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1.  Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis 
Molecular cancer research : MCR  2008;6(11):1786-1793.
Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2m/m) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and β-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on β-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone ApcMin/+ mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases β-catenin, cyclin D, and cell proliferation. Down-regulation of β-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2m/m mice develop colonic polyps and show an increase in small intestinal mucosa β-catenin and cyclin D protein levels compared with wild-type mice. ApcMin/+Per2m/m mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with ApcMin/+ mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of β-catenin and β-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control.
doi:10.1158/1541-7786.MCR-08-0196
PMCID: PMC4136553  PMID: 19010825
2.  Sunspot Dynamics Are Reflected in Human Physiology and Pathophysiology 
Astrobiology  2011;11(2):93-103.
Abstract
Periodic episodes of increased sunspot activity (solar electromagnetic storms) occur with 10–11 and 5–6 year periodicities and may be associated with measurable biological events. We investigated whether this sunspot periodicity characterized the incidence of Pap smear-determined cervical epithelial histopathologies and human physiologic functions. From January 1983 through December 2003, monthly averages were obtained for solar flux and sunspot numbers; six infectious, premalignant and malignant changes in the cervical epithelium from 1,182,421 consecutive, serially independent, screening Pap smears (59°9″N, 4°29″E); and six human physiologic functions of a healthy man (oral temperature, pulse, systolic and diastolic blood pressure, respiration, and peak expiratory flow), which were measured ∼5 times daily during ∼34,500 self-measurement sessions (44°56″N, 93°8″W). After determining that sunspot numbers and solar flux, which were not annually rhythmic, occurred with a prominent 10-year and a less-prominent 5.75-year periodicity during this 21-year study span, each biological data set was analyzed with the same curve-fitting procedures. All six annually rhythmic Pap smear-detected infectious, premalignant and malignant cervical epithelial pathologies showed strong 10-year and weaker 5.75-year cycles, as did all six self-measured, annually rhythmic, physiologic functions. The phases (maxima) for the six histopathologic findings and five of six physiologic measurements were very near, or within, the first two quarters following the 10-year solar maxima. These findings add to the growing evidence that solar magnetic storm periodicities are mirrored by cyclic phase-locked rhythms of similar period length or lengths in human physiology and pathophysiology. Key Words: Cervical infections—Cervical premalignancy—Geo-solar magnetic interactions—Pap smear—Schwabe cycle—10-year rhythm. Astrobiology 11, 93–103.
doi:10.1089/ast.2010.0574
PMCID: PMC3063695  PMID: 21391821
3.  Guideline-Based Peer-to-Peer Consultation Optimizes Pegfilgrastim Use With No Adverse Clinical Consequences 
Journal of Oncology Practice  2012;8(3 Suppl):e14s-e17s.
Active expert peer-to-peer consultation with prescribing oncologists can promote adherence to guidelines and lead to cost reductions without risk of neutropenic fever, with or without hospitalization, for patients with cancer.
Purpose:
Practice guidelines do not recommend the routine use of colony-stimulating factors when there is a low risk (< 10%) of febrile neutropenia (FN). We prospectively determined whether expert peer-to-peer consultation with prescribing oncologists would improve adherence to guidelines and whether there would be any adverse events associated with that adherence.
Methods:
Commencing in March 2010, we reviewed requests for pegfilgrastim from 22 community oncology practices comprising 78 physicians providing service to approximately 97,000 Medicare members. Paid claims data on all chemotherapy and supportive care medications were reviewed from fourth quarter (Q4) 2009 through third quarter (Q3) 2010. In total, 82 patients received pegfilgrastim. If the prescribed chemotherapy was associated with a low risk (< 10%) for FN, then a peer review was initiated. The treating physician made the final decision to use, or not use, pegfilgrastim, and no denials were issued.
Results:
A total of 245 units (1 unit = 6 mg) of pegfilgrastim were administered during the four quarters analyzed. Use in the low-risk category decreased from 52 units in Q4 2009 to 15 units in Q3 2010. The per-member per-month (PMPM) cost of pegfilgrastim decreased across quarters, with an average cost of $1.07 PMPM for Q4 2009 and $0.57 PMPM for Q3 2010. No studied patient was admitted for neutropenic fever.
Conclusion:
Active expert peer-to-peer consultation with prescribing oncologists can promote adherence to guidelines and potentially lead to significant cost reductions without significant risk of neutropenic fever, with or without hospitalization, for patients with cancer.
doi:10.1200/JOP.2012.000540
PMCID: PMC3348596  PMID: 22942828

Results 1-3 (3)