic bias in the prediction of positive and negative life events between European Americans and Japanese. Study 1 showed that European Americans compared with Japanese were more likely to predict positive events to occur to self than to others. The opposite pattern emerged in the prediction of negative events. Study 2 replicated these cultural differences. Furthermore, positive associations emerged between predictions and occurrence of life events 2 months later for both European Americans and Japanese. Across both studies, results of within-groups analyses indicated that both groups expected negative events to be more likely to occur to others than to self (optimistic bias). In addition, Japanese expected positive events to be more likely to occur to others than to self (pessimistic bias). However, European Americans failed to show the expected optimistic bias for positive events.

Investigation of the release behavior of diethylhexyl phthalate from the polyvinyl-chloride tubing for intravenous administration.

The release behavior of diethylhexyl phthalate (DEHP) from a polyvinyl-chloride (PVC) tube, which is part of an intravenous administration set, was investigated with the coexistence of polysorbate 80 (Tween 80) in various solutions such as physiological saline (PS), distilled water for injection (DWI) and glucose solution (TZ). The cumulative amount of DEHP released after 5 h was in the following order; PS, DWI > 50% TZ. From a comparison of the amount of released DEHP and the critical micelle concentration (CMC) of various solutions, the lower the CMC of the solution, the higher the amount of DEHP released from the PVC tubing. When the concentration of Tween 80 was kept constant at 1 mg/ml, the cumulative amount of DEHP released with a flow rate 90 ml/h was higher than that at 60 ml/h. These results suggest that the release of DEHP from the PVC tubing is closely correlated with the interaction of Tween 80 and DEHP such as the formation of micelles, the collision of micelles against the surface of the PVC tubing and the diffusion properties of DEHP and or Tween 80 in the liquid medium.

Single sc administration of insulin-like growth factor I (IGF-I) in normal men.

Total and free form of IGF-I in plasma increased in a dose dependent manner after sc IGF-I administration. Peak values of total IGF-I were obtained at 3-4 h after the administration, and then the values decreased gradually. However, peak values of free form of IGF-I were obtained at 2 h, and then rapidly decreased thereafter. The blood glucose, serum insulin and C-peptide levels decreased until 4 h after IGF-I administration in a dose dependent manner. Plasma IGF-II values significantly decreased at 4-12 h after IGF-I administration. Urinary urea nitrogen and sodium excretion decreased after IGF-I administration. Urinary GH excretion also decreased after 0.06 mg/kg IGF-I administration. These data demonstrate that IGF-I may play a role in glucose, protein and electrolyte metabolism, and plasma IGF-II levels and GH secretion might be regulated by IGF-I in man.

Comparison of urine cytology between the ileal conduit and Indiana pouch.

OBJECTIVE: To compare the cytomorphologic features of urine obtained from two different kinds of urinary diversions constructed after total bladder resection. STUDY DESIGN: The smears of urine from 11 ileal conduits and 6 Indiana pouches were evaluated. All patients underwent total bladder resection due to transitional cell carcinoma (TCC) or other kinds of cancer before urine diversion. RESULTS: The cytologic features of Indiana pouch urine include degenerated, small, round cells without columnar cells derived from intestinal epithelium. In ileal conduit urine, well-preserved columnar cells and degenerated, small, round cells were frequently observed. The columnar cells in ileal conduit urine exhibited cytologic features that should be distinguished from TCC cells. CONCLUSION: The method of reconstructing the urinary tract is important in urine cytology from urine diversions because the cytomorphologic features of urine are different between the two kinds of urinary diversions. Since columnar cells in ileal conduit urine might lead to misdiagnosis as TCC, special consideration is required to examine ileal conduit urine.

Symptomatic Chiari malformation and associated pathophysiology in pediatric and adult patients without myelodysplasia.

The clinical characteristics of eight pediatric and five adult patients with Chiari malformation were evaluated. Six pediatric and five adult patients had associated syringomyelia. All patients initially underwent a suboccipital craniectomy with upper cervical (C-1 and/or C-2) laminectomy and duraplasty, and/or shunting procedures. The clinical characteristics of the pediatric and adult groups were compared. The mean interval between onset of symptoms and operation was shorter in the pediatric group (3 yrs 6 mos) than in the adult group (7 yrs 1 mo). Pediatric patients without syringomyelia had the shortest mean interval of 1 year 8 months. Preoperatively, the clinical features were more severe in the adult patients than in the pediatric patients. Postoperatively, seven of eight pediatric patients improved and one stabilized, while two of five adult patients improved, one stabilized, and in two the disease continued to progress despite multiple corrective procedures. Cine magnetic resonance imaging revealed correction of the abnormal cerebrospinal fluid (CSF) flow at the craniovertebral junction and decreased to-and-fro movement in the syrinx after posterior fossa decompression, which were closely correlated with the improvement of clinical features in pediatric patients. However, adult patients required further procedures because of the multifactorial nature of the disease. Evaluation of abnormal CSF pathways at the craniovertebral junction is important for investigating the pathogenesis of Chiari malformation and associated syringomyelia.

[Effects of cernitin pollen-extract (Cernilton) on inflammatory cytokines in sex-hormone-induced nonbacterial prostatitis rats].

Cernitin pollen-extract (Cernilton, CN) is a preparation made from eight kinds of pollen and has been used for various prostatic diseases in Japan and Europe. We reported previously that CN possessed a recovery action on the sex-hormone-induced nonbacterial prostatitis in rats. To clarify the possible mechanism of action of CN, we investigated the effects of CN on inflammatory cytokines (IL-1 beta, IL-6 and TNF-alpha) in the same model. Aged Wistar rats were castrated and injected 17 beta-estradiol (0.25 mg/kg/day, s.c.) for 30 days. CN (630 and 1,260 mg/kg, p.o.) or testosterone (2.5 mg/kg, s.c.) was administered for the last 14 days of the treatment of 17 beta-estradiol. In control rats, prostatic IL-6 and TNF-alpha contents were increased approximately 2-3 fold, and acinar glandular inflammation and stromal proliferation were found histopathologically, as compared with those of intact rats. On the other hand, CN decreased the increased contents of cytokines in a dose-dependent manner. The histopathological changes mentioned above were restored in rats treated with 1,260 mg/kg. Testosterone also ameliorated them significantly. These results indicate that CN has an anti-inflammatory action, and that the inhibitory effect of CN on the prostatic inflammatory cytokine is an important factor in its action.

[Efficacy of simultaneous function and perfusion imaging on 99mTc-tetrofosmin myocardial scintigraphy].

The aim of this study was to determine whether the diagnosis for coronary artery disease (CAD) with 99mTc-tetrofosmin (Tf) myocardial scintigraphy was improved by the combination of function image and perfusion image as compared with perfusion alone. Tf myocardial scintigraphy was performed with one-day protocol (stress/rest) in 51 patients (CAD: 32, Non-CAD: 19) without previous myocardial infarction. Function image was obtained by first pass method, and perfusion image by SPECT. Number of diseased vessels was 14 in right coronary artery (RCA), 18 in left anterior descending (LAD), and 12 in left circumflex (LCX). Ischemia was diagnosed by 2 different parameters 1) perfusion image alone, 2) combination of perfusion image and regional ejection fraction (rEF). On perfusion image, accuracy was 53%, 94% and 86% in RCA, LAD, and LCX respectively. On perfusion + rEF, accuracy was 76%, 90% and 84% in RCA, LAD, and LCX respectively. Specificity in RCA was 45% on perfusion, 84% on perfusion + rEF. Sensitivity in RCA was 77% on perfusion, 54% on perfusion + rEF. LAD and LCX did not change by the addition of function image. By addition of function image, accuracy and specificity of diagnosis in area of RCA improved significantly (p < 0.01). Thus the addition of function image in Tf myocardial scintigraphy would be useful to improve the diagnosis, especially in region of RCA.