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Flavones, found in nature as secondary plant metabolites, have shown efficacy as anti-cancer agents. We have examined the binding of two flavones, 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone; FlavA) and 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone; FlavB), to phiX174 RF DNA using restriction enzyme activity assays employing the restriction enzymes Alw44, AvaII, BssHII, DraI, MluI, NarI, NciI, NruI, PstI, and XhoI. These enzymes possess differing target and flanking sequences allowing for observation of sequence specificity analysis. Using restriction enzymes that cleave once with a mixture of supercoiled and relaxed DNA substrates provides for observation of topological effects on binding. FlavA and FlavB show differing sequence specificities in their respective binding to phiX. For example, with relaxed DNA, FlavA shows inhibition of cleavage with DraI (reaction site 5′TTTAAA) but not BssHII (5′GCGCGC) while FlavB shows the opposite results. Evidence for tolological specificity is also observed, Molecular modeling and conformational analysis of the flavones suggests that the phenyl ring of FlavB is coplanar with the flavonoid ring while the phenyl ring of FlavA is at an angle relative to the flavonoid ring. This may account for aspects of the observed sequence and topological specificities in the effects on restriction enzyme activity. © 2013 Wiley Periodicals, Inc. Biopolymers 99: 530–537, 2013.

Prostate cancer is the most common noncutaneous malignancy in men. It is an excellent target for primary prevention. Vitamin E trials conducted for prevention of prostate cancer have had conflicting results with a lower incidence of prostate cancer in the ATBC trial and a higher incidence in the vitamin E arm of the SELECT trial. Most of the clinical trials with vitamin E have been limited to the alpha-tocopherol isoform alone. An increasing body of evidence suggests, however, that the gamma- and delta-isoforms of tocopherol and tocotrienols are more promising with regard to cancer prevention. This review tries to justify our assertion that the gamma- and delta-isoforms of tocopherol and tocotrienol might be superior as prostate cancer preventers.

Tocotrienols are members of the vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG-CoA reductase pathway through posttranslational degradation and to suppress the activity of transcription factor NF-κB could be the basis for some of these properties. Our studies indicate that γ- and δ-tocotrienols have potent antiproliferative activity in pancreatic cancer cells (Panc-28, MIA PaCa-2, Panc-1, and BxPC-3). Indeed both tocotrienols induced cell death (>50%) by the MTT cell viability assay in all four pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the AKT and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and δ-tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6 kinase) in addition to suppressing the activation of protein kinase AKT. Suppression of activation of AKT by γ-tocotrienol led to downregulation of p-GSK-3β and upregulation accompanied by nuclear translocation of Foxo3. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3-kinase/AKT and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and need further investigation.

Intermediate filaments have long been considered mechanical components of the cell that provide resistance to deformation stress. Practical experimental problems, including insolubility, lack of good pharmacological antagonists, and the paucity of powerful genetic models have handicapped the research of other functions. In single-layered epithelial cells, keratin intermediate filaments are cortical, either apically polarized or apico-lateral. This review analyzes phenotypes of genetic manipulations of simple epithelial cell keratins in mice and Caenorhabditis elegans that strongly suggest a role of keratins in apico-basal polarization and membrane traffic. Published evidence that intermediate filaments can act as scaffolds for proteins involved in membrane traffic and signaling is also discussed. Such a scaffolding function would generate a highly polarized compartment within the cytoplasm of simple epithelial cells. While in most cases mechanistic explanations for the keratin-null or overexpression phenotypes are still missing, it is hoped that investigators will be encouraged to study these as yet poorly understood functions of intermediate filaments.

The membrane mucin Muc4 has been shown to alter cellular behavior through both anti-adhesive effects on cell-cell and cell-extracellular matrix interactions and its ability to act as an intramembrane ligand for the receptor tyrosine kinase ErbB2. The ERK pathway is regulated by both cell-matrix and cell-cell adhesion. An analysis of the effects of Muc4 expression on ERK phosphorylation in mammary tumor and epithelial cells, which exhibit both adhesion-dependent growth and contact inhibition of growth, showed that the effects are density dependent, with opposing effects on proliferating cells and contact-inhibited cells. In these cells, cell-matrix interactions through integrins are required for activation of the ERK mitogenesis pathway. However, cell-cell interactions via cadherins inhibit the ERK pathway. Expression of Muc4 reverses both of these effects. In contact-inhibited cells, Muc4 appears to activate the ERK pathway at the level of Raf-1; this activation does not depend on Ras activation. The increase in ERK activity correlates with an increase in cyclin D(1) expression in these cells. This abrogation of contact inhibition is dependent on the number of mucin repeats in the mucin subunit of Muc4, indicative of an anti-adhesive effect. The mechanism by which Muc4 disrupts contact inhibition involves a Muc4-induced relocalization of E-cadherin from adherens junctions at the lateral membrane of the cells to the apical membrane. Muc4-induced abrogation of contact inhibition may be an important mechanism by which tumors progress from an early, more benign state to invasiveness.

Muc4 serves as an intramembrane ligand for the receptor tyrosine kinase ErbB2. The time to complex formation and the stoichiometry of the complex were determined to be

Muc4/Sialomucin complex (SMC) acts as an intramembrane ligand for the receptor tyrosine kinase ErbB2, inducing a limited phosphorylation of the receptor. Because Muc4/SMC is found at the apical surfaces of polarized epithelial cells and ErbB2 is often basolateral, the question arises as to whether these components become associated in polarized cells. To address this question, we examined the localization of these proteins in polarized human colon carcinoma CACO-2 cells. Dual color immunofluorescence analysis by confocal microscopy demonstrated the basolateral localization of the ErbB2 in these cells; it is primarily co-localized with E-cadherin at adherens junctions. Expression of apical Muc4/SMC in these cells by transient transfection results in the localization of the ErbB2 at the apical surface. Two-color confocal microscopy indicated that ErbB2 is colocalized with Muc4/SMC in the transfected cells but not in untransfected cells in the same culture. The change of localization of ErbB2 was confirmed by cell surface biotinylation of apical and basolateral proteins, followed by streptavidin precipitation and the subsequent detection of ErbB2 by immunoblotting. In contrast, Na+/K+-ATPase maintains its basolateral localization in Muc4/SMC-transfected cells, indicating that the translocation of ErbB2 is not the result of depolarization of the cells. A potential physiological role for the apical localization of ErbB2 is indicated by the fact that ErbB2 phosphorylated at tyrosine 1248 is found predominantly in Muc4/SMC-transfected cells, but not in untransfected cells, and is co-localized with the apical Muc4/SMC. The ability of Muc4/SMC to alter the localization of ErbB2, particularly a phosphorylated form of it, in epithelial cells, suggests that it has an important role in regulating ErbB2 signaling.

MUC1 and MUC4 are the two membrane mucins that have been best characterized. Although they have superficially similar structures and have both been shown to provide steric protection of epithelial surfaces, recent studies have also implicated them in cellular signaling. They act by substantially different mechanisms, MUC4 as a receptor ligand and MUC1 as a docking protein for signaling molecules. MUC4 is a novel intramembrane ligand for the receptor tyrosine kinase ErbB2/HER2/Neu, triggering a specific phosphorylation of the ErbB2 in the absence of other ErbB ligands and potentiating phosphorylation and signaling through the ErbB2/ErbB3 heterodimeric receptor complex formed in the presence of neuregulin. In contrast, MUC1 has a highly conserved cytoplasmic tail, which binds β-catenin, a key component of adherens junctions and a regulator of transcription, in a process that is tightly regulated by MUC1 phosphorylation. The specific localization of these membrane mucins to the apical surfaces of epithelial cells suggests that their signaling functions may be important as sensor mechanisms in response to invasion or damage of epithelia. BioEssays 25:66–71, 2003. © 2002 Wiley Periodicals, Inc.

Oxidative stress is a documented factor in the pathogenesis of inflammation and cancer. Vitamin E with its antioxidant properties holds promise for use in clinical practice. There are two main forms of vitamin E, tocopherols and tocotrienols. Palm oil contains almost 70% of tocotrienols. Tocotrienols exerts its antiproliferative activity against malignant cells but not on normal cells. Tocotrienols play an important role in counteracting cellular inflammatory response secondary to oxidative stress, thus exerting an anticancer property. Tocotrienols mediate function of NF-kappa B, STAT3 (signal transduction and activators), and COX-2. In addition to its role as an antioxidant and anti-inflammatory agent, tocotrienols also mediate multiple cell cycle pathways. More work needs to be done on animal models and in genetic models of pancreatic cancer to gather more data to eventually consider phase III clinical trial in human subjects.

Flavones, found in nature as secondary plant metabolites, have shown efficacy as anti-cancer agents. We have examined the binding of two flavones, 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone; FlavA) and 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone; FlavB), to phiX174 RF DNA using restriction enzyme activity assays employing the restriction enzymes Alw44, AvaII, BssHII, DraI, MluI, NarI, NciI, NruI, PstI, and XhoI. These enzymes possess differing target and flanking sequences allowing for observation of sequence specificity analysis. Using restriction enzymes that cleave once with a mixture of supercoiled and relaxed DNA substrates provides for observation of topological effects on binding. FlavA and FlavB show differing sequence specificities in their respective binding to phiX. For example, with relaxed DNA, FlavA shows inhibition of cleavage with DraI (reaction site (5') TTTAAA) but not BssHII ((5') GCGCGC) while FlavB shows the opposite results. Evidence for tolological specificity is also observed, Molecular modeling and conformational analysis of the flavones suggests that the phenyl ring of FlavB is coplanar with the flavonoid ring while the phenyl ring of FlavA is at an angle relative to the flavonoid ring. This may account for aspects of the observed sequence and topological specificities in the effects on restriction enzyme activity.

Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (>50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5–80 µM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones.

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.

In several human cancers, ErbB2 over-expression facilitates the formation of constitutively active homodimers resistant to internalization which results in progressive signal amplification from the receptor, conducive to cell survival, proliferation, or metastasis. Here we report on studies of the influence of ErbB2 over-expression on localization and signaling in polarized Caco-2 and MDCK cells, two established models to study molecular trafficking. In these cells, ErbB2 is not over-expressed and shares basolateral localization with ErbB3. Over-expression of ErbB2 by transient transfection resulted in partial separation of the receptors by relocalization of ErbB2, but not ErbB3, to the apical surface, as shown by biotinylation of the apical or basolateral surfaces. These results were confirmed by immunofluorescence and confocal microscopy. Polarity controls indicated that the relocalization of ErbB2 is not the result of depolarization of the cells. Biotinylation and confocal microscopy also showed that apical, but not basolateral ErbB2 is activated at tyrosine 1139. This phosphotyrosine binds adaptor protein Grb2, as confirmed by immunoprecipitation. However, we found that it does not initiate the canonical Grb2-Ras-Raf-Erk pathway. Instead, our data supports the activation of a survival pathway via Bcl-2. The effects of ErbB2 over-expression were abrogated by the humanized anti-ErbB2 monoclonal antibody Herceptin added only from the apical side. The ability of apical ErbB2 to initiate an altered downstream cascade suggests that subcellular localization of the receptor plays an important role in regulating ErbB2 signaling in polarized epithelia.

Mammary function is dependent on its three-dimensional organization, which is established and maintained by cell adhesive junctions linked through the membrane to the cell cytoskeleton. These junctions serve not only as structural elements, but also function as initiators and integrators of cell signals. In this review we discuss three types of glycoproteins whose interactions impinge on the function of mammary cell-cell junctions, cadherins, ErbB receptor tyrosine kinases and membrane mucins, as a microcosm of events regulating mammary cell behaviors. Actions of these components are integrated by the critical signaling element beta-catenin. When functioning properly, these glycoproteins, beta-catenin and associated signaling pathways mesh into a highly structured program for development and function of the gland. However, disruption or dysfunction of these glycoproteins or the signaling elements can lead to disorganization of the epithelia and ultimately to neoplasia.

Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. Treatment options are limited and novel therapeutic agents that can inhibit signaling pathways implicated in the proliferation and survival of pancreatic cancer cells are of interest. Tocotrienols are members of the vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side-chain that confers superior and mechanistically different anti-cancer properties on pancreatic cancer cells. The ability of tocotrienols to selectively inhibit the HMG CoA reductase pathway through post-translational degradation of HMG CoA reductase, inhibit the PI3/Akt, ERK pathways through downregulation of Her2/ErbB2 receptors as well as suppression of the activity of transcription factor NF kappa B, could be the basis for some of these properties. Recent studies have shown increase in cellular ceramide levels in cancer cells treated with tocopherols, leading to arrest in tumor proliferation and apoptosis. The actual mechanism of increase in ceramide levels is not clearly understood and is thought to be due to increased synthesis. We explored the hypothesis that the increase in ceramide on the cellular membrane could be due to increased transport from the ER to the membrane. The ARV1 (ACAT-related enzyme-2 required for viability) gene encodes an ER- localized protein involved in lipid homeostasis and ceramide transport in yeast and mammals. Deletion of the ARV-1 gene in yeast causes accumulation of ceramide in cytoplasm. Our previous work indicated that gamma-tocotrienol (GT3) has potent anti-proliferative activity in k-ras mutated pancreatic cancer cell (MIA-Paca-2) through the inhibitory effect on Akt, Ras/Raf/Erk and ErBb2 receptor as well as induction of apoptotic pathways through Fox-03 and GSK-3b. Our current data shows GT3 may decrease expression of caveolin, a cell survival marker, and cause up-regulation of ARV-1 that encodes a ceramide transport protein. We further show via HPLC (Babraham Bioscience Technologies Ltd, Cambridge, U.K) that total ceramide levels remain unchanged in the cell. There may be a change in ceramide (monoclonal anti-ceramide IgM, Sigma Chemicals) cellular distribution as indicated by immunofluorescence data. Upregulation of ARV-1 may be involved in increase in cellular ceramide transport or redistribution of ceramide to the cell membrane. Transport of ceramide to membrane lipid rafts or mitochondrial membrane channels may cause loss of survival signaling and induce apoptosis. Thus it is likely that GT3 apoptotic effect on k-ras mutated MIA-Paca2 cells is related not to changes in the total ceramide levels, but rather to its increased transport and redistribution. Further work is necessary in order to better understand the role of GT3 in ceramide redistribution in pancreatic cancer cells. Citation Format: Kanishka Chakraborty, Victoria P. Ramsauer, Janet W. Lightner, William L. Stone, Koyamangalath Krishnan. Gamma-tocotrienol upregulates the ceramide transporter, Arv-1, in pancreatic cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2106. doi:10.1158/1538-7445.AM2013-2106

Chemical differences in gamma-tocotrienol including the presence of an isoprenoid side chain are responsible for differences in cytotoxic potency of gamma-tocotrienol compared to alpha-tocopherol. Alpha-tocopherol has been shown to be ineffective in prostate cancer chemoprevention in the SELECT trial; in fact, there was an increased incidence of prostate cancer in the alpha-tocopherol arm indicative of deleterious effects. Therefore, we explored the cytotoxic effects of alpha-tocopherol (AT), gamma-tocopherol (GT) and gamma-tocotrienol (GT3) in prostate cancer cell lines, PC-3 (androgen independent) and LNCaP (androgen dependent). Prostate cancer cell lines were grown in culture and treated with various concentrations and duration with the vitamin E isoforms. Cytotoxicity was determined by MTT and cell viability assays. We also explored possible molecular mechanisms to further understand differences in effects between the tocopherols and tocotrienols. GT3 showed cytotoxic effects in a dose and time-dependent manner, in both cell lines. PC-3 cells were noted to be more sensitive to growth suppression effects of GT3 than LNCaP cells. GT did not show significant cytotoxicity on cell growth at any given dose or time end point, whereas AT may promote prostate cancer cell growth. We also found that the combination of AT (40um) with increasing dose concentration of GT3 showed less pronounced cytotoxicity at 24 hours, when compared with various concentrations of GT3 alone, again suggesting a possible antagonistic role of AT. Exposure of PC-3 and LNCaP cells to increasing dose of GT3 was also examined for p-AKT, p-Erk, p-ERBB2 and phospho-c-Jun activity via Western blot at various time points. Our results show a dose dependent up regulation of pc-Jun and p-Erk in GT3 treated cells. No effects were noted on p-Akt or p-ERBB2 at the time points and concentrations studied. Some earlier studies found JNK and MAPK/Erk activation as playing a central role in the tocopherol induced apoptosis. C-Jun is downstream effector in JNK signaling pathway, activates transcription factors, which in turn modulate gene expression, to generate appropriate biological responses leading to apoptosis. In contrast to Erk recognized role in cancer cells proliferation we found Erk 1/2 up-regulation in GT3 induced apoptosis. This finding has also been reported earlier in some studies on prostate and other cancer cell lines. Our work shows that GT3 has cytotoxic effects on prostate cancer cells and induces cellular apoptosis through the modulation of phospho-c-Jun and MAPK pathways, while AT has either none or promotes prostate cancer cell growth in culture. Further studies are under way to dissect the molecular mechanisms of c-Jun and Erk activation by gamma-tocotrienol in prostate cancer cells. Citation Format: Rashid Mahboob, Victoria P. Ramsauer, Janet W. Lightner, William L. Stone, Koyamangalath Krishnan. Gamma-tocotrienol not alpha-tocopherol is cytotoxic to prostate cancer cells through modulation of phospho-c-Jun and phospho-Erk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4351. doi:10.1158/1538-7445.AM2013-4351

To the Editor. Recently, Dr. DiPiro published an article in the Journal1 that discussed several aspects pertinent to the process of faculty recruitment, emphasizing an individual's “fit” within the culture of the hiring institution. In the present article, we discuss another aspect of “fitness” that became evident to our search committee during the 2010-2011 academic year. Our search committee was established in May 2010 to hire a tenure-track faculty member at the level of assistant/associate professor in the department of pharmaceutical sciences. The committee consisted of faculty members in the departments of pharmaceutical sciences and pharmacy practice. Throughout the year, the search committee met 4 times and discussed 48 applicants. The committee members recommended several applicants to the department chair for screening calls and interviewed 2 candidates on site. During a review of applications, the search committee members discovered that several applicants submitted teaching philosophies that contained text that could be found verbatim elsewhere. Specifically, portions of these documents had been copied from online sources and pasted into the application. Obviously, our enthusiasm for these and other candidates with similar issues was significantly diminished and their applications were not pursued further. Plagiarism is defined as “to steal and pass off (the ideas or words of another) as one's own, to use (another's production) without crediting the source, to commit literary theft, or to present as new and original an idea or product derived from an existing source.”2 Unfortunately, plagiarism is far too common. “Turnitin” reported 110 million instances of matched content found in 40 million papers submitted by students during a 10-month period.3 However, this problem is not limited to students. The occurrence of plagiarism in the scientific literature has been well documented.4,5 In fact, several publishers have implemented software programs to detect plagiarism in manuscripts submitted to their journals.5 Additionally, peer-reviewers for journals have been encouraged to be vigilant in searching for any matched content.6 Plagiarism in application materials is also not a new concept.7 Segal and colleagues reported plagiarism in medical residency application essays.8 In fact, this group found an evidence of plagiarism in more than 10% of essays submitted for a residency program at Brigham and Women's Hospital in Boston, Massachusetts. Although the rate of occurrence was higher among international students, plagiarism was observed in the application of US citizen as well. Surprisingly, students with academic honors were among those applicants with plagiarized application essays. A 2007 report in the journal Family Medicine also cites examples of plagiarism among applicants for medical fellowships, hypothesizing that the increased availability of content on the Web has led to a decreased awareness of the issue of plagiarism.9 The easy availability of technology may make plagiarism easier to commit, but it can also make it easier to detect.5,10 For instance, with some of our applicants, plagiarism was detected using a simple Google search. Faculty members are considered role models for students; their conduct has the potential to affect the reputation of the academic institution involved. As such, it is essential to check all application materials submitted by faculty applicants for any evidence of plagiarism. Faculty members have a responsibility to train students not only in their content areas, but also in areas such as research ethics. Additionally, because graduate students and postdoctoral trainees are the main group of applicants who apply for junior faculty positions, it would be helpful to educate graduate students and trainees about the negative impact of plagiarism on the educational system.10

Objective. To implement problem-based learning exercises in a pharmacy research elective course and assess the impact on students’ knowledge and confidence in their ability to analyze, design, and present basic research projects relevant to clinical areas. Design. Hands-on learning activities, including discussions on experimental design, development of collective diagrams, research planning, results analysis, data evaluation, and presentation design, were incorporated into the course and developed as team-based learning experiences. Assessment. Students gave a seminar presentation to peers and faculty members at the end of the semester and created posters for presentations at professional meetings. Students who decided to work on a continuation project during the following semester were expected to produce data that might be sufficient for the development of manuscripts for submission to scientific journals. Conclusions. Feedback from students revealed an appreciation and renewed interest in analyzing clinical issues with a much wider focus as well as increased understanding of and confidence in using data derived from basic science research.

Abstract: Pancreatic cancer is the fifth leading cause of cancer death in the United States. Alternate strategies to treat and prevent this cancer are urgently required. In this regard, novel therapeutic agents that can inhibit signaling pathways implicated in the proliferation and survival of pancreatic cancer cells are of immense interest. Tocotrienols are members of the Vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side-chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG CoA reductase pathway through post-translational degradation of HMG CoA reductase and to suppress the activity of transcription factor NFκβ could be the basis for some of these properties. Data: Our studies indicate that γ- and Δ-tocotrienol have potent anti-proliferative activity in pancreatic cancer cells (Panc-28, MIA-PACA-2 and BXPC-3). Indeed both tocotrienols induced cell death (> 50%) by the MTT cell viability assay in all three pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the Akt and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and Δ-Tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6k) in addition to suppressing the activation of protein kinase, Akt. Suppression of activation of Akt by gamma-tocotrienol led to downstream upregulation of Fox-03 and GSK-3b. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Conclusion: Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3/Akt and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and needs further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4490. doi:10.1158/1538-7445.AM2011-4490

The mevalonate pathway plays an important role in cancer biology and has been targeted previously with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. We hypothesize that combination of Simvastatin with Alendronate may have significant synergistic anti-carcinogenic potential in prostate cancer due to sequential blockade in the mevalonate pathway and will serve as a safer and better tolerated alternative than previously tried drugs. Simvastatin and alendronate sequentially inhibit HMG Co-A reductase and farnesyl pyrophosphate synthase enzymes respectively in the mevalonate pathway. This inhibition subsequently reduces isoprenoid synthesis including farnesyl pyrophosphate and geranylgeranylpyrophosphate. Prenylation (isoprenoid attachment) of G protein subunits and nuclear laminins help facilitate protein interactions in addition to termination of small GTPases’ activity. These proteins have important biological roles, including transmembrane signal transduction (RAS), cytoskeletal reorganization (RHO), gene expression (RAS), microtubule organization and nucleocytoplasmic transport. Inhibiting this pathway may have important anti-oncogenic effects through inhibition of processes such as tumor cell adhesion, migration, invasion, proliferation and induction of apoptosis. To test the hypothesis, we plated a predetermined number of 5000 PC3 cells into a 96 well plate and allowed them to adhere to the wells for an initial 24 hour incubation period using standard color free medium. Simvastatin and alendronate were prepared in various dose concentrations (simvastatin; 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, and 5.0µM and alendronate: 1, 2.0, 5.0. 10.0. 20.0, and 40.0µM). The cells were treated with simvastatin or alendronate alone, and then in various dose combinations. The cells with drug free medium were used as control. After 96 hour incubation, the quantity of living cells were determined via standard MTT assay and spectrophotometric analysis at 570nm and compared to the control group. Significant inhibition of PC3 cell growth was observed using simvastatin and alendronate alone as well as in combinations at low doses. Isobologram analysis was utilized as visual assessment of the drugs’ interaction with independent statistical analysis from calculations using total dose in a fixed-ratio combination and with calculated additive total dose for the same effect. Our results demonstrate synergistic inhibition of PC3 cell growth in vitro at various low dose combinations of simvastatin with alendronate. The fact that both of these drugs are commonly used in the population with no reported severe adverse effects from their combination offers a safe, effective and synergistic treatment option in the future treatment of prostate cancer. In vivo studies must be undertaken to explore these effects further. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4407. doi:10.1158/1538-7445.AM2011-4407