Publications by authors named "David Jarjoura"

106 Publications

Multi-Site Study of Provider Self-Efficacy and Beliefs in Explaining Judgments About Need and Responsibility for Advance Care Planning.

Am J Hosp Palliat Care 2020 Dec 9:1049909120979977. Epub 2020 Dec 9.

Department of Family and Community Medicine, Northeast Ohio Medical University, Rootstown, OH, USA.

Background And Objectives: We examined the impact of advance care planning (ACP) self-efficacy and beliefs in explaining skilled nursing facility (SNF) provider judgments about resident need and provider responsibility for initiating ACP conversations.

Research Design And Methods: This observational multi-site study of 348 registered nurses, licensed practical nurses, and social workers within 29 SNFs used an anonymous survey in which providers judged vignettes with assigned situational features of a typical SNF resident. Mixed modeling was used to analyze the vignette responses.

Results: Providers who had more negative beliefs about ACP were less likely to judge residents in need of ACP and less likely to feel responsible for ensuring ACP took place. Self-efficacy did not have a significant impact on judgments of need, but did significantly increase judgments of responsibility for ensuring ACP conversations. Providers with the highest levels of ACP self-efficacy were most likely to feel responsible for ensuring ACP conversations. In an exploratory analysis, these relationships remained the same whether responding to high or low risk residents (i.e., based on risk of hospitalization, type of diagnosis, functional status, and rate of declining health).

Discussion And Implications: Both negative beliefs about ACP and self-efficacy in one's ability to conduct ACP discussions were associated with professional judgments regarding ACP. The findings illustrate the importance of addressing negative beliefs about ACP and increasing provider ACP self-efficacy through education and policies that empower nurses and social workers.
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http://dx.doi.org/10.1177/1049909120979977DOI Listing
December 2020

In-Hospital Management of Sleep Apnea During Heart Failure Hospitalization: A Randomized Controlled Trial.

J Card Fail 2020 Aug 24;26(8):705-712. Epub 2020 Jun 24.

The Sleep Heart Program at the Ohio State University, Columbus, Ohio; Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio; The Center for Biostatistics, The Ohio State University, Columbus, Ohio.

Background: Obstructive sleep apnea (OSA) is associated with increased mortality and readmissions in patients with heart failure (HF). The effect of in-hospital diagnosis and treatment of OSA during decompensated HF episodes remains unknown.

Methods And Results: A single-site, randomized, controlled trial of hospitalized patients with decompensated HF (n = 150) who were diagnosed with OSA during the hospitalization was undertaken. All participants received guideline-directed therapy for HF decompensation. Participants were randomized to an intervention arm which received positive airway pressure (PAP) therapy during the hospitalization (n = 75) and a control arm (n = 75). The primary outcome was discharge left ventricular ejection fraction (LVEF). The LVEF changed in the PAP arm from 25.5 ± 10.4 at baseline to 27.3 ± 11.9 at discharge. In the control group, LVEF was 27.3 ± 11.7 at baseline and 28.8 ± 10.5 at conclusion. There was no significant effect on LVEF of in-hospital PAP compared with controls (P = .84) in the intention-to-treat analysis. The on-treatment analysis in the intervention arm showed a significant increase in LVEF in participants who used PAP for ≥3 hours per night (n = 36, 48%) compared with those who used it less (P = .01). There was a dose effect with higher hours of use associated with more improvement in LVEF. Follow-up of readmissions at 6 months after discharge revealed a >60% decrease in readmissions for patients who used PAP ≥3 h/night compared with those who used it <3 h/night (P < .02) and compared with controls (P < .04).

Conclusions: In-hospital treatment with PAP was safe but did not significantly improve discharge LVEF in patients with decompensated HF and newly diagnosed OSA. An exploratory analysis showed that adequate use of PAP was associated with higher discharge LVEF and decreased 6 months readmissions.
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http://dx.doi.org/10.1016/j.cardfail.2020.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484161PMC
August 2020

CE: Original Research: Advance Care Planning: An Exploration of the Beliefs, Self-Efficacy, Education, and Practices of RNs and LPNs.

Am J Nurs 2018 12;118(12):26-32

Ruth Ludwick is professor emerita of nursing at Kent State University, Kent, OH, as well as adjunct graduate faculty at Northeast Ohio Medical University, Rootstown. Kristin R. Baughman is an associate professor in the Department of Family and Community Medicine at Northeast Ohio Medical University, where Denise J. Kropp is a research associate. David Jarjoura is an independent consultant based in Marshall, NC. This research was supported by an educational grant from the Agency for Healthcare Research and Quality (grant no. RO3-HS022162). Contact author: Ruth Ludwick, The authors and planners have disclosed no potential conflicts of interest, financial or otherwise.

: Objective: This study compared the advance care planning (ACP)-related beliefs, sense of self-efficacy, education, and practices of RNs and LPNs.

Methods: Data were extrapolated from a larger multisite study that was conducted across seven counties in one midwestern state. The sample consisted of RNs and LPNs working in 29 urban skilled nursing facilities in zip code areas with greater than 10% African American residents. The survey tool, a self-administered written questionnaire, gathered data on participants' demographics and ACP-related beliefs, sense of self-efficacy, education, and practices. The two main outcome variables were the percentage of residents with whom a nurse discussed ACP and the timing of the most recent such discussion.

Results: A total of 136 RNs and 178 LPNs completed the survey. Multivariate mixed-model analysis of the two main outcome variables showed that negative beliefs were not significantly associated with the percentage of residents with whom nurses discussed ACP but were significantly associated with the timing of the most recent ACP discussion. Having higher levels of ACP-related self-efficacy and education were significantly and positively associated with both outcome variables. RNs and LPNs did not differ significantly in their ACP-related beliefs, but RNs reported significantly higher levels of self-efficacy and education than LPNs did.

Conclusions: There has been a paucity of research comparing RNs and LPNs regarding their ACP practices in skilled nursing facilities. Better education and policies that empower nurses to take a more active role are critical to increasing conversations about ACP. Further research exploring how the complementary roles of RNs and LPNs can be used to improve ACP processes and inform ACP policies is needed.
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http://dx.doi.org/10.1097/01.NAJ.0000549664.43827.ceDOI Listing
December 2018

Angiotensin Receptor Expression and Vascular Endothelial Dysfunction in Obstructive Sleep Apnea.

Am J Hypertens 2018 02;31(3):355-361

Department of Internal Medicine, The Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, The Ohio State University, USA.

Background: Obstructive sleep apnea (OSA) is associated with vascular endothelial dysfunction (VED) in otherwise healthy patients. The role of renin-angiotensin system (RAS) in the OSA induced VED is not well understood.

Methods: Recently diagnosed OSA patients with very low cardiovascular disease (CVD) risk (Framingham score <5%) were studied at diagnosis and after 12 weeks of verified continuous positive airway pressure (CPAP) therapy. Participants underwent biopsy of gluteal subcutaneous tissue at baseline and after CPAP. Microcirculatory endothelial expression of angiotensin receptors type-1 (AT-1) and type-2 (AT-2) was measured in the subcutaneous tissue using quantitative confocal microscopy techniques. The ex-vivo effect of AT-1 receptor blockade (ARB) on endothelial superoxide production was also measured before and after CPAP treatment.

Results: In OSA patients (n = 11), microcirculatory endothelial AT1 expression decreased from 873 (200) (fluorescence units) at baseline to 393 (59) units after 12 weeks of CPAP (P = 0.02). AT2 expression did not decrease significantly in these patients (479 (75) to 329 (58) post CPAP (P = 0.08)). The ex-vivo addition of the losartan to the microcirculatory endothelium resulted in decreased superoxide expression in the vascular walls from 14.2 (2.2) units to 4.2 (0.8) P < 0.001; while it had no effect on post-CPAP patient tissue (P = 0.64).

Conclusions: In OSA patients with no to minimal CVD risk, VED is associated with upregulation of AT-1 expression that is reversible with CPAP. Endothelial oxidative stress was reversible with ARB. RAS activation may play an important role in the development of early CVD risk in OSA patients.
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http://dx.doi.org/10.1093/ajh/hpx174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861541PMC
February 2018

Advance Care Planning in Skilled Nursing Facilities: A Multisite Examination of Professional Judgments.

Gerontologist 2019 03;59(2):338-346

Department of Family and Community Medicine, Northeast Ohio Medical University, Rootstown.

Background And Objectives: Lack of advance care planning (ACP) may increase hospitalizations and impact the quality of life for skilled nursing facility (SNF) residents, especially African American residents who may be less likely to receive ACP discussions. We examined the professional judgments of SNF providers to see if race of SNF residents and providers, and risk for hospitalization for residents influenced professional judgments as to when ACP was needed and feelings of responsibility for ensuring ACP discussions.

Research Design And Methods: Nurses and social workers (n = 350) within 29 urban SNFs completed surveys and rated vignettes describing eight typical SNF residents. Linear mixed modeling was used to examine factors that impacted ratings of need for ACP and responsibility for ensuring ACP.

Results: Neither the race of the provider, resident, nor the interaction of the two were associated with either outcome variable. In contrast, providers rated (on a 9-point scale) residents at high risk for hospitalization as more in need of ACP (estimate = 0.86, confidence interval [CI] 0.65, 1.07) and felt more responsible for ensuring ACP (estimate = 0.60, CI 0.42, 0.78).

Discussion And Implications: Research on ACP is continuing to evolve and these results show the primacy of disease trajectory variables on providers' judgments about ACP. Differences between providers indicate a need for stronger policies and education. Further, research comparing rural, suburban, and urban SNFs is needed to explore possible forms of structural racism such as residential and SNF segregation.
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http://dx.doi.org/10.1093/geront/gnx129DOI Listing
March 2019

Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor-positive breast cancer.

Eur J Cancer 2016 06 20;60:107-16. Epub 2016 Apr 20.

The Ohio State University Center for Biostatistics, Columbus, Ohio, USA. Electronic address:

Purpose: In premenopausal women with metastatic hormone receptor-positive breast cancer, hormonal therapy is the first-line therapy. Gonadotropin-releasing hormone analogue + tamoxifen therapies have been found to be more effective. The pattern of recurrence risk over time after primary surgery suggests that peri-operative factors impact recurrence. Secondary analyses of an adjuvant trial suggested that the luteal phase timing of surgical oophorectomy in the menstrual cycle simultaneous with primary breast surgery favourably influenced long-term outcomes.

Methods: Two hundred forty-nine premenopausal women with incurable or metastatic hormone receptor-positive breast cancer entered a trial in which they were randomised to historical mid-luteal or mid-follicular phase surgical oophorectomy followed by oral tamoxifen treatment. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess overall and progression-free survival (PFS) in the two randomised groups and by hormone-confirmed menstrual cycle phase.

Results: Overall survival (OS) and PFS were not demonstrated to be different in the two randomised groups. In a secondary analysis, OS appeared worse in luteal phase surgery patients with progesterone levels <2 ng/ml (anovulatory patients; adjusted hazard ratio 1.46, 95% confidence interval [CI]: 0.89-2.41, p = 0.14) compared with those in luteal phase with progesterone level of 2 ng/ml or higher. Median OS was 2 years (95% CI: 1.7-2.3) and OS at 4 years was 26%.

Conclusions: The history-based timing of surgical oophorectomy in the menstrual cycle did not influence outcomes in this trial of metastatic patients. ClinicalTrials.gov number NCT00293540.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052674PMC
http://dx.doi.org/10.1016/j.ejca.2016.03.011DOI Listing
June 2016

NK Cell-Mediated Antitumor Effects of a Folate-Conjugated Immunoglobulin Are Enhanced by Cytokines.

Cancer Immunol Res 2016 Apr 10;4(4):323-336. Epub 2016 Feb 10.

Department of Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH.

Optimally effective antitumor therapies would not only activate immune effector cells but also engage them at the tumor. Folate conjugated to immunoglobulin (F-IgG) could direct innate immune cells with Fc receptors to folate receptor-expressing cancer cells. F-IgG bound to human KB and HeLa cells, as well as murine L1210JF, a folate receptor (FR)-overexpressing cancer cell line, as determined by flow cytometry. Recognition of F-IgG by natural killer (NK) cell Fc receptors led to phosphorylation of the ERK transcription factor and increased NK cell expression of CD69. Lysis of KB tumor cells by NK cells increased by about 5-fold after treatment with F-IgG, an effect synergistically enhanced by treatment with IL2, IL12, IL15, or IL21 (P< 0.001). F-IgG also enhanced the lysis of chronic lymphocytic leukemia cells by autologous NK cells. NK cells significantly increased production of IFNγ, MIP-1α, and RANTES in response to F-IgG-coated KB target cells in the presence of the NK cell-activating cytokine IL12, and these coculture supernatants induced significant T-cell chemotaxis (P< 0.001). F-IgG-coated targets also stimulated FcR-mediated monocyte effector functions. Studies in a murine leukemia model confirmed the intratumoral localization and antitumor activity of F-IgG, as well as enhancement of its effects by IL12 (P =0.05). The antitumor effect of this combination was dependent on NK cells and led to decreased tumor cell proliferation in vivo Thus, F-IgG can induce an immune response against FR-positive tumor cells that is mediated by NK cells and can be augmented by cytokine therapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818694PMC
April 2016

Options and Considerations for Adaptive Laboratory Experiments.

Stat Biosci 2015 Oct 25;7(2):348-366. Epub 2014 Nov 25.

Center for Biostatistics, The Ohio State University, 2012 Kenny Road, Columbus, OH 43221, U.S.A.

Motivated by laboratory experiments that fail to reach significance, we developed a small sample size approach to designing a subsequent experiment that controls overall type I error and achieves sufficient conditional power. We focus on experiments with leukemia cells, and use a specific example in Chronic Lymphocytic Leukemia to discuss unanticipated patient variance and difficult to predict interaction effect sizes. We emphasize the importance of achieving significance in the first run of an experiment, which results in simplifying the multiple considerations usually associated with interim analysis and decision making in adaptive clinical trials. Within the context of combination testing for an adaptive laboratory experiment, we show that a range of reasonable options for the futility cut-off, effect size estimation, and significance level for the first run provide similar power and expected overall sample size. We contrast this approach to a naive procedure in which a second unplanned experiment is run based on non-significance in the first experiment, and data are combined as if they were obtained from one run.
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http://dx.doi.org/10.1007/s12561-014-9123-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4628833PMC
October 2015

Timing of adjuvant surgical oophorectomy in the menstrual cycle and disease-free and overall survival in premenopausal women with operable breast cancer.

J Natl Cancer Inst 2015 Jun 19;107(6):djv064. Epub 2015 Mar 19.

International Breast Cancer Research Foundation, Madison, WI (RRL); University of the Philippines Manila, Philippine General Hospital, Manila, Philippines (AL, GU, ADP, RD, OB); Hospital K, Hanoi, Vietnam (NVD, LHQ, NDL, TVT); Clarient Pathology Services, Aliso Viejo, CA (DCA); East Avenue Medical Center, Manila, Philippines (JS); Vicente Sotto Hospital, Cebu, Philippines (SSS); Rizal Medical Center, Manila, Philippines (RML, MHA); Hue Central Hospital, Hue, Vietnam (NDT); National Institute of Oncology, Rabat, Morocco (NB); Santo Tomas University Hospital, Manila, Philippines (NN); Danang General Hospital, Danang, Vietnam (TTQ); The Ohio State University Center for Biostatistics, Columbus, OH (GSY, EMH, DJ (ret.).

Background: For women with hormone receptor-positive, operable breast cancer, surgical oophorectomy plus tamoxifen is an effective adjuvant therapy. We conducted a phase III randomized clinical trial to test the hypothesis that oophorectomy surgery performed during the luteal phase of the menstrual cycle was associated with better outcomes.

Methods: Seven hundred forty premenopausal women entered a clinical trial in which those women estimated not to be in the luteal phase of their menstrual cycle for the next one to six days (n = 509) were randomly assigned to receive treatment with surgical oophorectomy either delayed to be during a five-day window in the history-estimated midluteal phase of the menstrual cycles, or in the next one to six days. Women who were estimated to be in the luteal phase of the menstrual cycle for the next one to six days (n = 231) were excluded from random assignment and received immediate surgical treatments. All patients began tamoxifen within 6 days of surgery and continued this for 5 years. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess differences in five-year disease-free survival (DFS) between the groups. All statistical tests were two-sided.

Results: The randomized midluteal phase surgery group had a five-year DFS of 64%, compared with 71% for the immediate surgery random assignment group (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 0.91 to 1.68, P = .18). Multivariable Cox regression models, which included important prognostic variables, gave similar results (aHR = 1.28, 95% CI = 0.94 to 1.76, P = .12). For overall survival, the univariate hazard ratio was 1.33 (95% CI = 0.94 to 1.89, P = .11) and the multivariable aHR was 1.43 (95% CI = 1.00 to 2.06, P = .05). Better DFS for follicular phase surgery, which was unanticipated, proved consistent across multiple exploratory analyses.

Conclusions: The hypothesized benefit of adjuvant luteal phase oophorectomy was not shown in this large trial.
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http://dx.doi.org/10.1093/jnci/djv064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838061PMC
June 2015

Sleep disordered breathing and post-discharge mortality in patients with acute heart failure.

Eur Heart J 2015 Jun 29;36(23):1463-9. Epub 2015 Jan 29.

Sleep Heart Program, The Ohio State University, Columbus, OH, USA Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA.

Background: Hospitalizations for heart failure are associated with a high post-discharge risk for mortality. Identification of modifiable predictors of post-discharge mortality during hospitalization may improve outcome. Sleep disordered breathing (SDB) is the most common co-morbidity in heart failure patients.

Design, Setting, And Participants: Prospective cohort study of patients hospitalized with acute heart failure (AHF) in a single academic heart hospital. Between January 2007 and December 2010, all patients hospitalized with AHF who have left ventricular ejection fraction (LVEF) ≤ 45% and were not already diagnosed with SDB were the target population.

Main Outcomes And Measures: Patients underwent in-hospital attended polygraphy testing for SDB and were followed for a median of 3 years post-discharge. Mortality was recorded using national and state vital statistics databases.

Results: During the study period, 1117 hospitalized AHF patients underwent successful sleep testing. Three hundred and forty-four patients (31%) had central sleep apnoea (CSA), 525(47%) patients had obstructive sleep apnoea (OSA), and 248 had no or minimal SDB (nmSDB). Of those, 1096 patients survived to discharge and were included in the mortality analysis. Central sleep apnoea was independently associated with mortality. The multivariable hazard ratio (HR) for time to death for CSA vs. nmSDB was 1.61 (95% CI: 1.1, 2.4, P = 0.02). Obstructive sleep apnoea was also independently associated with mortality with a multivariable HR vs. nmSDB of 1.53 (CI: 1.1, 2.2, P = 0.02). The Cox proportional hazards model adjusted for the following covariates: LVEF, age, BMI, sex, race, creatinine, diabetes, type of cardiomyopathy, coronary artery disease, chronic kidney disease, discharge systolic blood pressure <110, hypertension, discharge medications, initial length of stay, admission sodium, haemoglobin, and BUN.

Conclusions: This is the largest study to date to evaluate the effect of SDB on post-discharge mortality in patients with AHF. Newly diagnosed CSA and OSA during AHF hospitalization are independently associated with post-discharge mortality.
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http://dx.doi.org/10.1093/eurheartj/ehu522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465635PMC
June 2015

Endothelial nitric oxide synthase uncoupling: a novel pathway in OSA induced vascular endothelial dysfunction.

Respir Physiol Neurobiol 2015 Feb 19;207:40-7. Epub 2014 Dec 19.

The Sleep Heart Program, the Ohio State University, Columbus, OH, United States; Division of Pulmonary Critical Care and Sleep, The Davis Heart and Lung Research Institute and Division of Cardiovascular Medicine, the Ohio State University, Columbus, OH, United States. Electronic address:

The mechanism of vascular endothelial dysfunction (VED) and cardiovascular disease in obstructive sleep apnea (OSA) is unknown. We performed a comprehensive evaluation of endothelial nitric oxide synthase (eNOS) function directly in the microcirculatory endothelial tissue of OSA patients who have very low cardiovascular risk status. Nineteen OSA patients underwent gluteal biopsies before, and after effective treatment of OSA. We measured superoxide (O2(•-)) and nitric oxide (NO) in the microcirculatory endothelium using confocal microscopy. We evaluated the effect of the NOS inhibitor l-Nitroarginine-Methyl-Ester (l-NAME) and the NOS cofactor tetrahydrobiopterin (BH4) on endothelial O2(•-) and NO in patient endothelial tissue before and after treatment. We found that eNOS is dysfunctional in OSA patients pre-treatment, and is a source of endothelial O2(•-) overproduction. eNOS dysfunction was reversible with the addition of BH4. These findings provide a new mechanism of endothelial dysfunction in OSA patients and a potentially targetable pathway for treatment of cardiovascular risk in OSA.
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http://dx.doi.org/10.1016/j.resp.2014.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297730PMC
February 2015

Follicular thyroid cancers demonstrate dual activation of PKA and mTOR as modeled by thyroid-specific deletion of Prkar1a and Pten in mice.

J Clin Endocrinol Metab 2014 May 10;99(5):E804-12. Epub 2014 Feb 10.

Departments of Molecular, Virology, Immunology, and Medical Genetics (D.R.P., P.K.M., A.A.L., J.M.K., L.S.K.) and Veterinary Biosciences (K.M.D.L.P.), Center for Biostatistics (L.Y., X.Z., D.J.), and Division of Endocrinology, Diabetes, and Metabolism (M.S., M.D.R., L.S.K.), The Ohio State University, Columbus, Ohio 43210; Department of Pediatrics (V.V.V.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814; and National Hormone and Peptide Program (A.F.P.), Harbor-UCLA Medical Center, Torrance, California 90509.

Context: Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC.

Objective: The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC.

Design: We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors.

Setting: The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals.

Patients: Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases.

Interventions: There were no interventions.

Main Outcome Measures: Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression.

Results: Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement.

Conclusions: These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.
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http://dx.doi.org/10.1210/jc.2013-3101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010710PMC
May 2014

Bone mineral density following surgical oophorectomy and tamoxifen adjuvant therapy for breast cancer.

Cancer 2013 Nov 20;119(21):3746-52. Epub 2013 Aug 20.

International Breast Cancer Research Foundation, Madison, Wisconsin.

Background: In premenopausal women treated for breast cancer, loss of bone mineral density (BMD) follows from menopause induced by chemotherapy or loss of ovarian function biochemically or by surgical oophorectomy. The impact on BMD of surgical oophorectomy plus tamoxifen therapy has not been described.

Methods: In 270 Filipino and Vietnamese premenopausal patients participating in a clinical trial assessing the impact of the timing in the menstrual cycle of adjuvant surgical oophorectomy on breast cancer outcomes, BMD was measured at the lumbar spine and femoral neck before this treatment, and at 6, 12, and 24 months after surgical and tamoxifen therapies.

Results: In women with a pretreatment BMD assessment and at least 1 other subsequent BMD assessment, no significant change in femoral neck BMD was observed over the 2-year period (-0.006 g/cm2 , -0.8%, P = .19), whereas in the lumbar spine, BMD fell by 0.045 g/cm2 (4.7%) in the first 12 months (P < .0001) and then began to stabilize.

Conclusions: Surgically induced menopause with tamoxifen treatment is associated with loss of BMD at a rate that lessens over 2 years in the lumbar spine and no significant change of BMD in the femoral neck.
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http://dx.doi.org/10.1002/cncr.28302DOI Listing
November 2013

Glycovariant anti-CD37 monospecific protein therapeutic exhibits enhanced effector cell-mediated cytotoxicity against chronic and acute B cell malignancies.

MAbs 2013 Sep-Oct;5(5):723-35. Epub 2013 Jun 7.

Integrated Biomedical Science Graduate Program; The Ohio State University; Columbus, OH USA; Division of Hematology, Department of Internal Medicine; The Ohio State University; Columbus, OH USA.

TRU-016 is a SMIP(TM) (monospecific protein therapeutic) molecule against the tetraspanin transmembrane family protein CD37 that is currently in Phase 2 trials in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). In an attempt to enhance the ADCC function of SMIP-016, the chimeric version of TRU-016, SMIP-016(GV) was engineered with a modification in a glycosylation site in the Fc domain. The wild-type and glycovariant SMIP proteins mediate comparable Type I antibody-like direct cytotoxicity in the presence of anti-human Fc crosslinker and show a similar tyrosine phosphorylation pattern post-treatment. However, NK cells stimulated with the SMIP-016(GV) exhibit enhanced activation and release 3-fold more interferon-γ compared with SMIP-016. SMIP-016(GV) shows enhanced ADCC function against cells expressing CD37 with NK cell effectors derived from both normal and CLL-affected individuals. Enhanced ADCC is observed against CLL cells and is sustained at concentrations of SMIP-016(GV) as low at 5E(-6) µg/mL on cells expressing minimal CD37 antigen. In support of the biological relevance of this, SMIP-016(GV) mediates effective ADCC against primary acute lymphoblastic leukemia (ALL) cells with low surface expression of CD37. Collectively, these data suggest potential use of the novel therapeutic agent SMIP-016(GV) with enhanced effector function for B cell malignancies, including CLL and ALL therapy.
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http://dx.doi.org/10.4161/mabs.25282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3851225PMC
May 2014

Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells.

Biomaterials 2013 Aug 28;34(26):6185-93. Epub 2013 May 28.

Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.

Despite advances in chemo and immunotherapeutic agents for B chronic lymphocytic leukemia (B-CLL), the undesirable adverse side effects due to non-specific cellular uptake remain to be addressed. We identified anti-CD37 monoclonal antibody immunoliposomes (ILs) as vehicles for targeted delivery to B chronic lymphocytic leukemia cells. To achieve maximal benefits for all patients, a new strategy of dual-ligand immunoliposomes (dILs) was developed. A combinatorial antibody microarray technology was adapted to quickly identify optimal antibody combinations for individual patient cells. For proof-of-concept, a B-cell specific antibody, either anti-CD19 or anti-CD20, was combined with anti-CD37 to construct dILs with enhanced selectivity and efficacy. Consistent with data from the antibody microarray, these dILs provided highly specific targeting to both leukemia cell lines and B-CLL patient cells. Compared with the single antibody ILs, the anti-CD19/CD37 dILs clearly demonstrated superior delivery efficiency and apoptosis induction to B-CLL patient cells, whereas the anti-CD20/anti-CD37 dILs were found to be the most efficient for delivery to leukemia cell lines. In addition, it was observed that anti-CD37 ILs without payload drug mediated effective CD37 cross-linking and induced potent apoptosis induction. The anti-CD19/CD20 dILs showed the improved cell apoptosis induction compared to either anti-CD19 ILs or anti-CD20 ILs. Our findings suggest that the dual-ligand ILs may provide a preferred strategy of personalized nanomedicine for the treatment of B-cell malignancies.
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http://dx.doi.org/10.1016/j.biomaterials.2013.04.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756150PMC
August 2013

Development of p21 activated kinase-targeted multikinase inhibitors that inhibit thyroid cancer cell migration.

J Clin Endocrinol Metab 2013 Aug 24;98(8):E1314-22. Epub 2013 May 24.

Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio 43210, USA.

Context: The p21 activated kinases (PAKs) are a family of serine/threonine kinases that are downstream effectors of small GTPase Cdc42 and Rac. PAKs regulate cell motility, proliferation, and cytoskeletal rearrangement. PAK isoform expression and activity have been shown to be enhanced in cancer and to function as an oncogene in vivo. PAKs also have been implicated in cancer progression.

Objective: In thyroid cancer, we have previously determined that PAK overactivation is common in the invasive fronts of aggressive tumors and that it is functionally involved in thyroid cancer cell motility using molecular inhibitors. We report the development of two new PAK-inhibiting compounds that were modified from the structure OSU-03012, a previously identified multikinase inhibitor that competitively blocks ATP binding of both phosphoinositide-dependent kinase 1 (PDK1) and PAK1.

Results: Seventeen compounds were created by combinatorial chemistry predicted to inhibit PAK activity with reduced anti-PDK1 effect. Two lead compounds were identified based on the ability to inhibit PAK1 activity in an ATP-competitive manner without discernible in vivo PDK1 inhibitory activity in thyroid cancer cell lines. Both compounds reduced thyroid cancer cell viability. Although they are not PAK-specific on a multikinase screening assay, the antimigration activity effect of the compounds in thyroid cancer cells was rescued by overexpression of a constitutively active PAK1, suggesting this activity is involved in this biological effect.

Conclusions: We have developed 2 new multikinase inhibitors with anti-PAK activity that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.
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http://dx.doi.org/10.1210/jc.2012-3937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733855PMC
August 2013

The proteasome inhibitor carfilzomib functions independently of p53 to induce cytotoxicity and an atypical NF-κB response in chronic lymphocytic leukemia cells.

Clin Cancer Res 2013 May 20;19(9):2406-19. Epub 2013 Mar 20.

College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.

Purpose: The proteasome consists of chymotrypsin-like (CT-L), trypsin-like, and caspase-like subunits that cleave substrates preferentially by amino acid sequence. Proteasomes mediate degradation of regulatory proteins of the p53, Bcl-2, and nuclear factor-κB (NF-κB) families that are aberrantly active in chronic lymphocytic leukemia (CLL). CLL remains an incurable disease, and new treatments are especially needed in the relapsed/refractory setting. We therefore investigated the effects of the proteasome inhibitor carfilzomib (CFZ) in CLL cells.

Experimental Design: Tumor cells from CLL patients were assayed in vitro using immunoblotting, real-time polymerase chain reaction, and electrophoretic mobility shift assays. In addition, a p53 dominant-negative construct was generated in a human B-cell line.

Results: Unlike bortezomib, CFZ potently induces apoptosis in CLL patient cells in the presence of human serum. CLL cells have significantly lower basal CT-L activity compared to normal B and T cells, although activity is inhibited similarly in T cells versus CLL. Co-culture of CLL cells on stroma protected from CFZ-mediated cytotoxicity; however, PI3K inhibition significantly diminished this stromal protection. CFZ-mediated cytotoxicity in leukemic B cells is caspase-dependent and occurs irrespective of p53 status. In CLL cells, CFZ promotes atypical activation of NF-κB evidenced by loss of cytoplasmic IκBα, phosphorylation of IκBα, and increased p50/p65 DNA binding, without subsequent increases in canonical NF-κB target gene transcription.

Conclusions: Together, these data provide new mechanistic insights into the activity of CFZ in CLL and support phase I investigation of CFZ in this disease.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644010PMC
May 2013

Toll-like receptor 2 ligands regulate monocyte Fcγ receptor expression and function.

J Biol Chem 2013 Apr 15;288(17):12345-52. Epub 2013 Mar 15.

Department of Internal Medicine, Ohio State University, Columbus, Ohio 43210, USA.

Fcγ receptor (FcγR) clustering on monocytes/macrophages results in phagocytosis and inflammatory cytokine production, which serve to eliminate antibody-opsonized targets and activate neighboring immune cells. Toll-like receptor 2 (TLR2), which recognizes a range of both bacterial and fungal components, elicits strong proinflammatory responses in these cells when stimulated by ligands, either natural or synthetic. Thus, we explored the possibility that TLR2 agonists could strengthen FcγR activity within the context of antibody therapy. Human peripheral blood monocytes treated with the TLR2 agonist Pam2CSK4 showed significantly enhanced FcγR-mediated cytokine production as well as phagocytic ability. An examination of the molecular mechanism behind this enhancement revealed increased expression of both FcγRIIa and the common γ subunit following Pam2CSK4 treatment. Interestingly however, expression of the inhibitory receptor FcγRIIb was also modestly increased. Further investigation revealed that Pam2CSK4 also dramatically decreased the expression of SHIP, the major mediator of FcγRIIb inhibitory activity. Using a murine Her2/neu solid tumor model of antibody therapy, we found that Pam2CSK4 significantly enhanced the ability of anti-Her2 antibody to reduce the rate of tumor growth. To verify that the FcγR enhancement was not unique to the diacylated Pam2CSK4, we also tested Pam3CSK4, a related triacylated TLR2 agonist. Results showed significant enhancement in FcγR function and expression. Taken together, these findings indicate that TLR2 activation can positively modulate FcγR and suggest that TLR2 agonists should be considered for testing as adjuvants for antitumor antibody therapy.
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http://dx.doi.org/10.1074/jbc.M113.449983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636918PMC
April 2013

CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer.

Springerplus 2013 Dec 15;2(1):52. Epub 2013 Feb 15.

International Breast Cancer Research Foundation, 505 S Rosa Rd Ste 35E, Madison, WI 53719 USA.

Background: While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results.

Findings: In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case-control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease. We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control.

Conclusions: This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70 ng.ml), endoxifen may promote recurrence.
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http://dx.doi.org/10.1186/2193-1801-2-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3584248PMC
December 2013

Modulation of sodium/iodide symporter expression in the salivary gland.

Thyroid 2013 Aug 17;23(8):1029-36. Epub 2013 Jul 17.

Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA.

Background: Physiologic iodide-uptake, mediated by the sodium/iodide symporter (NIS), in the salivary gland confers its susceptibility to radioactive iodine-induced damage following (131)I treatment of thyroid cancer. Subsequent quality of life for thyroid cancer survivors can be decreased due to recurrent sialoadenitis and persistent xerostomia. NIS expression at the three principal salivary duct components in various pathological conditions was examined to better our understanding of NIS modulation in the salivary gland.

Methods: NIS expression was evaluated by immunohistochemistry in human salivary gland tissue microarrays constructed of normal, inflamed, and neoplastic salivary tissue cores. Cumulative (123)I radioactivity reflecting the combination of NIS activity with clearance of saliva secretion in submandibular and parotid salivary glands was evaluated by single-photon emission computed tomography/computed tomography imaging 24 hours after (123)I administration in 50 thyroid cancer patients.

Results: NIS is highly expressed in the basolateral membranes of the majority of striated ducts, yet weakly expressed in few intercalated and excretory duct cells. The ratio of (123)I accumulation between parotid and submandibular glands is 2.38±0.19. However, the corresponding ratio of (123)I accumulation normalized by volume of interest is 1.19±0.06. The percentage of NIS-positive striated duct cells in submandibular salivary glands was statistically greater than in parotid salivary glands, suggesting a higher clearance rate of saliva secretion in submandibular salivary glands. NIS expression in striated ducts was heterogeneously decreased or absent in sialoadenitis. Most ductal salivary gland tumors did not express NIS. However, Warthin's tumors of striated duct origin exhibited consistent and intense NIS staining, corresponding with radioactive iodine uptake.

Conclusions: NIS expression is tightly modulated during the transition of intercalated to striated ducts and striated to excretory ducts in salivary ductal cells. NIS expression in salivary glands is decreased during inflammation and tumor formation. Further investigation may identify molecular targets and/or pharmacologic agents that allow selective inhibition of NIS expression/activity in salivary glands during radioactive iodine treatment.
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http://dx.doi.org/10.1089/thy.2012.0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752512PMC
August 2013

Comparative assessment of clinically utilized CD20-directed antibodies in chronic lymphocytic leukemia cells reveals divergent NK cell, monocyte, and macrophage properties.

J Immunol 2013 Mar 15;190(6):2702-11. Epub 2013 Feb 15.

Integrated Biomedical Science Graduate Program, The Ohio State University, Columbus, OH 43210, USA.

CD20 is a widely validated, B cell-specific target for therapy in B cell malignancies. Rituximab is an anti-CD20 Ab that prolongs survival of chronic lymphocytic leukemia (CLL) patients when combined with chemotherapy. Ofatumumab and GA101 (obinutuzumab) are CD20-directed Abs currently being developed as alternative agents to rituximab in CLL based upon different properties of enhanced direct cell death, NK cell-mediated Ab-dependent cellular cytotoxicity, or complement-dependent cytotoxicity. Despite widespread study, ofatumumab and GA101 have not been compared with each other, nor studied for their interactions with monocytes and macrophages which are critical for the efficacy of anti-CD20 Abs in murine models. In CLL cells, we show that direct cell death and complement-dependent cytotoxicity are greatest with GA101 and ofatumumab, respectively. GA101 promotes enhanced NK cell activation and Ab-dependent cellular cytotoxicity at high Ab concentrations. Ofatumumab elicits superior Ab-dependent cellular phagocytosis with monocyte-derived macrophages. GA101 demonstrated reduced activation of monocytes with diminished pERK, TNF-α release, and FcγRIIa recruitment to lipid rafts. These data demonstrate that GA101 and ofatumumab are both superior to rituximab against CLL cells via different mechanisms of potential tumor elimination. These findings bear relevance to potential combination strategies with each of these anti-CD20 Abs in the treatment of CLL.
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http://dx.doi.org/10.4049/jimmunol.1202588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631574PMC
March 2013

Massage timing affects postexercise muscle recovery and inflammation in a rabbit model.

Med Sci Sports Exerc 2013 Jun;45(6):1105-12

Division of Sports Medicine, Department of Family Medicine, The Ohio State University, Columbus, OH 43221, USA.

Purpose: This study compared the effect of immediate versus delayed massage-like compressive loading (MLL) on peak isometric torque recovery and inflammatory cell infiltration after eccentric exercise (EEX).

Methods: Eighteen skeletally mature New Zealand White rabbits were instrumented with peroneal nerve cuffs for the stimulation of hindlimb tibialis anterior muscles. After a bout of EEX, rabbits were randomly assigned to an MLL protocol (0.5 Hz, 10 N, 15 min) that started immediately post-EEX, 48 h post-EXX, or no-MLL control and performed for four consecutive days. A torque-angle (T-Θ) relationship was obtained for 21 joint angles pre- and post-EEX and after four consecutive days of MLL or no-MLL. Muscle wet weights and immunohistochemical sections were obtained after final treatments.

Results: EEX produced an average 51% ± 13% decrease in peak isometric torque output. The greatest peak torque recovery occurred with the immediate application of MLL. There were differences in torque recovery between immediate and delayed MLL (P = 0.0012), immediate MLL and control (P < 0.0001), and delayed MLL and control (P = 0.025). Immunohistochemical analysis showed 39.3% and 366.0% differences in the number of RPN3/57 and CD11b-positive cells between immediate (P = 0.71) and delayed MLL (P = 0.12). The area under the T-Θ curve showed a difference for immediate (P < 0.0001) and delayed (P = 0.0051) MLL as compared with control. Exercise produced an average 10° ± 0.2° rightward shift from preexercise peak isometric torque angle. Control, immediate MLL, and delayed MLL produced an average leftward angular shift from the postexercise angle (P = 0.28, P = 0.03, and P = 0.47, respectively).

Conclusion: Post-EEX, immediate MLL was more beneficial than delayed MLL in restoring muscle function and in modulating inflammatory cell infiltration. These findings invite similar human studies to make definitive conclusions on optimal timing of massage-based therapies.
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http://dx.doi.org/10.1249/MSS.0b013e31827fdf18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3632662PMC
June 2013

Milatuzumab-conjugated liposomes as targeted dexamethasone carriers for therapeutic delivery in CD74+ B-cell malignancies.

Clin Cancer Res 2013 Jan 3;19(2):347-56. Epub 2012 Dec 3.

Division of Hematology, The Comprehensive Cancer Center, Division of Pharmaceutics and Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.

Purpose: Corticosteroids are widely used for the treatment of B-cell malignancies, including non-Hodgkin lymphoma, chronic lymphocytic leukemia (CLL), and acute lymphoblastic leukemia; however, this class of drug is associated with undesirable off-target effects. Herein, we developed novel milatuzumab-conjugated liposomes as a targeted dexamethasone carrier for therapeutic delivery in CD74(+) B-cell malignancies and explored its effect against the disease.

Experimental Design: The targeting efficiency of milatuzumab-targeted liposomes to CD74(+) cells was evaluated in vitro. The effect of CD74-targeted liposomal dexamethasone was compared with free dexamethasone in primary CLL cells and cell lines in vitro. The therapeutic efficacy of CD74-targeted liposomal dexamethasone was evaluated in a Raji-severe combined immunodeficient (SCID) xenograft model in vivo.

Results: Milatuzumab-targeted liposomes promoted selective incorporation of carrier molecules into transformed CD74-positive B cells as compared with CD74-negative T-cells. The CD74-dexamethasone-targeted liposomes (CD74-IL-DEX) promoted and increased killing in CD74-positive tumor cells and primary CLL cells. Furthermore, the targeted drug liposomes showed enhanced therapeutic efficacy against a CD74-positive B-cell model as compared with free, or non-targeted, liposomal dexamethasone in SCID mice engrafted with Raji cells in vivo.

Conclusions: These studies provide evidence and support for a potential use of CD74-targeted liposomal dexamethasone as a new therapy for B-cell malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793126PMC
January 2013

Targeted nanoparticle delivery overcomes off-target immunostimulatory effects of oligonucleotides and improves therapeutic efficacy in chronic lymphocytic leukemia.

Blood 2013 Jan 19;121(1):136-47. Epub 2012 Nov 19.

Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.

Several RNA-targeted therapeutics, including antisense oligonucleotides (ONs), small interfering RNAs, and miRNAs, constitute immunostimulatory CpG motifs as an integral part of their design. The limited success with free antisense ONs in hematologic malignancies in recent clinical trials has been attributed to the CpG motif-mediated, TLR-induced prosurvival effects and inefficient target modulation in desired cells. In an attempt to diminish their off-target prosurvival and proinflammatory effects and specific delivery, as a proof of principle, in the present study, we developed an Ab-targeted liposomal delivery strategy using a clinically relevant CD20 Ab (rituximab)-conjugated lipopolyplex nanoparticle (RIT-INP)- and Bcl-2-targeted antisense G3139 as archetypical antisense therapeutics. The adverse immunostimulatory responses were abrogated by selective B cell-targeted delivery and early endosomal compartmentalization of G3139-encapsulated RIT-INPs, resulting in reduced NF-κB activation, robust Bcl-2 down-regulation, and enhanced sensitivity to fludarabine-induced cytotoxicity. Furthermore, significant in vivo therapeutic efficacy was noted after RIT-INP-G3139 administration in a disseminated xenograft leukemia model. The results of the present study demonstrate that CD20-targeted delivery overcomes the immunostimulatory properties of CpG-containing ON therapeutics and improves efficient gene silencing and in vivo therapeutic efficacy for B-cell malignancies. The broader implications of similar approaches in overcoming immunostimulatory properties of RNA-directed therapeutics in hematologic malignancies are also discussed.
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http://dx.doi.org/10.1182/blood-2012-01-407742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3538326PMC
January 2013

Workplace based mindfulness practice and inflammation: a randomized trial.

Brain Behav Immun 2013 Jan 16;27(1):145-54. Epub 2012 Oct 16.

Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, United States.

We have developed a low dose Mindfulness-Based Intervention (MBI-ld) that reduces the time committed to meetings and formal mindfulness practice, while conducting the sessions during the workday. This reduced the barriers commonly mentioned for non-participation in mindfulness programs. In a controlled randomized trial we studied university faculty and staff (n=186) who were found to have an elevated CRP level,>3.0 mg/ml, and who either had, or were at risk for cardiovascular disease. This study was designed to evaluate if MBI-ld could produce a greater decrease in CRP, IL-6 and cortisol than an active control group receiving a lifestyle education program when measured at the end of the 2 month interventions. We found that MBI-ld significantly enhanced mindfulness by 2-months and it was maintained for up to a year when compared to the education control. No significant changes were noted between interventions in cortisol, IL-6 levels or self-reported measures of perceived stress, depression and sleep quality at 2-months. Although not statistically significant (p=.08), the CRP level at 2-months was one mg/ml lower in the MBI-ld group than in the education control group, a change which may have clinical significance (Ridker et al., 2000; Wassel et al., 2010). A larger MBI-ld effect on CRP (as compared to control) occurred among participants who had a baseline BMI <30 (-2.67 mg/ml) than for those with BMI >30 (-0.18 mg/ml). We conclude that MBI-ld should be more fully investigated as a low-cost self-directed complementary strategy for decreasing inflammation, and it seems most promising for non-obese subjects.
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http://dx.doi.org/10.1016/j.bbi.2012.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3528077PMC
January 2013

Use of the hollow fiber assay for the discovery of novel anticancer agents from fungi.

Methods Mol Biol 2012 ;944:267-77

College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.

The hollow fiber assay (HFA) is a drug discovery tool to aid investigators in the prioritization of lead compounds identified by in vitro testing for further development in animal models of disease. In the HFA, cells are cultured in hollow fibers containing pores of a diameter (500 kDa) large enough for proteins and other macromolecules to enter, but too small for the cells to escape. The fibers are filled with cells, sealed and placed in the peritoneal cavity of immunodeficient mice. The mice undergo a predetermined treatment regimen after which the fibers are retrieved and the cells evaluated for activity of a target relevant to the disease modeled. The HFA combines advantages of both in vitro and in vivo assay systems. It uses the same cell lines used in culture systems, is a rapid assay, and requires fewer animals and less test substance than conventional xenograft systems. Like traditional in vivo assays, the test substance is evaluated in a live animal, which affords an initial assessment of associated toxicity and pharmacokinetic properties of the test substance.
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http://dx.doi.org/10.1007/978-1-62703-122-6_20DOI Listing
March 2013

Chemical Diversity of Metabolites from Fungi, Cyanobacteria, and Plants Relative to FDA-Approved Anticancer Agents.

ACS Med Chem Lett 2012 Jul;3(8):645-649

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, P.O. Box 26170, Greensboro, NC 27402.

A collaborative project has been undertaken to explore filamentous fungi, cyanobacteria, and tropical plants for anti-cancer drug leads. Through principal component analysis, the chemical space covered by compounds isolated and characterized from these three sources over the last four years was compared to each other and to the chemical space of selected FDA-approved anticancer drugs. Using literature precedence, nine molecular descriptors were examined: molecular weight, number of chiral centers, number of rotatable bonds, number of acceptor atoms for H-bonds (N,O,F), number of donor atoms for H-bonds (N and O), topological polar surface area using N,O polar contributions, Moriguchi octanol-water partition coefficient, number of nitrogen atoms, and number of oxygen atoms. Four principal components explained 87% of the variation found among 343 bioactive natural products and 96 FDA-approved anticancer drugs. Across the four dimensions, fungal, cyanobacterial and plant isolates occupied both similar and distinct areas of chemical space that collectively aligned well with FDA-approved anticancer agents. Thus, examining three separate re-sources for anticancer drug leads yields compounds that probe chemical space in a complementary fashion.
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http://dx.doi.org/10.1021/ml300105sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443637PMC
July 2012

Pharmacokinetics and tissue disposition of lenalidomide in mice.

AAPS J 2012 Dec 7;14(4):872-82. Epub 2012 Sep 7.

Division of Pharmaceutics, College of Pharmacy, 230 Parks Hall, 500W. 12th Avenue, Columbus, Ohio 43210, USA.

Lenalidomide is a synthetic derivative of thalidomide exhibiting multiple immunomodulatory activities beneficial in the treatment of several hematological malignancies. Murine pharmacokinetic characterization necessary for translational and further preclinical investigations has not been published. Studies herein define mouse plasma pharmacokinetics and tissue distribution after intravenous (IV) bolus administration and bioavailability after oral and intraperitoneal delivery. Range finding studies used lenalidomide concentrations up to 15 mg/kg IV, 22.5 mg/kg intraperitoneal injections (IP), and 45 mg/kg oral gavage (PO). Pharmacokinetic studies evaluated doses of 0.5, 1.5, 5, and 10 mg/kg IV and 0.5 and 10 mg/kg doses for IP and oral routes. Liquid chromatography-tandem mass spectrometry was used to quantify lenalidomide in plasma, brain, lung, liver, heart, kidney, spleen, and muscle. Pharmacokinetic parameters were estimated using noncompartmental and compartmental methods. Doses of 15 mg/kg IV, 22.5 mg/kg IP, and 45 mg/kg PO lenalidomide caused no observable toxicity up to 24 h postdose. We observed dose-dependent kinetics over the evaluated dosing range. Administration of 0.5 and 10 mg/kg resulted in systemic bioavailability ranges of 90-105% and 60-75% via IP and oral routes, respectively. Lenalidomide was detectable in the brain only after IV dosing of 5 and 10 mg/kg. Dose-dependent distribution was also observed in some tissues. High oral bioavailability of lenalidomide in mice is consistent with oral bioavailability in humans. Atypical lenalidomide tissue distribution was observed in spleen and brain. The observed dose-dependent pharmacokinetics should be taken into consideration in translational and preclinical mouse studies.
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http://dx.doi.org/10.1208/s12248-012-9401-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475844PMC
December 2012

A scoring system for the prognosis and treatment of malignant bowel obstruction.

Surgery 2012 Oct 26;152(4):747-56; discussion 756-7. Epub 2012 Aug 26.

Division of Surgical Oncology, The Ohio State University College of Medicine, Columbus, OH 43210-1240, USA.

Background: Malignant bowel obstruction is a common result of end-stage abdominal cancer that is a treatment dilemma for many physicians. Little has been reported predicting outcomes or determining the role of surgical intervention. We sought to review our experience with surgical and nonsurgical management of malignant bowel obstruction to identify predictors of 30-day mortality and of who would most likely benefit from surgical intervention.

Methods: A chart review of 523 patients treated between 2000 and 2007 with malignant bowel obstruction were evaluated for factors present at admission to determine return to oral intake, 30-day mortality, and overall survival. Propensity score matching was used to homogenize patients treated with and without surgery to identify those who would benefit most from operative intervention.

Results: Radiographic evidence of large bowel obstruction was predictive of return to oral intake. Hypoalbuminemia and radiographic evidence of ascites or carcinomatosis were all predictive of increased 30-day mortality and overall survival. A nomogram of 5 identified risk factors correlated with increased 30-day mortality independent of therapy. Patients with large bowel or partial small bowel obstruction benefited most from surgery. A second nomogram was created from 4 identified risk factors that revealed which patients with complete small bowel obstruction might benefit from surgery.

Conclusion: Two nomograms were created that may guide decisions in the care of patients with malignant bowel obstruction. These nomograms are able to predict 30-day mortality and who may benefit from surgery for small bowel obstruction.
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http://dx.doi.org/10.1016/j.surg.2012.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792226PMC
October 2012

Dual targeting of the cyclin/Rb/E2F and mitochondrial pathways in mantle cell lymphoma with the translation inhibitor silvestrol.

Clin Cancer Res 2012 Sep 12;18(17):4600-11. Epub 2012 Jul 12.

Department of Internal Medicine, College of Medicine, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.

Purpose: During cell-cycle progression, D-cyclins activate cyclin-dependent kinases (CDKs) 4/6 to inactivate Rb, permitting E2F1-mediated S-phase gene transcription. This critical pathway is typically deregulated in cancer, and novel inhibitory strategies would be effective in a variety of tumors. The protein synthesis inhibitor silvestrol has potent activity in B-cell leukemias via the mitochondrial pathway of apoptosis, and also reduces cyclin D1 expression in breast cancer and lymphoma cell lines. We hypothesized that this dual activity of silvestrol would make it especially effective in malignancies driven by aberrant cyclin D1 expression.

Experimental Design: Mantle cell lymphoma (MCL), characterized by elevated cyclin D1, was used as a model to test this approach. The cyclin D/Rb/E2F1 pathway was investigated in vitro using MCL cell lines and primary tumor cells. Silvestrol was also evaluated in vivo using an aggressive model of MCL.

Results: Silvestrol showed low nanomolar potency both in MCL cell lines and primary MCL tumor cells. D-cyclins were depleted with just 10 nmol/L silvestrol at 16 hours, with subsequent reductions of phosphorylated Rb, E2F1 protein, and E2F1 target transcription. As showed in other leukemias, silvestrol caused Mcl-1 depletion followed by mitochondrial depolarization and caspase-dependent apoptosis, effects not related to inhibition of CDK4/6. Silvestrol significantly (P < 0.0001) prolonged survival in a MCL xenograft model without detectable toxicity.

Conclusions: These data indicate that silvestrol effectively targets the cyclin/CDK/Rb pathway, and additionally induces cytotoxicity via intrinsic apoptosis. This dual activity may be an effective therapeutic strategy in MCL and other malignancies.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-0839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677230PMC
September 2012