Pingfu Fu

Case Western Reserve University School of Medicine , Cleveland, Ohio, United States

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Publications (90)432.83 Total impact

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    ABSTRACT: Background/Purpose This study was designed to evaluate the response and toxicity of sorafenib alone or when combined with carboplatin and paclitaxel in patients with platinum-sensitive, recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (EOC). Methods Patients with recurrent platinum-sensitive EOC with no more than 2 prior courses of chemotherapy were randomized to single-agent sorafenib 400 mg twice daily or combination sorafenib 400 mg bid (days 2-19) with IV carboplatin (AUC 6) and IV paclitaxel 175 mg/m(2) (S+C/T) every 3 weeks. Single agent sorafenib could cross over to combination upon progression. Results Patients were initially randomized to either arm, however, due to poor accrual, sorafenib arm was prematurely closed. A total of 13 patients were evaluable for response to sorafenib and 23 patients were evaluable for response to S+C/T. Objective response rate (RR) was 15 % for patients on sorafenib vs. 61 % for patients on S+C/T (p = 0.014); stable disease was seen in 62 % and 35 %, respectively. Clinical benefit rate (CBR) at 4 months (mos.) was 69 % for S and 65 % for S+C/T. The median progression free survival was 5.6 months on sorafenib vs. 16.8 months on S+C/T (p = 0.012) and there was no significant difference of overall survival between two arms (p = 0.974) with median overall survival 25.6 months under sorafenib vs. 25.9 months on S+C/T. Patients remained on trial for a median of 7.8 cycles on sorafenib and 5.4 cycles on S+C/T. Conclusion Sorafenib, alone or in combination with carboplatin and paclitaxel, has activity in patients with platinum-sensitive EOC. Sorafenib in combination with carboplatin and paclitaxel improved RR and PFS; however, there were increased grade and frequencies of toxicities.
    Investigational New Drugs 03/2014; · 3.50 Impact Factor
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    ABSTRACT: Dysfunction of the apoptotic pathway in prostate cancer cells confers apoptosis resistance towards various therapies. A novel strategy to overcome resistance is to directly target the apoptotic pathway in cancer cells. Apigenin, an anticancer agent, selectively toxic to cancer cells induces cell cycle arrest and apoptosis through mechanisms which are not fully explored. In the present study we provide novel insight into the mechanisms of apoptosis induction by apigenin. Treatment of androgen-refractory human prostate cancer PC-3 and DU145 cells with apigenin resulted in dose-dependent suppression of XIAP, c-IAP1, c-IAP2 and survivin protein levels. Apigenin treatment resulted in significant decrease in cell viability and apoptosis induction with the increase of cytochrome C in time-dependent manner. These effects of apigenin were accompanied by decrease in Bcl-xL and Bcl-2 and increase in the active form of Bax protein. The apigenin-mediated increase in Bax was due to dissociation of Bax from Ku70 which is essential for apoptotic activity of Bax. Apigenin treatment resulted in the inhibition of class I histone deacetylases and HDAC1 protein expression, thereby increasing the acetylation of Ku70 and the dissociation of Bax resulting in apoptosis of cancer cells. Furthermore, apigenin significantly reduced HDAC1 occupancy at the XIAP promoter, suggesting that histone deacetylation might be critical for XIAP downregulation. These results suggest that apigenin targets inhibitor of apoptosis proteins and Ku70-Bax interaction in the induction of apoptosis in prostate cancer cells and in athymic nude mouse xenograft model endorsing its in vivo efficacy.
    Apoptosis 02/2014; · 4.07 Impact Factor
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    ABSTRACT: Objectives Sorafenib is a multi-tyrosine kinase inhibitor of Raf kinase, VEGFR, and PDGFR. Angiogenesis is important for growth and progression of SCLC. This trial was conducted to evaluate whether the combination of cisplatin and etoposide plus concurrent and sequential sorafenib could prolong survival in patients with previously untreated SCLC. Methods Previously untreated patients with extensive stage SCLC were treated with cisplatin and etoposide days 1, 2, 3 for four cycles, concurrent with sorafenib 200 mg orally bid starting day 1 cycle 1. Patients with no disease progression after four cycles continued sorafenib 400 mg orally bid as maintenance for maximum of 12 months. The primary endpoint was 1 year survival with response rate and safety as secondary endpoints. Results A total of 18 patients were enrolled with 17 evaluable patients. One patient had a complete response, seven patients had a partial response (overall response rate of 47 %) and one patient had stable disease. Overall median survival was 7.4 months and 1 year survival was 25 %. The most common treatment-related adverse events included fatigue, anorexia, rash, diarrhea, neutropenia and weight loss. Grade 5 GI bleeding, pulmonary hemorrhage and neutropenia occurred in one pt (6 %) each. Accrual was halted on the basis of safety profile as well as preliminary efficacy data. Conclusions The combination of platinum based chemotherapy and sorafenib has significant toxicity at current dose levels and is associated with disappointing efficacy data.
    Investigational New Drugs 01/2014; · 3.50 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored. Through examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS). There was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%. There is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time.
    Clinical Lung Cancer 12/2013; · 2.04 Impact Factor
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    ABSTRACT: Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. Single-agent dasatinib does not have clinical activity in metastatic PDAC.
    The Oncologist 09/2013; · 4.10 Impact Factor
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    ABSTRACT: Forkhead box O (FoxO) transcription factors play an important role as tumor suppressor in several human malignancies. Disruption of FoxO activity due to loss of PTEN and activation of PI3K/Akt is frequently observed in prostate cancer. Apigenin, a naturally occurring plant flavone, exhibits anti-proliferative and anti-carcinogenic activities through mechanisms which are not fully defined. In the present study we show that apigenin suppressed prostate tumorigenesis in TRAMP mice through the PI3K/Akt/FoxO signaling pathway. Apigenin-treated TRAMP mice (20 and 50 μg/mouse/day, 6 days per week for 20 weeks) exhibited significant decrease in tumor volumes of the prostate as well as completely abolished distant organ metastasis. Apigenin treatment resulted in significant decrease in the weight of genitourinary apparatus (P<0.0001), dorsolateral (P<0.0001) and ventral prostate (P<0.028), compared with the control group. Apigenin-treated mice showed reduced phosphorylation of Akt(Ser473) and FoxO3a(Ser253) which correlated with its increased nuclear retention and decreased binding of FoxO3a with 14-3-3. These events lead to reduced proliferation as assessed by Ki-67 and cyclin D1, along with upregulation of FoxO-responsive proteins BIM and p27/Kip1. Complementing in vivo results, similar observations were noted in human prostate cancer LNCaP and PC-3 cells after apigenin treatment. Furthermore, binding of FoxO3a with p27/Kip1 was markedly increased after 10 and 20 μM apigenin treatment resulting in G0/G1 phase cell cycle arrest which was consistent with the effects elicited by PI3K/Akt inhibitor, LY294002. These results provide convincing evidence that apigenin effectively suppressed prostate cancer progression, at least in part, by targeting the PI3K/Akt/FoxO signaling pathway.
    Carcinogenesis 09/2013; · 5.64 Impact Factor
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    ABSTRACT: ABSTRACT Vancomycin-resistant enterococcal (VRE) blood stream infections (BSI) pose significant hazards to patients with hematologic malignancy. We compared and examined VRE BSI rates, patient characteristics, and clinical outcomes for two cohorts of patients; those who did and did not undergo hematopoietic cell transplant (HCT). In this single institution study, we retrospectively analyzed records of consecutive patients from 1998 through 2011. Over this 14 year period, VRE was identified in 14% of all BSI in HCT patients with a cumulative rate of 1.9% (48/2581 BSI/patient). VRE was identified in 10% of all BSI in non-HCT patients with a cumulative rate of 1.1% (35/3154 BSI/patient). Transplant patients who developed VRE BSI tended to be younger, hospitalized more frequently, were exposed to vancomycin therapy frequently, and were more likely to have had a central venous catheter removed. VRE remains a significant cause of morbidity and mortality, as 22 deaths were directly or indirectly attributed to this infection. Both HCT and non-HCT patients are susceptible to VRE infection and are equally at risk for adverse outcomes related to VRE BSI.
    Leukemia & lymphoma 09/2013; · 2.40 Impact Factor
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    ABSTRACT: Uracil misincorporation into DNA is a consequence of pemetrexed inhibition of thymidylate synthetase. The base excision repair (BER) enzyme, uracil DNA glycosylase (UNG) is the major glycosylase responsible for removal of misincorporated uracil. We previously illustrated hypersensitivity to pemetrexed in UNG(-/-) human colon cancer cells. Here, we examined the relationship between UNG expression and pemetrexed sensitivity in human lung cancer. We observed a spectrum of UNG expression in human lung cancer cells. Higher levels of UNG are associated with pemetrexed resistance and are present in cell lines derived from pemetrexed-resistant histological subtypes (small cell and squamous cell carcinoma). Acute pemetrexed exposure induces UNG protein and mRNA, consistent with up-regulation of uracil-DNA repair machinery. Chronic exposure of H1299 adenocarcinoma cells to increasing pemetrexed concentrations established drug-resistant sublines. Significant induction of UNG protein confirmed up-regulation of BER as a feature of acquired pemetrexed resistance. Co-treatment with the BER inhibitor, methoxyamine (MX) overrides pemetrexed resistance in chronically exposed cells, underscoring the utility of BER directed therapeutics to offset acquired drug resistance. Expression of UNG-directed siRNA and shRNA enhanced sensitivity in A549 and H1975 cells, and in drug-resistant sublines, confirming that UNG up-regulation is protective. In human lung cancer, UNG deficiency is associated with pemetrexed-induced retention of uracil in DNA that destabilizes DNA replication forks resulting in DNA double strand breaks and cell death. Thus, in experimental models, UNG is a critical mediator of pemetrexed sensitivity that warrants evaluation to determine clinical value.
    Molecular Cancer Therapeutics 07/2013; · 5.60 Impact Factor
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    ABSTRACT: The utility of cutaneous biopsies in directing the management of post-hematopoietic cell transplant (HCT) eruptions remains uncertain. We retrospectively analyzed 439 consecutive HCT procedures for malignant hematologic disorders performed at our institution between January 2005 and December 2012; 192 patients underwent 430 cutaneous biopsies. The clinical and dermatopathologic diagnosis differed in 240 cases (56%). Biopsy results led to a change in therapy in 69 (16%) episodes. 17 of 69 management changes occurred in response to a clinical diagnosis of graft-versus-host disease, and resulted in augmentation of systemic immunosuppression. The management was modified with similar frequencies with respect to concordance or discordance between the clinical and histopathologic diagnosis (p = 0.51). We used classification and regression tree (CART) analysis, a decision-modeling technique, to predict the biopsy yield as expressed by impact on management in the allogeneic and autologous setting. The models were cross-validated and then tested against a validation subset, and maintained a high negative predictive value and high specificity. While skin biopsies may not be mandatory for either diagnostic or therapeutic reasons, in carefully chosen circumstances this procedure can yield extremely important data. We believe a prospective study should be undertaken in order to evaluate current practice data and to validate our decision tree models.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2013; · 3.15 Impact Factor
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    ABSTRACT: Introduction This study aimed to assess the safety and tolerability of the multitargeted tyrosine kinase inhibitor, vandetanib (V), in combination with two chemotherapeutic agents, oxaliplatin (O) and docetaxel (D) in advanced gastroesophageal (GE) cancer. Methods This was a Phase I study (NCT00732745) with a standard 3 + 3 dose escalation design. The primary aim was to determine the optimal dose of the combination of vandetanib and OD chemotherapy. Results Initial treatment for the first cohort consisted of oxaliplatin at 100 mg/m2 on day 1, docetaxel at 35 mg/m2 on days 1 and 8 and vandetanib 100 mg PO daily of 21-day treatment cycles. As dose limiting toxicity (DLT) was reached in 2 out of 3 patients in cohort 1 (one grade 3 and one grade 4 diarrhea with dehydration), 6 patients were treated then at dose level -1 (O 80 mg/m2 on day 1, D 30 mg/m2 on days 1 and 8, V 100 mg PO daily days 1-21) in which no further DLTs were observed. This dose was established as maximum tolerated dose and is the recommended phase 2 dose. 8 out of 9 enrolled patients had adenocarcinoma. At dose level 1, 1 of the 3 patients had a documented partial response and 2 patients had stable disease. At dose level -1, 1 of 6 patients achieved a complete response, 2 of 6 patients had stable disease, and 3 of 6 patients had progressive disease. Conclusions Vandetanib added to oxaliplatin and docetaxel showed manageable toxicity and limited activity in advanced GE cancer.
    Investigational New Drugs 04/2013; · 3.50 Impact Factor
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    ABSTRACT: PURPOSE: High-dose-rate (HDR) brachytherapy boost in prostate cancer allows dose escalation and delivery of higher biologically effective dose (BED). We evaluated the outcomes of intensity-modulated radiation therapy (IMRT) and HDR boost in a community setting. METHODS AND MATERIALS: Between July 2003 and April 2008, 148 patients with prostate cancer were treated at Cancer Center of Irvine using two transperineal implants performed 1 week apart (22Gy delivered in four fractions divided between two insertions and delivered twice daily), followed by IMRT (50.4Gy). Hormonal therapy was given for 1 year to all patients with Gleason score of 8 or higher. RESULTS: Patient characteristics are as follows: median age at treatment, 71 years; American Joint Committee on Cancer Group IIB, 53%; Gleason score of 7, 41%; and Gleason score of 8 or higher, 14%. Median followup was 49 months, and median prostate-specific antigen (PSA) nadir was 0.15ng/mL. The 4-year actuarial biochemical disease-free survival (bDFS) was 96.8/81% by Phoenix/PSA lower than 0.5ng/mL criteria. According to National Comprehensive Cancer Center Clinical Practice Guidelines-defined recurrence risk groups, 4-year bDFS for low risk was 100/92.9%, intermediate risk was 100/86.7%, and high risk was 94/75.4% by Phoenix/PSA lower than 0.5ng/mL criteria. No statistically significant difference in bDFS was detected by either failure criteria based on risk group, lymph node risk, or initial PSA. Treatment was well tolerated. Subacute/late genitourinary and gastrointestinal toxicities were limited to 10% and 5%, respectively of all patients. CONCLUSIONS: Prostate IMRT plus HDR brachytherapy boost was well tolerated with appropriate PSA response and bDFS at 4 years, demonstrated in a community setting. This treatment schema provides a high BED, comparable with hypofractionated prostate regimens previously reported in the literature. Higher BED delivery should be explored in further dose escalation studies.
    Brachytherapy 02/2013; · 1.22 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is a disease for which little recent therapeutic advance has been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore the use of surrogate endpoints in SCLC has not been explored. Through examining SCLC trials published in the Journal of Clinical Oncology (8,471 patients from 66 trials between 1983-2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary endpoints for all trials and sought to discover surrogate endpoint for overall survival (OS). There were increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% of trials in 2006-2010 [p=0.001]) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010 [p=0.005]). 72.2% of trials published in 1986-1996 failed to report a primary endpoint whereas only 5.56% of trials in 2006-2010 failed to do so (p=0.004). Of phase II trials, primary endpoint was identified as RR in 65%, OS in 25%, and PFS in 10%. There is a strong correlation between RR and both PFS (p=0.013) and OS (p=0.012) in extensive-stage disease (ED). RR (p=0.029) exhibits a negative trend over time with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for LD (p=0.036) and ED (p=0.058). We found no change in overall survival (p=0.383) over time.
    Clinical Lung Cancer 01/2013; · 2.04 Impact Factor
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    ABSTRACT: Disease aggressiveness remains a critical factor to the progression of prostate cancer. Transformation of epithelial cells to mesenchymal lineage, associated with the loss of E-cadherin, offers significant invasive potential and migration capability. Recently, Special AT-rich binding protein (SATB1) has been linked to tumor progression. SATB1 is a cell-type restricted nuclear protein, which functions as a tissue-specific organizer of DNA sequences during cellular differentiation. Our results demonstrate that SATB1 plays significant role in prostate tumor invasion and migration and its nuclear localization correlates with disease aggressiveness. Clinical specimen analysis showed that SATB1 was predominantly expressed in the nucleus of high-grade tumors compared to low-grade tumor and benign tissue. A progressive increase in the nuclear levels of SATB1 was observed in cancer tissues compared to benign specimens. Similarly, SATB1 protein levels were higher in a number of prostate cancer cells viz. HPV-CA-10, DU145, DUPro, PC-3, PC-3M, LNCaP and C4-2B, compared to non-tumorigenic PZ-HPV-7 cells. Nuclear expression of SATB1 was higher in biologically aggressive subclones of prostate cancer cells with their respective parental cell lines. Furthermore, ectopic SATB1 transfection conferred increased cell motility and invasiveness in immortalized human prostate epithelial PZ-HPV-7 cells which correlated with the loss of E-cadherin expression. Consequently, knockdown of SATB1 in highly aggressive human prostate cancer PC-3M cells inhibited invasiveness and tumor growth in vivo along with increase in E-cadherin protein expression. Our findings demonstrate that SATB1 has ability to promote prostate cancer aggressiveness through epithelial-mesenchymal transition.
    PLoS ONE 01/2013; 8(1):e53527. · 3.73 Impact Factor
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    ABSTRACT: Background: Anaplastic Thyroid Cancer (ATC) is a rare but highly aggressive malignancy with a median survival of 3-5 months. The BRAF oncogeneis mutated to its active form in up to 24% of ATC cases. Sorafenib is a tyrosine kinase inhibitor which acts on raf-1 serine/threonine kinase. In preclinical mouse models sorafenib inhibits growth of ATC xenografts and improves survival. No study of sorafenib in ATC has been conducted. We conducted a multi-institutional phase II trial of sorafenib in patients with anaplastic thyroid carcinoma who had failed up to two previous therapies. Methods: The primary endpoint of the trial was RECIST-defined imaging response rate. Twenty patients with ATC were treated with sorafenib 400 mg twice daily. Results: Two of 20 patients had a partial response (10%) and an additional 5 of 20 (25%) had stable disease. The duration of response in the two responders was 10 and 27 months respectively. For the patients with stable disease the median duration was 4 months (range 3-11 months). The overall median PFS was 1.9 months with a median and 1-year survival of 3.9 months and 20% respectively. Toxicity was manageable and as previously described for sorafenib including hypertension and skin rash. Conclusion: Sorafenib has activity in ATC but at a low frequency and similar to our previous experience with fosbretabulin. One patient with a response had previously progressed on fosbretabulin. Toxicities were both predictable and manageable.
    Thyroid: official journal of the American Thyroid Association 10/2012; · 2.60 Impact Factor
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    ABSTRACT: INTRODUCTION: Despite the well characterized clinical course of 'pure' SCLC, there have not been many data on combined SCLC, ie, tumors, which contain both small-cell and non-small-cell components. MATERIALS AND METHODS: We analyzed 1628 consecutive cases of lung cancer (1200 NSCLC, 428 SCLC) at our institution over the past decade. We identified 22 patients with C-SCLC. The pathologic and clinical characteristics of these patients were reviewed. Survival analysis was performed and prognostic factors were assessed. These data were compared with the results obtained from our 406 pure SCLC patients who presented during the same time period. RESULTS: The most common pathology was combined small-cell and large-cell with 16 cases followed by combined small- and squamous-cell carcinoma (3 cases), 2 cases of small-cell and nonspecified NSCLC, and 1 case of small cell and adenocarcinoma. Overall survival was significantly higher in C-SCLC patients compared with pure SCLC (median 15 vs. 10.8 months; P = .035). Surgery was significantly more common in this group of patients (45% vs. 3% in the pure small cell group; P < .0001). No difference in overall survival was observed in patients with C-SCLC and patients with pure SCLC, that did not receive surgery (P = .64). CONCLUSION: Patients with combined SCLC carry a better prognosis than those with pure small-cell variety and are more likely to undergo surgery.
    Clinical Lung Cancer 09/2012; · 2.04 Impact Factor
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    ABSTRACT: The pi-class glutathione S-transferase (GSTP1) actively protect cells from carcinogens and electrophilic compounds. Loss of GSTP1 expression via promoter hypermethylation is the most common epigenetic alteration observed in human prostate cancer. Silencing of GSTP1 can increase generation of reactive oxygen species (ROS) and DNA damage in cells. In this study we investigated whether loss of GSTP1 contributes to increased DNA damage that may predispose men to a higher risk of prostate cancer. We found significantly elevated (103%; P < 0.0001) levels of 8-oxo-2'-deoxogunosine (8-OHdG), an oxidative DNA damage marker, in adenocarcinomas, compared to benign counterparts, which positively correlated (r = 0.2) with loss of GSTP1 activity (34%; P < 0.0001). Silencing of GSTP1 using siRNA approach in normal human prostate epithelial RWPE1 cells caused increased intracellular production of ROS and higher susceptibility of cells to H(2) O(2) -mediated oxidative stress. Additionally, human prostate carcinoma LNCaP cells, which contain a silenced GSTP1 gene, were genetically modified to constitutively express high levels of GSTP1. Induction of GSTP1 activity lowered endogenous ROS levels in LNCaP-pLPCX-GSTP1 cells, and when exposed to H(2) O(2) , these cells exhibited significantly reduced production of ROS and 8-OHdG levels, compared to vector control LNCaP-pLPCX cells. Furthermore, exposure of LNCaP cells to green tea polyphenols caused reexpression of GSTP1, which protected the cells from H(2) O(2) -mediated DNA damage through decreased ROS production compared to nonexposed cells. These results suggest that loss of GSTP1 expression in human prostate cells, a process that increases their susceptibility to oxidative stress-induced DNA damage, may be an important target for primary prevention of prostate cancer. © 2012 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 07/2012; · 4.27 Impact Factor
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    ABSTRACT: Hematopoietic stem and progenitor cells (HPCs) are necessary for long-term survival. Genomic instability and persistent DNA damage may cause loss of adult stem cell function. The mismatch repair (MMR) pathway increases replication fidelity and defects have been implicated in malignant hematopoietic diseases. Little, however, is known about the role MMR pathway failure plays in the aging process of human HPCs. We hypothesized that loss of MMR occurs in HPCs as a process of human aging. We examined microsatellite instability and expression of the MMR genes MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in HPCs and colony-forming cell-derived clones (CFCs) from human donors aged 0 to 86 years. CFCs from donors > 45 years had a greater frequency of microsatellite instability and CD34(+) progenitors lacking MLH1 expression and protein than individuals ≤ 45 years. Loss of MSH2 did not correlate with age. Thus, a potentially early event in the normal human aging process is microsatellite instability accumulation in normal human HPCs associated with the loss of MLH1 protein expression.
    Blood 06/2012; 120(16):3229-36. · 9.06 Impact Factor
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    ABSTRACT: Transplantation of CD34(+) hematopoietic reconstituting cells (HRC) is an important treatment modality. The cells needed for clinical hematopoietic reconstitution after myeloablation most commonly derive from bone marrow which have been mobilized into the peripheral blood. The number of CD34(+) cells in mobilized blood samples is used to indicate the appropriateness of transplantation although it does not evaluate the two necessary functions for successful transplantation: long-term reconstitution mediated by cells with self-renewing proliferation and short-term hematopoietic differentiation mediated by progenitor cells. Using a novel high-resolution immunophenotyping technology on a flow cytometric platform, we have assessed uniformly mobilized CD34(+) cells for expression levels of 16 molecules previously associated with HRC function and sought correlations of these expression data with functional short-term assays for colony formation that do predict successful transplantation. We found that colony-forming units were significantly correlated with HoxB4 expression, which was explained by the number of CD34(+) cells in the samples. However, analysis of colony-forming units normalized to the CD34(+) cell count revealed a significant negative correlation with HoxB4 expression. Thus, increased levels of HoxB4 enhance CD34(+) cell number via self-renewing expansion but concomitantly depreciate the capacity for short-term differentiation per cell. Our findings demonstrate the translation of experimental findings into a clinical setting and suggest that the expression level of HoxB4 in CD34(+) cells can be used as a measure of a sample's appropriateness for transplantation. © 2012 International Society for Advancement of Cytometry.
    Cytometry Part A 04/2012; · 3.71 Impact Factor
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    ABSTRACT: The statistical analysis of continuous longitudinal data may be complicated since quantitative levels of bioassay cannot always be determined. Values beyond the limits of detection (LOD) in the assays may not be observed and thus censored, rendering complexity to the analysis of such data. This article examines how both left-censoring and right censoring of HIV-1 plasma RNA measurements, collected for the study on AIDS-related Non-Hodgkin's lymphoma (AR-NHL) in East Africa, affects the quantification of viral load and explores the natural history of viral load measurements over time in AR-NHL patients receiving anticancer chemotherapy. Data analyses using Monte Carlo EM algorithm (MCEM) are compared to analyses where the LOD or LOD/2 (left censoring) value is substituted for the censored observations, and also to other methods such as multiple imputation, and maximum likelihood estimation for censored data (generalized Tobit regression). Simulations are used to explore the sensitivity of the results to changes in the model parameters. In conclusion, the antiretroviral treatment was associated with a significant decrease in viral load after controlling the effects of other covariates. A simulation study with finite sample size shows MCEM is the least biased method and the estimates are least sensitive to the censoring mechanism.
    Statistical Methods in Medical Research 04/2012; · 2.36 Impact Factor
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    ABSTRACT: Relapsed small cell lung cancer (SCLC) carries a poor prognosis. Topoisomerase I and II inhibitors and DNA-damaging agents are considered among the most active agents against SCLC. Rebeccamycin analog (RA, Becatecarin) is an antitumor antibiotic with inhibitory activity against both topoisomerase I and II, and DNA-intercalating properties. We performed a phase-II trial of RA in relapsed, sensitive SCLC with the primary end point of response rate. Patients with previously treated SCLC who relapsed more than 60 days after the completion of first-line chemotherapy were treated with RA-administered intravenously at a dose of 140 mg/m on days 1 to 5 of 21-day cycles for a maximum of six cycles. Eligibility included Eastern Cooperative Oncology Group performance status 0 to 2 and adequate organ function. A two-stage design was employed. Twenty evaluable patients were enrolled. Median age was 61 years. Two patients (10%) had a partial response and six had stable disease. The clinical benefit rate was 40% (95% confidence interval [CI], 23-64%). The median progression-free survival was 2 months (95% CI, 1.2-5.2 months). The median survival was 6.7 months (95% CI, 3.3-8.0 months). No treatment-related deaths occurred. Grade-4 neutropenia and thrombocytopenia occurred in 23% and 14% of the patients, respectively. In conclusion, RA has single-agent activity in relapsed, sensitive SCLC with manageable toxicities but is unlikely to provide any superiority compared to existing agents for this disease.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2012; 7(4):751-4. · 4.55 Impact Factor

Publication Stats

1k Citations
218 Downloads
432.83 Total Impact Points

Institutions

  • 2004–2014
    • Case Western Reserve University School of Medicine
      • • Department of Epidemiology and Biostatistics
      • • Department of Medicine
      Cleveland, Ohio, United States
  • 2002–2014
    • Case Western Reserve University
      • • Department of Urology (University Hospitals Case Medical Center)
      • • Division of Hematology and Oncology
      • • Department of Medicine (University Hospitals Case Medical Center)
      • • Department of Pathology (University Hospitals Case Medical Center)
      Cleveland, Ohio, United States
  • 2010
    • West Virginia University
      Morgantown, West Virginia, United States
  • 2009
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
    • Uganda Virus Research Institute
      Entebbe, Central Region, Uganda
  • 2007
    • Canadian Society for Epidemiology and Biostatistics 
      Canada
    • US Oncology
      The Woodlands, Texas, United States
  • 2003–2007
    • Aultman Hospital
      Canton, Ohio, United States
    • Cleveland State University
      Cleveland, Ohio, United States
  • 2005
    • Uganda Cancer Institute
      Kampala, Central Region, Uganda
    • University of Nairobi
      • College of Health Sciences
      Nairobi, Nairobi Province, Kenya