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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3526-3526
    Abstract: 3526 Background: Organized colorectal cancer (CRC) screening programs currently cover Canadians aged ≥50 at average-risk of developing CRC and have contributed to declining CRC incidence. Rising incidence of early-onset CRC in individuals 〈 50 has led to lowering of the recommended screening start age to 45 rather than 50 in some jurisdictions. We used OncoSim, a publicly-available simulation tool, to model the effects of earlier screening initiation on Canadian CRC incidence, mortality and healthcare costs. Methods: OncoSim uses Canadian population and cancer registry data to simulate a representative sample of individuals from birth to death. We modeled four scenarios: no screening in average-risk individuals, screening initiation at age 50, initiation age lowered to 45 in 2022, and initiation age lowered to 40 in 2022. Each includes 32 million simulated participants. In the model, average-risk screening involves biennial FIT, available to all simulated participants regardless of family history with participation of 60% at the first recruitment attempt and 80% for repeat screening. Participants with a family history in all 4 scenarios were eligible for additional screening by colonoscopy every 5 years. Results: In our model, earlier screening yields reduced CRC incidence and mortality with increasing benefit over time. By 2051, screening initiation at age 45 or 40 reduces age-standardized incidence by 3.4% and 4.8% respectively, and age-standardized mortality by 3.3% and 4.6% respectively, compared to initiation at age 50. Screening initiation at age 45 yields 3,848 additional quality-adjusted life-years (QALYs) in 2051 at a cost of $9,350 per QALY gained and a 5% increase in colonoscopies performed. Initiation at age 40 yields 6,255 additional QALYs at $16,350 per QALY gained and a 9% increase in colonoscopies. The difference in screening costs compared to screening from age 50 is consistent year-to-year after 2024. In 2051 screening costs increase by $75mil and $155mil per year with initiation at ages 45 and 40 respectively, while costs of cancer management (including diagnosis, treatment, recurrence, palliative and end of life care) decrease by $42mil and $57mil respectively. Conclusions: Our model predicts that lowering the CRC screening initiation age for average-risk Canadians to 45 or 40 could reduce CRC incidence and mortality. Costs per QALY gained are high in the first few decades but decrease over time. Costs are modest after 30 years of screening compared to other life-preserving interventions such as dialysis. Our results suggest that lowering the screening age in Canada may be warranted, but further investigation is needed to assess capacity for increased colonoscopy demand.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Molecules, MDPI AG, Vol. 23, No. 11 ( 2018-11-14), p. 2967-
    Abstract: Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies. However, the TLX protein possesses a non-canonical ligand-binding domain (LBD), which lacks a ligand-binding pocket (conventionally targeted in case of nuclear receptors) that complicates the development of small molecule inhibitors of TLX. Herein, we utilized a rational structure-based design approach to identify small molecules targeting the Atro-box binding site of human TLX LBD. As a result of virtual screening of ~7 million molecular structures, 97 compounds were identified and evaluated in the TLX-responsive luciferase reporter assay. Among those, three chemicals demonstrated 40–50% inhibition of luciferase-detected transcriptional activity of the TLX orphan nuclear receptor at a dose of 35 µM. The identified compounds represent the first class of small molecule inhibitors of TLX transcriptional activity identified via methods of computer-aided drug discovery.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2008644-1
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  • 3
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 5 ( 2022-02-26), p. 2588-
    Abstract: The Myc family of transcription factors are involved in the development and progression of numerous cancers, including prostate cancer (PCa). Under the pressure of androgen receptor (AR)-directed therapies resistance can occur, leading to the lethal form of PCa known as neuroendocrine prostate cancer (NEPC), characterized among other features by N-Myc overexpression. There are no clinically approved treatments for NEPC, translating into poor patient prognosis and survival. Therefore, there is a pressing need to develop novel therapeutic avenues to treat NEPC patients. In this study, we investigate the N-Myc-Max DNA binding domain (DBD) as a potential target for small molecule inhibitors and utilize computer-aided drug design (CADD) approaches to discover prospective hits. Through further exploration and optimization, a compound, VPC-70619, was identified with notable anti-N-Myc potency and strong antiproliferative activity against numerous N-Myc expressing cell lines, including those representing NEPC.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
    In: JAMA Oncology, American Medical Association (AMA)
    Abstract: Recent US guideline updates have advocated for colorectal cancer (CRC) screening to begin at age 45 years in average-risk adults, whereas Canadian screening programs continue to begin screening at age 50 years. Similarities in early-onset CRC rates in Canada and the US warrant discussion of earlier screening in Canada, but there is a lack of Canadian-specific modeling data to inform this. Objective To estimate the association of a lowered initiation age for CRC screening by biennial fecal immunochemical test (FIT) with CRC incidence, mortality, and health care system costs in Canada. Design, Setting, and Participants/Exposures This economic evaluation computational study used microsimulation modeling via the OncoSim platform. Main Outcomes and Measures Modeled rates of CRC incidence, mortality, and health care costs in Canadian dollars. Results This analysis included 4 birth cohorts (1973-1977, 1978-1982, 1983-1987, and 1988-1992) representative of the Canadian population accounting for previously documented effects of increasing CRC incidence in younger birth cohorts. Screening initiation at age 45 years resulted in a net 12 188 fewer CRC cases, 5261 fewer CRC deaths, and an added 92 112 quality-adjusted life-years (QALYs) to the cohort population over a 40-year period relative to screening from age 50 years. Screening initiation at age 40 years yielded 18 135 fewer CRC cases, 7988 fewer CRC deaths, and 150 373 QALYs. The cost per QALY decreased with younger birth cohorts to a cost of $762 per QALY when Canadians born in 1988 to 1992 began screening at age 45 years or $2622 per QALY with screening initiation at age 40 years. Although costs associated with screening and resulting therapeutic interventions increased with earlier screening, the overall health care system cost of managing CRC decreased. Conclusions and Relevance This economic evaluation study using microsimulation modeling found that earlier screening may reduce CRC disease burden and add life-years to the Canadian population at a modest cost. Guideline changes suggesting earlier CRC screening in Canada may be justified, but evaluation of the resulting effects on colonoscopy capacity is necessary.
    Type of Medium: Online Resource
    ISSN: 2374-2437
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
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  • 5
    In: Current Oncology, MDPI AG, Vol. 28, No. 3 ( 2021-04-21), p. 1558-1570
    Abstract: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and second leading cause of cancer death in Canada. Organized screening programs targeting Canadians aged 50 to 74 at average risk of developing the disease have contributed to decreased rates of CRC, improved patient outcomes and reduced healthcare costs. However, data shows that recent incidence reductions are unique to the screening-age population, while rates in people under-50 are on the rise. Similar incidence patterns in the United States prompted the American Cancer Society and U.S. Preventive Services Task Force to recommend screening begin at age 45 rather than 50. We conducted a review of screening practices in Canada, framing them in the context of similar global health systems as well as the evidence supporting the recent U.S. recommendations. Epidemiologic changes in Canada suggest earlier screening initiation in average-risk individuals may be reasonable, but the balance of costs to benefits remains unclear.
    Type of Medium: Online Resource
    ISSN: 1718-7729
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2270777-3
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  • 6
    Online Resource
    Online Resource
    Royal Society of Chemistry (RSC) ; 2019
    In:  RSC Advances Vol. 9, No. 41 ( 2019), p. 23570-23578
    In: RSC Advances, Royal Society of Chemistry (RSC), Vol. 9, No. 41 ( 2019), p. 23570-23578
    Type of Medium: Online Resource
    ISSN: 2046-2069
    Language: English
    Publisher: Royal Society of Chemistry (RSC)
    Publication Date: 2019
    detail.hit.zdb_id: 2623224-8
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