Pingfu Fu

Case Western Reserve University, Cleveland, Ohio, United States

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Publications (113)567.78 Total impact

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    ABSTRACT: CD30 is a cytokine receptor belonging to the tumor necrosis factor superfamily (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of Hodgkin's disease and anaplastic large cell lymphoma. There have been sporadic reports of CD30 expression in non-lymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (N = 83) were examined for CD30 expression by immunohistochemistry. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with either tumor grade, stage or survival. Examination of four mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 01/2015; DOI:10.1158/1535-7163.MCT-14-0972 · 6.11 Impact Factor
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    ABSTRACT: Unlike lung adenocarcinoma, little progress has been made in the treatment of squamous cell lung carcinoma (SCC). The Cancer Genome Atlas (TCGA) has recently reported that receptor tyrosine kinase signaling pathways are altered in 26% of SCC tumors, validating the importance of downstream Signal Transducers and Activators of Transcription 3 (STAT3) activity as a prime therapeutic target in this cancer. In the present report we examine the status of an endogenous inhibitor of STAT3, called Protein Inhibitor of Activated STAT3 (PIAS3), in SCC and its potential role in this disease. We examine PIAS3 expression in SCC tumors and cell lines by immunohistochemistry of a tissue microarray and western blotting. PIAS3 mRNA expression and survival data are analyzed in the TCGA data set. SCC cell lines are treated with curcumin to regulate PIAS3 expression and cell growth. PIAS3 protein expression is decreased in a majority of lung SCC tumors and cell lines. Analysis of PIAS3 mRNA transcript levels demonstrated that low PIAS3 levels predicted poor survival; Cox regression analysis revealed a hazard ratio of 0.57 (95% CI: 0.37-0.87), indicating a decrease in the risk of death by 43% for every unit elevation in PIAS3 gene expression. Curcumin treatment increased endogenous PIAS3 expression and decreased cell growth and viability in Calu-1 cells, a model of SCC. Our results implicate PIAS3 loss in the pathology of lung SCC and raise the therapeutic possibility of upregulating PIAS3 expression as a single target that can suppress signaling from the multiple receptor tyrosine kinase receptors found to be amplified in SCC. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Cancer Medicine 01/2015; 4(3). DOI:10.1002/cam4.372
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    ABSTRACT: Purposes: To establish the efficacy and toxicities of concurrent bevacizumab and docetaxel with radiation for locally advanced HNSCC. Materials/Methods: Patients with previously untreated HNSCC received standard daily radiotherapy with concurrent weekly docetaxel (20 mg/m(2) ) and biweekly bevacizumab (5 mg/kg). Biweekly bevacizumab was then continued for up to one year following radiotherapy. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival, patterns of failure, and toxicities of treatment. Results: Thirty patients were recruited. With median follow-up of 38 months, the 3 year PFS, OS, locoregional recurrence free survival and distant metastasis free survival was 61.7%, 68.2%, 84.5%, and 80.5%, respectively. The most common local toxicities were mucositis and dermatitis. Two patients developed hemorrhage. There was no grade 5 toxicity. Conclusions: The combination of bevacizumab, docetaxel and radiotherapy is tolerable and effective in HNSCC. This regimen is worthy of further study in appropriate subset of patients receiving chemoradiation therapy. Head Neck, 2014.
    Head & Neck 10/2014; DOI:10.1002/hed.23813 · 3.01 Impact Factor
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    ABSTRACT: Purpose: Deregulation of STAT3 activation is a hallmark of many cancer cells and the underlying mechanisms are subject to intense investigation. We examined the extent of PIAS3 expression in mesothelioma cells and human tumor samples and determined the functional effects of PIAS3 expression on STAT3 signaling. Experimental design: We evaluated the expression of PIAS3 in mesothelioma tumors from patients and correlated the expression levels with the course of the disease. We also measured the effects of enhanced PIAS3 activity on STAT3 signaling, cellular growth and viability in cultured mesothelioma cells. Results: Gene expression databases revealed that mesotheliomas have the lowest levels of PIAS3 transcripts among solid tumors. PIAS3 expression in human mesothelioma tumors is significantly correlated with overall survival intervals (p = 0.058). The high expression of PIAS3 is predictive of a favorable prognosis and decreases the probability of death within one year after diagnosis by 44%. PIAS3 expression is functionally linked to STAT3 activation in mesothelioma cell lines. STAT3 down regulation with siRNA or enhanced expression of PIAS3 both inhibited mesothelioma cell growth and induced apoptosis. Mesothelioma cells are sensitive to curcumin and respond by the induction of PIAS3. Corroborative evidence has been obtained from STAT3 inhibition experiments. Exposure of the cells to a peptide derived from the PIAS3 protein which interferes with STAT3 function resulted in apoptosis induction and the inhibition of cell growth. Conclusion: These results suggest that PIAS3 protein expression impacts survival in mesothelioma patients and that PIAS3 activation could become a therapeutic strategy.
    Clinical Cancer Research 08/2014; 20(19). DOI:10.1158/1078-0432.CCR-14-1233 · 8.19 Impact Factor
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    ABSTRACT: Docetaxel (DTX) chemotherapy remains a standard-of-care for metastatic castration-resistant prostate cancer (CRPC). DTX modestly increases survival, yet results in frequent occurrence of side-effects and resistant disease. An alternate chemotherapy with greater efficacy and minimal side-effects is needed. Acquisition of metabolic aberrations promoting increased survival and metastasis in CRPC cells include constitutive activation of Akt, loss of adenosine monophosphate-activated protein kinase (AMPK) activity due to Ser-485/491 phosphorylation, and over-expression of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (HMG-CoAR). We report that combination of simvastatin (SIM) and metformin (MET), within pharmacological dose range (500nM to 4microM SIM and 250microM to 2mM MET), significantly and synergistically reduces C4-2B3/B4 CRPC cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. Combination of SIM and MET decreased Akt Ser-473 and Thr-308 phosphorylation and AMPKalpha Ser-485/491 phosphorylation, increased Thr-172 phosphorylation and AMPKalpha activity as assessed by increased Ser-79 and Ser-872 phosphorylation of acetyl-CoA carboxylase and HMG-CoAR, respectively; decreased HMG-CoAR activity, and reduced total cellular cholesterol and its synthesis in both cell lines. Studies of C4-2B4 orthotopic NCr-nu/nu mice further demonstrated that combination of SIM and MET (3.5-7.0microg/g body weight SIM and 175-350microg/g body weight MET) daily by oral gavage over 9-week period significantly inhibited primary ventral prostate tumor formation, cachexia, bone metastasis, and biochemical failure more effectively than 24microg/g body weight DTX intraperitoneally-injected every three weeks, 7.0microg/g/day SIM, or 350microg/g/day MET treatment alone, with significantly less toxicity and mortality than DTX, establishing combination SIM and MET as a promising chemotherapeutic alternative for metastatic CRPC.
    Molecular Cancer Therapeutics 08/2014; 13(10). DOI:10.1158/1535-7163.MCT-14-0451 · 6.11 Impact Factor
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    ABSTRACT: The effects of heightened microbial translocation on B cells during HIV infection are unknown. We examined the in vitro effects of HIV and lipopolysaccharide (LPS) on apoptosis of CD27(+) IgD(-) memory B (mB) cells from healthy controls. In vivo analysis was conducted on a cohort of 82 HIV+ donors and 60 healthy controls. In vitro exposure of peripheral blood mononuclear cells (PBMCs) to LPS and HIV led to mB cell death via the Fas/Fas ligand (FasL) pathway. Plasmacytoid dendritic cells (pDCs) produced FasL in response to HIV via binding to CD4 and chemokine coreceptors. HIV and LPS increased Fas expression on mB cells in PBMCs, which was dependent on the presence of pDCs and monocytes. Furthermore, mB cells purified from PBMCs and pretreated with both HIV and LPS were more sensitive to apoptosis when cocultured with HIV-treated pDCs. Blocking the interferon receptor (IFNR) prevented HIV-stimulated FasL production in pDCs, HIV-plus-LPS-induced Fas expression, and apoptosis of mB cells. In vivo or ex vivo, HIV+ donors have higher levels of plasma LPS, Fas expression on mB cells, and mB cell apoptosis than controls. Correspondingly, in HIV+ donors, but not in controls, a positive correlation was found between plasma FasL and HIV RNA levels and between Fas expression on mB cells and plasma LPS levels. This work reveals a novel mechanism of mB cell apoptosis mediated by LPS and HIV through the Fas/FasL pathway, with key involvement of pDCs and type I IFN, suggesting a role for microbial translocation in HIV pathogenesis. IMPORTANCE This study demonstrates that lipopolysaccharide (LPS) and type I interferon (IFN) play an important role in memory B cell apoptosis in HIV infection. It reveals a previously unrecognized role of microbial translocation in HIV pathogenesis.
    Journal of Virology 07/2014; 88(19). DOI:10.1128/JVI.00682-14 · 4.65 Impact Factor
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    ABSTRACT: Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation - a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.
    PLoS Pathogens 06/2014; 10(6):e1004198. DOI:10.1371/journal.ppat.1004198 · 8.14 Impact Factor
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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; DOI:10.1007/s10637-014-0078-5 · 2.93 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; DOI:10.1007/s10495-014-0971-6 · 3.61 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 02/2014; 88(2):506-507. DOI:10.1016/j.ijrobp.2013.11.139 · 4.18 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; 32(2). DOI:10.1007/s10637-013-0061-6 · 2.93 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 01/2014; 53(1). DOI:10.1002/mc.21939 · 4.77 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; DOI:10.1016/j.cllc.2013.12.001 · 3.22 Impact Factor
  • International Journal of Radiation OncologyBiologyPhysics 10/2013; 87(2):S372-S373. DOI:10.1016/j.ijrobp.2013.06.976 · 4.18 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; 18(10). DOI:10.1634/theoncologist.2013-0255 · 4.54 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; DOI:10.1093/carcin/bgt316 · 5.27 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; 55(6). DOI:10.3109/10428194.2013.842983 · 2.61 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):9-9. DOI:10.1158/1538-7445.AM2013-9 · 9.28 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; DOI:10.1158/1535-7163.MCT-13-0172 · 6.11 Impact Factor
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    ABSTRACT: Triple-negative breast cancer comprises 10% to 15% of newly diagnosed breast cancer and lacks expression of the estrogen, progesterone, and human epidermal growth factor receptor 2/neu receptors. Many such tumors are basal like, a molecular intrinsic subtype of breast cancer associated with poor clinical outcomes. Patients with early-stage basal-like triple-negative breast cancer are at a high risk for relapse and may, therefore, benefit from novel therapies, including immunotherapy. MUC1 is a tumor antigen expressed on adenocarcinomas and represents an ideal target for MUC1-based vaccination. We evaluated 52 cases of early-stage basal-like triple-negative breast cancer for MUC1 expression by immunohistochemistry. The intensity of staining was graded according to the intensity (negative [0], positive [1], or strongly positive [2]) and percentage (0%-100%) of tumor cells staining for MUC1. An overall score of 0 to 2.0 was calculated for each case by multiplying the intensity of staining by the percentage of tumor cells staining positively. Four staining patterns for MUC1 were identified: apical, cytoplasmic, membranous, and combination. Of the 52 cases of basal-like triple-negative breast cancers, 49 (94%) were positive for MUC1 expression. The mean score was 0.90 (range, 0-1.9). Cases were evenly distributed over this range, where most (67%) exhibited moderate to strong MUC1 expression (score, 0.5-1.90), 27% demonstrated weak MUC1 expression, and 6% lacked MUC1 expression. There was a significant difference in MUC1 score and percent MUC1+ cells in favor of the combination pattern. This study indicates that a large proportion of early-stage basal-like triple-negative breast cancer expresses MUC1 and provides a rationale for MUC1-based immunotherapy in this high-risk patient cohort.
    Human pathology 07/2013; 44(10). DOI:10.1016/j.humpath.2013.04.010 · 2.81 Impact Factor

Publication Stats

2k Citations
567.78 Total Impact Points

Institutions

  • 2004–2015
    • Case Western Reserve University
      • • Case Comprehensive Cancer Center
      • • Department of Oral Pathology
      • • Department of Epidemiology and Biostatistics
      Cleveland, Ohio, United States
  • 2004–2014
    • Case Western Reserve University School of Medicine
      • • Department of Urology
      • • Department of Epidemiology and Biostatistics
      • • Department of Pathology
      • • Department of Medicine
      Cleveland, Ohio, United States
  • 2009
    • The Ohio State University
      Columbus, Ohio, United States
  • 2006–2008
    • University of Pittsburgh
      • Department of Cell Biology and Physiology
      Pittsburgh, Pennsylvania, United States
  • 2007
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Canadian Society for Epidemiology and Biostatistics 
      Canada
    • Comprehensive Cancer Centers of Nevada
      Las Vegas, Nevada, United States
  • 2003–2007
    • 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