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1.  Quality of Care for Comorbid Conditions During the Transition to Survivorship: Differences Between Cancer Survivors and Noncancer Controls 
Journal of Clinical Oncology  2013;31(9):1140-1148.
Building on previous research documenting differences in preventive care quality between cancer survivors and noncancer controls, this study examines comorbid condition care.
Using data from the Surveillance, Epidemiology, and End Results (SEER) –Medicare database, we examined comorbid condition quality of care in patients with locoregional breast, prostate, or colorectal cancer diagnosed in 2004 who were age ≥ 66 years at diagnosis, who had survived ≥ 3 years, and who were enrolled in fee-for-service Medicare. Controls were frequency matched to cases on age, sex, race, and region. Quality of care was assessed from day 366 through day 1,095 postdiagnosis using published indicators of chronic (n = 10) and acute (n = 19) condition care. The proportion of eligible cancer survivors and controls who received recommended care was compared by using Fisher's exact tests. The chronic and acute indicators, respectively, were then combined into single logistic regression models for each cancer type to compare survivors' care receipt to that of controls, adjusting for clinical and sociodemographic variables and controlling for within-patient variation.
The sample matched 8,661 cancer survivors to 17,322 controls (mean age, 75 years; 65% male; 85% white). Colorectal cancer survivors were less likely than controls to receive appropriate care on both the chronic (odds ratio [OR], 0.88; 95% CI, 0.81 to 0.95) and acute (OR, 0.72; 95% CI, 0.61 to 0.85) indicators. Prostate cancer survivors were more likely to receive appropriate chronic care (OR, 1.28; 95% CI, 1.19 to 1.38) but less likely to receive quality acute care (OR, 0.75; 95% CI, 0.65 to 0.87). Breast cancer survivors received care equivalent to controls on both the chronic (OR, 1.06; 95% CI, 0.96 to 1.17) and acute (OR, 0.92; 95% CI, 0.76 to 1.13) indicators.
Because we found differences by cancer type, research exploring factors associated with these differences in care quality is needed.
PMCID: PMC3595422  PMID: 23401438
2.  Plant WEE1 kinase is cell cycle regulated and removed at mitosis via the 26S proteasome machinery 
Journal of Experimental Botany  2013;64(7):2093-2106.
In yeasts and animals, premature entry into mitosis is prevented by the inhibitory phosphorylation of cyclin-dependent kinase (CDK) by WEE1 kinase, and, at mitosis, WEE1 protein is removed through the action of the 26S proteasome. Although in higher plants WEE1 function has been confirmed in the DNA replication checkpoint, Arabidopsis wee1 insertion mutants grow normally, and a role for the protein in the G2/M transition during an unperturbed plant cell cycle is yet to be confirmed. Here data are presented showing that the inhibitory effect of WEE1 on CDK activity in tobacco BY-2 cell cultures is cell cycle regulated independently of the DNA replication checkpoint: it is high during S-phase but drops as cells traverse G2 and enter mitosis. To investigate this mechanism further, a yeast two-hybrid screen was undertaken to identify proteins interacting with Arabidopsis WEE1. Three F-box proteins and a subunit of the proteasome complex were identified, and bimolecular fluorescence complementation confirmed an interaction between AtWEE1 and the F-box protein SKP1 INTERACTING PARTNER 1 (SKIP1). Furthermore, the AtWEE1–green fluorescent protein (GFP) signal in Arabidopsis primary roots treated with the proteasome inhibitor MG132 was significantly increased compared with mock-treated controls. Expression of AtWEE1–YFPC (C-terminal portion of yellow fluorescent protein) or AtWEE1 per se in tobacco BY-2 cells resulted in a premature increase in the mitotic index compared with controls, whereas co-expression of AtSKIP1–YFPN negated this effect. These data support a role for WEE1 in a normal plant cell cycle and its removal at mitosis via the 26S proteasome.
PMCID: PMC3638832  PMID: 23536609
Arabidopsis thaliana; bimolecular fluorescence complementation (BiFC); BY-2 cell line; CDKA/B; cell cycle; F-box; green fluorescent protein (GFP); mitosis; Nicotiana tabacum; 26S proteasome SKIP1; WEE1.
3.  Gene dosage effect of WEE1 on growth and morphogenesis from arabidopsis hypocotyl explants 
Annals of Botany  2012;110(8):1631-1639.
Background and Aims
How plant cell-cycle genes interface with development is unclear. Preliminary evidence from our laboratory suggested that over-expression of the cell cycle checkpoint gene, WEE1, repressed growth and development. Here the hypothesis is tested that the level of WEE1 has a dosage effect on growth and development in Arabidospis thaliana. To do this, a comparison was made of the development of gain- and loss-of-function WEE1 arabidopsis lines both in vivo and in vitro.
Hypocotyl explants from an over-expressing Arath;WEE1 line (WEE1oe), two T-DNA insertion lines (wee1-1 and wee1-4) and wild type (WT) were cultured on two-way combinations of kinetin and naphthyl acetic acid. Root growth and meristematic cell size were also examined.
Key Results
Quantitative data indicated a repressive effect in WEE1oe and a significant increase in morphogenetic capacity in the two T-DNA insertion lines compared with WT. Compared with WT, WEE1oe seedlings exhibited a slower cell-doubling time in the root apical meristem and a shortened primary root, with fewer laterals, whereas there were no consistent differences in the insertion lines compared with WT. However, significantly fewer adventitious roots were recorded for WEE1oe and significantly more for the insertion mutant wee1-1. Compared with WT there was a significant increase in meristem cell size in WEE1oe for all three ground tissues but for wee1-1 only cortical cell size was reduced.
There is a gene dosage effect of WEE1 on morphogenesis from hypocotyls both in vitro and in vivo.
PMCID: PMC3503502  PMID: 23065633
Arabidopsis thaliana; cell cycle; development; growth; hypocotyl; tissue culture; WEE1
4.  Preventive care in prostate cancer patients: following diagnosis and for five-year survivors 
Prostate cancer is the most common male cancer. Survival rates are high, making preventive care maintenance important. Factors associated with prostate-cancer cases’ preventive care in the short-term (Year 1) and long-term (Year 5), and how survivors’ care compares to non-cancer controls, require study.
This retrospective, controlled SEER-Medicare study included loco-regional prostate cancer cases age ≥66 in fee-for-service Medicare diagnosed in 2000 and surviving ≥12 months, and non-cancer controls matched to cases on socio-demographics and survival. Outcomes included influenza vaccination, cholesterol screening, and colorectal cancer screening. Independent variables were number of physician visits, physician specialties visited, initial prostate cancer treatment, socio-demographic characteristics, and case–control status.
There were 13,507 cases and 13,507 controls in Year 1, and 10,482 cases and 10,482 controls in Year 5. In Years 1 and 5, total number of visits (6/6 outcomes) and primary care provider (PCP) visits (5/6 outcomes) were most consistently associated with preventive care receipt. In Year 1, prostate cancer cases were more likely than controls to receive influenza vaccination (48% vs. 45%) but less likely to receive colorectal cancer screening (29% vs. 31%) (both p<0.0001). In Year 5, prostate cancer cases remained more likely than controls to receive influenza vaccination (46% vs. 44%; p<0.0001).
Differences in survivors’ short-term preventive care did not lead to worse long-term preventive care. The number of physician visits, particularly PCP visits, are important factors associated with appropriate care.
Implications for Cancer Survivors
PCP involvement in prostate cancer patients’ care is critical both during treatment and for long-term survivors.
PMCID: PMC3700346  PMID: 21553320
Prostate cancer; Preventive care; Survivorship
5.  Misclassification of incident conditions using claims data: impact of varying the period used to exclude pre-existing disease 
Estimating the incidence of medical conditions using claims data often requires constructing a prevalence period that predates an event of interest, for instance the diagnosis of cancer, to exclude those with pre-existing conditions from the incidence risk set. Those conditions missed during the prevalence period may be misclassified as incident conditions (false positives) after the event of interest.
Using Medicare claims, we examined the impact of selecting shorter versus longer prevalence periods on the incidence and misclassification of 12 relatively common conditions in older persons.
The source of data for this study was the National Cancer Institute’s Surveillance, Epidemiology, and End Results cancer registry linked to Medicare claims. Two cohorts of women were included: 33,731 diagnosed with breast cancer between 2000 and 2002, who had ≥ 36 months of Medicare eligibility prior to cancer, the event of interest; and 101,649 without cancer meeting the same Medicare eligibility criterion. Cancer patients were followed from 36 months before cancer diagnosis (prevalence period) up to 3 months after diagnosis (incidence period). Non-cancer patients were followed for up to 39 months after the beginning of Medicare eligibility. A sham date was inserted after 36 months to separate the prevalence and incidence periods. Using 36 months as the gold standard, the prevalence period was then shortened in 6-month increments to examine the impact on the number of conditions first detected during the incidence period.
In the breast cancer cohort, shortening the prevalence period from 36 to 6 months increased the incidence rates (per 1,000 patients) of all conditions; for example: hypertension 196 to 243; diabetes 34 to 76; chronic obstructive pulmonary disease 29 to 46; osteoarthritis 27 to 36; congestive heart failure 20 to 36; osteoporosis 22 to 29; and cerebrovascular disease 13 to 21. Shortening the prevalence period has less impact on those without cancer.
Selecting a short prevalence period to rule out pre-existing conditions can, through misclassification, substantially inflate estimates of incident conditions. In incidence studies based on Medicare claims, selecting a prevalence period of ≥24 months balances the need to exclude pre-existing conditions with retaining the largest possible cohort.
PMCID: PMC3602098  PMID: 23496890
Incidence; Prevalence; Misclassification; Look back; Medical claims; Medicare
6.  Arabidopsis T-DNA insertional lines for CDC25 are hypersensitive to hydroxyurea but not to zeocin or salt stress 
Annals of Botany  2010;107(7):1183-1192.
Background and Aims
In yeasts and animals, cyclin-dependent kinases are key regulators of cell cycle progression and are negatively and positively regulated by WEE1 kinase and CDC25 phosphatase, respectively. In higher plants a full-length orthologue of CDC25 has not been isolated but a shorter gene with homology only to the C-terminal catalytic domain is present. The Arabidopis thaliana;CDC25 can act as a phosphatase in vitro. Since in arabidopsis, WEE1 plays an important role in the DNA damage/DNA replication checkpoints, the role of Arath;CDC25 in conditions that induce these checkpoints or induce abiotic stress was tested.
arath;cdc25 T-DNA insertion lines, Arath;CDC25 over-expressing lines and wild type were challenged with hydroxyurea (HU) and zeocin, substances that stall DNA replication and damage DNA, respectively, together with an abiotic stressor, NaCl. A molecular and phenotypic assessment was made of all genotypes
Key Results
There was a null phenotypic response to perturbation of Arath;CDC25 expression under control conditions. However, compared with wild type, the arath;cdc25 T-DNA insertion lines were hypersensitive to HU, whereas the Arath;CDC25 over-expressing lines were relatively insensitive. In particular, the over-expressing lines consistently outgrew the T-DNA insertion lines and wild type when challenged with HU. All genotypes were equally sensitive to zeocin and NaCl.
Arath;CDC25 plays a role in overcoming stress imposed by HU, an agent know to induce the DNA replication checkpoint in arabidopsis. However, it could not enhance tolerance to either a zeocin treatment, known to induce DNA damage, or salinity stress.
PMCID: PMC3091795  PMID: 20647223
Arabidopsis thaliana; cell-cycle checkpoints; hydroxyurea; root growth; NaCl; zeocin
7.  Perturbation of cytokinin and ethylene-signalling pathways explain the strong rooting phenotype exhibited by Arabidopsis expressing the Schizosaccharomyces pombe mitotic inducer, cdc25 
BMC Plant Biology  2012;12:45.
Entry into mitosis is regulated by cyclin dependent kinases that in turn are phosphoregulated. In most eukaryotes, phosphoregulation is through WEE1 kinase and CDC25 phosphatase. In higher plants a homologous CDC25 gene is unconfirmed and hence the mitotic inducer Schizosaccharomyces pombe (Sp) cdc25 has been used as a tool in transgenic plants to probe cell cycle function. Expression of Spcdc25 in tobacco BY-2 cells accelerates entry into mitosis and depletes cytokinins; in whole plants it stimulates lateral root production. Here we show, for the first time, that alterations to cytokinin and ethylene signaling explain the rooting phenotype elicited by Spcdc25 expression in Arabidopsis.
Expressing Spcdc25 in Arabidopsis results in increased formation of lateral and adventitious roots, a reduction of primary root width and more isodiametric cells in the root apical meristem (RAM) compared with wild type. Furthermore it stimulates root morphogenesis from hypocotyls when cultured on two way grids of increasing auxin and cytokinin concentrations. Microarray analysis of seedling roots expressing Spcdc25 reveals that expression of 167 genes is changed by > 2-fold. As well as genes related to stress responses and defence, these include 19 genes related to transcriptional regulation and signaling. Amongst these was the up-regulation of genes associated with ethylene synthesis and signaling. Seedlings expressing Spcdc25 produced 2-fold more ethylene than WT and exhibited a significant reduction in hypocotyl length both in darkness or when exposed to 10 ppm ethylene. Furthermore in Spcdc25 expressing plants, the cytokinin receptor AHK3 was down-regulated, and endogenous levels of iPA were reduced whereas endogeous IAA concentrations in the roots increased.
We suggest that the reduction in root width and change to a more isodiametric cell phenotype in the RAM in Spcdc25 expressing plants is a response to ethylene over-production. The increased rooting phenotype in Spcdc25 expressing plants is due to an increase in the ratio of endogenous auxin to cytokinin that is known to stimulate an increased rate of lateral root production. Overall, our data reveal important cross talk between cell division and plant growth regulators leading to developmental changes.
PMCID: PMC3362767  PMID: 22452972
8.  Impact of Hemodialysis Catheter Dysfunction on Dialysis and Other Medical Services: An Observational Cohort Study 
Practice guidelines define hemodialysis catheter dysfunction as blood flow rate (BFR) <300 mL/min. We conducted a study using data from DaVita and the United States Renal Data System to evaluate the impact of catheter dysfunction on dialysis and other medical services. Patients were included if they had ≥8 consecutive weeks of catheter dialysis between 8/2004 and 12/2006. Actual BFR <300 mL/min despite planned BFR ≥300 mL/min was used to define catheter dysfunction during each dialysis session. Among 9,707 patients, the average age was 62,53% were female, and 40% were black. The median duration of catheter dialysis was 190 days, and the cohort accounted for 1,075,701 catheter dialysis sessions. There were 70,361 sessions with catheter dysfunction, and 6,33 1 (65.2%) patients had at least one session with catheter dysfunction. In multivariate repeated measures analysis, catheter dysfunction was associated with increased odds of missing a dialysis session due to access problems (Odds ratio [OR] 2.50; P < 0.001), having an access-related procedure (OR 2.10; P < 0.001), and being hospitalized (OR 1.10; P = 0.001). Catheter dysfunction defined according to NKF vascular access guidelines results in disruptions of dialysis treatment and increased use of other medical services.
PMCID: PMC3299278  PMID: 22518313
9.  Patterns of Hemodialysis Catheter Dysfunction Defined According to National Kidney Foundation Guidelines As Blood Flow <300 mL/min 
Blood flow rate (BFR) <300 mL/min commonly is used to define hemodialysis catheter dysfunction and the need for interventions to prevent complications. The objective of this study was to describe patterns of unplanned BFR <300 mL/min during catheter hemodialysis using data from DaVita dialysis facilities and the United States Renal Data System. Patients were included if they received at least eight weeks of hemodialysis exclusively through a catheter between 08/04 and 12/06, and catheter hemodialysis was the first treatment modality following diagnosis of end-stage renal disease (first access), or it immediately followed at least one 30-day period of dialysis exclusively through a fistula or graft (replacement access). Actual BFR <300 mL/min despite a planned BFR ≥300 mL/min defined catheter dysfunction during each dialysis session. There were 3,364 patients, 268,363 catheter dialysis sessions, and 19,118 (7.1%) sessions with catheter dysfunction. Almost two-thirds of patients had ≥1 catheter dysfunction session, and 30% had ≥1 catheter dysfunction session per month. Patients with catheter as a replacement access had a higher rate of catheter dysfunction than those with a catheter as first access (hazard ratio: 1.13; P = 0.04). Catheter dysfunction affects almost one-third of catheter dialysis patients each month and two-thirds overall.
PMCID: PMC3236458  PMID: 22187643
10.  Infused Therapy and Survival in Older Patients Diagnosed with Metastatic Breast Cancer who Received Trastuzumab 
Cancer Investigation  2011;29(9):573-584.
We used Surveillance, Epidemiology, and End Results-Medicare data (2000-2006) to describe treatment and survival in women diagnosed with metastatic breast cancer (MBC) who received trastuzumab. There were 610 patients with a mean age of 74 years. Overall, 32% received trastuzumab alone and 47% received trastuzumab plus a taxane. In multivariate analysis, trastuzumab plus chemotherapy was associated with a lower adjusted cancer mortality rate (Hazard Ratio [HR] 0.54; 95% Confidence Interval [CI] 0.39-0.74; p < .001) than trastuzumab alone among patients who received trastuzumab as part of first-line therapy. Adding chemotherapy to first-line trastuzumab for metastatic breast cancer is associated with improved cancer survival.
PMCID: PMC3212922  PMID: 21929325
Breast cancers; Chemotherapy; Outcomes research
11.  Comparing Care for Breast Cancer Survivors to Non-Cancer Controls: A Five-Year Longitudinal Study 
Deficiencies in care for cancer survivors may result from unclear roles for primary care providers (PCPs) and oncology specialists in follow-up.
To compare cancer survivors’ care to non-cancer controls.
Retrospective, longitudinal, controlled study starting 366 days post-diagnosis.
Stage 1-3 breast cancer survivors age 65+ diagnosed in 1998 (n = 1961) and matched non-cancer controls (n = 1961).
Using the SEER-Medicare database, we examined the number of visits to PCPs, oncology specialists, and other physicians; receipt of influenza vaccination, cholesterol screening, colorectal cancer screening, bone densitometry, and mammography; and whether care receipt was associated with physician mix visited.
Survivors were consistently less likely to receive influenza vaccination, cholesterol screening, colorectal cancer screening, and bone densitometry but more likely to receive mammograms than controls (all p < 0.05). Over time, colorectal cancer screening and mammography decreased and influenza vaccination increased for both groups (all p < 0.0001). Trends over time in care receipt were similar for survivors and controls. In Year 1, survivors had more visits to PCPs but fewer visits to other physicians than controls (both p < 0.05). Over time, survivors’ visits to PCPs and other physicians increased and to oncology specialists decreased (all p < 0.0001). Controls’ visits to PCPs increased (p < 0.0001) faster than survivors’ (p = 0.003). Controls’ visits to other physicians increased (p < 0.0001) at a rate similar to survivors. Survivors who visited both a PCP and oncology specialist were most likely to receive each service.
Better coordination between PCPs and oncology specialists may improve care for older breast cancer survivors.
PMCID: PMC2659148  PMID: 19156470
breast cancer; preventive care; survivorship
12.  Trends in Follow-up and Preventive Care for Colorectal Cancer Survivors 
As cancer patients transition from treatment to survivorship, the responsibility of primary care providers (PCPs) versus oncology specialists is unclear.
To explore (1) physician types (PCPs versus oncology specialists) survivors visit during survivorship year 1, (2) preventive care received, (3) how preventive care receipt relates to physician types visited, and (4) trends in physician types visited and preventive care received over time.
Retrospective cross-sectional study of 5 cohorts of cancer survivors in survivorship year 1.
Twenty thousand sixty-eight survivors diagnosed with stage 1–3 colorectal cancer between 1997 and 2001.
Using the SEER-Medicare database, we assessed the mean number of visits to different physician types, the percentage of survivors receiving preventive services, how receipt of preventive services related to physician types visited, and trends over time in physician visits and preventive care.
There was a trend over time of increased visits to all physician types, which was statistically significant for oncology specialists and other physicians (p < .001) but not PCPs. The percentage of survivors receiving preventive services remained relatively stable across the 5 cohorts, except for an increase in bone densitometry (p < .05). Survivors who visited both a PCP and oncology specialist were most likely to receive each preventive care service (p < .05).
Oncology specialist follow-up in survivorship year 1 is intensifying over time. Survivors not being followed-up by both PCPs and oncology specialists were less likely to receive preventive care. Clarifying the roles of PCPs and oncology specialists during follow-up can improve the quality of care for survivors.
PMCID: PMC2359475  PMID: 18197456
preventive care; cancer survivors; coordination of care

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