Dept. of Biochemistry and Molecular Biology, University of Maryland School of Medicine, USA
Obscurins, encoded by the single OBSCN gene, are giant cytoskeletal proteins containing tandem adhesion and signaling domains, including an active RhoGEF motif that directly binds and activates RhoA. The OBSCN gene is highly mutated in breast cancer resulting in a 2-fold reduction of its mRNA levels. Consistent with this, obscurin proteins are nearly lost from breast cancer cell lines and human biopsies, independently of their hormonal status or molecular differentiation. Loss of giant obscurins from breast epithelial cells confers them with a survival and growth advantage following exposure to common chemotherapies. Obscurindepleted breast epithelial cells fail to form adhesion junctions, undergo epithelial-to-mesenchymal transition and generate primary and secondary mammospheres bearing markers of cancer-initiating cells. Moreover, obscurin-deficient breast epithelial cells display markedly increased motility as a sheet in 2-dimensional (2D) substrata and individually in confined spaces, increased invasion in 3D matrices, and extend microtentacles mediating the attachment of circulating tumor cells to the endothelium, an advantage that persists even after paclitaxel treatment. More importantly, loss of giant obscurins from breast epithelial cells promotes primary tumor formation and lung colonization in vivo. These major phenotypic alterations appear to be the result of reduced RhoA activity and increased PI3K/Akt activity. Collectively, our findings reveal that loss of giant obscurins from breast epithelium results in disruption of cell–cell contacts and acquisition of a mesenchymal phenotype that leads to enhanced tumorigenesis, migration and invasiveness in vitro and in vivo by affecting RhoA- and PI3K/Akt-mediated processes. In addition, our data suggest that loss of obscurins may represent a selective advantage for breast cancer cells during metastasis, and that treatment with paclitaxel may exacerbate this advantage by preferentially allowing obscurin-deficient stem-like cells to attach to the endothelium at distant sites, a first step towards colonizing metastatic tumors. To the contrary, treatment of obscurin-depleted breast cancer cells with PI3K inhibitors, currently in phase III clinical trials, appears to be highly beneficial by reducing their survival, growth, motility and invasive capabilities.
Biography:
Aikaterini Kontrogianni-Konstantopoulos received her Ph.D. from the Department of Cell Biology at Baylor College of Medicine in Houston, TX. After graduating from Baylor, she joined the laboratory of Dr. E.J. Benz, Jr., in the Division of Hematology, at Johns Hopkins University, School of Medicine as a post-doctoral fellow. In 2007, she joined the Department of Biochemistry and Molecular Biology in the University of Maryland School of Medicine as Assistant Professor, and in 2012 was promoted to Associated Professor. Her research focuses on the elucidation of the roles of cytoskeletal and membrane-associated proteins as structural and signaling mediators. Using the muscle and epithelial cell as model systems, my laboratory has pioneered the molecular and functional characterization of the obscurin subfamily and its binding partner Myosin Binding Protein-C slow in health and disease. Her research has been funded by several organizations, including NIH, Muscular Dystrophy Association and American Heart Association.
1Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, USA
2Department of Epidemiology, School of Public Health, Rutgers, The State University of New Jersey, USA
Pancreatic cancer (PaCA) is one of the most lethal human cancers and is the fourth leading cause of cancer-related deaths in the United States. However, there are currently no established recommendations for prevention of PaCA using pharmacological agents. Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its effects on inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the key underlying molecular mechanisms for the inhibitory effects of metformin on PaCA progression remain largely unknown. Using RNA sequencing followed by the confirmation of RT-PCR and Western blotting, we found that metformin significantly decreased the mRNA and protein levels of RET (REarranged during Transfection), a single-pass transmembrane receptor tyrosine kinase (RTK). RET and its ligand, glial cell-derived neurotrophic factor (GDNF), are strongly expressed in PaCA and correlated to invasion and reduced survival after surgical resection. GDNF, as a chemoattractant for PaCA cells, can activate RET to induce tumor progression, migration and invasion in vitro and in vivo. We further demonstrated that metformin significantly inhibited GDNF-induced migration and invasion of PANC-1 cells. These data indicate that targeting RET with metformin or the combination of metformin and RET inhibitors may be an attractive and novel strategy for the prevention and treatment of PaCA progression and metastasis. To further examine the inhibitory effects of metformin on the growth and spread of PaCA tumors in humans, further in vitro and in vivo studies are warranted to investigate how metformin modulates RET signaling to inhibit the progression and metastasis of PaCA. Such studies have potential clinical significance using metformin as adjuvant preventive and therapeutic options for PaCA prevention and treatment.
Biography:
Dr. Xiang-Lin Tan received a M.D. degree from Tongji Medical College, and a Ph.D in Epidemiology from German Cancer Research Center at Heidelberg University. He was a Postdoctoral fellow at Wadsworth Center and Albert-Einstein College of Medicine, and a Senior Research Fellow at Mayo Clinic. He is currently an Assistant Professor of Medicine and Epidemiology at Rutgers Cancer Institute of New Jersey. Dr. Tanʼs current research is focusing on repurposing exiting drugs for prostate and pancreatic cancer prevention and treatment. He is an Editorial Reviewer Board member of several international journals, and reviewed articles for more than 10 peer-reviewed journals.
Zestern Biotechnique LLC and Yantai Zestern Biotechnique Co. LTD, USA
The completion of the human genome projects marks the arrival of genomic research era, where genetic information is accumulated and analyzed in an unprecedentedly speed in the last decadesto significantly change the world of Cancer research. In contrast, proteomic research in Cancer Research is clearly lagging behinddue to lacking of high throughput method in immunoblot analysis. While antigen-antibody interaction serves as the basis of immunoblot research, it faces a long-lasting challenge of cross-reactivity of antibodies. In this talk, a novel method, Zestern analysis, is demonstrated to address this issue with clear advantages of simple, fast, specific and quantifiable, suitable for high throughput analysis of protein samples. The method follows a standard dot blot protocol until the formation of immunocomplexon the membrane. An elution step is added in Zestern analysis where a competing molecule based on the epitope of detecting antibody is used to liberate the detection antibody from the immunocomplex into elution solution for direct quantification. A working system of Zestern analysis is shown in this talk where both the tagged and endogenous proteins were analyzed using this method under various experimental conditions. Continuing exploration of this method may revolutionize the field of proteomic research with direct impact on high throughput immunoblot analysis to move the field of Cancer Research forward.
Biography:
Jiandi Zhang received his Doctorate from Department of Cell Biology, Duke University with Drs. Yusuf Hannun and Lina Obeid on the lipid mediators and chemotherapeutic agent-induced apoptosis. He went on to complete his postdoc training with Nobel Laureates Drs. Mike Brown and Joe Goldstein at UT Southwestern Medical Center working on IRS-2 and insulin signaling pathway. Dr. Zhang continued to work on insulin signaling pathway and regulatory effect of SirT1 on this pathway with several independent publications. In 2012, he patented Zestern technique as the improved immunoblot technique of Western blot and Dot blot analyses. Right now, he serves as the Founder and CEO of Zestern Biotechnique LLC to promote this technique in the field of protein analysis. He believes the adoption of this technique in basic research and clinical studies would significantly improve the efficiency and accuracy of protein analysis over existing immunoblot methods.
French National Institute of Health (INSERM), France
Most scientific literature reports that aging favors the development of cancers. Each type of cancer, however, initiates and evolves differently, and their natural history can start much earlier in life before their clinical manifestations. The incidence of cancers is spread throughout human life span, and is the result of pre- and post-natal aggressions, individual susceptibility, developmental changes that evolve continuously throughout an individualʼs life, and time of exposure to carcinogens. Finally, during human senescence, the incidence declines for all cancers. Frequently, the progression of cancers is also slower in aged individuals. There are several possible explanations for this decline at the tissue, cell, and molecular levels, which will be described. It is time to ask why some tumors are characteristic of either the young, the aged, or during the time of a decline in the reproductive period, and finally, why the incidence of cancers declines late during senescence of human beings. These questions need to be addressed before the origin of cancers can be understood.
Biography:
Dr. Alvaro Macieira-Coelho completed an MD at the University of Lisbon, Portugal, was an intern at the University Hospital, and completed a PhD at the University of Uppsala, Sweden. He was appointed Head of the Department of Cell Pathology, Cancer Institute, Villejuif, France and Research Director at the French National Institute of Health. He has authored 150 peer-reviewed articles and published nine books.
Awards: Fritz Verzar prize, University of Vienna; Doctor Honoris Causa, University of Linköping; Johananof International visiting professor, Mario Negri Institute, Milan; Seeds of Science Career prize, Lisbon.
School of Medicine, Johns Hopkins University, USA
Disparities in screening mammography use persist among low-income women, even those who are insured, despite the proven mortality benefit. We evaluated the prevalence of breast cancer screening non-adherence among hospitalized women and their receptivity to inpatient screening mammography as a novel approach to increase breast cancer screening rate. A cross sectional study was conducted among 250 hospitalized women age 50-75 years, admitted to medicine service at Johns Hopkins Bayview Medical Center in early 2012. Approximately one-third of women enrolled were African American, and 61% of the study population reported an annual household income of < $20,000. 41% were overdue for screening, of which, 13% never had a mammogram. Thirty-two percent of the women were at high risk for breast cancer (Gail score ≥1.7%). The most commonly reported barriers to screening mammograms were failure to remember appointments, and lack of transportation. We also evaluated the socio-demographic and clinical comorbidities risk factors associated with non-adherence. After adjustment of all these predictors, three variables were found to be independently associated with non-adherence to breast cancer screening: low income (OR=3.81, 95%CI; 1.84–7.89), current or ex-smoker (OR=2.29, 95%CI; 1.12–4.67), and history of stroke (OR=2.83, 95%CI; 1.21–6.60). Although most women believed that it is important for healthcare providers to discuss breast cancer screening while patients are in the hospital, 72% were willing to pay out of pocket a mean of $83.41 (95% CI, $71.51-$95.31) in advance towards inpatient screening mammogram.
Conclusions: A significant number of hospitalized women from lower socioeconomic class are non-adherent and at high risk of developing breast cancer. Because hospitalization creates the scenario wherein patients are in close proximity to healthcare resources, at a time when they may be reflecting upon their health status, strategies could be employed to counsel, educate, and motivate these patients towards health maintenance.
Biography:
Dr. Waseem Khaliq M.D, M.P.H is faculty at Johns Hopkins University School of Medicine, Baltimore. He earned his medical degree at King Edward Medical College, Pakistan and Masterʼs in Public Health (MPH) from University of Minnesota, Minneapolis. He completed his medical training in medicine at University of Illinois, Urbana. His research interest includes breast cancer screening and treatment disparities, breast cancer risk stratification, and breast cancer chemoprevention. He has published several manuscripts and serves as an editorial board member and reviewer for many medical journals.
1Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University, USA
2Department of Urology, Johns Hopkins University, USA
3Department of Oncology, Johns Hopkins University, USA
Bladder cancer stem/progenitor cells (CSC) contribute to tumor maintenance and resistance to therapy and accumulated evidence suggest that chronic carcinogen exposure induce “stemness” in different in vitro and in vivo models. Therapeutic targeting of CSCs could improve treatment response and prolong patient survival. Here we used our recently published in vitro chronic arsenic (As) exposed models to characterize the property of bladder CSC due to As exposure. We hypothesized that urothelial stem cells have a survival selection advantage during carcinogen exposure such as As, and it facilitates their malignant transformation and in acquiring selective phenotypes similar to CSC.
As-exposed cells displayed more aggressive phenotype than As unexposed cells in a time dependent manner. In gene set enrichment analysis of expression array of chronic As exposed and unexposed cells; EGFR, COX2 and YAP1 were top-ranked oncogenic signature based on enrichment score in As-exposed cells. Further analysis indicated that several known basal cell markers were overexpressed in As exposed cells in comparison with As unexposed cells. Because the presence of urothelial CSCs in basal-type provides a biological explanation for their aggressive behaviors, we assessed the influence of As on generating CSC phenotypes. Our results showed that As exposure was associated with overabundance of potential CSCs characterized by sphere formation, self-renewal capacity, redifferentiation, and chemotherapy resistance. To explore global association of As exposure and CSC generation, we used the Human Stem Cell RT2 Profiler™ PCR Array and found that SOX2 has been gradually overexpressed in line with acquired spheroid formation and self-renewal capacities. Moreover, SOX2 mRNA expression was significantly higher UC cell lines and As exposed cells, especially in the spheroid cells; and in urine from As exposed normal than from controls. Stable silencing of SOX2 reduces in vitro CSCs properties and also in vivo tumorigenicity. COX2 and YAP1 are also frequently overexpressed in UC cell lines, and inhibition of COX2 or YAP1 reduced SOX2 expression. Interestingly, the inhibition of COX2 and YAP1 expression inversely induced YAP1 and COX2 expression, respectively which also reflect in primary UC tumors. Combination treatment with COX2 and YAP1 inhibitors reduced SOX2 expression and suppressed spheroid formation significantly than single agent. In conclusion, chronic As exposure induces CSCs with SOX2 overexpression, an important CSC factor for UC. COX2 and YAP1 coordinately regulate SOX2 expression, and mutually compensate for the reduction of expression of SOX2 to maintain CSCs. Thus targeting the COX2/YAP/SOX2 signaling axis eliminates urothelial CSCs.
Biography:
Dr. Hoque is an Associate Professor of Otolaryngology-Head & Neck Surgery, Urology and Oncology at Johns Hopkins University School of Medicine. His major research interests includes: a) To understand molecular biologic basis of head and neck, lung and genitourinary cancer b) To develop and validate genetic and epigenetic approach for early cancer diagnosis, cancer risk assessment and cancer prognosis and c) To identify molecular alterations due to environmental exposures such as active smoking, passive smoking and arsenic. He has published over 95 papers in reputed journals and has been serving as an editor and/or editorial board member of several bio-medical journals.
Department of Natural and Forensic Sciences, Albany State University, USA
Cooking of meat at high temperature such as frying or barbeque causes production of heterocyclic amines (HCAs). At least a dozen of HCAs are found in cooked meat. The 2-amino-1-methyl-6-phenylimidazo[4-5-b]pyridine (PhIP) is abundant and most potent HCA. Several studies have shown that PhIP can induce tumors in breast, prostate and colon cells and in rodent models. It is shown that PhIP causes DNA mutation, promote tumor growth and promote invasiveness of cancer cells. Metabolism of PhIP results in the formation of free radicals (ROS) and PhIP metabolites are known to produce DNA adduct and DNA strand breaks. Phytochemicals are known to inhibit cytotoxic and genotoxic effects. Therefore, we hypothesized that the right combination of antioxidants and or phytochemical (naturally present in fruits, vegetables and spices) along with grilled meat should be capable of suppressing the PhIP induced cytotoxicity and breast cancer. Therefore, a model system using human breast epithelial cells (MCF 10A) was developed to test various antioxidants in presence or absence of PhIP. We have tested four vitamin (C, K3, D3, and E), Gingerol (6 and 10), N-acetyl cysteine, glutathione and curcumin at varying concentrations. The protective effect of these compounds was evaluated using cell viability assay, DCF assay to quantify ROS production, Comet assay to quantify the DNA damage and DNA adduct formation by immunofluorescence method. Results indicate that presence of these compounds improves cell viability as compared to PhIP treated group. However, curcumin co-treated cells showed significant differences and PhIP induced cell cytotoxicity was consistently reverted to normal. Gene expression analysis indicates that curcumin interact via multiple molecular targets, suggesting that curcumin appears to be an effective anti-PhIP food additive.
Biography:
Dr. Ashok Jain is a professor of biology at Albany State University, Albany, GA and program coordinator for Biotechnology program. Dr. Jain has received research funding from NIH, DOD and USDA. Dr. Jain is also serving as MARC U*STAR project director. His research focuses on prevention of breast cancer. He has published more than 35 papers in reputed journals and has been serving as reviewer for six journals of international repute.
Clinical Research Center, The 2nd Affiliated Hospital, Zhejiang University School of Medicine, China
Translation Eukaryotic translation initiation factors (eIFs) are important for protein synthesis of both normal and malignant cells. Deregulated protein synthesis may promote cell growth, proliferation, invasion and metastasis which lead to the development and progression of cancer. As the largest and the most complicate eIF, eIF3 is the core protein complex which cooperates with other eIFs and plays an important role in the initiation of protein synthesis. EIF3is composed of 13 subunits, and only subunits eIF3a, 3b, 3c, 3e, 3f and 3h are indispensable for the core function of eIF3, while other subunits may possess other functions than translation initiation. Aberrant expressions of eIF3 subunits in various tumors have been observed and nuclear localization of eIF3a, 3e and 3k have been reported. Recent studies showed that eIF3g also plays roles in the cytoskeleton network and caspase-mediated apoptosis. We previously found that eIF3g was significantly up-regulated in the multidrug resistant K562 leukemia cells (K562/ADR). In our current work, we found that eIF3g is also up-regulated in breast cancer cell that are multidrug resistant. We further investigated the nuclear distribution of eIF3g and identified nuclear proteins that may interact with eIF3g in breast cancer cells by co-immuno precipitation and mass spectrometry, and confirmed by cross linking and confocal co-localization observation. These findings indicate that eIF3g also has non-translation initiation functions in breast cancer. (Sponsored by grant from National Natural Science Foundation of China 81172516)
Biography:
Jiang Cao obtained his PhD degree from Zhejiang Medical University (now Zhejiang University School of Medicine). He is currently working in Clinical Research Center, the 2nd Affiliated Hospital, Zhejiang University School of Medicine. His research focuses on the molecular mechanisms involved in development and progression of cancer and has published more than 40 papers in reputed journals.
Department of Microbiology, Tumor- and Cell Biology, Karolinska Institutet, Sweden
The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A–null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk−/− mice and mice treated with anti–VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A–independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.
Biography:
Patrik Andersson received his B.Sc. at the age of 21 within biomedical sciences and is now pursuing his Ph.D. studies on the topic of tumor lymph-and heme angiogenesis in promoting metastasis. He is receiving his training at the Karolinska Institutet, Sweden under the supervision of Professor Yihai Cao. He was invited as a speaker at the prestigious Gordon Conference in angiogenesis (2013) and at the International Cancer and Prevention methods conference (2015). He has obtained several research and travel grants, and has co-authored ten peer-reviewed articles either published or under current revision.
1Yeditepe University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Turkey
2Department of Molecular Biology and Genetics, BilGen, Genetics and Biotechnology Research Center, Faculty of Science, Bilkent University, Turkey
3CancerSystems Biology Laboratory, Graduate School of Informatics, Middle East Technical University, Turkey
New series of benzothiazole-piperazine derivatives are synthesized and their cytotoxic activities are evaluated on colorectal (HCT-116), breast (MCF-7) and hepatocellular (HUH-7) cancer cell lines by sulforhodamine B assay. Results are compared with 5-fluorouracil as reference compound.
Dihalo substituted compounds BTP-2 (N-(6-ethoxybenzothiazole-2-yl)-2-[4-(2,6-dichlorobenzyl)piperazinyl]acetamide) (HCT-116:GI50 =0.4 µM; HUH-7: GI50 =0.7 µM; MCF-7: GI50 =2.6 µM) and BTP-7 (N-(6-ethoxybenzothiazole-2-yl)-2-[4-(4-bromo-2-fluorobenzyl)piperazinyl]acetamide)(HCT-116:GI50 =0.9 µM; HUH-7: GI50 =0.3 µM; MCF-7: GI50 =12.2 µM) are found to have highest cytotoxic activities in all studied cancer cell lines.
Biography:
Professor Yarim has completed his Ph.D from Hacettepe University and postdoctoral studies from ETH-Zürich. Professor Yarim has studied anticancer drug design and she has authored several peer-reviewed reports. She has served on numerous review committees for the National Science Foundation in Turkey. She has served on the editorial boards for the Pharmacologia. She is a member of the QSAR Society.
Graduate School of Pharmaceutical Sciences, Chiba University, Japan
Solid cancer nests are acidified below pH 6.5, although normal tissues and blood are usually maintained at pH around 7.4 in mammals. Such acidification of cancer nests may change the efficacy of anti-cancer drugs when their target molecules are enzymes whose activity is dependent on pH. We measured the inhibitory effect of approximately 300 compounds at pH 6.7 and 7.5, and five compounds, lovastatin, cantharidin, manumycin A, doxorubicin, and ionomycin, showed a high activity to inhibit cancer cell proliferation at pH 6.7, while their inhibitory effect was very low at pH 7.5. We focused our work on statins because clinical investigations had already revealed the therapeutic effect of statins on human cancers. It has been reported recently that statins inhibit cancer growth in mice. Statins have been used as a drug against hyperlipidemia because statins inhibit cholesterol synthesis and no effect on cancer cell proliferation had been reported in vitro until our study. Our further investigations have revealed that the inhibition of cell proliferation by statins is caused by the decrease in the synthesis of geranylgeranyl diphosphate used for protein prenylation but not in cholesterol synthesis. Statins are generally accepted to be a safe drug without serious side effects, such as immune system dysfunction. Our data showed that the inhibitory effect of statins on immune cells is negligible in medium whose pH is close to blood pH. These results suggest that anti-cancer drugs specific to acidic areas are useful for cancer chemotherapy with low side effects. We found that the expression of approximately 700 genes was elevated at acidic pH, suggesting that many other anti-cancer drugs whose efficacy increases in acidic cancer nests could be found besides statins. Our in vitro assay method may promote exploitation of new anti-cancer drugs specific to acidic areas, which improves cancer chemotherapy.
Biography:
Hiroshi Kobayashi received his Ph.D. in Biochemistry from University of Tokyo in 1974. After his postdoctoral training at Colorado University Medical Center, he started to study adaptation strategies of microorganisms to acidic environments at Chiba University in 1978. His recent research is focused on mammalian cell functions under acidic conditions from 1996 at Graduate School of Pharmaceutical Sciences, Chiba University. He retired in March 2012 and is now Professor Emeritus at Chiba University. He works as an associate editor of International Immunopharmacology published by Elsevier B.V. from 2014.
University of Illinois at Chicago, USA
FOXM1 is an oncogenic transcription factor that is overexpressed in majority of human cancers and it is a potential target for anticancer drugs. We identified proteasome inhibitors as the first type of drugs that target FOXM1 in cancer cells. Moreover, we found that HSP90 inhibitor PF-4942847 that does not act as proteasome inhibitor also suppresses FOXM1. Chaperone HSP70 is induced after treatment with both proteasome/HSP90 inhibitors and after heat-shock stress and we identified this chaperone as a novel negative regulator of FOXM1 after proteotoxic stress. We showed that FOXM1 and HSP70 interact in cancer cells following proteotoxic stress and FOXM1/HSP70 interaction led to inhibition of FOXM1 binding to target gene promoters, including its own (auto-regulation loop). Inhibition of FOXM1 transcriptional auto-regulation by HSP70 leads to suppression of FOXM1 protein expression because of its auto-regulation. Therefore, we propose here that HSP70 is the universal negative regulator of FOXM1 after proteotoxic stress. In contrast, HSP70 inhibition increased FOXM1 expression and simultaneous inhibition of FOXM1, and HSP70 dramatically augmented the sensitivity of human cancer cells to apoptosis induced by different anticancer drugs. Our study advocates exploring the combination of FOXM1 and HSP70 inhibitors as potential therapeutics for cancer treatment. Overall, our results suggest that HSP70 chaperone induced by proteotoxic stress inhibits FOXM1 oncogene by previously unknown mechanism.
Biography:
Andrei L Gartel, PhD, is an Associate Professor in the Department of Medicine at the University of Illinois at Chicago, and is the academic editor of PLOS ONE. He is the author of 86 peer-review publications that include more than 20 reviews. He has more than 8500 citations and his h-index is 36. His scientific interests include cancer, cell cycle, protein-protein interactions, regulation of CDK inhibitor p21 and regulation of oncogenic transcription factors FOXM1, and c-Myc. Specifically his lab is interested in identification of new FOXM1 inhibitors. He received his funding from NIH, DOD and private companies/foundations.
National Institute of Standards and Technology, Gaithersburg, USA Oregon Health and Science University, USA
National Center for Advancing Translational Sciences, National Institutes of Health, USA
Ionizing radiation and most chemotherapeutic agents kill tumor cells by damaging DNA. The efficacy of DNA-damaging agents may be influenced by increased DNA repair capacity in tumors that results from overexpression of DNA repair proteins. Inhibition of activities of these proteins in tumors is a promising approach to enhance the efficacy of DNA damage-based therapy. Intense efforts are underway worldwide to find inhibitors of DNA repair proteins. Of these proteins, DNA glycosylases are involved in the first step of base excision repair mechanism by removing modified DNA bases. Despite the successes with other proteins of this repair pathway, the development of inhibitors has been lagging for DNA glycosylases. Recently, several DNA glycosylases including NEIL1, OGG1 and NTH1 were identified as potential targets in combination therapeutic strategies. We designed experiments to discover small molecule inhibitors of NEIL1 as the proof-of-principle glycosylase. A fluorescence-based assay was developed to detect both glycosylase and AP lyase activities of NEIL1. We screened small molecule libraries for inhibitors of NEIL1 activities. Several purine analogs were found, whose postulated presence in the active site of NEIL1 fits with the paradigm of NEIL1 action on damaged purines. We also applied gas chromatography/isotope-dilution tandem mass spectrometry to measure the effect of small molecule inhibitors on glycosylase activities of NEIL1, OGG1 and NTH1. The release of modified DNA bases known as substrates of these enzymes was measured in the presence and absence of the inhibitors. These data revealed that several of the purine analogs were general glycosylase inhibitors with one compound being the most effective inhibitor for all three enzymes. However, there were significance differences in inhibition of enzymatic activities among these DNA glycosylases. Overall, this work forms the foundation for the future discovery of DNA repair inhibitors as drugs in cancer therapy for the entire family of DNA glycosylases.
Biography:
Dr. Dizdaroglu has obtained his PhD at the Karlsruhe Technical University, Germany, and subsequently worked for seven years at the Max-Planck-Institute for Radiation Chemistry, Germany, before moving to US in 1978. He has been at the National Institute of Standards and Technology (NIST) for more 30 years. In 2006, Dr. Dizdaroglu was conferred upon the rank of NIST Fellow. He published more than highly cited 230 papers. Dr. Dizdaroglu received numerous scientific awards including the Hillebrand Prize of the American Chemical Society and the Gold Medal Award of the US Department of Commerce. He was also awarded two Honorary Doctorates.
1Department of Cell and Molecular Biology, Northwestern University, USA
2Specialized Chemistry Center, The University of Kansas, USA
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, USA
4Center for Cancer Research, National Cancer Institute, USA
In the last decade a number of studies have indicated the importance of ribosomal biogenesis as a fundamental process controlling epithelial to mesenchymal transition (EMT) both during embryogenesis and cancer development. Studies toward understanding the underlying mechanisms responsible of neurocristopathies and metastasis have shown that the up-regulation of ribosomal biogenesis is important for promoting efficient EMT, migration and invasion. One cellular marker of metastatic potential is the perinuclear compartment (PNC), a unique structure adjacent to the nucleolus which indicates an elevated state of transcription and assembly of ribosomal components, and correlates clinically with metastasis of solid tumors. Screening and optimizing for disassemblers of the PNC, we identified metarrestin, a well-tolerated orally-bioavailable small molecule able to block metastasis in three different mouse cancer xenograft models of breast, prostate and pancreatic human cancers. In vitro, Mearrestin blocks migration and invasion of metastatic tumoral cells at nontoxic doses. Pull down studies identified EEF1A (EEF1A1 and EEF1A2) as the main binding partner of metarrestin. We then sought to validate this target by through siRNA treatments, evaluation of the levels of nascent pre-rRNA, visualization of nucleolar structure changes by immunofluorescence of key proteins. The results indicated that metarrestin blocks a previously unknown function of EEF1Ainvolved inthe up-regulation of the transcriptional activity of RNA Polymerase I. Metarrestinʼs modulation of Pol I-EEF1A-dependent function impacts ribosome synthesis and nucleolar structure without affecting other classical functions of this protein such as its role in translation elongation and protein synthesis. Our studies represent a broad and novel way to block the progression of tumorgenesis toward metastasis and open the door to the development of a new generation of nontoxic anticancer agents specifically blocking metastasis.
Biography:
Dr. Juan Marugan has been involved for more than 20 years in translational sciences, with extensive experience as a team leader of programs at lead optimization stage, many of which have been licensed to pharmaceutical companies, producing also several molecules that advanced toward pre-clinical development and clinical trials. His job responsibilities include lead discovery and optimization with early ADME and pharmacokinetics profiling, managing internal and external resources, structure-activity relationship optimization, chiral separation, and in vivo studies. He is also very familiar in other areas of translation such as structure-based drug design, high-throughput screening, enzymatic and cell assays, and in vivo disease models.
Dr. Marugan serves since 2008 as team leader within the division of preclinical innovation of NCATS. Previously he held positions of increase responsibilities in several pharmaceutical companies from research scientist to head of pre-clinical drug research.
Department of Pharmacology, Faculty of Medicine, Université de Montréal, Canada
Triple-negative breast cancers (TNBC) are a highly invasive type of breast cancer and associated with poor prognostic. The Epidermal Growth Factor Receptor (EGFR)is overexpressed and regulates cellular proliferation as well as invasiveness. Drugs inhibiting its activity have however shown limited effects mainly due to the development of resistance. There is therefore a need to identify new therapeutic targets for the design of alternative therapies. We and others have shown that the Ras-related ADP-ribosylation factors (ARF) are another class of small GTPases regulating key features of cancer cells. Here, we report that ARF1 is highly expressed in cells and tumor tissue of the most aggressive and advanced subtypes of breast cancers. Knock down of ARF1 expression impairs the ability of breast cancer cells to proliferate, migrate and degrade the extracellular matrix. Furthermore, growth of primary tumors as well as lung metastasis is reduced in a murine xenograft model when expression of the GTPase is inhibited. To understand how ARF1 contributes to invasiveness, we used a poorly invasive breast cancer cell line, MCF7 (ER+), and examined the effects of overexpressing ARF1 to levels similar to that found in invasive cell lines. Our findings demonstrate that increased levels of ARF1 lead to the epithelial-mesenchymal transition (EMT). Mechanistically, ARF1 controls cell–cell adhesion through ß-catenin and E-cadherin. In addition, this GTPase promotes oncogenic Ras activation and expression of EMT inducers such as snail and slug. We further show that ARF1 overexpression enhances MCF7 cell invasion, proliferation and even resistance to treatment with the chemotherapeutic agent, etoposide. In vivo, ARF1 overexpressing MCF7 cells are able to form more metastases to the lung. Overall, our results identify ARF1 as a molecular switch of cancer progression and thus suggest that limiting the expression/activation of this GTPase could help improve outcome for breast cancer patients.
Biography:
Dr. Claing received her PhD in Pharmacology from the Université de Sherbrooke, in Canada. She then joined the laboratory of Robert J Lefkowitz at Duke University as a post-doctoral fellow where she began to be interested in the function ARF proteins plays in mediating receptor-mediated cellular responses. She is currently professor of Pharmacology at the Université de Montréal. Her research team studies the molecular basis of cell migration and proliferation, with emphasis on the basic mechanism by which ARF proteins controls intracellular signaling. She is recognized for her pioneering research aimed at unraveling the function of ARF1 in breast cancer.
Departments of Environmental Health Sciences and Oncology, Johns Hopkins University, USA
Abnormal DNA methylation patterns including global hypomethylation and focal promoter hypermethylation are hallmarks of cancer cells. Global hypomethylation and promoter hypermethylation of tumor suppressor genes contribute to the cancer biogenesis. However, it remains to be determined how cancer cells obtain these abnormal methylation patterns and how such patterns exactly contribute to oncogenesis. Currently, it has been broadly accepted that de novo DNA methyltransferases 3a/3b (DNMT3a/3b) methylate the unmethylated cytosines to initiate the methylation patterns in the genome of early embryos, and subsequently, these patterns are faithfully copied from parental strands to daughter strands during DNA replication by maintenance DNMT1. This ‘two-step’ model highlights the importance of DNMT1 maintenance in transmitting epigenetic information to next generations of cells. Because of this importance, inhibitor drugs specifically targeting DNMT1 have been developed and used in clinical trials. Despite promising results against hematologic malignancies, the efficacy of DNMT1 inhibitors in solid tumors has been “disappointing”, raising the concern of the guiding ‘two-stepʼ model.
To determine the mechanism of the establishment and maintenance of DNA methylation patterns, we have examined genome-wide DNA methylation patterns in mouse embryonic stem (ES) cells and DNMT-deficient ES cells. Indeed, investigations suggest that both maintenance DNMT1 and de novo DNMT3a/3b function complementarily and simultaneously to establish and maintain methylation patterns. These results partially explain the limitations of inhibiting only one DNMT1 enzyme in current trials, because DNMT3a/3b still methylate CpGs. Furthermore, data demonstrate that even complete demethylation in the genome surprisingly only de-silenced a minority of genes in the genome. Only genes with low CpG density tend to be re-activated. Lastly, we demonstrate that maintenance DNMT1 activity is crucial for inhibition of retrotransposon long terminal repeats (LTRs), whereas de novo DNMT3a/3b activities are for suppressing retrotransposon long interspersed nuclear elements (LINEs). Our novel mechanistic insights of the establishment and maintenance of DNA methylation patterns help to develop next-generation DNMT inhibitor drugs.
Biography:
Dr. Zhibin Wang obtained his Ph.D from the Ohio State University. He started his biomedical research with the development of chromatin immunoprecipitation plus deep sequencing (ChIP-seq) method in the National Heart, Lung, and Blood Institute. His pioneering reports shed lights on what kind of “histone code” in the human genome and revealed the binding of corepressor histone deacetylase (HDAC) for active genes instead of broadly accepted silent genes. The resulting concept changes are important for the understanding/development/application of HDAC inhibitors in the treatment of cancers. New model for the establishment and maintenance of DNA methylation patterns also helps the application of the DNMT inhibitor drugs for cancers.
1Department of Forest Products and Biotechnology, Kookmin University, Korea
2Department of Wood Science and Technology, Chonbuk National University, Korea
Polyphenols are abundant non-nutrients in our diet as they are present in the fruits, vegetables, cereals, beverages and tea. Several epidemiological studies have repeatedly shown an inverse relationship between the risk of cancer development and the consumption of polyphenols rich diet. Polyphenols targets cancer cells by various mechanisms such as estrogenic or antiestrogenic activity, antiproliferation, induction of cell cycle arrest or apoptosis, suppression angiogenesis, regulation of the host immune system and cellular signalling pathways. In the present study, we report a novel mechanism of action of the polyphenolic mixtures, Pinoradiol® studied against breast cancer which is one of the most prevalent cancer types among women worldwide at present, using human cancer cell lines. First, we observed that Pinoradiol® induced an extensive cytoplasmic vacuolation in breast cancer cells, MCF-7. Those vacuoles were mostly caused by lysosomal dilation evidenced by reduced acridine orange red and lysotracker green fluorescence intensity, and cytosolic distribution of lysosomal aspartyl protease, cathepsin-D. Mechanistic investigations revealed that Pinoradiol® induced increased production of ROS was responsible for the loss of lysosomal membrane integrity evidenced from improved lysosomal function in the presence of an antioxidant, n-acetylcysteine. Next we found that Pinoradiol® induced breast cancer cell death was independent of caspases. Moreover, Pinoradiol® caused an accumulation of LC-3 and its associated protein, p62, confirming the blockade of autophagic flux at the maturation stage, which might be the loss of lysosomal function. Collectively, our study reveal a novel mechanism underlying Pinoradiol® induced breast cancer cell death involving ROS mediated lysosomal membrane permeabilization.
Acknowledgement: The financial support of the present study was from Forest Science & Technology projects (Project No. S211315L010110), Forest Service, Republic of Korea.
Biography:
Dr. Young-Kyoon Kim is from the Department of Forest Products and Biotechnology and he is the Dean of College of forest Science. He has served as a professor in Kookmin University since 1994. He is also the Principal Investigator of Forest material Bioindustrialization Research Center, Forest Science & Technology, Korea. He worked as a Research Scientist in the US Department of Agriculture, Agricultural Research Service (USDA-ARS), Western Regional Research Center (WRRC), Albany, California (2011-2012). He also worked in Scripps Institution of Oceanography, University of California, San Diego, La Jolla (1992-1994). He received a B.A. from the Kangweon National University in 1985, and M.A. from Seoul National University in 1987, and a Ph.D. in Natural Products from University of California at Berkeley in 1992.
School of Pharmacy, Health Science Center, Xiʼan Jiaotong University, PR China
Introduction: The Eph receptor tyrosine kinases and their plasma-membrane-anchored Ephrin ligands play a pivotal role in angiogenesis, cell proliferation and migration in many different cell types and tissues[1]. EphrinB2 ligand expressed in various tumor cells is related to its high vascularity. EphrinB2 is a transmembrane subclass ligand and its reverse signaling is mediated by the EphrinB2 cytoplasmic domain, which contains a PDZ binding motif that can interact with signaling molecules [2,3]. So, regulation of EphrinB2 signaling might be useful to simultaneously interfere with the function of VEGFR2 and VEGFR3 which act together during angiogenesis[4]. Taspine isolated from Radix et RhizomaLeonticis was a kind of aporphines alkaloid. The aim of this study is to investigate the action of taspine derivatives which inhibit tumor angiogenesis by targeting EphrinB2 and regulating its pathway.
Methods: Over-expressed Ephrin B2 cells, non-small lung carcinoma cell line A549, NCI-H1299 and NCI-H460 were used to study the cell proliferation, which was used to screen active compounds from taspine derivatives. The cell membrane chromatography (CMC) and binging assay were used to confirm the target. The biological activities of screened active compound were evaluated by cell assays and angiogenesis model of CAM in vivo and TMA in vitro. In addition, EphrinB2 expression and signaling players were investigated by Western Blotting.
Results: The cell proliferation results indicated that No.1822, No.T27 and No. T9 among the taspine derivatives showed good inhibition on over-expressed EphrinB2 cells and lung cancer cells. At the same time, No.1822 could act on EphrinB2 cell membrane stationary phase and interact on EphrinB2. The cell binging assay exerted the consistent result of No.1822 with CMC. Angiogenesis models in intro and in vivo showed the obvious inhibition on the angiogenesis treated by No.1822. The obtained data of western blotting indicated No.1822 inhibited EphrinB2 expression and PDZ protein PICK1. Accordingly, it was associated with the down-regulation of PI3K/AKT/mTOR and MAPK signal pathway molecules, such as Akt, mTOR, Erk1/2, PLCγ, etc.
Conclusions: No.1822, a taspine derivative, showed good retention activity on EphrinB2CMC stationary phase and could target EphrinB2, and regulate PI3K/AKT/mTOR and MAPK signal pathway, which contributed to its inhibition on tumor angiogenesis.
Acknowledgements: This work was supported by the National Natural Science Foundation of China (Grant no. 81370088), the Fundamental Research Funds for the Central Universities of Zhuizong, and the Supporting Plan of Education Ministryʼs New Century Excellent Talents (Grant no. NCET-13-0467).
Biography:
Dr. Yanmin Zhang is a professor of School of Pharmacy, Health Science Center, Xiʼan Jiaotong University of China, member of Chinese Pharmaceutical Association. Yanmin Zhang received his B.S. in chemistry and Ph.D. in pharmaceutical analysis. He began his independent career in 1999. He is currently the director of molecular pharmacology program and a full professor at school of Pharmacy of Xiʼan Jiaotong University, and assistant research scientist in the Biodesign Institute of Arizona State University, USA. Research interests in the Yanmin Zhang Group are at the interface of pharmacy and biology focused on screening and activity evaluation of small molecular drug for antitumor, studies of molecular mechanism of bioactive natural products and drug process analysis in vivo. He has published more than 100 papers including CDDs, Sci Rep, JCMM, Cancer Lett, et al. and holden 21 patents.
School of Psychological Sciences, Tel-Aviv University, Israel
The talk will deal with the issue of the psychological correlates for cancer. Psychological correlates of a disease are personality tendencies or responses that can be shown to be risk factors for the disease and possibly contribute also to remission and recovery from the disease. Previous attempts to identify such correlates in oncology have failed, mainly because the psychological variables that have been assessed were likely to be affected by the disease itself (e.g., depression) and not enough consideration has been paid to medical variables. A set of studies launched at the Psychooncology Research Center approached the issue from the point of view of the innovative theory and methodology of the cognitive orientation theory. The major thesis of this theory is that physiological processes that may be precursors of diseases are affected by psychological factors that are beliefs of four types (about oneself, about reality, about rules and norms and about goals) referring to themes that have been identified as relevant for a particular disease. Questionnaires assessing different kinds of cancer diseases have been prepared on the basis of the cognitive orientation theory. Studies showed that the questionnaires have enabled identifying correctly cancer patients, such as breast cancer, colon cancer, thyroid cancer and prostate cancer. For example, themes that constitute the personality correlates of colorectal cancer were found to include tendencies for compulsiveness, perfectionism, and self control. The talk will present studies concerning mainly breast cancer and colon cancer. Our claim is that the identified tendencies constitute potentially sources of tension and may be considered as psychological risk factors in oncology. The effects of psychological interventions based on the identified variables will be presented.
Biography:
Shulamith Kreitler is a professor of psychology at Tel Aviv University, has established the Unit for Psychooncology at the Ichilov Hospital in Tel Aviv and since 2007 is the head of the psychooncology research center at Sheba Medical Center, Tel Hashomer. She is a certified clinical and health psychologist and has taught at Harvard, Princeton and Yale, as well as in Argentina and Vienna, Austria. Her research is in personality and cognition, with an emphasis on psychological factors involve in the occurrence of oncological diseases and coping with them. Her books include Handbook of Chronic Pain (2007), Pediatric Psycho-Oncology: Psychosocial Aspects and Clinical Interventions (2004, 2012).
The Hong Kong University of Science and Technology, Hong Kong
Proper organ development requires the precise regulation of both the total number of cells (cell proliferation) and the types of cells (cell differentiation). During cell proliferation, Cdt1 mediated loading of DNA helicase (Mcm2-7) to replication origins is required for DNA replication. And Hox gene activation is necessary for embryonic cell differentiation. It has been shown that these two processes are linked through the cell cycle-regulator Geminin and the homeodomain-containing transcription factors Hox. To understand the molecular mechanism involved, we determined the solution structures of Geminin-Hox, Orc6-DNA, G-quadruplexand Cdt1-Mcm6 complexes by nuclear magnetic resonance (NMR) spectroscopy and conducted biochemical study to delineate the structural basis of this mutual regulation. In addition, we found that histone H4-K20 methyltransferase SET8 is a new cell-cycle regulator and plays an important role in the developmental program of metazoans. We are studying the human DNA replication initiation and its relationship with EBV mediated cancers (These works are supported by RGC, HMRF, NSFC, and AoE/M-06/08)
Biography:
Dr. Guang Zhu is a Professor of Division of Life Science, The Hong Kong University of Science and Technology. He obtained his B. Sc and M. Sc in physics. He studied for his Ph.D degree at University of Maryland and National Institutes of Health, USA, specialized in biomolecular NMR spectroscopy. Currently Dr. Guang ZHUʼs research focuses on structure-functional study of human proteins in DNA replication. Studies on the molecular mechanisms of proteins involved in DNA replication provide basis for structure-based drug design against cancer. He has published more than 81 peer-reviewed reports. He has served on the editorial boards of International Journal of Spectroscopy and Chinese Journal of Magnetic Resonance.
1Center for the Study of Chronic Metabolic Diseases, School of System Biology, George Mason University, USA
2Research Center for Medical Genetics RAMS, Russian Federation
3Institute of Chemical Biology and Fundamental Medicine SB RAS (ICBFM SB RAS), Russia
4Atlas Biomed Group, Russia
An assesement of cell-free circulating DNA (cfDNA) fragments, or Liquid biopsy, is indeispensable for early diagnosi and non-invasing monitoring of cancer. However, the majority of the cfDNA studies aim at relatively simple search for cancer-driving mutations or particular variants associated with susceptibility and resistance to targeted therapy. Important, inderstudied properties of cfDNA may become either a treasure trove for mining of novel cancer biomarkers or even indicate that cfDNA, by itself, could be a therapeutical target. The fragmentation patterns of cfDNA are non-random. They reflect fragmentation of DNA during apoptosis, that in turn, may associate with epigenetic landscapes. Circulating nucleotide fragments copy number depends on the nucleosomal positioning in given DNA locus. PCR primer systems may be tuned to the regions that would produce higher DNA amplification outcomes. Sensitivity of detection can be increased by simultanious isolation of “free” DNA molecules and these adsorbed to cellsʼ surface. The prevalence of certain DNA fragments may directly reflect nucleosome positioning within certain loci and serve as a proxy for gene expression levels. This opens a novel field in biomarker research, tentatively called “fragmentomics”. Moreover, cfDNA fragments are biologically active as they are enriched in 8-oxo-dG. The oxidized DNA is a stress signal released in response to oxidative stress. It might contribute to systemic abscopal effects of localized irradiation treatments. The mass release of oxidized DNA that accompanies apoptotic and necrotic processes in radio- and chemotherapy treated tumors may aid survival of residual cancer cells and even instigate their resistance to further treatment. The selective removal of oxidized DNA from the bloodstream or the block of respective oxidized DNA-dependent signaling may be developed as an adjuvant treatment. Current research is funded by Russian Ministry of Science and Education under the project ID# RFMEFI60714X0098
Biography:
Dr. Ancha Baranova, a specialist in the area of functional genomics of complex human diseases, is an Associate Professor in the School of Systems Biology, College of Science, George Mason University in Fairfax, Virginia, USA, and Principal Investigator at Russian Centre for Medical Genetics, Moscow. Dr. Baranovaʼs major academic contributions are in the field of personalized medicine. A significant part of Dr. Baranovaʼs efforts is dedicated to in silico analysis of the publicly available datasets. Dr. Baranova employs a multidisciplinary approach in order to broaden research perspective in the genetics of complex human diseases.
Department of Surgery, Faculty of Medicine, Alexandria University, Egypt
Background: Colorectal cancer (CRC) is a major health problem with high mortality rates. New clinical biomarkers and therapeutic targets are needed for early diagnosis and adequate tumor staging. MicroRNAs are a family of small noncoding RNAs that are involved in regulation of gene expression. They are aberrantly expressed in many types of carcinomas. MicroRNA-21 (miR-21) was found to be up-regulated in several cancers and is therefore very promising as a clinical biomarker and therapeutic target.
Aim: The aim of the study was to assess the microRNA 21 expression in colon cancer tissues and adjacent nontumor tissues to evaluate its potential role in tumor diagnosis and its relation to clinicopathological features of colon cancer.
Methods: Total RNA was extracted with small RNA enrichment from the tissues samples of colon cancer as well as their adjacent non-tumor tissues taken from 60 patients. After reverse transcription, the expression of microRNA-21 was measured using quantitative real-time PCR.
Results: Expression levels of microRNA-21 in colon cancer was significantly higher than that their adjacent non-tumor tissues (p<0.001). Furthermore, high expression of microRNA-21 was associated with lymphovascular invasion, advanced tumor invasion, presence of lymph node, distant metastasis, advanced tumor Stage and high tumor grade of differentiation. On the other hand, micoRNA 21 expression was not significantly associated with age, sex, tumor size or tumor location.
Conclusion: MicroRNA 21 can differentiate tumor from adjacent non-tumor tissue with high diagnostic accuracy. It can also predict the presence of advanced tumor invasion, lymph node and distant metastasis in patients with colon cancer, which could help in tumor staging, and customized clinical management of colon cancer.
Biography:
Dr. Abdelhamid Ghazal is a Professor of General Surgery at the faculty of medicine-Alexandria University in Alexandria-Egypt. He obtained his masters in general surgery in 1998 and his MD in general surgery from the University of Alexandria in 2004. Dr. Abdelhamid Ghazal is experienced in laparoscopic surgeries, Diagnostic and therapeutic endoscopy. His academic professional experience dates since 1998 in teaching and supervision of medical students and general surgery residents in Alexandria Main University Hospital. He supervised surgery master and MD students since 2004. Dr. Abdelhamid Ghazal has many publications in international, peer reviewed journals concerning hepatic resection, pancreatic tumors, laparoscopic and endoscopic biliary surgery, elective and emergency colonic surgeries.
*Dept. of Pathology, Dalhousie University, Canada
Pulmonary Pathologist and Cytopathologist, Queen Elizabeth II Health Sciences Centre
Senior Scientist, Beatrice Hunter Cancer Research Institute, Canada
Lung cancer is the leading cause of death from cancer for both men and women worldwide. Majority of lung cancer patients are in the advanced stage at the time of diagnosis and palliative management with chemotherapy and/or radiation being the treatment of choice. The overall response rate is low with a five year survival for a late stage disease being only about 4-5%. These conventional methods also cause significant cytotoxicity /adverse effects to the patients. Recent advances in lung cancer molecular genotyping provide the basis for personalized targeted therapy. It targets the individualʼs genetic makeup with encouraging clinical outcomes for highly selected lung cancer patients. Current treatment options are available against lung cancer cells exhibiting mutations of the genes encoding the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) by inhibiting tyrosine-kinases associated with the mutant genes. There are a variety of mutant genes in lung cancer cells which cause cancer cell proliferation, and many of these genes are mutually exclusive. Over 600 cases of surgically resected non-small cell lung cancer including adenocarcinoma, squamous cell carcinoma, large cell carcinoma and a miscellaneous group were selected for the study and all of them were investigated by molecular analysis for six possible gene mutations including KRAS, EGFR, ALK, BRAF, PIK3CA, and HER2 in a multiplexed fashion. The results of the molecular tests were crossed against the clinical data and pathological findings for each case to determine any correlations among them. The analysis yielded positive correlations between presence of a mutation with gender, survival rate, cancer type, vascular invasion and smoking history. The study provides valuable information of lung cancer molecular profiling in the clinical setting with significant impact in the clinical practice.
Biography:
Dr. Zhaolin Xu, MD, FRCPC, FCAP, is a professor in the Department of Pathology, Dalhousie University, and a pulmonary pathologist and cytopathologist in the Queen Elizabeth II Health Sciences Centre in Halifax, Canada. He obtained Fellowship Certifications from both the Royal College of Physicians and Surgeons of Canada and the American Board of Pathology. In addition Dr. Xu is a cancer researcher and holds the position of Senior Scientist in the Beatrice Hunter Cancer Research Institute, Canada. He is the Expert Panel Member in the Lung National Cancer Pathology and Staging Multidisciplinary Expert Panel, Canadian Partnership against Cancer (CPAC). He is also the Chair of Pathology Working Group and Network Member, Pan-Canadian Lung Cancer Screening Network, CPAC, and Medical Advisory Committee Member, Lung Cancer Canada.
1Department of Laboratory medicine, Daegu Catholic University Medical Center, South Korea
2Department of Surgery, Daegu Catholic University Medical Center, South Korea
Background: To detect circulating colorectal cancer cells, we had developed melanoma associated gene (MAGE) A1-6 and human telomerase reverse transcriptase (hTERT) RT-PCR system. We applied the system for the patients of colorectal cancer patients to detect circulating tumor cells
Methods: We have used 59 bloods of colorectal cancer patients and 50 bloods from the patients of benign diseases. The patients had been evaluated and diagnosed at the Daegu Catholic University Medical Center. After removal of red blood cells, cancer cells were enriched by magnetic separation with anti-CD45 microbeads (Miltenyi Biotec, Auburn, CA). The CD45 negative cells were extracted with RN easy Mini Kit (Qiagen, Duesseldorf, Germany). To amplify the MAGE A1-6 and the hTERT gene, gene specific RT-nested PCR and oligo-dT RT PCR were used using Light Cycler Fast Start DNA Master SYBR Green I (Roche, Mannheim, Germany). GAPDH gene was used as a control gene.
Results: In the blood of benign diseases, MAGE A1-6, hTERT and the MAGE + hTERT gene RT PCR showed the specificities of 92.0%, 88.0% and 80.0%. In the blood of colorectal cancer patients, MAGE A1-6, hTERT and the MAGE + hTERT gene RT PCR showed the sensitivities of 25.0%, 33.9%and 47.5%. Compared with the positive rates of T1 and T2 stage (N=15), those of T3 and T4 state (N=44) were significantly higher: hTERT 13.3% vs. 29.5%, MAGE A1-6 26.7% vs. 36.4% and MAGE + hTERT 26.7% vs. 54.5%.
Conclusion: MAGE A1-6 and hTERT gene RT PCRshowed good result for CTCs detection in the patients of colorectal cancer patients. MAGE A1-6 and hTERT gene RT PCR results correlated with their T stage of colorectal cancer.
Biography:
Professor Chang-Ho Jeon received his M.D. at the University of KeiMyung (South Korea). He obtained specialist degrees in Laboratory Medicine at YeungNam University (South Korea). From 1989 to 1995, He worked as Associate Professor at Medical School of DongGuk University, in Pohang, Korea. In 1995, He moved to Medical School of Daegu Catholic University, then have worked for this University as a Professor of Laboratory Medicine. From 2008 to 2012, He had worked as a Director of adult stem cell research center in Daegu Catholic University Medical Center. In 2008, 2012, and 2013, Heobtained a distinguished scholarship award from Korean Association of Quality Assurance, Korean Society of Laboratory Medicine and Korean Cancer Association respectively. From 2015 he is working as a vice president of Korean society of genetic and molecular diagnosis. Main fields of his interest are Molecular diagnosis of Cancer, Circulating tumor cells and anti-cancer drug susceptibility. Hehas authored and co-authored about 100 scientific articles.
The Israeli Center for Interdisciplinary Research in Chronobiology, University of Haifa, Israel
Background: The most dramatic environmental change that took place on our planet during the twenty century and is still going these days is the disappearance of dark nights by artificial light at night (ALAN). Throughout evolution humans as other organisms developed under light/dark cycles of 24h an important signal for the entrainment of our biological clockand expresses the rotation of our plant on its axis. If in the first decays of electrical illumination incandescent bulbs were used and as those are considered inefficient in regards to energy saving, in the last five decaysan increase in energetically efficient bulbs which emit short wavelength (SWL) illumination is noted. Under natural conditions SWL-lighting appears at day time and is efficient in suppressing pineal melatonin production. The objectives of our study were: 1) to test the following nexus – ALAN, melatonin suppression, epigenetic modifications and breast cancer (BC) cells proliferation in an animal model. 2) To assess melatonin suppression in response to different illumination types in regards to wavelength.
Materials and Methods: Female BALB/c mice acclimated to short day (8L:16D) were inoculated with 4T1mice BC-cells subcutaneously so tumor size could be calculated with time. Mice were interfered at the middle of the dark period with white LED or Carbon lighting at the same intensity and for the same duration. At the end of the experiments about four weeks, urine was collected for measuring the amount of the melatonin metabolite 6-sulfatoxymelatonin (6-SMT). The tumor was removed and DNA was extracted for measuring global DNA methylation (GDM) levels.
Results: The nexus was revealed and we can further show that SWL-illumination and in particularly LED suppresses melatonin production. This suppression results in hypo-methylation which presumably increases BC-cell proliferation.
Conclusions: The aggressive penetration of the LED-technology into our indoor and outdoor illumination by the name of energy saving should be reconsidered and very carefully calculated. No doubt as SWL-illumination suppresses melatonin production such illumination sources cannot be used for ALAN. As incubation period of BC in humans is between 10-15 years and our results show the involvement of epigenetic modifications which are reversible, efforts should be made to discover what is the threshold from which the direction is nor reversible? We assume that this can be a breakthrough in BC-prevention.
Biography:
Abraham Haim is a full (Emeritus) professor from the University of Haifa. After many years of studying the response mainly of rodents to changes in photoperiod as an initial signal for seasonal acclimatization, he became interested in the reproductive and metabolic responses to light interference what is known today as light pollution. So this became his main topic of research where among others we developed an animal model to test the relations between breast cancer development and exposure to different illuminations. He is the Head of Israeli Center for Interdisciplinary Research in Chronobiology and the Vice president of the Israeli Lighting Society, vice chair of LONNE one of EU, COST programs. Together with collogues and students he has published over 180 scientific papers in pre-reviewed journals. Together with Prof. Portnov, he has published a book entitled: Light Pollution as a New Risk factor for Human Breast and Prostate Cancer, published by Springer, 2013.
Helmholtz-Zentrum Dresden - Rossendorf Institute of Radiopharmaceutical Cancer Research, Germany
Glioblastoma multiforme is the most aggressive type of primary brain tumor with a median overall survival (OS) ofabout 12 months. Brain metastases are the most common form of brain tumors and significantly outnumber primarybrain tumors, with the majority originating from lung cancer, especially non–small cell lung cancer (NSCLC). Despite aggressive treatment, their prognosis is also poor with a median OS of approximately 7 months after diagnosis. Treatment of those tumors remains one of the most challenging tasks in clinical oncology. Although new molecular pathways in tumor biology are being constantly discovered, translation of basic science achievements into clinical practice is rather slow. Major obstacles in resistance to therapy are heterogeneityof brain tumors, multiple genetic alterations, and their diffuse, infiltrative behavior. Hence identifying and investigating pathways related to tumor etiology and growth is highly important. Positron emission tomography (PET) offers the potential to identifykey signaling pathways in brain tumors involving neurotransmitters and -modulators and to discover drugs which may be used for their therapy.
One of the most important prerequisites for PET is the development and evaluation of radio labelled ligands in order to investigate brain functions in living human subjects. Fluorine-18 is currently the most favorable radionuclide that is routinely used for radiolabeling because of its half-life of 109.8 min. The use of PET radio ligands provides brain images of transport, metabolic and neurotransmission processes on the molecular level. PET is currently the most sensitive and specific method for this type of studies. Through integration of chemical/radiochemical, pharmaceutical/radiopharmaceutical, biochemical and radiopharmacological basic research, computational chemistry and with the aid of nuclear medicine diagnostic new approaches in brain tumor treatment will be made available. The presentation will focus on the strategy of radiotracer development bridging from basic science to biomedical application focusing on targets of major importance for the mentioned tumors such as cannabinoid, sigma and nicotinic alpha7 receptors.
Biography:
Peter Brust received his M.S. in Immunology in 1981 and his Ph.D. in Neuroscience from Leipzig University in 1986. He worked as a postdoctoral fellow at Montreal Neurological Institute and Johns Hopkins University Baltimore from 1990-1991. He joined the Research Center Rossendorf (now known as Helmholtz-Zentrum Dresden-Rossendorf, HZDR) in 1992 and headed the Department of Biochemistry. Since 2002 he works in Leipzig first at the Institute of Interdisciplinary Isotope Research and since 2010, after operational transfer, again at HZDR where he leads the Department of Radiopharmaceutical Cancer Research. Since 2010 he is Professor of Radiopharmacy at Leipzig University.
1Department of Cancer Systems Imaging, MD Anderson Cancer Center, USA
2Department of Bioengineering, Rice University, USA
3Department of Applied Chemistry, USA
4Huntington Medical Research Institutes, USA
5Veterinary Medicine & Surgery, MD Cancer Center, USA
6Genitourinary Medical Oncology, MD Anderson Cancer Center, USA
Many prostate cancers (PCa) detected by screening are indolent (will not leave the prostate) however, 90% of patients will receive immediate treatment. What is needed is a diagnostic tool that allows the whole prostate to be examined and is directly correlated to the metastatic behavior of the tumor. We are using a multi-prong approach to discover the metabolic changes in PCa. (1) We are metabolic profiling tumor and normal prostate tissue. (2) We are metabolic profiling both the intracellular and extracellular metabolites of four human prostate cancer cell lines with different degrees of metastatic behavior. (3) We are exploring the reduction of cell proliferation with metabolic inhibitors for therapeutic treatment. (4) We are following the progression of PCa with hyperpolarized magnetic resonance (MR) agents in PCa animal models. Hyperpolarization allows for over >10,000 fold sensitivity enhancement using MR. Polarization (signal enhancement) can be retained on the metabolites of the hyperpolarized molecule allowing for in vivo real time metabolic profiling.
Results: We observe significant differences in uptake of glutamine and the amount of intracellular glutamine, differences in phosphocholine and glycerophosphocholine, and differences in intracellular succinate levels between aggressive versus nonaggressive cell lines and in PCa tissue versus normal prostate tissue. In addition, in our hands we see no significant difference in the glycolytic rate (production of lactate) between the indolent and aggressive PCa cell lines in culture. Using dynamic nuclear polarization, we are designing new in vivo methods for interrogating metabolic pathways such as hyperpolarized choline and glutamine derivatives.
Conclusions: Metabolic profiling has revealed significant differences in metabolism between indolent and aggressive PCa. By using metabolic profiling, we can determine which specific metabolic inhibitors could be utilized to reduce tumor burden and with hyperpolarization this metabolic profiling can be performed in vivo.
Biography:
Dr. Niki Zacharias is an Assistant Professor in the Department of Cancer Systems Imaging at the University of Texas MD Anderson Cancer Center. She received her PhD in chemistry from California Institute of Technology in 2003. Prior to her faculty appointment, she was the James G. Boswell Fellow between Huntington Medical Research Institute and California Institute of Technology. As a chemical biologist, she is focused on utilizing chemical methods (imaging, magnetic resonance, hyperpolarization, fluorescence) to probe biological systems.
1Department of Family Medicine and Public Health, Division of Behavioral Medicine, University of California San Diego, USA
2Department of Family Medicine and Public Health, Division of Epidemiology, University of California San Diego, USA
Until recently, telomeres were thought to be inherited, and therefore genetically determined. More recent evidence demonstrates telomere length may also be associated with and potentially modified by lifestyle. Telomeres are DNA structures that have been implicated in the process of aging. The strong correlation of shorter telomeres with aging, and chronic diseases such as cancer, is well documented. However, although it may seem counterintuitive, cancer stem cells display longer telomere length, although individuals at risk for cancer show shorter telomere length. This conundrum merits additional prospective research.
During this presentation, we describe the current cross-sectional associations between certain behaviors, such as physical activity and nutrition, as well as demographic variables and their association with telomere length, vitality of stem cells, and cancer. In addition, we will provide a clearer understanding of the p16 and p21/p53 pathways. Activation of the p16 pathway is known to contribute to aging. However, the inactivation of p16 is associated with the development of several cancers, while p21 and p53 appear to extend longevity. We will discuss their dynamics related to telomere length, telomerase activity, lifestyle behaviors, and cancer. We will also present information about how stem cells compared to cancer stem cells proliferate, and the cancer-aging hypothesis. In summary, this presentation will include current research on the relationships among lifestyle, telomere length, stem cells, and cancer.
Biography:
Lorena Martin, Ph.D. is an applied behavioral scientist, quantitative methodologist, and exercise physiologist at the University of California San Diego. She is also a graduate faculty member at Northwestern University and Visiting Scientist at the Salk Institute for Biological Studies. Her research focuses on the relationships among lifestyle behaviors, telomere length, stem cells, and Cancer. Her training and expertise is transdisciplinary; such that she has been able to integrate the above mentioned topics to produce a more inclusive hypothesis for future transdisciplinary research.
1ARC Centre of Excellence in Advanced Molecular Imaging, La Trobe University, Australia
2CSIRO Materials Science and Engineering (CMSE), Australia
3Monash University, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Australia
4CSIRO Materials Science and Engineering (CMSE), Australia
5RMIT, School of Applied Sciences, College of Science, Engineering and Health, Australia
G protein-coupled receptors (GPCRs) are key pharmaceutical targets in a number of biological diseases and until the recent introduction of Lipidic Cubic Phase (LCP) crystallization, otherwise known as in meso crystallization, these protein structure have been extremely difficult to solve. LCP crystallization has been successful in solving the structures of a number of GPCRs. However, understanding the process of LCP crystallization is limited. The butyrate G-protein coupled receptors (GPCRs), GPR41 and GPR43, have been implicated in colorectal cancer. To date their function has not been elucidated as low levels of protein expression and difficulties in producing diffraction quality crystals have hindered their structural determination. In meso crystallization, which uses an artificial lipid membrane matrix to facilitate crystal growth, is becoming an increasingly successful crystallization technique, particularly for GPCRs. We report herein the lipid membrane matrix structural characterization for GPR41 and GPR43 within two lipid self-assembly systems (monoolein and phytantriol) commonly used for in meso crystallization and comment on their suitability for crystallizing these GPCRs. Synchrotron small angle X-ray scattering (SAXS) studies were used to determine the initial phase and uptake of these receptors within the lipid matrix and investigate the role of cholesterol in this process. The self-assembled lipid nanostructure was retained in the presence of GPR43 for both lipids but was destabilized for GPR41 in the phytantriol lipid system. The structural changes to the lipid matrix upon protein incorporation were greater for cholesterol-doped systems, potentially indicative of increased receptor uptake.
Elucidating GPCRs structures using conventional crystallography can be challenging due to the size of the crystals grown during in meso crystallization. An alternative and new method of development is serial femtosecond crystallography at an X-ray Free Electron Laser (XFEL) source. These sources are able to generate data from nano-crystals enabling structure determination to be carried out on such finite crystal sizes. This has led the way for new nano-crystallography developments.
Biography:
Dr. Darmanin completed her PhD at Monash University, Melbourne in 2006 where she focused on protein crystallography solving ultra high resolution structure of Aldose Reductase. After completion of her PhD she moved to CSIRO, Melbourne in 2007 and during her post doctorate she setup a G protein coupled receptor laboratory and gained expertise in Synchrotron Science and Electron Crystallography specializing in developing new methods for solving structures of GPCRs and in meso crystallization. She continued on at CSIRO after her Post Doc as project leader and continued to grow the area of in meso crystallization of GPCRs in Australia developing protocols and trying to understand the process of in meso crystallization to help solve GPCR structures. Recently, 2015 she has moved to La Trobe University, Melbourne to continue her work in in meso crystallization and led the X-ray Free Electron Laser group providing expertise in this new exciting field for structure determination of difficult proteins.
1State Key Laboratory of Natural and Biomimetic Drugs, Peking University Health Science Center, China
2Keaise Center for Clinical Laboratory, China
3The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, China
Developing a novel and efficient biomarker for detecting malignant tumors is essentialfor the early-stage diagnosis of cancer. Thioredoxin reductase is a critical catalytic enzyme involved in the biosynthesis of deoxyribonucleotidesandregulation of cellular redox state, and found to be overexpressed in multiple types of cancer. Mechanistically, TrxR has been known to mediate multiple biological processes in cancer cells, including cell cycle progression, cell apoptosis, and ROS accumulation; while several TrxR inhibitors were also designed as anticancer drugs and are currently under clinical trials. By using our patent-protected and China FDA-approved TrxR detection assay, plasma TrxR activities of > 10,000 clinical subjects (malignant tumor patient vs. healthy subject) were measured and data were collected for statistical analyses. As a result, plasma TrxR activity level was observed to be significantly higher in malignant patients (TrxR> 12.0 U/mL) compared with normal group (TrxR< 4.0 U/mL) or non-malignant patients. Interestingly, TrxR activation in tumor samples was dramatically reduced after various anti-cancer treatment including surgery and radio-/chemo-therapy. All these evidences suggest that TrxR activity is an effective clinical biomarker of hyperplasia and carcinoma, and can be applied to detect tumor at early-stage and monitor the therapeutic outcome. Therefore, this study willsignificantly impact our current view on the clinical biomarker in hyperplasia and carcinoma.
Biography:
Dr. Hanwei Yin received his Ph.D from Northwestern University in Cellular and Cancer Biology. He joined Keaise Medicine in 2015, and is currently the director of R&D department. He has published many papers studying the mechanism of benign and malignant tumor development, including the characterization of TrxR as a novel clinical biomarker in hyperplasia and carcinoma, and study of TrxR inhibitors in clinical trials. He is currently leading a group to develop a combinational approach using TrxR with other biomarkers in the early-stage diagnosis and treatment of cancer.
NonInvasive Tehnologies LLC, Johns Hopkins University Bloomberg School of Public Health, USA
Human colonic mucosa is known to be renewed every five days. We pioneered the discovery that these exfoliated cells are viable and that they can be isolated in their pristine state from a small sample of stool (0.5 gm) yielding a heterogenous population of about 20 million cells. These cells exhibit a strong oncolytic activity across a broad spectrum of human cancers mediated via the existence of a novel heterodimeric IgA/IgG chimeric immunoglobulin that can be generated in vitro against human cancers via a lineage-directed differentiation of these GIP-C cells. This antibody has been shown to arrest human colon cancer xenotransplants in nude mice. This technology has opened a new approach to rapid production of therapeutic antibodies to cancer as well as infectious agents such as HIV, Ebola and Marburg without generating a hybridoma.
Biography:
Padmanabhan Nair, Ph.D. (1956) Royal Institute of Science, Bombay (Mumbai), India; Research Officer, (1958-1960) All-India Institute of Medical Sciences, New Delhi, India; Fulbright Scholar and McCollum-Pratt Fellow,(1960-19963) The Johns Hopkins University, Baltimore, Maryland; Head of Medical Research,(1963- 1983) Sinai Hospital of Baltimore, Inc; Research Scientist (1983-1998) Beltsville Human Nutrition Research Center, ARS, USDA, Beltsville, Maryland; Founding President and CEO, (2000) NonInvasive Technologies LLC, Elkridge, Maryland; Adjunct Professor of International Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland.
Adjunct Prof., Dept. of Family & Community Medicine, New York Medical College, USA
Director of Medical Research, Heart Disease Research Foundation; USA
President, International College of Acupuncture & Electro-Therapeutics; USA
Introduction: The author had found that the optimal dose of Vitamin D3 400 I.U. has safe & very effective anticancer effects, while commonly used 2000~5000 I.U. of Vit. D3 gives a 2~3 times increase in cancer markers. We found Taurine has a similar effect.
Method:Using very strong Electromagnetic Field (EMF) Resonance phenomenon between 2 identical molecules with identical weight for which U.S. patent was given in 1993, non-invasive measurement became possible without expensive bulky measuring instrument. Effects of optimal dose of Vitamin D3 & Taurine were compared.
Results:We examined the concentration of Taurine in normal internal organs and in cancer & other malignanciesʼ tissue. We found that Taurine levels in normal tissue are 4~6ng. But in the cases with malignancies, the amount of Taurine was strikingly reduced to less than 0.25ng in adenocarcinoma of the esophagus, stomach, colon, prostate, breast, and lung. Therefore we determined first what the optimal dose of Taurine would be for the average healthy adult, which we found to be 175mg of Taurine instead of commonly used 500mg. Since in cancer patients Taurine is markedly reduced at least 1/16~1/24th of its normal value, we examined the effect of the optimal dose of Taurine on cancer patients. In a patient with normal tissue, the effects of one optimal dose of Taurine usually lasted one day. However in a cancer patient, the effect did not last as long, and required Taurine 3 times/day. This dosage for cancer patients produced a very significant change in cancer associated parameters, such as Oncogene C-fosAb2 &Integrin α5β1, being reduced to less than 1/1,000th. The optimal dose of Taurine 175mg with omega 3 fish oil (EPA 180mg & DHA 120mg) & cilantro 3 times/day, significantly increases urinary excretion of these cancer parameters, toxic metals, & microorganisms. Thus, optimal dose of Taurine can be used as new safe, effective, economical & non-invasive treatment for various cancer patients together with optimal dose of ω3 fish oil & cilantro.
Discussion: Use of optimal dose of Taurine of about 175mg is very important. Since most of Taurine is available as 500mg tablet or capsule of 500mg powder, people often use 500mg(which is about 3 times over dose), without evaluating optimal dose. In cancer patients, instead of using toxic overdose, it is important to use more frequently optimal dose. Anti-cancer effect as well as urinary excretion effect of bacteria, virus, fungus, and toxic metals& substances are superior with optimal dose of Taurine compared with optimal dose of Vitamin D3.
Biography:
Yoshiaki Omura received Oncological Residency training at Cancer Institute of Columbia University & Doctor of Science Degree through research on Pharmaco-Electro-Physiology of Single Cardiac Cells in-vivo and in-vitro from Columbia Uni.. He studied & researched on EMF Resonance phenomenon between 2 identical molecules at graduate experimental physics dept., Columbia Uni.. He published over 270 original research articles, many chapters, & 9 books. He is currently Adjunct Prof. of Family & Community Medicine, NY Medical College; Director of Medical Research, Heart Disease Research Foundation of NY; President & Prof. of Intʼl College of Acupuncture & Electro-Therapeutics, NY; Editor in Chief, Acupuncture & Electro-Therapeutics Research, Intʼl Journal of Integrative Medicine, (indexed by 17 major intʼl Indexing Periodicals); Editor of Integrative Oncology. Formerly, he was also Adjunct Prof. or Visiting Prof. in Universities in USA, France, Germany, Italy, Ukraine, Brazil, Portugal, Turkey, Serbia, Japan, Korea, Taiwan, & China.
1Pharmaceutical Sciences Department, Rutgers University, USA
2Pace Analytical Laboratories, USA
3Biological and Environmental Sciences, California University of Pennsylvania, USA
Resistance to the chemotherapy drug cisplatin is a common cause of treatment failure in ovarian cancer. Many studies have focused on agents that might reverse resistance once it has developed. For example, berberine, an isoquinoline alkaloid that interferes with folate cycle enzymes, has been found to induce apoptosis in cisplatin resistant cells. We have pursued an alternative to the resistance reversal strategy: the prevention of the development of resistance. This strategy requires that cells predictably develop resistance to a high dose of cisplatin that effectively inhibits non-resistant tumor cells. For this study, A2780 (Addex) human ovarian tumor cells were cultured in nutrient medium (F12/DMEM plus 7% FBS) alone or with a low, pretreatment dose of 7.5 µM cisplatin (Sigma Aldrich). After 24 hours in pre-treatment conditions, cells were counted and replicate cultures exposed to the high dose of 15 µM cisplatin. After 24 hours in this high dose, cells were counted again. In non-pretreated cells, high dose cisplatin decreasedcell survival to 51.8 (6.5) % of control cultures. In contrast, cisplatin pretreatment resulted in 90.6 (9.7) % survival following the high dose. Thus, this pretreatment resulted in the rapid induction of resistance. We then employed this protocol to test whether berberinecan prevent the development of this resistance. Replicate cultures were pretreated with either 21 µM or 53 µM berberinehydrochloride (Sigma Aldrich) alone or with 7.5 µM cisplatin pretreatment. Pretreatment with berberine alone had no effect on cell sensitivity to high dose cisplatin: 50.3 (6.1) % survived the subsequent high-dose cisplatin, virtually the same response as cultures with no pretreatment. The addition of berberineon the same day as the cisplatin pretreatment prevented resistance and maintained sensitivity similar to that of controls: 45.3 (5.9) % of cells survived following high dose cisplatin. The results suggest that berberine pretreatment prevents the development of cisplatin resistance in this protocol, perhaps by preventing the overexpression of folate cycle enzyme genes. Further studies are underway to investigate whether this is the case.
Funded by a grant from Commonwealth of PA University Biologists.
Biography:
Paula B Caffrey received her Ph.D. from Rutgers University in 1989. Her graduate research, performed with K. Irwin Keating, explored the interdependence of Se- and Zn- requirements in aquatic systems. As a post doc in Gerald D. Frenkelʼs labat Rutgers Newark, she studied seleniumʼs effect on drug resistant tumor cells. Following postdoctoral projects at UCSD Cancer Center and Georgetown Medical School, she resumed her collaboration with Dr. Frenkelas a Research Associateat Rutgers from 1995-2007. They developed models of drug resistant ovarian cancer to identify agents that can prevent this resistance. Their findings resulted in a Phase 1 clinical trial at the New Jersey Cancer Institute. Since 2007, Dr. Caffrey has held the position of Assistant Professor at the California University of Pennsylvania, where she mentors research students and continues collaboration with Dr. Frenkelonthe prevention of drug resistance inSCLC lung cancer and ovarian cancer.
Helen Dowling Institute, Center for Psycho-oncology, The Netherlands
Director, PRO-health.org, The Netherlands
Objective: In an experimental study we were aiming to show the effects of communication training for health care providers at a cancer ward in order to improve the quality and quantity of the patient education, and satisfaction with the care by the cancer patients.
Methods: A three years in-service communication training was held at a cancer ward of a general hospital. Pre- and post data were collected in an experimental study about (1) the quality and quantity of the communication of nurses, physicians and other HCPs towards patients and colleagues (n=22) as well as the satisfaction of the cancer patients with the quality of the care (n= 90).
Results: The communication training raised significantly the quality and quantity of the communication towards patients and with colleagues. Also the satisfaction of the patients about the quality of care did increase. However, the long-term implementation of these benefits was not-successful.
Conclusion: In-service communication training is an important mean to raise on the long term the quality of patient education at cancer departments in hospitals. Lasting implementation of the benefits requires although attention to organizational obstacles, budgetary conditions, leadership factors at the ward, and the application of an organizational oriented theoretical frame work.
Practice implications: Improvement of patient education at cancer wards does not only require educational means, organizational facilities and professional training, but may be improved too by in-service communication training This may increases the quality of the patient centered care and oncology wards, but attention is needed to a theoretical implementation framework to guide a lasting effects.
Biography:
Adriaan Visser (1941), PhD, social psychologist, thesis (1984) on the methodology of the measurement of patient satisfaction. He worked the rest of his life as health psychologist, engaged in education of students at Dutch universities and colleges on psychology, nursing, research in health care, implementation of health care changes, writing, and editor of several journals. Grants and publications about health promotion, patient education, patient satisfaction, organization of health care, methodology, dental care, diabetes, suicide, contraception, aging, chronically diseases, cancer, palliative care, PNI, depression, mindfulness, creative art, and spirituality. He is the Director of PRO-Health.org, a company for Publications, Research, and Organizational development in Healthcare Organizations.
State Key Laboratory of Bioelectronics, Southeast University, China
The early efficient diagnosis and therapy of some important disease like cancers is still a hot topic in the relative areas involving in patient care and treatments. The multidrug resistance (MDR) is often one of the major obstacles in relevant therapies due to disease-causing organisms to withstand a wide variety of structurally and functionally distinct drugs or chemicals. Diagnosis and therapy in combination with nanotechnology may offer an alternative promising and overcome the difficulty. And the early diagnosis based on some smart supramolecules and nano-biotechnology could be crucial for a successful treatment of cancers.
This study has established some ultrasensitive and intelligently supramolecules and multi-functional nanoprobes as well as multi-mode imaging techniques for real-time dynamic analysis of biomolecules/ cells/tissues. Meanwhile, we have developed a new strategy for the fast and high sensitive recognition of the target biomolecules and cancer cells by combining the supramolecular probes and functionalized nano-interface with the spectra-electrochemical study. Especially, the ultrasensitive in vivo bio-imaging of cancer cells and diseased tissues has been realized through in situ biosynthesized near-infrared fluorescence nanoclusters, establishing creative methods for non-invasive molecular diagnosis and treatment of some difficult diseases like cancers, thus paving the novel path for cancer diagnosis and treatment.
Acknowledgment: This work is supported by the National Natural Science Foundation of China (81325011, 21327902, and 21175020) and National High Technology Research & Development Program of China (2015AA020502).
Biography:
Dr. Xuemei WANG is currently a full professor in Southeast University, Nanjing, China. She got her PhD degree in Chemistry from Nanjing University in 1995; From February of 1995 to June of 1996 she a lecturer in Department of Chemistry in Nanjing University. In 1996 she got the Alexander von Humboldt fellowship in Germany and engaged in the research of supramolecular chemistry and bio-recognition. After returning to China in February of 1998, she joined school of Biological Science and Medical Engineering, Southeast University. In 2000, she was awarded Hong Kong Croucher Research Fund and Chinese Chemical Society Youth Award in Chemistry. She was elected in New Century Talent Supporting Project in China in 2005 and won Chinese Young Woman Scientist Award in 2007. In 2013, she won The National Science Fund for Distinguished Young Scholar in China. Her current research interests include nanomedicine, bio-imaging and biomedical sensors, especially focusing on the design of multifunctional nanostructures for nanomedicine, in vivo self-bio-labelling and multimode bio-imaging of tumors through in-situ biosynthesized biocompatible metal nano-clusters, and biosensors based on functionalized nanoscaled probes.
1Department of Natural and Phamaceutical Sciences; Elizabeth City State University, University of North Carolina, USA
2Department of Chemistry, Morgan State University, USA
3Department of Pathology, Koraminos Cancer Center, Wayne State University, USA
African American men have disproportionately high incidence and mortality rates of prostate cancer when compared to other ethnic groups in the United States. The identification of molecular factors that contribute to this disparity could improve diagnosis and therapeutic intervention. MicroRNA-146a suppresses prostate cancer transformation from androgen-dependent to-independent cells, suppresses a kinase coding gene which reduces cell proliferation, invasion, and metastasis to human bone marrow endothelial cell monolayers, and is dysregulated by latent membrane protein 1 (LMP1) which contributes substantially to the oncogenic potential of Epstein-Barr virus. It is projected that microRNA-146a and other microRNAs may one day become biomarkers for clinical diagnosis and prognosis of several types of cancer including prostate. Novel rhenium compounds have shown anti cancer properties specially in prostate cancer. Therefore, the purpose of this study was to determine the miRNA 146a expression profile in novel African American and Caucasian prostate cell lines at each clinical stage of prostate cancer progression and also to study the anti cancer properties of two novel organorheniumpentylcarbonate (RPC) compounds. The miR-146a expression profile was investigated using novel African American and Caucasian prostate cell lines representing each pathological stage: benign, androgen dependent and independent tumors. Relative miRNA expression was determined by qRT-PCR, miRNA plate assay and smart flare technology after isolating total RNA from the cells and the exosomes from the tumor microenvironment. Cytotoxicity studies of the RPC compounds were done by using MTT and Trypan Blue assay. Our initial data showed a several fold increase for miR-146a in African American prostate cancer cell line in comparison to the benign and Caucasian prostate cancer cell lines. The RPC compounds showed bioactivity in all the lines and significant anti cancer effects. To date, we are unaware of any studies that compare the miRNA146a profile of prostate cancer among two racial groups. Our study suggests that miRNA146a is upregulated in prostate cancer cell line derived from African American(AA) patient than Caucasians(CA) and could possibly contribute to the aggressiveness associated in African American patients with prostate cancer. We also found out that the novel organorhenium compounds are bioactive and have anti prostate cancer properties. Farther studies are currently getting conducted in our laboratory on the anti cancer role of these rhenium compounds and investigations on miR146a expression in other prostate cancer cell lines derived from AA and CA patients.
Acknowledgement: This research is supported by a grant from the Borroughs Wellcome Fund, NSF-LSAMP, NIH-MARC and a Disability Supplement from NIH-NCI.
Biography:
Dr. HirendraNath Banerjee received his BS with honors and MD degree from Calcutta University, India, MS in Molecular Biology from Conolly College of Pharmacy and Health Sciences at Long Island University, NY and Ph.D. in Molecular Biology from Howard University Cancer Center, Washington, D.C. Dr. Banerjee did his post doctoral training at Yale University Medical School and Medical University of South Carolina before joining Elizabeth City campus of the University of North Carolina where he is now a tenured Professor in the department of Natural, Pharmacy and Health Sciences. Dr. Banerjee did a sabbatical at Rockefeller University under the mentorship of nobel laureate Dr. Gunter Blobel in studying the cell biology of nuclear pore complexʼs. Dr. Banerjeeʼs current research involves cancer biology and Efferocytosis.
John D. Dingell VA Medical Center and Wayne State University, USA
The concept that pluripotent cancer stem cells (CSCs) are involved in the development and progression of many types of malignancies, including colorectal cancer (CRC), is now well accepted. Earlier, we reported that patients with ≥3 adenomas (High-risk for CRC) exhibit a marked increase in CSCs in the colon than those without adenomas. Although the regulatory mechanisms for this increase in CCSs are poorly understood, we have suggested a role for secondary bile acids in the intestine, specifically deoxycholic (DCA) and lithocholic (LCA) acids, bio-transformed by gut microbiota, in regulating this process. Indeed, we observed a marked rise in Fusobacterium nucleatum and Enterobacterium (both are associated with CRC) in High-risk CRC patients. An opposite phenomenon was noted for the anti-inflammatory Bifidobacteria and also for the probiotic Lactobacillus acidophilus. Among the secondary bile acids, DCA and LCA are thought to be the most significant with respect to the development of CRC. Interestingly, we found the levels of DCA and LCA in the colon of High-risk CRC patients to be markedly higher than those at lower risk for CRC. We also found DCA and LCA to induce stemness in normal human colonic epithelial cells, as evidenced by increased colonosphere formation and elevated expression of several CSC markers as well as p-EGFR, c-myc and MMP-2, accompanied by a marked rise in lncRNAs, specifically CCAT2 and HOTAIR, which are known to be upregulated in CRC. Our observations suggest that alterations in specific gut micro-organisms resulting in increase in DCA and LCA that induce stemness in colon mucosal cells could partly be responsible for the development of sporadic CRC.
Biography:
Dr. Adhip PN Majumdar, received his MS and Ph.D. degrees from the University of London, England, and D.Sc (Doctor of Science) degree in Gastroenterology from the University of Aarhus, Denmark. Dr. Majumdar has been a Professor at Wayne State University since 1992. He also holds the post of Senior Research Career Scientist at the Detroit VA Medical Center. Over the past several years Dr. Majumdarʼs work has been streamlined to uncover the biochemical and physiological pathways governing the growth of gastrointestinal (GI) tract. He has published over 196 original scientific articles in peer-review journals and a multitude of book chapters and review articles. As reflected by the literature published from Dr. Majumdarʼs lab, he is particularly interested in elucidating the patho-physiology of age-related changes in the GI mucosa specifically those that lead to malignancy. To this end, Dr. Majumdar has begun to investigate the role of pluripotent, self-renewing CSCs in the development and progression of GI malignancies. Dr. Majumdar has been continually funded by the VA and NIH and is considered one of the nationʼs leading investigators in gastrointestinal aging and cancer.
Department of Oncology-Pathology, Karolinska Institutet, CCK, Karolinska University Hospital, Sweden
Tumor cell heterogeneity constitutes a major challenge in cancer treatment. It has been shown thatinteractions between genetically different tumor cell subclonesin glioblastomacan affect the overall tumor growth.
To identify further signaling pathways and factors that contribute to interclonal effects we have usedthe U343 cell culture system, which consists of a panel of cell clones derived from a single glioblastomatumor, including U343MG, U343MGa, U343MGa31L and U343MGaCl2:6.
Here we show that U343MG cells have invasive capacity in vitro and express elevated mRNA levels of mesenchymal genes, including SNAI2, LAMC1 and FN1. In contrary, the other clones are less invasive and express high mRNA levels of the stem cell factor SOX2 and the astrocytic marker GFAP. By genomic copy number analysis a set of common gains and losses indicated a common ancestor, while specific alterations illustrated how the different clones had evolved. By co-culture and conditioned media experiments we found that U343MG elicited differentiation and growth inhibitory effects on U343MGaCl2:6 in co-culture via Notch signaling, and inhibited the proliferation of U343MGa31L via secreted factors. Gene-expression, proteomicand functional genomic approaches will pinpointthe specific pathways that elicit these inter-clonal effects.
Our studies show that different tumor cell subclones in a single glioblastomamay affect each otherʼs growth and differentiation via secreted and cell-associated factors. Massive single-cell analyses and further studies of fresh tumor samples will tell what combinations of interacting cell types may prevail in glioblastoma. Knowledge about cell-to-cellcommunicationin glioblastomamayprovidenovel therapeutic targets.
Biography:
Monica Nistér is a professor of pathology since 2002 at the Department of Oncology – Pathology, Karolinska Institutet, Karolinska University Hospital, Sweden. Her major research interests are to characterize the cancer cell heterogeneity and cancer stem cells in brain cancer, and to study the involvement of growth factor stimulation and p53 loss of function as well as epigenetic mechanisms and mitochondrial dynamics in cancer. Dr. Nistér has authored 120 peer-reviewed articles, a majority of whichin the cancer field, especially onbrain cancer. She has a PhD degree in Pathology (Tumor Biology) from Uppsala University in 1987 and became professor of experimental pathology at the same university in 1999.
1Sidney Kimmel Comprehensive Cancer Center, Baltimore, USA
2NIH, USA
Ascorbic acid is being used by complementary medicine practitioners to treat cancer, infections, and other conditions. Annual administration of more than 355,000 doses of intravenous (IV) ascorbic acid for more than 10,000 patients has been documented, although total industry sales are more than double that amount. The average prescribed dose is 28 grams every 4 days. Complications reported have been minimal, with fatigue reported in 1.2% of patients overall and rare reports of phlebitis and kidney stones. A long period of controversy over the efficacy of ascorbic acid in cancer patients began in 1976. Ewan Cameron with Linus Pauling published a retrospective study of untreatable cancer patients that demonstrated a survival benefit of 321 days with IV and oral ascorbic acid vs. 38 days for controls. In contrast, a 1979 Mayo Clinic study did not replicate this finding, although ascorbic acid was delivered only orally instead of IV. Phase 1 and 2 clinical trials in 2012, 2013, and 2014 demonstrated safety and anti-tumor activity for high dose IV ascorbic acid. These studies warranted testing the efficacy of IV ascorbic acid in randomized, placebo-controlled clinical trials. At high doses, ascorbic acid is very poorly bioavailable when delivery orally. Maximal oral administration has been shown to result in concentrations of no more than 0.2 mM, far below therapeutic levels. The effective therapeutic concentration of ascorbic acid is high, and can only be achieved with intravenous dosing. Thus the findings of the 1979 Mayo Clinic study, which used oral administration only, do not conflict with Cameron and Paulingʼs findings that used IV plus oral administration.
A recent study of high dose IV ascorbic acid in ovarian cancer patients indicated that ascorbic acid treatment combined with standard chemotherapy (paclitaxel) reduces certain toxicities associated chemotherapy and might increase survival.
Dr. Channing Paller is conducting a randomized phase 2 clinical trial comparing docetaxel plus IV ascorbic acid (1g/kg, 3 times per week) versus docetaxel plus IV fluid (placebo) in mCRPC patients. The primary outcomes will be PSA response and reduction of chemotherapy-related toxicities. Key secondary outcomes include radiographic progression free survival, safety, quality of life, and the need for dose reductions of docetaxel. Laboratory correlates including pharmacokinetics of ascorbic acid and docetaxel and oxidative stress levels. Biomarkers of resistance to docetaxel will also be investigated. This clinical trial activates in spring 2016 and will be conducted at Johns Hopkins University and partnering sites.
Biography:
Channing J Paller, M.D, is Assistant Professor of Oncology at the Johns Hopkins University School of Medicine. Dr. Paller earned her M.D. at Harvard Medical School and completed her medical residency at the Johns Hopkins Hospital, where she was a member of the Osler Housestaff Program, and her Fellowship in Medical Oncology at the Johns Hopkins Kimmel Cancer Center. As an investigator, Dr. Paller is focused on translational research and clinical trials of developmental therapeutics in prostate and other solid tumors. Dr. Paller actively participates in the Johns Hopkins Kimmel Cancer Center Phase I program, with a concentration on the rigorous evaluation of natural products. She focuses on novel clinical trials of immunotherapy (TGFBR inhibitor) and natural products in men with prostate cancer or other solid tumors including pomegranate, muscadine grape skin, vitamin C, and mistletoe.
1Research Service, Minneapolis VA Healthcare System, USA
2Division of Hematology, Oncology and Transplantation, University of Minnesota, USA
3Hematology/Oncology Section, Minneapolis VA Healthcare System, USA
Introduction: Mesothelioma therapy is a highly fatal disease with limited therapeutic options. Pemetrexed forms the backbone of first line chemotherapy in mesothelioma. The major mechanism of action of pemetrexed is thought to be via inhibition of the folic acid synthesis pathway via inhibition of thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Low expression of the endogenous CDK4/CDK6 inhibitor and tumor suppressor p16INK4A has been demonstrated in up to 50-90% of mesothelioma tumors. Inhibition of CDK4 has been shown to be associated with decreased levels of thymidylate synthase and cell cycle arrest at the G1/S transition. Decreased levels of thymidylate synthase have been associated with increased response to pemetrexed in some studies.
Hypothesis: Palbociclib will sensitizemesothelioma cells to pemetrexed-based therapy.
Results: Previously, we have demonstrated that palbociclib inhibits mesothelioma cell proliferation, inhibits retinoblastoma protein phosphorylation, and results in cell cycle arrest. Mesothelioma cells in culture were treated with palbociclib and pemetrexed alone and in combination. At concentrations at 100 µM or greater, single agent palbociclib was associated with decreased cell proliferation versus single agent pemetrexed. At higher concentrations of palbociclib and pemetrexed (> 100 nM), no additive or synergistic effects were observed for the combination therapy against mesothelioma cell lines. Preliminary results are consistent with at least an additive effect on cell proliferation in H2373 and H2461 mesothelioma cells at 1 µM palbociclib plus 10 nM pemetrexed. In H2373 cells treatment with palbociclib at 10 µM results in complete inhibition of phosphorylation of site T826 in Rb, while treatment with 1 µM palbociclib results in partial inhibition of phosphorylation at the same site. Treatment with 100 nM pemetrexed plus 1 µM palbociclib resulted in complete inhibition of phosphorylation at T826.
Conclusion: Pemetrexed affects Rb phosphorylation and may sensitize mesothelioma cells to treatment with CDK4/6 inhibitor palbociclib. Further investigation of this combination approach may be useful for mesothelioma treatment.
Biography:
Mark Klein, M.D. is an Assistant Professor of Medicine at the University of Minnesota and a staff physician at the Minneapolis VA Healthcare System. He earned his M.D. from the University of Iowa and did internal medicine residency and hematology/oncology fellowship training at the University of Minnesota. His laboratory research interests include identifying new treatment strategies against mesothelioma and small cell lung cancer and therapeutic peptide design and development.
Assistant Professor, Harvard Medical School, USA
Ovarian cancer has a high mortality rate and despite initially robust clinical responses to platinum and taxane-based chemotherapy, most patients will relapse within 2 years following diagnosis. Drug-resistant self-renewing cancer stem cells, which evade the anti-cancer effects of systemic chemotherapy, have emerged as a key player responsible for tumor recurrence. Identifying the chemoresistance signatures of cancer stem cells is an important step for designing new strategies for therapeutic intervention in recurrent tumors. Multiple studies have now defined cancer stem cells (CSCs) as having an increased tumorigenic ability in serial transplantation experiments conducted in tumor xenografts. This assay, however, may not be entirely accurate in clearly identifying CSCs. Nevertheless, there is enough evidence to support the idea that CSCs are necessary to initiate and propagate tumor diversity. In addition, CSCs are studied in multiple solid tumors, including ovarian cancer, due to their intrinsic chemoresistance properties. Thus, while non-CSCs have been shown to be sensitive to available therapies, CSCs are enriched in response to treatment and regenerate an increasingly platinum resistant tumor. Furthermore, similar to normal stem cells, CSCs are likely shielded from damage and injury by the tumor niche microenvironment, which makes it difficult to target them therapeutically.
The cellular origin of ovarian cancer stem cells has been difficult to identify. Multiple stem cell models have been proposed. One model proposes that CSCs can originate either from somatic adult stem cells or from progenitor non-stem cells. The ovarian surface epithelium and distal fallopian tube, which are tumor initiation sites, consist of both adult stem cells and also progenitor cells that are relatively undifferentiated and capable of differentiating into distinct morphological subtypes. We have recently found that ovarian cancer and somatic stem cells share common molecular pathways and markers, which is consistent with the model that some cancer stem cells may either arise from adult stem cells or most likely evolve to mimic somatic stem cell properties. Clearly, the identification of key CSC markers and pathways and their efficient use in the design of targeted therapies are necessary before such treatments can be meaningfully implemented in the clinic. Our research presentation will detail key aspects of CSC-driven tumor chemoresistance in ovarian cancer, outline methods of efficiently targeting CSCs, and discuss the implications of using these novel therapies in the clinical setting.
Biography:
Dr. Dinulescu is an Assistant Professor at Harvard Medical School. She received her Ph.D. from Oregon Health and Science University and completed her postdoctoral studies in the field of Cancer Genetics at MIT. Dr. Dinulescuʼs research interests focus on cancer biology, malignancies of the gonads and reproductive tract, with a special emphasis on ovarian cancer research and endometriosis. Our laboratory is actively investigating the key contribution of cancer stem cells (CSCs) to tumor chemoresistance. Our current studies focus on better understanding the mechanism of stem cell signaling in the maintenance of the CSC niche and ovarian tumorigenesis. The aim is to harness the power of nanotechnology to develop improved “homing” technologies for the delivery of therapeutic agents specifically targeting and sensitizing ovarian cancer cells, including CSCs, in a spatio-temporal fashion.
Department of Internal Medicine, National Taiwan University College of Medicine, Taiwan
Purpose: To evaluate the risk of oral cancer associated with metformin use.
Methods: The reimbursement database of the National Health Insurance in Taiwan was used. Patients with type 2 diabetes mellitus at an onset age of 25-74 years during 1999-2005 and newly treated with either metformin (n=288198, “ever users of metformin”) or other antidiabetic drugs (n=16263, “never users of metformin”) were followed for at least 6 months for oral cancer until December 31, 2011. The treatment effect of metformin (for ever versus never users, and for tertiles of cumulative duration of therapy) was estimated by Cox regression adjusted for propensity score (PS) or incorporated with the inverse probability of treatment weighting (IPTW) using PS.
Results: The respective numbers of incident oral cancer in ever users and never users were 1273 (0.44%) and 119 (0.73%), with respective incidences of 92.7 and 163.6 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) suggested a significantly lower risk [0.584 (0.483-0.707) for PS-adjusted model, and 0.562 (0.465-0.678) for IPTW model]. In tertile analyses, the PS-adjusted hazard ratios (95% confidence intervals) for the first (<21.5 months), second (21.5-45.9 months) and third (>45.9 months) tertile of cumulative duration were 1.403 (1.152-1.708), 0.557 (0.453-0.684) and 0.152 (0.119-0.194), respectively; and were 1.244 (1.024-1.511), 0.526 (0.429-0.645) and 0.138 (0.108-0.176), respectively, for IPTW.
Conclusions: Metformin may significantly reduce the risk of oral cancer, especially when the cumulative duration is more than 21.5 months.
Biography:
Dr. Chin-Hsiao Tseng is a senior attending physician at the Department of Internal Medicine, National Taiwan University Hospital, a full professor at the Department of Internal Medicine, National Taiwan University College of Medicine and an adjunct research fellow at the National Health Research Institutes in Taiwan. He had been appointed as the directors of the Division of Endocrinology and Metabolism, and the Department of Medical Research and Development at the National Taiwan University Hospital Yun-Lin Branch from August 2006 to July 2008. He has published more than 200 refereed papers and more than 10 book chapters in either English or Chinese on arsenic-related health problems and the relationship between diabetes mellitus and cancer. He has been invited to write an article entitled “Arsenic-induced diabetes mellitus” for “Encyclopedia of Metalloproteins”; and invited as a consultant to the “Workshop on the Potential Role of Environmental Chemicals in the Development of Diabetes and Obesity” organized by the National Institute of Environmental Health Sciences/National Toxicology Program, US Department of Health and Human Services, which was held in North Carolina on January 10-13, 2011. Prof. Tseng has also been invited by the International Agency for Research on Cancer/World Health Organization to serve as an expert in the working group for the monograph volume 108 on “Carcinogenicity of some drugs and herbal medicines” held in Lyon, France in 2013. Prof. Tseng has been invited as a Lead Guest Editor for a Special Issue on “Diabetes and Cancer: Epidemiological, Clinical, and Experimental Perspectives” for Experimental Diabetes Research, which has been published in 2012. He has gained more than 20 research awards and has been invited to referee for scientific papers for more than 200 times by more than 100 international medical journals and to give lectures for several hundred times. He is currently serving as a member of the editorial advisory board of several medical journals including Current Diabetes Reviews, World Journal of Pharmacology, World Journal of Cardiology, World Journal of Diabetes, Open Diabetes Journal and Journal of Environmental Science and Health, Part C.
Biology Department, UAE University, UAE
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death worldwide. The prognosis of patients with HCC is usually poor; hence, a novel approach against HCC is essential for a better therapeutic outcome. Saffron and its active constituents were reported to have antioxidant, anti-inflammatory, and anti-tumor properties. The aim of this study was to investigate chemopreventive action of crocin, one of the promising active constituents of saffron, against diethylnitrosamine (DEN)-induced liver cancer in rats, and the possible mechanisms by which crocin exerts its anti-tumor effects. Findings reported herein demonstrated the anti-proliferative and pro-apoptotic properties of crocin when administrated in DEN-treated rats. Additionally, crocin exhibited anti-inflammatory properties that inhibited NF-kB, among other inflammatory markers. According to our network analysis, NF-kB was identified as a regulatory hub, and therefore, a candidate therapeutic drug target. Together, these findings nominates crocin as a candidate chemopreventive and therapeutic agent against HCC.
Biography:
Amr Amin has completed his PhD at University of Illinois at Chicago, and received a post-doctoral training in the field of molecular genetics at the University of Pennsylvania School of Medicine. He started his academic career at UAE University where he serves now as a Full Professor of Cell Biology. Amrʼs research focuses on ways to control cancer, particularly liver cancer. He published many research articles and reviews and serves as reviewer and as an editorial member of many specialized peer-reviewed journals. He is also a member of many specialized societies and the sole recipient of many scientific awards.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, USA
Perturbations in the adipocytokines-profile, especially higher levels of leptin, are a major cause of breast tumor progression and metastasis. The focus of this talk is to discuss the impact of obesity on cancer with a special focus on breast cancer, discuss the underlying molecular mechanisms and discuss the potential therapeutic opportunities.
Biography:
Sharma attained her PhD in Oncology followed by postdoctoral training at University of Maryland and Johns Hopkins University. Dr. Sharma is an Associate Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Her lab focuses on investigating the molecular links between obesity and cancer, emphasizing aspects that have potential clinical significance. They are exploring new strategies to disrupt obesity-cancer connection using a variety of approaches. Their overall goal is to understand the molecular networks by which obesity affects carcinogenesis and discover novel agents to effectively disrupt obesity-cancer axis.
University of California San Francisco, USA
Introduction: Modified measles virus (MV) is an effective oncolytic virus and is currently being investigated in clinical trials for various cancer types. An advantage of using MV is the ease of retargetingthe virus to a receptor of choice. We investigated the use of cystineknot proteins (CKP) to direct MV activity. CKP are short polypeptides that bind their targets with high affinity. A library of these proteins has been made, and a CKP that binds αvβ3 and αvβ5integrins with single digit nanomolar affinity has been isolated. We have used this CKP to target MV to the integrins.
Methods: MV genome was modified to express the integrin-binding CKP at the C-terminus of a mutated H protein that does not bind to its normal receptor CD46. We tested the virus for specificity to integrinsby assessing cell killing and MV replication in vitro.
Results: MV-CKP killed and replicated in glioblastoma, medulloblastoma, DIPG and breast cancer cells, which express the target integrins. The virus did not kill and did not replicate in cells in which αvintregrin expression was knocked down with anαv-integrin antisense lentivirus. MV-CKP activity was competitively blocked by echistatin, an integrin binding peptide. When the CKP was cleaved from the virus at an inserted protease site, virus activity was abrogated.
Conclusions: These results indicate that CKP can be used to selectively target MV. Because the integrins of interest are expressed by tumor cells and tumor-associated endothelium and because the CKP used has been shown to localize to tumor when injected IV, MV-CKP may be potentially effective as IV therapy, a major step forward in the use of MV. In addition, the CKP library can be screened for other targeted CKPs of interest. Importantly, the use of CKP to target viruses is applicable to many viruses other than MV.
Biography:
Sangeet Lal is a postdoctoral scholar in the lab of Corey Raffel at UCSF. He has createda modified oncolytic measles virus (MV) targeting tumor-specific receptors and is investigating the efficacy of MV for the treatment of pediatric brain cancers using immune-competent murine models. At OHSU, he performed research of clinical interest showing that simultaneous expression of αv integrin and HER2, a tyrosine kinase receptor, is required for the invasion of Her2-positive breast cancer cells in brain microenvironment. The interaction between αv integrin and HER2 regulates the localization of HER2 on cell membrane. During Ph.D., Sangeet studied the role of calpain2 protease in the invasion of glioblastoma tumor cellsand developed a novel in vivo orthotopicxenograft model of zebrafish tomonitor invasion of transplanted glioblastoma cells in the brain of living animals. Sangeet has published 6 papers with another 4 in peer-review or preparation stage and presented his research(oral and poster) at international meetings. His long-term goalis to develop as a notable scientist in the field of translational brain cancer research and therapy.
Haromaya University, Ethiopia
Inorder to determine the rate of expression of ER/PR in invasive breast cancer we have reviewed the results of invasive breast cancer cases. A total of 456 breast cancer cases were tested for ER and PR at Tikur Anbessa specialized Hospital, Addis Ababa, from 2008 – sept.,2010 G.C.
63.7% were ER positive and 49.2% were PR positive.
The expression of both ER and PR is seen in higher rates with male breast cancer than with female breast cancer. Disease progression was seen with higher frequency with lymph node involvement and it is statistically significant (p=0.118), increasing tumor stage statistically significant (p=0.018), invasive lobular carcinoma not statistically significant (p=0.211), surgical margin involvement not statistically significant (p=0.06), and higher tumor histologic grade statistically significant (p=0.045) and with ER positivity statistically significant (p=0.015).
Large number of female breast cancer patients had history of hormonal contraceptive use. (42.6%)
Biography:
Getamesay Kebede is an Assistant Professor of Clinical Pathology has been working professionally since 2010 at Haromaya University, Ethiopia. He has written a paper on breast cancer and has ongoing studies on tuberculosis and on infant mortality. Getamesay received his doctorate degree in medicine at Gondar University in Gondar, Ethiopia and speciality in Clinical Pathology at Addis Ababa University, Ethiopia.
Chairman, Edogawa Hospital, Japan
Regorafenib is an oral multikinese inhibitor with proven activity in metastatic colorectal cancer (mCRC) patients who have a benefit with salvage line chemotherapy for progression free and overall survival. We evaluated four patients who received initial dose of regorafenib 160mg once a daily which dose could not continue each cycles. However, severe toxicity of initial dose has resulted in the clinical use of a reduced dose of regorafenib 120mg as an initial dose for other patients. Best objective response of partial response (PR) was 17% and stable disease (SD) was 17% and disease control rate was 34%. These PR cases of medication terms were 9 (6.5 months) and 6 (5 months) cycles, respectively. The most common AEs of under grade 2 were HFSR (58.3%), fatigue (50%), liver dysfunction and anemia (33.3%), leukopenia (25%) and hypertension (16.7%). There was no chemotherapy-related death. Despite a reduced initial dose of regorafenib, we recognized to remarkable two PR cases and favorable SD cases. We suggest to initial dose of regorafenib which might be started 120mg, because of severe adverse events. If a patient of our method had a tolerable adverse event, regorafenib will be able to be a dose escalation or not.
Biography:
Dr. Hiroshi Osawa Medicine Doctor (Ph.D.-medicine) now is a chairman of department of Oncology and Hematology in Edogawa Hospital Tokyo, Japan. Dr. Hiroshi Osawa graduated the Teikyo university school of medicine, Tokyo, Japan, 1990. He got his Specialist in Oncology and Hematology, Medicine Doctorʼs degree (Ph.D.) at the Tokyo Jikei University, Tokyo. And Dr. Hiroshi Osawa had learned clinical research, molecular biology and cancer cell signaling at Cancer Institute Hospital(four years), Tokyo, Japan and he researched resistance in TGF-beta 1 correlates with aberrant expression of TGF-beta receptor II in human B-cell lymphoma cell line at National Institute on Aging(three and half years) as a research fellow, Baltimore, USA. Currently Dr. Hiroshi Osawa has been focusing clinical phase studies and researches on gastrointestinal tract field include of these adverse events.
Dept. of Developmental Biology and Cancer Research, Faculty of Medicine, Hebrew University, Israel
In recent years it has become apparent that the non-malignant stroma surrounding tumors plays a critical role in the processes of tumor initiation, growth and metastatic progression. In this context the part neutrophils play has been a matter of debate. Neutrophils are the most abundant leukocytes in the human circulation and are usually associated with inflammation and with fighting infections. In cancer, neutrophils were shown to provide a variety of pro-tumor functions including secretion of tumor promoting cytokines, degradation of the ECM, immune suppression and more. In contrast, neutrophils were also shown to have the capacity to kill disseminated tumor cells either through direct cytotoxicity or via antibody dependent cytotoxicity. These conflicting reports suggest that although neutrophils are largely viewed as a homogeneous population they may consist of distinct subsets with significantly different properties. Indeed, we identified a heterogeneous subset of low-density neutrophils (LDN) that appears transiently in self-resolving inflammation but accumulates continuously with cancer progression. While high-density neutrophils (HDN) maintain a pro-inflammatory, anti-tumor phenotype, LDN present with a reduced inflammatory profile, impaired neutrophil function and acquire immunosuppressive properties. In early tumor development HDN are the predominant neutrophil subpopulation giving neutrophils, in general, an anti-tumor phenotype. However, with tumor progression, LDN are preferentially propagated to the extent that they become the dominant circulating neutrophil subpopulation. When this happens the overall neutrophil contribution switches from anti- to pro-tumor. Our observations identify dynamic changes in neutrophil subpopulations and provide a mechanistic explanation to mitigate the controversy surrounding neutrophil function in cancer.
Biography:
Dr. Granot did his B.Sc, M.Sc and PhD at the Hebrew University in Jerusalem. His PhD thesis (2000-2005) dealt with the degradation pattern of StAR, a unique protein that is involved with steroid hormone synthesis. He then did a postdoctoral fellowship at the Hebrew University (2005-2007) where he focused on organ size control using pancreatic beta-cells as a model. Next, he did a postdoctoral fellowship at Memorial Sloan-Kettering, New-York, NY, USA (2007-2012). During this fellowship Dr. Granot focused on neutrophils, a subset of white blood cells that has the capacity to limit the metastatic spread. The understanding of this new role for neutrophils is very limited and requires further studies. Currently Dr. Granot is a PI at the Hebrew University in Israel, where he studies neutrophil versatility in cancer and the mechanisms that mediate tumor cell recognition and elimination by neutrophils.
Shanghai Jiao Tong University School of Medicine, China
The tumor associated antigen OVA66 which is firstly defined by serological analysis of human ovary cancer of recombinant cDNA expression library, has been demonstrated to be highly expressed in the majority of malignant tumors. We constructed a eukaryotic expression vector pFlag-OVA66 to establish an OVA66 stably over-expressed mouse fibroblast NIH3T3 cell line. The OVA66 over-expressed NIH3T3 cells exhibited several significantly malignant changes, the S and G2/M phage was markedly increased whereas the G1/G0 phage was decreased in the total cell cycle, indicating that the over-expression of OVA66 is able to promote cell cycling and proliferation. MTT and colony formation assay validated that OVA66 promotes the cell growth and colony formation in vitro. NIH3T3 cells with the over-expression of tumor antigen OVA66 displayed more resistance to the cell apoptosis induced by 5-FU. In vivo assay of the tumor xenograft studies in nude mice revealed the OVA66 over-expressed NIH3T3 cells were capable of forming tumors in the nude mice compared to the NIH3T3-mock cells with low expression of OVA66. Analysis of the phosphorylation of AKT and ERK1/2 stimulated with serum indicated a hyper activation of ERK1/2 MAPK and PI3K/AKT pathway in OVA66 stably over-expressed NIH3T3 cells. The results suggesting that OVA66 as a novel tumor antigen with its strong tumorigenic ability might be a novel target for the early detection, prevention and treatment of tumor in the future.
Biography:
Ge Hai-liang is a professor of Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine. He graduated from Shanghai Second Medical University in 1977 majoring in medicine. Then he obtained the Master Degree in Nuclear Medicine of Ruijin Hospital, Shanghai Second Medical University in 1985 and got the Doctor Degree in Immunology of Shanghai Second Medical University in 1991. He worked on research as a postdoctoral fellow in the Department of Microbiology and Immunology, University of California, San Francisco, U.S.A. from 1992 to 1995. In 1998 and 2002, he studied in School of Medicine, University of Michigan and School of Medicine, University of Pittsburgh, U.S.A. as a visiting professor respectively.
Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China
Gastric cancer is the primary cause of cancer-specific mortality worldwide. PODXL (podocalyxin-like protein or podocalyxin) is a cell-surface glycoprotein that belongs to CD34 family of sialomucins. PODXL-v1 is widely expressed on vascular endothelium, mesothelial cells, and platelets; in contrast, PODXL-v2, a truncated short form of PODXL is specifically expressed or up-regulated in numerous cancer cell types as well as in small blood vessels in tumor tissues. There remains considerable interest in generating monoclonal antibodies (mAbs) directed against specific tumor targets for antigen (Ag) discovery, diagnosis and therapy. MS17-38 mAb was generated by live cells HTS and was demonstrated to bind to a specific conformational epitope of PODXL-v2 on GC cells. PODXL-v2 expression inhibition by PODXL-v2 siRNA or the PODXL-v2-neutralizing antibody MS17-38 resulted in inhibition of GC cell growth and prevention of GC cell migration in vitro. Furthermore, in vivo studies demonstrated that MS17-38 mAb can potently inhibit tumor growth and prevent MKN-45 metastasis to the lungs in nu/nu mouse models. Finally, high expression of PODXL-v2 was associated with advanced GC stage and short survival time (P<0.01). Additional engineering of this mAb into chimeric or humanized forms could permit development of MS17-38 for diagnosis, staging or therapy of human malignancy. Our findings indicate that PODXL-v2 is specifically expressed in the extracellular matrix of GC, and MS17-38 mAb directed against a conformational epitope of PODXL-v2 identified through HTS can functionally inhibit GC cancer cell growth and migration/metastasis both in vitro and in vivo. MS17-38 is a promising functional antibody directed against GC that could potentially be developed into a therapeutic mAb for clinical application.
Biography:
Dr. Zhang Dong-qing is a professor in the Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, China. He graduated from Shanghai Second Medical University in 1985 majoring in medicine. Then he obtained the Master Degree in Shanghai Institute of Immunology, Shanghai Second Medical University in 1991. He worked on research as a postdoctoral fellow in the Department of Nerve immunology research institute McGill University from 1997 to 1998; Also, in 2005 he studied in Yale University School of Medicine, as a visiting professor.
1Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, China
2State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, China
3Laboratory of Genetic Medicine and Immnology, Weill Cornell Medical College in Qatar, Qatar
Tumor initiation andgrowth depend on its microenvironmentin which cancer associated fibroblasts (CAFs)in tumor stroma play an important role. Prostaglandin E2 (PGE2) and interleukin (IL)-6 signal pathways are involved in the crosstalk between tumor and stromal cells. However, how PGE2-mediated signaling modulates this crosstalk remains unclear. Here, we show that microRNA (miR)-149 links PGE2 and IL6 signaling mediating the crosstalk between tumor cellsand CAFs in gastric cancer (GC). miR-149 inhibited fibroblast activationby targeting IL6 and miR-149 expression was substantially suppressed in the CAFs of GC. miR-149 negatively regulated CAFs and their effect on GC development both in vitro and in vivo. CAFs enhanced epithelial to mesenchymal transition (EMT) and the stem-like properties of GC cells in a miR-149-IL6-dependent manner. In addition to IL6, PGE2 receptor2 (PTGER2/EP2) was revealed as another potential target of miR-149in fibroblasts. Furthermore, H. pylori infection, a leading cause of human gastric cancer, was able to inducecyclooxygenase-2 (COX-2)/PGE2 signaling and to enhance PGE2 production, resulting in thehypermethylation of miR-149 in CAFs and increased IL6 secretion. Our findings indicate that miR-149 mediates the crosstalk between tumor cellsand CAFs in GC and highlight the potential of interfering miRNAs in stromal cells to improve cancer therapy.
1Department of Pediatrics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
2 Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, P.R. China
ERp19, a mammalian thioredoxin-like protein, plays a key role in defense against endoplasmic reticulum stress. It belongs to families of protein disulfide isomerase (PDI) whose members have been implicated in cancer development including breast cancer, ovarian cancer and gastrointestinal cancer. Recently, little is known regarding ERp19 function in gastric cancer (GC). Therefore, the aim of our study is to investigate the expression and prognostic value of ERp19 in GC patients and to explore the role of ERp19 in tumorigenicity. The expression of ERp19 in human GC tissues was detected by immunohistochemical staining and real-time PCR. Statistical analysis of clinical cases revealed that the expression levels of ERp19 were higher in tumor tissues compared with the non-tumor tissues. And the expression levels of ERp19 were correlated with tumor size, lymph node involvement and poor prognosis of GC patients. Furthermore, ERp19 knockdown dramatically suppressed gastric cancer cell growth, inhibited cell migration/invasion and downregulated the phosphorylation of FAK and paxillin. Whereas ERp19 over-expression did reversely. On the basis of these data, we indicated that ERp19 contributes to the tumorigenicity and metastasis via activation of the FAK signaling pathway, and may function as an oncogene in GC. In conclusion, ERp19 is expected to become a new diagnostic and prognostic marker and a novel target of the treatment of GC.
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