Day 2 :
- Track 3: Advances in Cancer Detection, Imaging, Management & Prevention
Track 4: Tumor Science
Track 5: Novel Approaches to Cancer Therapeutics
Track 6: Cancer Therapy and Clinical Cancer Research
University of Arkansas for Medical Sciences, USA
Sandip K Mishra
Institute of Life Sciences, India
Institute of Life Sciences, India
Title: Unravelling the mechanism of ERR beta behind its role as a tumor suppressor and contribution of specifi c miRNAs and co-regulators in breast cancer cell lines
Time : 09:35-09:55
Sandip K Mishra has been an active researcher in the fi eld of epigenetics of breast cancer, since his postdoctoral training in UT MD Anderson Cancer Center, Houston, TX. Before that, his Doctoral thesis was on Molecular Gerontology. He served as a faculty in the Department of Neurosurgery, UT MD Anderson Cancer Center, Houston, TX before moving to a reputed National Institute under Department of Biotechnology, Govt. of India as a senior scientist. Now he is serving as a tenured senir scientist equivalent to Professor and Principal Investigator of Cancer Biology Laboratory. He has published several papers in high impact peer reviewed journals. He is serving on the editorial boards for the Journal of Cancer Science and Research . He is also serving as the Associate Editor of World Journal of Cancer Research , He is an active member of AACR, USA. He has several grants from funding agencies of Govt.of India. Since he started his career in India towards the end of the year 2007, under his guidance one graduate student was already awarded Ph.D. degree. Six more graduate students are working for their Doctoral degrees under his guidance. Besides postdoctoral student, technicians and other project staffs are also working under him. He has been honored with several awards including Amgen Award during his postdoctoral training in UT MDACC. In recent past, his fi ndings was accepted as late breaking abstract in AACR meeting.
Our study provides the fi rst evidence that ERRβ, which is a coregulator of ERα also acts as a potential tumour-suppressor molecule in breast cancer. Our current report also provides novel insights into the entire cascade of ERRβ signalling events, which may lead to BCAS2-mediated blockage of the G1/S transition and inhibition of the epithelial to mesenchymal transition through FST-mediated regulation of E-cadherin. Importantly, matrix metalloprotease 7, which is a classical mediator of metastasis and Ecadherin cleavage, was also restricted as a result of ERRβ-mediated FST overexpression. Estrogen receptor-α (ER-α) has been reported to control the expression of genes involved in a wide variety of biological processes, including reproduction, development, and breast tumor progression. Th e fi rst level of regulation of these genes depends on two types of transcriptional activity of ERα such as ligand independent carried by AF-1 domain and ligand dependent which involve the AF-2 domain of ERα. Second level regulation involves participation of coactivators, Corepressors and chromatin remodeling complexes. We have previously shown that the metastasis-associated protein-1 (MTA1), a component of histone deacetylase and nucleosome remodeling complexes, represses ER-driven transcription by recruiting histone deacetylases to the oestrogen receptor element (ERE)-containing target gene chromatin in breast cancer cells. Using yeast two-hybrid screening to clone MTA1-interacting proteins, we identifi ed a previously uncharacterized molecule, which we named as MTA1-interacting coactivator (MICoA). Because chromatin is a highly dynamic structure and because MTA1 and MICoA could be detected within the same complex, these fi ndings suggest that MTA1 and MICoA might transmodulate functions of each other and any potential deregulation of MTA1 is likely to contribute to the functional inactivation of the ER pathway, presumably by derecruitmenting MICoA from ER target promoter chromatin. Overall, our study also identifi ed six dicer-processed miRNAs which are regulated by BCAS2. Out of six, expression status of four miRNAs mark disease progression; and two new miRNAs although being reported for the fi rst time in breast cancer, require attention of the scientifi c community due to their highly important targets which are frequently deregulated in breast cancer. Hence our future studies will be directed towards the study of the deregulated signaling pathways aff ected by the identifi ed miRNAs and thereby validating the role of BCAS2 in microRNA-mediated gene silencing during development of breast cancer. For identifi cation of the Dicerprocessed miRNAs regulated by BCAS2, we isolated total RNA aft er knocking down BCAS2 in MCF-7, and performed microRNA profi ling of the samples in Aff ymetrix miRNA 3.0 platform. Summarized fl ow chart of the data analyses has been shown in. All samples were processed in triplicates, raw data were collected as Cel fi les, normalized against quality control and baseline transformed. Th e overall miRNA expression pattern in the microRNA experiments have been shown in. Both the box-whiskar plot and profi le plot interpret that the miRNA intensity values for the knock-down samples has been much constricted to the upper and lower quartiles with the maximum and minimum values restricted compared to control as well indicating the obvious regulation of expression of a signifi cant amount of miRNA population. Aft er normalization, one-way ANNOVA method was applied for derivation of diff erentially expressed miRNAs with a p-value cut-off of 0.05. Th ese shortlisted miRNAs included miRNAs with insignifi cant fold changes. Considering the minimum fold change of >2, 6 miRNAs were identifi ed; namely: miR-let-7b, miR-139-3p, miR-4720-5p, miR-486-3p, miR-589 and miR-639. let-7 has been reported to be associated with self renewal of tumor-initiating cells in breast cancer. miR-139-3p has been shown to be upregulated in grade 3 infl ammatory breast cancers and downregulated in ER-positive breast cancers. miR-4720-5p is being reported fi rst-time to be expressed in breast cancer cells. Most important implication of this fi nding remains in the fact that this miRNA has 4 conserved binding sites predicted for ERα as per Target Scan 6.2. miR-486-3p seems to be simultaneously upregulated with miR-139-3p in grade 3 breast cancers in addition to being overexpressed in infl ammatory breast carcinoma (IBC). miR-589 has been reported to be downregulated in metastatic breast cancer. miR-639 has not been yet reported to be directly associated with breast cancer; however, its predicted targets from TargetScan and miRanda i.e., CAT, PTPRJ and CYP11B2 have been shown to be involved. Overall, our study resulted in identifi cation of six Dicer-processed miRNAs which are regulated by BCAS2. Out of six, expression status of four miRNAs mark disease progression; and two new miRNAs although being reported for the fi rst time in breast cancer, require attention of the scientifi c community due to their highly important targets which are frequently deregulated in breast cancer.
Juan Jose Marugan has been involved for more than twenty years in the translational fi eld working in several aspects of drug discovery in academia, pharmaceutical industry and NIH. He is the author of more than 50 peer review publications and 31 patents, he also has extensive experience as team leader of programs in preclinical lead optimization (Antivirals, Antibiotics, Cardiovascular, CNS, Oncology, Rare and Neglected Diseases, etc.), with many of them advancing toward preclinical development or clinical trials. Since 2008 he holds a group leader position at NCATS.
While the advances in cancer biology and treatment have signifi cantly reduced cancer mortality over all, pancreatic cancer remains a deadly disease. Th e American Cancer Society estimates about 45,220 new cases and 38,460 deaths from pancreatic cancer alone in the United States for the year 2013. Survival rates, which rank among the lowest for any solid organ cancer, have not changed over the last three decades. 72 to 90 percent of patients succumb to the disease within the fi rst year aft er receiving a diagnosis of pancreatic cancer. Reports of long term survival or cure are anecdotal in nature, even for patients where an early disease state was treated with complete surgical resection as the disease inevitably recurs. Th e failure of decades of eff ort is partly due to the lack of strategies that are eff ectively against metastasis, the cause for nearly all pancreatic cancer deaths. We have identifi ed and developed a fi rst in class compound, Metarrestin, that selectively blocks metastasis in an orthotopic pancreatic metastatic cancer model without any detectable adverse impact on tested animals. Metarrestin was identifi ed from a high-throughput high-content screen (HTS) that was followed by an extensive medicinal chemistry optimization campaign, against a cellular subnuclear structure, the perinucleolar compartment (PNC), whose formation refl ects the metastatic capability of cancer cells. Metarrestin has excellent oral bioavailability and tolerability displaying also shows promising results in metastatic xenograft models of prostate and breast cancer. Rational for this new therapeutic approach, together with medicinal chemistry, pharmacokinetics and biological results will be presented.
First Nations University of Canada, Canada
Time : 10:15-10:35
Carrie Bourassa is a Professor of Indigenous Health Studies at the First Nations University of Canada and the Special Advisor to the President, Research. She completed her PhD (Social Studies) in 2008. Her book, based on her dissertation was released in the fall of 2012 entitled Métis Health: The Invisible Problem. She is proud to be the successful Nominated Principal Investigator on a Canada Foundation for Innovation Grant that funded the Indigenous Community-based Health Research Labs at FN Univ. Her research interests include the impacts of colonization on the health of First Nations and Métis people; creating culturally safe care in health service delivery; Indigenous community-based health research methodology; Indigenous HIV/AIDS research; Indigenous end of life care, Indigenous dementia research and Indigenous women’s health.
This lecture will examine the needs of Aboriginal patients at end of life. Results of previous research conducted by our team validate fi ndings from other researchers who consistently suggest that end of life services based on palliative care philosophy are underutilized by ethnic minorities due to cultural barriers. Th e lecture is based on a community-based research project that focused on one culture in need of these services: Aboriginal cultures in Canada. Using Community Action Research methodology, this research put into action recommendations made in the literature to: (1) inform end of life health care providers of culturally sensitive protocol when dealing with Aboriginal families through videos, lectures and pamphlets; (2) inform the community of end of life care services (increase awareness); and (3) increase Aboriginal families’ use of these services. When Aboriginal families experience the passing of a loved one in hospital, they encounter an effi cient bio-technical healthcare system that oft en makes it impossible to follow appropriate cultural traditions. Our community-based activity strives to prevent further mental anguish in hospital at a time of loss by nurturing principles of cultural safety. In this 23-minute video, we carry messages of traditionally minded Aboriginal Elders to health care providers to promote understanding of what is important in passing from this world to the next. Th e video moves through moments in the storyline of the dying person. Our Elders come from a diversity of First Nations in Canada but do not speak for others. Meanings are not conveyed in any universal sense, but developed in individual stories. Th e video is followed by a brief presentation that uses the research to examine what can be done to create culturally safe, patient and family centered care for Aboriginal patients at end of life.
Federal University of Espirito Santo, Brazil
Time : 10:35-10:55
Debora Dummer Meira is Pharmacyst specialized in Biochemistry, Master’s Pharmaceutical Sciences and PhD in Biosciences/Molecular Oncology at Brazilian National Cancer Institute. She has studied tumor molecular biology and therapeutics for more than 15 years and has authored several peer-reviewed reports. She is a member of the Scientifi c Brazilian Pharmaceutical Society in Oncology and President of Espirito Santo section. She also has experience in Pharmaceutical Sciences, Targeted therapies in Oncology, Cancer Immunology & immunotherapy and Cancer Chemoprevention. Currently, is she is Professor and Researcher at Federal University of Espírito Santo looking for agents to reverse, suppress and prevent carcinogenic progression and New Drugs in Cancer Immunotherapy.
This lecture will focus on a variety of topics related to tumour immunology & immunotherapy for clinical evaluation of candidate therapeutics for treating several types of tumors, and will include discussion of: Hallmarks of Cancer: Applications to cancer medicine; Targeted therapies in medical oncology: successes, failures and next steps; Infl ammation in the genesis and perpetuation of cancer; Linking stress system activity and immunity dysregulation to cancer development and progression: infl ammation in the genesis and perpetuation of cancer; Prognostic value and rationale of immunotherapy development; Antibody therapy of cancer/Immunotherapy: combination and dosing schedule are key; Identifi cation of therapeutic targets for Immunomodulation and Cancer chemoprevention. In addition to these subjects, attendees of this lecture will be familiarized with the need for rigorous and stringent testing of candidate immunotherapeutics, so that only the most promising therapies are advanced to clinical trial evaluation of effi cacy when treating patients in the era of Translational Oncology, from the bench to the bedside.
Hasan Erdogan has completed his MD at Firat University, Turkey and received PhD in Physiology at Inonu University, School of Medicine. He is an Associated Dean of Namik Kemal University, Faculty of Medicine. He is also a Lecturer at the Department of Physiology of Basic Medical Sciences. He has published more than 25 papers in reputed journals which have been cited more than 680 times.
Anticancer drugs have severe side eff ects and its clinical usage for cancer therapy is limited by its toxicity. It is important to prevent the side eff ects of anticancer drugs in cancer chemotherapy. Our studies have shown that there are some agents that mostly diminish the side eff ects of anticancer drugs. For instance, an antineoplastic agent bleomycin challenge provokes severe pulmonary fi brosis. Melatonin and Ginkgo bilobaare are highly promising agents in protecting bleomycin-induced lung fi brosis. Most studies have shown that doxorubicin -an anthracycline antibiotic with broad activity against haematological malignancies- has limited clinical usage owing to its cardiotoxicity. Erdosteine and Caff eic Acid Phenethyl Ester protect the myocardial tissue from doxorubicin induced cardiotoxicity. Which mechanisms are underlying the useful eff ects of those agents? Antioxidant eff ects, anti-apoptotic pathway, anti-angiogenic mechanism, so on. It is more important to determine which the most protective agent is against toxicity of anticancer drug. Additionally, it is important to know which types of cancers are protected by those agents.
Institute for Pharmaceutical Sciences, Switzerland
Time : 11:15-11:35
Jonathan Hall is a faculty of Institute for Pharmaceutical Sciences, Switzerland
The mainstream pharmaceutical industry today considers RNA to be an undrugable target and RNA drugs to be too diffi cult to develop. To advance RNA as drugs and targets requires progress in three key areas: New classes of potent and selective ligands; new techniques to characterize RNA-ligand interactions so as to understand and improve their properties in vivo; and methods to identify RNAs that drive disease-associated pathways. MicroRNAs (miRNA) are small RNAs which bind to the 3’-UTRs of mRNAs and regulate gene expression. Th eir complex biosynthesis proceeds via a primary miRNA transcript and a shorter pre-miRNA precursor, both of which comprise stem-loop structures. As miRNA precursors are functional RNAs in their own right, so ligands which inhibit their biogenesis will be of value. Two high profi le examples are the precursors of miR- 122 and let-7. Using techniques developed to dissect the steps of miRNA processing, we show how ligands can be designed to bind pre-miRNAs and interfere with their processing. Th ese ligands are being investigated for their value in the treatment of cancer and HCV.
University of Toronto, Canada
Title: Anti-microRNA-378a enhances wound healing process by up-regulating integrin beta-3 and vimentin
Time : 11:35-11:55
Dr. Burton Yang received his Ph.D. degree from the University of Manitoba in 1992, followed by a postdoctoral training in Manitoba Institute of Cell Biology. He moved Harvard Medical School for a second postdoctoral training in 1993. Dr. Yang took a position as a scientist in Sunnybrook Health Sciences Centre and an assistant professor at the Department of Laboratory Medicine and Pathobiology, University of Toronto in 1995. He was promoted to associate professor in 2001 and professor in 2007. Dr. Yang is currently a Career Investigator for Heart and Stroke Foundation of Ontario. Dr. Yang’s group has been working on the extracellular matrix, especially in the area of proteoglycan. Dr. Yang’s group undertakes the approaches of RNA interference including siRNAs and microRNAs to study the roles of matrix molecules in angiogenesis. Dr. Yang has developed a system to study the role of microRNA in tumor growth and angiogenesis in vitro and in vivo. Three approaches are taken to study miRNA function in transgenic mice expressing miR-17, versican 3’UTR, which can bind endogenous miRNAs and relieve mRNAs for translation, and anti-miR-378 construct.
One criterion for microRNA identifi cation is based on their conservation across species, and prediction of miRNA targets by empirical approaches using computational analysis relies on the presence of conservative mRNA 3’UTR. Because most miRNA target sites identifi ed are highly conserved across diff erent species, it is not clear whether miRNA targeting is speciesspecifi c. We aligned all 3’UTRs of fi bronectin and observed signifi cant conservation of all 20 species. Twelve miRNAs were predicted to target most fi bronectin 3’UTRs, but rodent fi bronectin showed potential binding sites for fi ve diff erent miRNAs. One of them, the miR-378, contained a complete matching seed-region for all rodent fi bronectin, which could not be found in any other species. We have previously demonstrated that expression of miR-378 promoted tumorigenesis and angiogenesis by targeting human Fus-1 and Sufu. Consistent with this result, we found that ectopic expression of miR-378 inhibited cell diff erentiation and promoted cell invasion. To understand the specifi c targeting of miR-378 on fi bronectin, we expressed miR- 378 in mouse breast cancer cells and found that overexpression of miR-378 enhanced cancer cell proliferation, migration, invasion, and colony formation, resulting in inhibition of tumor growth. Induced expression of fi bronectin produced opposite results, while silencing fi bronectin displayed similar eff ects as miR-378. To understand how miR-378 works, we generated transgenic mice expression miR-Pirate378 can not only arrest the functions of mature miRNAs by binding to them but it can also induce the “mis-processing” of the target miRNA producing a non-functional truncated miRNA. Th is approach involves generating an expression construct that produces a RNA fragment with sixteen repeat sequences. Th e construct is named miR-Pirate or microRNA-interacting RNA producing imperfect RNA and tangling endogenous miRNA. Th e transcript of the construct contained mismatches to the seed region, and thus it would not target the potential targets of the miRNA under study. Th e homology of the construct is suffi ciently high allowing the transcript to block miRNA functions. Th e functions of the construct were validated in cell cultures, in tumor formation assays, and in transgenic mice stably expressing this construct. We showed that miR-Pirate378 transgenic mice display enhanced wound healing. Expression of vimentin and 3 integrin, two important modulators of wound healing, is elevated remarkably in the transgenic mice. To explore the possibility of adopting this approach in gene therapy, we transfected cells with synthetic miR-Pirate and obtained the results we expected. Th e miR-Pirate, expressed by the construct or synthesized chemically, was found to be able to specifi cally pirate and silence a mature miRNA through its dual roles and thus could be clinically applied for miRNA intervention. Migration assays showed a greater mobility in the miR-Pirate378-transfected cells, which was due to up-regulation of vimentin and 3 integrin. Both molecules were confi rmed as targets of miR-378, and thus their expression could be rescued by miR-Pirate378. Overexpression of vimentin also contributed to fi broblast diff erentiation, and up-regulation of 3integrin was responsible for increased angiogenesis. Treatment with miR-Pirate378 conjugated to nanoparticle enhanced wound healing in mice. Th us, we have demonstrated that knockdown of miR-378 could increase the expression of its target proteins, vimentin and 3 integrin, which accelerated fi broblast migration and diff erentiation in vitro and enhanced wound healing in vivo.
Syracuse University, USA
Title: The promise of sonodynamic therapy: Using ultrasonic irradiation and chemotherapeutic agents as a treatment modality
Time : 11:55-12:15
Matthew Trendowski is a faculty in Syracuse University, USA. His expertise includes molecular biology, cell biology and cancer research.
Sonodynamic therapy (SDT) is showing promise as a potentially vital alternative to traditional cancer treatment modalities. SDT is a form of ultrasound therapy in which chemotherapeutic agents known as sonosensitizers are administered to increase the effi cacy of ultrasound’s preferential damage on neoplastic cells. Th e attractive features of SDT emerges from the ability to focus ultrasound energy on malignancy sites buried deep in tissues and to locally activate a preloaded sonosensitizer. Furthermore, SDT has shown to induce cell damage in many cancer types and appears to be a versatile treatment method. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. Th is known fact invariably gives rise to the idea of grossly enlarging tumor cells to increase their already noticeable size diff erence with normal cells. Cytochalasin B is a known pharmacological agent that disrupts the actin cytoskeleton and inhibits cytokinesis by interfering with formation of the contractile ring as well as the development of the cleavage furrow. Consequently, the cell does not divide and an immature actin cytoskeleton remains. However, the cell continues to form nuclei and eventually becomes grossly enlarged and multinucleated. Such cells invariably have more DNA targets, increasing the likelihood of apoptosis. Furthermore, the multinucleated cells have a large cell volume, making them more susceptible for direct cell destruction. Preferential damage of malignant cells is actually easily attainable as normal cells exposed to cytochalasin B exit the cell cycle and enter a resting state until suffi cient actin levels are restored. Th erefore, only malignant cells that have lost the ability to enter the rest phase will become grossly enlarged and multinucleated, providing an ideal target for ultrasonic irradiation. Work from our lab has indicated that cytochalasin B does indeed only damage leukemia cells, leaving normal blood cells, unaff ected. Th e designated cell line has been promyleocytic leukemia U937 cells as they are a frequent choice for in vitro studies. Th e U937 cells have routinely become grossly enlarged and multinucleated, providing an ideal target based on size. Th e typical erythrocyte is 6-8μm, while leukocytes fair slightly better with a range of 10-15μm and an average of 12 μm. By contrast, work from our lab has shown that cytochalasin B treated leukemia cells easily grow in excess of 20 μm with some reaching 40 μm in diameter aft er enough exposure. Such cells have reduced cytoskeletal integrity and are easy targets for ultrasonic irradiation. Furthermore, cytochalasin B treated leukemia cells are substantially multi nucleated as cytokinesis is inhibited. Th is provides plenty of targets for a nucleic acid directed agent such as cisplatin or doxorubicin to attack. Th e proposed therapeutic approach could provide for a potent clinical method to treat leukemias and other hematological malignancies. Ultrasound can be directed towards any area of the body, allowing for search and destroy methods to be created in which there is no place for malignant cells to hide. Preferential damage should be substantially increased when a cytochalasin B-nucleic acid agent drug cocktail is applied to ultrasonic irradiation as leukemia cells will be most aff ected by the treatment. SDT has even been shown to reverse drug resistance in K562/A02 leukemia cells when doxorubicin, another nucleic acid agent is combined with ultrasound. Such results are promising and further substantiate SDT as a viable treatment modality. By using cytochalasin B and a nucleic acid agent as sonosensitizers, the author proposes that ultrasonic irradiation will signifi cantly cripple leukemia cell populations, creating a basis to promote the therapeutic approach for in vivo and eventual clinical studies.
Nanjing Medical University, China
Title: Up-regulation of 91H promotes tumor metastasis and predicts poor prognosis for patients with colorectal cancer
Time : 12:35-12:55
Shukui Wang completed his PhD from Nanjing Medical University in 2006. He further studied in Stanford University as a visiting Scholar in 2006. He is the Vice President of Nanjing Hospital affi liated to Nanjing Medical University. His research was focused on tumor pathogenesy, gene therapy. He has published more than 40 SCI papers in reputed journals. He is a peer reviewer of many Journals such as WJG, WJMA, Molecular Genetics and Genomics, BMC Medical Genetics and Lung Cancer.
Background: Long noncoding RNAs (lncRNAs) play widespread roles in gene regulation and cellular processes. However, the functional roles of lncRNAs in colorectal cancer (CRC) are not yet well elucidated. Th e aim of the present study was to measure the levels of lncRNA 91H expression in CRC and evaluate its clinical signifi cance and biological roles in the development and progression of CRC. Methods: 91H expression and copy number variation (CNV) were measured in 72 CRC tumor tissues and adjacent normal tissues by real-time PCR. Th e biological roles of 91H were evaluated by MTT, scratch wound assay, migration and invasion assays, and fl ow cytometry. Results: 91H was signifi cantly overexpressed in cancerous tissue and CRC cell lines compared with adjacent normal tissue and a normal human intestinal epithelial cell line. Moreover, 91H over expression was closely associated with distant metastasis and poor prognosis in patients with CRC, except for CNV of 91H. Multivariate analysis indicated that 91H expression was an independent prognostic indicator, as well as distant metastasis. Our in vitro data indicated that knockdown of 91H inhibited the proliferation, migration, and invasiveness of CRC cells. Conclusions: 91H played an important role in the molecular etiology of CRC and might be regarded as a novel prognosis indicator in patients with CRC.
Sao Paulo University School of Medicine, Brazil
Time : 13:40-14:00
Vanessa Jacob Victorino is a Biologist and has completed her MD from State University of Londrina - Brazil and she is now completing her PhD studies from Sao Paulo University School of Medicine - Brazil. She has published 14 papers in reputed journals and has 10 research awards. Her main research fi eld of interest is metabolic and oxidative alterations in distinct subtypes of breast cancer.
Modifi cations of the mitochondria in tumors have been presented in the literature, as most cancer cells have to support metabolic transformation in order to promote their proliferation and survival. One of the hallmark alterations of tumor cell metabolism is known as the Warburg Eff ect, which tumor cells prefer deriving energy through glycolysis, opposed to the more effi cient process of oxidative phosphorylation. Defective oxidative phosphorylation will lead to production of reactive oxygen species (ROS), which may enhance cell transformation and ultimately lead to tumor initiation, promotion, and progression. Th e high metabolic rate of cancer cells drives their intracellular ROS up to an intermediate level, resulting in a shift in redox balance. Th e peroxisome proliferator-activated receptor- coactivator- 1 (PGC-1) family members are main regulators of several mitochondrial genes. PGC-1α e β have been considered as main regulators of energy homeostasis of the cell and it has been demonstrated that variations of PGC-1s expression occur in tumor cells in order to promote cell survival. Th us, it is known that breast cancer cells display several mechanisms to promote their survival involving redox-signaling pathways and modifying their metabolism. Th e mechanisms by which PGC-1s act to control tumor cells proliferations are not completely understood. During this lecture, it will be discussed recent fi ndings regarding redox and metabolic changes in distinct breast cancer subtypes with a special focus in PGC-1s family members.
Hubei Zhong Shan Hospital, P.R. China
Title: Population-based study of automated DNA image cytometry as a screening method for cervical cancer in rural areas of China
Time : 14:00-14:20
Sun Xiaorong works in Hubei Zhong Shan Hospital, P.R. China.
Introduction: Worldwide, cervical cancer is the third most common cancer among women and over 85% of cervical cancer
occurs in developing countries. It is estimated that China accounts for 14% of the world’s annual incidence of cervical cancer
and 12% of the world’s annual mortalities related to cervical cancer. Th ere is no national screening program for cervical cancer
in China. Screening remains opportunistic and is centered in large cities. 60% of the Chinese population resides in rural areas,
where 90% of incidents of cervical cancer cases might occur. Th ese areas lack suffi cient cytopathologists and cytotechnicians to
interpretate Pap cytology specimens. Th e purpose of this study is to compare automated DNA Image cytometry (DNA ICM)
and liquid-based cytology (LBC) as primary screening methods for cervical cancer and precancerous lesions.
Materials and methods: Our population-based screening program was made possible by the Wuhan government. 15 rural
areas in Wuhan were selected for the study. Cervical samples from the women were collected by a brush and placed into a
cytofi xative solution. Two slides were prepared from each sample using a cytospin. Th e Papanicolaou method was used to stain
one slide for manual cytology examination based on TBS criteria, while the other slide was stained with Feulgen for automated
DNA ICM analysis. Cervical histological biopsies were performed on women whose Pap tests showed LSILs and above and/or
when automated DNA ICM analyses reported at least 3 cells with abnormal aneuploidy (≥5C).
Results: A total of 181,455 women from rural areas in Wuhan were screened using both LBC and automated DNA ICM.
Th e mean age of the women was 39 years, and the age range was 35 to 45 years. We compared the results of automated DNA
ICM to those of LBC. Th e rate of positive detection by automated DNA ICM was 5.4% in women with negative Pap tests and
98.7% in women with HSIL Pap tests. 1,498 women had cervical histological follow-ups. Of these women, CIN1+ lesions were
diagnosed in 525 cases (35.1%), including 7 cases of invasive cervical cancer (0.47%). Th e correlation between histological
fi ndings and LBC and automated DNA ICM results is being analyzed.
Th e preliminary results suggest that automated DNA ICM might be used in countries where it would be diffi cult to introduce population based cervical cancer screening due to the lack of cytopathologists and cytotechnologists.
Zestern Biotechnique LLC, USA
Time : 14:20-14:40
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. He 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 fi eld of protein analysis. He believes the adoption of this technique in basic research and clinical studies would signifi cantly improve the effi ciency and accuracy of protein analysis over existing immunoblot methods.
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 signifi cantly change the world of Cancer research. In the meantime, proteomic research in Cancer Research is clearly lagging behind due to technical limitation. While antigen-antibody interaction serves as the basis of proteomic research, it faces a long-lasting challenge of cross-reactivity of antibodies. In this talk, a novel method, Zestern analysis, is proposed to solve this problem, with clear advantages of simple, fast, specifi c and quantifi able, suitable for multi-well format analysis of protein samples. It follows a standard dot blot protocol until the formation of immunocomplex containing both antigen of interest and detection antibody on the membrane. An elution step is added in Zestern analysis before the detection step to ensure the specifi city of the analysis. Taking advantage of the reversibility of antibody-antigen interaction, small peptide bearing the protein sequence of the antigen of the interest is used in elution solution to liberate the detection antibody from the immunocomplex into elution solution for direct quantifi cation. Continuing exploration of this method may revolutionize the fi eld of proteomic research with direct impact on high throughput immunoblot analysis to move the fi eld of Cancer Research forward.
University of Illinois, USA
Time : 14:40-15:00
Gnanasekar Munirathinam has been studying prostate cancer molecular biology and experimental therapeutics for over 10 years, during which time he has authored several peer-reviewed publications. He has served on the editorial boards for Oncology Letters, Pharmacologia, Journal of Oncology and Biomarkers Research, American Journal of Cancer Biology, American Journal of Clinical Cancer Research, American Journal of Cancer Therapeutics and Pharmacology, and he is an Academic Editor for PLOS ONE. He has also served on the advisory board of RNAi Research and Therapeutics Conferences organized by Global Technology Community. He has received several awards and honors throughout his career.
This lecture will address a variety of topics related to the development of natural compounds derived from dietary and herbal plant sources for experimental evaluation of candidate therapeutics for treating prostate cancer, and will include discussion of topics: Bioactive compounds from various natural sources, cellular pathways contributing to disease progression, molecular drug targets, pre-clinical animal models of prostate cancer; acquired resistance to therapy; bioavailability issues; and novel combination therapies with natural compounds. In addition to these subjects, attendees of this lecture will be familiarized with the need for rigorous and stringent testing of alternative candidate therapeutics as current conventional treatments are not eff ective against advanced prostate cancer and oft en associated with side eff ects. Th is seminar talk will also highlight the usefulness of natural products in chemo preventive measures against prostate cancer.
University of Texas Medical School, USA
Title: Transanal endoscopic video assisted rectal cancer resection, new techniques addressing neoplasms
Time : 15:00-15:20
Ali Mahmood graduated from Baylor University. Upon completion of medical school in New York, he matriculated at St. Joseph Mercy Oakland / Wayne State University for his general surgery training. Upon completion of his residency he pursued a fellowship in colon and rectal surgery at the Ferguson Clinic, Michigan State University. He is board certifi ed by the American Board of Surgeons. He has authored numerous papers published in peer reviewed journals. He has delivered multiple talks and presentations at national and international conventions. He was awarded the Alexander J. Walt award in 2008, one of two top awards given at the Michigan Chapter of the American College of Surgeons. He was selected as Faculty for the International Endovascular and Laparoscopic Congress in New York, 2006. He serves as a reviewer for Radiology Case Reports journal and served as a reviewer for Contemporary Surgery. He is appointed Faculty and an Assistant Professor in the Michael E. DeBakey Department of Surgery at Baylor College of Medicine. His primary interest in the fi eld of colorectal surgery is colon and rectal cancer, along with benign diseases such as Crohn’s disease, ulcerative colitis and diverticular disease. He presently serves as Chairman of Surgery at Methodist Sugar Land hospital. He is an appointed member to the medical executive committee at St. Luke’s Sugar Land hospital. He is an appointed member to the committee on cancer for Methodist Sugar Land hospital.
Background: Early rectal cancer beyond the reach of conventional instruments has resulted in major abdominal and pelvic operations. As visualization is compromised beyond 6-8 cm, proximal to the anal verge, there have been several innovations and techniques to address T1 and T2 rectal cancer in the mid to upper rectum. Transanal Endoscopic Microsurgery (TEM) was a technique that had garnered some success, however with expensive instrumentation along with limitations in instrument mobility, this technology was not applicable to many patients. Transanal Endoscopic Video Assisted (TEVA) rectal resection off ers a cheap and readily accessible media to address rectal cancer. Objective: Th e objective of this study was to evaluate the safety and effi cacy of TEVA rectal resection. Th is is a rather new technique and has the propensity to avoid a major pelvic dissection and its associated morbidity. Methods: From August 2010 to July 2013, all consecutive cases of TEVA rectal resection were examined and evaluated. Th e size of the cancer, T invasion, lymph node status and distance from the anal verge were recorded. Th e margins following resection were evaluated. Th e disease free occurrence was followed and recorded. Individual surgical techniques were compared. Results: 30 TEVA cases were retrieved. Th e average distance from the anal verge was 7.3 cm with a deviation of +/- 2.0 cm. Th e tumor size median was 2 cm. Th e T status was T1 or less for 25/30 (83.3%) with the remaining 5 lesions being T2. Margins for all lesions were negative. Th ere was a single episode of returning to the operating room to increase a negative proximal margin, from 1 mm to 2.8 mm. Th e average length of stay was 0.7 days. Th ere was a single outlier that stayed in the hospital for 3 days due to cardiac issues that arose peri-operatively. All follow up has rendered the patients disease free. Signifi cance: Rectal cancer that is found between 6-10 cm proximal to the anal verge, that is staged at T1 or less can be successfully resected without performing a radical pelvic dissection. Th is has been made possible though TEVA rectal resection. Patients are spending less than 24 hours in the hospital. Th eir return to work and quality of life is not compromised in comparison to formal oncologic surgery. Th us so far, the disease free survival has been excellent. Th is is yet another technique that can and will be utilized in the management of cancer.
Kuwait University, Kuwait
Title: A ‘switch’ model for de-repression of translation of transfected RNA heteroduplexes in breast cancer cells
Time : 15:20-15:40
Yunus A Luqmani graduated from Chelsea College, University of London and obtained his PhD in Neurochemistry from Imperial College, followed by Postdoctoral research at Max Planck Institut fur Biophysikalische Chemie, Gottingen. After further appointments at various London institutes, including Queen Elizabeth College, Ludwig Institute for Cancer Research at Royal Marsden Hospital, St George’s and Charing Cross Hospitals, he was appointed Associate Professor at Kuwait University in 1994 where he is currently Professor and Chairman, Dept. of Pharmaceutical Chemistry in the Faculty of Pharmacy. His research work focuses on identifying cellular processes that are implicated in resistance to endocrine therapy of breast cancer.
The aim of this work was to construct a proof of principle model system to test a mechanism for inducing production of protein from externally introduced RNA as a novel means of inducing selective cell death dependent upon over-expression of endogenous genes. mWasabipIVT2.0 plasmid was modifi ed to include 2 short tandem repeats of human estrogen receptor (ER) coding sequence followed by a Kozak initiation sequence, coding sequence of eGFP and 3’ untranslated rabbit β globin polyadenylation signal sequences. An upstream 5’ T7 promoter was utilised for in vitro transcription and capped, polyadenylated transcripts were translated in rabbit reticulocytes before and aft er hybridisation to short oligos complementary to the ER sequence to ensure that only un-hybridised RNA produced eGFP, detectable by western blotting. Anticipated production of the eGFP with un-hybridised but not with the hybridised duplex RNA (that should prevent ribosomal processing of the transcript) when transfected into ER negative MDA231 cells, was determined by eGFP fl uorescence. Transfection of the prehybridized RNA into ER expressing MCF7 cells was expected to result in a competitive transfer of the ER oligos from the construct onto cellular ER mRNA permitting translation of the eGFP; preliminary experiments indeed showed partial switch on off expression from the RNA/ER duplex. Substitution of the eGFP with pertussis toxin sequence resulted in signifi cant cell death 72h post-transfection in both MCF7 and MDA231 with un hybridised transcripts. Further experiments are needed to optimize dosing of hybridized transcripts to obtain a diff erential killing eff ect between ER expressing and non-expressing cells.
Hong Kong Baptist University, China
Time : 15:40-16:00
Dr Ko obtained his bachelor degree at the University of Toronto, Canada in Toxicology and Nutritional Sciences. He then continued his doctoral study at the University of Hong Kong and obtained a PhD in Pharmacology. Dr Ko had lectured in the Medical School of the University of Hong Kong for years and had been actively involved in many research projects. He had published around 100 journal papers and conference proceedings. His research focuses on the signaling pathways of anti-carcinogenic chemotherapeutic drugs, with special interest in the actions of herbal terpenoids and flavonoids in treating colon and liver cancers. Dr Ko is currently the subject coordinator of Pharmacology, Clinical Anatomy & Embryology, and Introduction to Medicine & Diseases.
Background: Glucose-regulated proteins (GRP) are induced in the cancer microenvironment to promote tumor survival, metastasis and drug resistance. In our previous studies, AST was obtained from the medicinal plant Astragalus membranaceus, which possesses anti-tumor and pro-apoptotic properties in colon cancer cells and tumor xenograft . Th e present study aimed to investigate the involvement of GRP in endoplasmic reticulum (ER) stress-mediated apoptosis during colon cancer development, with focus on the correlation between AST-evoked regulation of GRP and calpain activation. Methods: Th e eff ects of AST on GRP and apoptotic activity were assessed in HCT 116 human colon cells. GRP78 gene silencing was performed to confi rm the importance of GRP in anticancer drug activities. Modulation of GRP and calpains was also studied in tumorxenograft . Results: ER stress-mediated apoptosis was induced by AST, as shown by elevation in both spliced XBP-1 and CHOP levels, with parallel up-regulation of GRP. Nevertheless, the initial increase in calpain activity as well as calpain I and II protein level was gradually declined at later stage of drug treatment. Besides, the induction of GRP was partly reversed by calpain inhibitors, with concurrent promotion of AST-mediated apoptosis. Th e knockdown of GRP78 by gene silencing resulted in higher sensitivity of colon cancer cells to AST-induced apoptosis and reduction of colony formation. Th e association between calpains and GRP78 had been confi rmed by immunofl uorescence staining and immunoprecipitation. Modulation of GRP and calpains by AST was similarly demonstrated in nude mice xenograft , leading to tumorgrowth inhibition. Conclusion: Our fi ndings exemplify that calpains, in particular calpain II, play a permissive role in the modulation of GRP78 and consequent regulation of ER stress-induced apoptosis. Combination of calpain inhibitors and AST could exhibit a more pronounced pro-apoptotic eff ect. Th ese results help to envisage a new therapeutic approach in colon cancer by targeting calpain and GRP.
Indiana University Health, USA
Time : 16:15-16:35
Hesham Mourad is a Doctor of Pharmacy graduated in 2011. He completed a general pharmacy residency in 2012. After that he worked as clinical pharmacist in a community teaching hospital primarily in critical care and outpatient oncology practice. He co-authored two oncology related case reports which he participated in the treatment decision making process. one case was published in the Journal of the National Comprehensive Cancer Network and the other case was published in Journal of Oncology Pharmacy Practice. He is also board certifi ed pharmacotherapy specialist.
This lecture will review the current role for bendamustine in refractory Hodgkin’s Lymphoma. Several articles and case reports will be reviewed and evaluated to defi ne the current role of bendamustine in those patients. Also recommendations from the current guidelines will be evaluated based on those articles. In addition to these subjects, attendees of this lecture will able to decide when to use bendamustine in those selected patient.
Cairo University, Egypt
Title: Application of data mining techniques to explore predictors of HCC in Egyptian patients with HCV related chronic liver disease
Time : 16:35-16:55
Dalia A Omran is a faculty in Cairo University, Egypt. She has 23 publications and 42 citations.
Background & Aims: Hepatocellular carcinoma (HCC) is the second most common malignancy in Egypt. Data mining is a method of predictive analysis which can explore tremendous volumes of rich information to discover hidden patterns and relationships. We aim to develop a non-invasive algorithm for prediction of HCC. Th is algorithm should be economical, reliable, easy to apply and acceptable by domain experts. Methods: Th is cross sectional study enrolled 315 patients with hepatitis C virus (HCV) related chronic liver disease (CLD); 135 HCC, 116 cirrhotic patients without HCC and 64 patients with chronic hepatitis C. Using data mining analysis, we constructed decision tree learning algorithm to predict HCC. Results: Decision tree algorithm was able to predict HCC with recall (sensitivity) 83.5% and precession (specifi city) 83.3% using only routine data. Th e correctly classifi ed instances were 259 (82.2%), and the incorrectly classifi ed instances were 56 (17.8%). Out of 29 attributes, serum alpha fetoprotein (AFP), with an optimal cutoff value of ≥50.3 ng/ml was selected as the best predictor of HCC. To a lesser extent, male sex, presence of cirrhosis, AST>64U/L, and ascites were variables associated with HCC. Conclusion: Data mining analysis explores data to discover hidden patterns and enables the development of models to predict HCC utilizing routine data as an alternative to CT and liver biopsy. Th is study has highlighted a new cutoff for AFP (≥50.3 ng/ ml). Presense of a score of > 2 risk variables (out of 5) can successfully predict HCC with a sensitivity of 96% and specifi city of 82%.
Tokyo University of Science, Tokyo
Time : 16:55-17:15
Fumio Sugawara has fi nished his PhD from Tohoku University in 1979 and was a Researcher at RIKEN. Then he was promoted by Tokyo University of Science in 1996. Since then he has published more than 200 papers in Chemistry and Biology research.
Experimental techniques in basic research have been dramatically developed and incessantly been upgraded. Authors have extensively studied about isolation of bioactive compounds from natural products and identifi cation of their biological targets using the T7 phage display technology. Th ese studies contribute to our understanding the molecular basis underlying the mechanisms of action for the bioactive compounds as well as generating new chemotherapeutics for clinical applications, so called “molecular target drugs” like greevec. Among the number of compounds with unique structures and bioactivities, sulfoquinovosylacylglycerol (SQAG), a sulfoglycolipid from sea algae, has been discovered to be a strong anti-angiogenic radiosensitizer on tumor radiotherapy. In an eff ort to our collaboration work with several research groups over the past decade, CG-0321 has been generated to be a promising lead compound of SQAG for clinical practice and almost completed the preclinical evaluations on 2013. Furthermore, in our recent in vivo live imaging studies at Radiation Biology Branch/ NCI/NIH, we have found CG-0321 modulates the biophysical conditions on tumor microenvironment, which may strikingly result in a radiosensitization. Here, we will present our recent achievement of SQAG work as a contribution to cancer therapy, with introducing the state-of-the-art biochemical and biomedical technologies used in our studies. We also discuss about the paradigm shift on drug targeting for development of new cancer chemotherapeutics, caused by the advancement of technology.
University of California, USA
Title: MicroRNAs in frequently deleted loci of prostate cancer: Novel players in disease progression, recurrence and metastasis
Time : 17:15-17:35
Sharanjot Saini is an Assistant Professor in the Department of Urology at UCSF/SFVAMC. Her research is primarily focused on understanding the molecular basis of progression and metastasis of prostate cancer. She completed her Post-doctoral training at University of Massachusetts Medical School Worcester and the University of California, San Francisco (UCSF)/SFVAMC. She currently holds a NCI RO1 Grant from the NIH and has authored over 42 peer reviewed papers and 4 book chapters. She is a reviewer and editor for major oncology journals.
A major clinical challenge in prostate cancer is the elucidation of pathways of tumor progression, recurrence and metastasis, which could lead to the design of better diagnostic and therapeutic strategies against the disease. Th is lecture will address the role of novel microRNA (miRNA) genes located at frequently deleted genomic region in prostate cancer epithelial-to mesenchymal transition (EMT), recurrence and metastasis. Th e most frequent alteration in the prostate oncogenome is the loss of chromosome (chr) 8p21 that has been traditionally associated with the loss of homeodomain protein, NKX3.1, that plays important roles in prostate carcinogenesis. Genomic deletions of this region increase signifi cantly with tumor grade and are associated with poor prognosis in prostate cancer suggesting the critical involvement of this region in prostate cancer progression. Recent genomic studies suggest that this region harbors alternative tumor suppressor genes apart from NKX3.1. However, the identity of these tumor suppressors has largely remained elusive. Our studies support a novel, paradigm shift ing hypothesis that this frequently deleted locus is associated with a cluster of miRNA genes that are lost in prostate cancer and play an important mechanistic role in prostate cancer progression and metastasis by regulating Epithelial-mesenchymal transition (EMT). Also, these miRNA genes regulate prostate cancer tumor-initiating cells, implicating a role in prostate cancer recurrence. Th ese studies have high transformative potential in the fi eld of prostate cancer and will potentially identify new agents for diagnosis, prognosis and therapy of advanced prostate cancer.
Nanjing Medical University, China
Title: Imaging of osteolytic bone metastasis from breast cancer with new integrin αvβ3 receptor targeted radiotracer: 68Ga-DOTA-RGD2
Time : 17:35-17:55
Zizheng Wang has completed his MD at the age of 35 years from Nanjing Medical University. He is the Director of Nanjing Nuclear Medicine Center, affi lated to Nanjing Medical University. His research was focused on receptor targeted tumor imaging and therapy with specifi c radiotracers such as radiolabelling NOTA-OC, DOTA-OC (somatostatin), RGD peptides (integrin αvβ3), folate analogue or derivants (folate), PSMA targeting peptides (prostate specifi c membrane antigen). He has get patents and tried his best to transform it into clinic. He has published more than 5 papers in reputed journals.
This study was to investigate the value of integrin αvβ3 targeted microPET/CT imaging with 68Ga-DOTA-RGD2 as radiotracer
for the detection of breast cancer osteolytic bone metastases. we prepared 68Ga-DOTA-RGD2 via one-step method. Animal
model with Parathyroid hormone (PTH)–induced osteolysis in the calvarium was established and served as PTH Group (BP).
Biodistribution study of 68Ga-DOTA-RGD2 was carried out in BP. Animals with injection of same volume of saline instead of
PTH was served as Control group (BC). Integrin receptor block study was done with pre-injection of high dose of DOTARGD
2. 68Ga-DOTA-RGD2 and 18F-NaF microPET/CT imaging were perfromed respectively and radiotracer distribution were
compared between BP and BC. Breast cancer osteolyic bone metastases was established via intrcardial injection of breast cancer
cells (MDA-MB 231). 68Ga-DOTA-RGD2 microPET/CT imaging were perfromed for the detection of breast cancer osetolytic
bone metastases. Animals were sacrifi ced and bone lesions were harvested for pathological examination. We found that 68Ga-
DOTA-RGD2 was stable in vitro and its radiopurity was as high as (96.4±2.1)% 3h aft er its preparation. Its blood elimination
was fast while its uptake by the liver and kidneys were relatively low. It was discharged soon aft er its intravenous injection. In
the BP group, regional uptake of 68Ga-DOTA-RGD2 in osteolytic lesion of calvarium (%ID/g) reached peak (5.14±0.65 ) 60 min
aft er tail vein injection. It was signifi cantly more than that in BC group (2.06±0.35，t=7.81，P<0.05). Bone radiotracer uptake
ratio of osteolytic lesion to normal calvrium （O/N）was compared based microPET/CT imaging. Bone O/N of 68Ga-DOTARGD
2 was (6.1±0.97), signifi cantly greater than that of 18F-NaF (1.2±0.33,t=10.17, P<0.05). 68Ga-DOTA-RGD2 microPET/CT
imaging was able to demonstrate the ostelytic bone metastasis in calvarium, thoracic vertebrae and lung metastasis. Th ey were
confi rmed by pathology results. According to our results, 68Ga-DOTA-RGD2, as new integrinαvβ3 receptor targeting radiotracer,
was potential for positive imaging and early detection of oseolytic lesion or breast cancer osteolytic bone metastasis.
- Track 3: Advances in Cancer Detection, Imaging, Management & Prevention
Track 4: Tumor Science
Track 5: Novel Approaches to Cancer Therapeutics
Track 6: Cancer Therapy and Clinical Cancer Research
New York Medical College, USA
University of St. Thomas, USA
Time : 09:40-10:00
John Abraham is a Professor at the University of St. Thomas in St. Paul, Minnesota. He has a 20-year career of medical device design, basic research, and litigation (burn injury and intellectual property expert). His research focuses on the application of heat transfer and fl uid mechanics to various biomedical situations including treatment of benign and cancerous growths. He has in his name approximately 200 papers, conference presentations, books, and book chapters on applied and fundamental thermal sciences. He serves on the editorial board of many journals and has edited the Advances in Numerical Heat Transfer, Advances in Heat Transfer, and the Handbook of Numerical Heat Transfer. He also edited a special edition of International Journal of Heat and Mass Transfer focusing on biological applications of heat transfer. His technical area is thermal sciences which includes heat transfer and fl uid mechanics applied to the human body. His recent projects involve scald injuries, cryosurgery, thermal ablation, neurostimulation, implanted medical device safety, catheter design, stem- cell treatments, cardiovascular disease and aneurysm assessment.
While there any many varied treatments for cancer, one emerging non-medical approach is the use of cryosurgery. Cryosurgery involves the freezing of tissues in order to cause their subsequent death. A standard protocol is complicated by the nature of cellular injury which is governed by complex biological mechanisms. For instance, tissue which is frozen very quickly results in intracellular ice formation and the subsequent damage to cellular membranes. Alternatively, for cases with slow freezing, the water is able to pass out of the cells and freezes in the extracellular spaces, thereby resulting in cell injury by dehydration. Regardless of the mechanism of cellular injury, for clinical settings it is essential that the treating physician is able to visualize the size, shape and position of the targeted area. When cryo-surgical probes are used in the treatment, their number, placement, temperature setting, and treatment duration are factors which determine the treated region. Here, we use advanced numerical simulation along with patient-specifi c kidney geometries. In the computational model, the tumors can be placed arbitrarily to match those of the patient. Th e soft ware allows the treating physician to experiment with various techniques and to perfect the ultimate procedure in a virtual environment prior to real-life treatment. In this way, it is possible to more accurately target the tumor to ensure it is completely enclosed in the treatment zone meanwhile minimize the damage to nearby healthy tissue. Th e simulations can be carried out in less than four minutes so that their employment is not onerous to the physician.
University of Lyon, France
Time : 10:00-10:20
François Lux is former student from Ecole Normale Superieure de Lyon and has received its PhD in 2007. He was recruited as an Associate Professor in University Lyon 1 in 2009. Since its recruitment by University Lyon 1, he has authored more than 25 publications on nanoparticles for medical applications in peer reviewed journals. He is the coordinator of French ANR program Gd-Lung that evaluates the interest of AGuIX nanoparticles for lung pathologies and co-organizer of nanohybrides meetings that cares about the interest of hybrid nanoparticles for biomedical applications.
This lecture will take place in the fi eld of nanomedicine and will present a new theragnostic compound with high radiosensitizing effi ciency. Th e approach is based on the use of a family of ultrasmall nanoparticles (AGuIX) that can be followed by MRI and can deliver very high doses in the vicinity of the nanoparticle under irradiation. First, a fast description of the synthesis and the characterization of the nanoparticles will be proposed. Th e particles are made of polysiloxane network and are surrounded by gadolinium chelates. AGuIX particles present high radio sensitizing eff ect that will then be illustrated by in vitro experiments on radio resistant cells under diff erent types of irradiations (photons at diff erent energies, ion). Th ese experiments point out the interest of nanoscale dose deposition for radiotherapy treatment. Th e behavior of the nanoparticles aft er intravenous injection in tumor bearing animals will also be presented. Eff ective passive accumulation of the nanoparticles in the tumors due to enhanced permeability and retention eff ect is observed by MRI, fl uorescence imaging and/or scintigraphy (aft er labelling by an adapted radioactive isotope). Even at low doses of nanoparticles in the tumor, in vivo experiments of radiotherapy show an important increase of the lifespan of tumor bearing rodents. Th ese results are really encouraging for a further transfer to clinical applications.
Eliane Campos Coimbra is a Biologist with Master in Genetics (2007) and PhD in Therapeutic Innovation (2012) at Federal University of Pernambuco. Currently she is Postdoctoral research fellow of the Laboratory of Molecular Studies and Experimental Therapy (LEMTE) at Department of Genetics, Federal University of Pernambuco. Her research focuses on HPV infection and cervical cancer, including the development of vaccinal strategies and evaluation of mRNA and microRNA expression changes, to understanding the molecular basis of cervical carcinogenesis and to identify potential biomarkers.
This lecture will address topics related to the search for potential biomarkers for cervical cancer. Th e fi rst part of this lecture will present the prevalence of cervical cancer on a worldwide scale; the interplay between high-risk HPV and host cell molecules in cervical cancer development; and the need for robust biomarkers. In the second part, the topics will focus on critical parameters to achieve reliable qPCR results in obtaining mRNA and miRNA markers for cervical cancinogenesis; and will include discussions on: Th e careful evaluation of expression stability of candidate reference genes; the importance of including cervical premalignant lesions in gene stability analyzes; the use of individual samples x pool of samples; the use of multiple reference genes; the use of a single reference gene. Th erefore, attendees of this lecture will be familiarized with the needs for rigorous validation of reference genes in qPCR assays to identify reliable biomarkers for cervical carcinogenesis.
University of Kansas, USA
Title: Antibody against CD44s inhibits pancreatic tumor initiation and post-radiation recurrence in mice
Time : 10:40-11:00
Liang Xu is an Associate Professor in University of Kansas, USA. He has 87 publications and 3, 511 citations.
CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes of patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. Th is strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s aff ect pancreatic cancer initiation or recurrence aft er radiotherapy. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time PCR and immunoblot; levels were correlated with patient survival times. We studied the eff ects of anti-CD44s in mice with human pancreatic tumor xenograft s, and used fl ow cytometry to determine eff ects on TICs. Changes in CD44s signaling were examined by real-time PCR, immunoblot, reporter assay, and in vitro tumorsphere formation assays. Th e levels of CD44s were signifi cantly higher in pancreatic cancer than adjacent non-tumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months, compared to 43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and post-radiation recurrence of pancreatic xenograft tumors in mice. Th e antibody reduced the number of TICs in cultured pancreatic cancer cells and in xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s downregulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited STAT3-mediated cell proliferation and survival signaling. Th e TIC marker CD44s is upregulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and post-radiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the tumors. Strategies to target CD44s might be developed to block pancreatic tumor formation and post-radiotherapy recurrence in patients.
Martin Rocken is Professor and Chairman of a large dermatology department, with a strong focus on clinical, experimental and translational oncology. He is member of major societies namely the German Academy of Sciences. He is/was executive board member of major journals, funding and research organizations. His lab, supported by public funds, characterized major signals allowing the antigen-specifi c induction of either TH1 or TH2 cells in vivo, fi rst in mice and then in humans, and established immune-based therapies. Recently, they fi rst described that immunity can arrest cancer by inducing senescence, a permanent growth arrest, even in the absence of killing.
Growing cancers are characterized by infi ltrating cancer cells, neo-angiogenesis and a cellular infi ltrate with immunosuppressive properties. As it is strongly believed that cancer immune-control strictly relies on the killing of individual cancer cells, and multiple approaches enhance the activity of tumor-reactive killer cel ls. While generally accepted, this view confl icts with the observation that effi cient anti-cancer immunity rarely eradicates cancer. Th us, effi cient immunotherapy of metastatic melanoma causes cancer regression and stable growth arrest rather than cancer eradication. Recent data now show that adaptive immunity can arrest cancers through signals mediated by the TH1 cytokines interferon (IFN) and tumor necrosis factor. When signaling together, IFN and TNF can induce a permanent growth arrestin cancers that is named senescence. Simultaneous action of IFN and TNF activates the p16/Rb-senescence pathway in a large spectrum of cancers. Effi cient activation oft he p16/Rb-senescence pathway drives even advanced cancers into senescence. Importantly, the TH1 cytokines IFN and TNF also induce senescence in a large spectrum of human cancers. Such senescent cancers share many similarities with premalignant tumors, including their failure to grow in an immune-incompetent environment. As cytokine-induced senescence can also arrest established cancers, treatment of established cancers by TH1 cytokines is currently investigated.
Janssen R&D, USA
Time : 11:20-11:40
Jeannie Rojas is a Sr. Director with Janssen Research & Development, a Johnson & Johnson Pharmaceutical Company. Her last six years at Janssen have been with Centyrex, a Janssen Internal Venture which focuses on alternative scaffold therapeutics. Prior to Centyrex, she has held positions of increasing responsibility in R&D and Clinical Pharmacology. She has a PhD from the Department of Chemistry at the University of Pennsylvania.
Centryrins, a novel class of alternative scaff old protein based on a consensus fi bronectin domain, are being developed to be the next generation of biological therapeutics. Centyrins also have biophysical properties ideally suited for cancer imaging and detection applications. Centyrins, which provide the specifi city of an antibody, are rapidly developed to new targets of interest using in vitro display. Centyrins are easy to manufacture in multiple expression systems and have been engineered to be of low potential immunogenicity. Centyrins can be stored at room temperature and are mono-dispersed at high protein concentrations. Th e molecules are stable over a wide range of pH and have multiple sites amenable to site specifi c labeling and chemical coupling. Lastly, Centyrins are modular in nature and have been successfully engineered as bi-specifi c and higher order multimers. With a molecular weight of just 10 KDa, Centyrins are an ideal size for applications requiring a short half- life, though the molecules are also compatible with several half-life extension strategies if a longer half-life is required. Th e small size and robust biophysical properties make them amenable to multiple delivery methods allowing for high concentrations at the site of disease, while simultaneously lowering toxicity to non-target organs. In addition, due to their small size, Centryins may penetrate further into tissues resulting in higher sensitivity for imaging applications. In this presentation, the latest in vivo and in vitro data will be presented to showcase the highly desirable biophysical properties of the Centyrin molecule as cancer therapeutics, imaging and detection agents.
Université de Sherbrooke, Canada
Title: Irradiation of mouse mammary gland stimulates the migration of triple negative breast cancer cells and development of lung metastases
Time : 11:40-12:00
Benoit Paquette is a radiobiologist who studies the biological consequences of radiation therapy. His research is oriented towards improving radiotherapy for brain and breast cancer, as well as preventing cancer cell invasion induced by radiation. His team has pioneered the use of the Gamma Knife for irradiating localized patches of cortex in rodents. Two clinical trials based on results obtained in his laboratory are currently underway in brain tumor patients. He is the Director of the Department of Nuclear Medicine and Radiobiology, University of Sherbrooke, and he is the Vice-president of the International Society of Radiobiology in French Language.
Emergence of migratory phenotype is believed to be the consequence of acquired mutations in cancer cells. Alone, this mutation-based hypothesis cannot explain the progression of all tumors. Since infl ammation can be associated with the promotion of metastases, it is important to determine whether radiation-induced infl ammation in healthy breast could stimulate the migration of cancer cells and ultimately favor the formation of metastases. Our study was done with the D2A1 breast cancer cells which are triple negative (TNBC), a subgroup of breast cancer at higher risk of early recurrence. A single mammary gland of Balb/c mice was irradiated with 4 fractions of 6 Gy given at 24h interval. Aft er the last irradiation, D2A1 breast cancer cells were implanted close to the nipple. Th is protocol eliminated confounding eff ects that could occur by irradiating the tumor and the mammary gland at the same time, such as selection of a subpopulation of cancer cells that could be more likely to migrate. Pre-irradiation of mammary gland before implantation increased the migration of cancer cells, the quantity of circulating cancer cells and the number of lung metastases. Th ese adverse eff ects were associated with induction of pro-infl ammatory molecules such as COX-2 and IL-6. In conclusion, we propose an alternative mechanism to explain the higher risk of early recurrence for TNBC based on pro-migratory molecules induced by radiation.
National Cancer Institute, USA
Title: Countering tumor progression by targeting of a driver of the epithelial-mesenchymal transition
Time : 12:00-12:20
Claudia Palena is an Investigator and the Head of the Immunoregulation Group in the Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda. She received her PhD degree in Biochemistry from the National University of Rosario, Rosario, Argentina, in 2000, and subsequently completed a Postdoctoral Fellowship in the Laboratory of Tumor Immunology and Biology, NCI. She has published extensively in the area of human tumor antigen discovery and cancer vaccines. Her current research is focused on the development of novel immunotherapeutic approaches aimed at targeting critical events in tumor progression with the ultimate goal of designing vaccine(s) platform(s) and combinatorial therapies for the prevention and/or treatment of metastases in human cancer.
The epithelial-mesenchymal transition (EMT) constitutes a relevant process during the progression of carcinomas, as it mediates the conversion of stationary, epithelial tumor cells into mesenchymal-like, invasive cancer cells. We recently identifi ed the T-box transcription factor brachyury, a molecule predominantly expressed in human tumors but only rarely expressed in normal adult tissues, as a novel driver of the EMT process in human carcinoma cells. Brachyury was demonstrated to induce the expression of molecules associated with the mesenchymal phenotype, human tumor cell motility and invasiveness in vitro, as well as metastatic propensity in xenograft models. Analysis of expression in multiple human tumor tissues demonstrated a preferential expression of Brachyury in higher stage lung tumors, suggestive of a role of Brachyury in human lung cancer progression. Analysis of breast cancer tissues also revealed expression of Brachyury in primary breast tumor samples as well as in 100% of breast cancer metastatic lesions analyzed by immunohistochemistry. We have now shown a positive correlation between Brachyury expression in epithelial tumor cells and features of tumor stemness, including resistance in response to treatment with various chemotherapeutic agents or radiation. In search for an approach to target tumor cells with high levels of brachyury, we have characterized its immunogenicity and developed brachyury-based cancer vaccine platforms, one of which is currently undergoing Phase I clinical testing. We hypothesize that the eradication of brachyury-expressing tumor cells via immunotherapeutic approaches could be effi cient at eliminating tumor cells with invasive/metastatic potential as well as tumor resistance to conventional therapies.
INS- National Institute of Health, France
Time : 13:05-13:25
Jerzy Trojan currently works in INS- National Institute of Health, France.
Strategy of immune-gene therapy based on anti-gene anti IGF-I approach (antisense/triple helix) established in the experimental treatment of murineglioma, hepatoma and teratocarcinoma has permitted to stop the development of cancer structures in tumour bearing animals. Th e eff ectiveness of anti-gene anti IGF-I therapy was evaluated in clinical treatment principally of brain malignant tumour – glioblastomamultiforme (six cases), and then in cancers of liver, colon, ovary, uterus and prostate (two cases of each). Th e glioblastomapatients treated by classical surgery followed by radiotherapy were “vaccinated” by injection of genetically modifi ed cancer cells: cultured cancer cells, originated from tumor removed during surgery, were transfected by antisense/triple helix anti IGF-I expression vectors. Th e PBL cells of treated patients have demonstrated an increasing level of T CD8+CD28+ cells with characteristic switch from CD8+11b+ to CD8+11b- aft er every of the three vaccinations. Th e minimum survival of treated glioblastomapatients was 19 months and maximum 24 months (in two cases three and four years, respectively). Other cancer patients were supervised up to 19 months. Th e described Phase I trial presents promising results - an increase in immune response goes together with life span. Th ese results have confi rmed the role of immune phenomenon present in antisense anti IGF-I strategy investigated in preclinical experiments – suppression of animal tumours treated by the same cellular gene therapy inducing T CD8+ response.
Ramani Ramchandran has studied how astrocytes directly infl uence tumor cell invasion and metastasis in vivo. He has authored or co-authored 48 research articles/books. He serves on the editorial board of Vascular Cell and PLoS ONE journals, and is an expert reviewer for several leading journals including Cancer Research, FASEB, Journal of Biological Chemistry, Nature, Blood, PNAS, Circulation Research, and Nature Communications. He is a member of the American Association of Cancer Research in addition to other organizations. He has served on numerous review committees for the NIH, including his current membership in the VCMB study section.
Brain metastasis is a defi ning component of tumor pathophysiology, and the underlying mechanisms responsible for this phenomenon are not well understood. Current dogma is that tumor cells stimulate and activate astrocytes, and this mutual relationship is critical for tumor cell sustenance in the brain. Here, we provide evidence that primary rat neonatal and adult astrocytes secrete factors that proactively induced human lung and breast tumor cell invasion and metastasis capabilities. Among which, tumor invasion factors namely matrix metalloprotease-2 (MMP-2) and MMP-9 were partly responsible for the astrocyte media-induced tumor cell invasion. Inhibiting MMPs reduced the ability of tumor cell to migrate and invade in vitro. Further, injection of astrocyte media-conditioned breast cancer cells in mice showed increased invasive activity to the brain and other distant sites. More importantly, blocking the preconditioned tumor cells with broad spectrum MMP inhibitor decreased the invasion and metastasis of the tumor cells, in particular to the brain in vivo. Collectively, our data implicate astrocyte-derived MMP-2 and MMP-9 as critical players that facilitate tumor cell migration and invasion leading to brain metastasis.
University of Antwerp, Belgium
Title: Heart disease and malignancy in one and the same patient: How to deal with it from cardiologic point of view. An overview
Time : 13:45-14:05
Wilhelm P. Mistiaen graduated as MD at the University of Antwerp in 1984. In 1994, he completed a surgical training and registered as surgeon. He completed his fi rst PhDin 1999 and a second one in 2009 at the same university. Currently, he is lecturer and associate professor of Anatomy and of Pathology at the University of Antwerp / Artesis-Plantijn University College.The focus of interest is complications after aortic valve replacement. Another focus is heart disease in patients with (prior) malignancy. Several manuscripts appeared on these topics. He is a regular reviewer for the European Journal of Cancer Prevention.
Cardiovascular disease and cancer are leading causes of mortality. Due to common risk factors, both conditionscan be present simultaneously or subsequently in one patient. A systematic literature search reveals that the presence of malignancy in cardiac patients series varies between 1.9 and 4.2%. In patients with simultaneous disease, the most threatening disease should be treated fi rst. Th is is usually the heart disease. If percutaneous coronary intervention is preferred, an antithrombotic treatment protocol has to be observed. Resulting bleeding and thrombotic tendencies have to be taken into account in the subsequent treatment of the malignancy.Using coronary artery bypass graft ing, combined or two-staged procedures are possible. A combinedoperation has the advantage of one admission and one anesthesia. It also avoids tumor progression during while waiting for a second operation in a staged procedure. Th irty-day mortality (between 4-7% in most series) and 5-year survival (up to 60%) aft er the combined procedure are comparable to results in patients without malignancy. Postoperative infection is problematic in patients with hematologic malignancies.In patients with heart disease aft er malignancy treated with curative intent,postoperative hospital mortality seems comparable to patients without prior malignancy. Five-year survival can be up to 80%, but the only existing large series with suffi ciently long-term follow-up indicates that the time interval between cancer treatment and cardiac surgery plays a dominant role: if this is below 2 years, 5-year mortality, especially due to metastasis, rises from 11 to 58%. In conclusion, aggressive treatment of both conditions in selected patients is worthwhile.
King George’s Medical University, India
Time : 14:05-14:25
Neetu Singh has been selected to join more than 350 cancer researchers from prominent research institutions in 31 countries in a project called “The Halifax Project” that hopes to tackle cancer’s complexity. During her Post-Doctoral training from CSIR-CDRI, Lucknow, she was actively involved in Molecular Cancer Research with projects ranging from the clinical study of association of gene-polymorphisms in Breast-Cancer, to meta-analysis and investigation of the synergistic therapeutic effect of polyphenols in combination with current drugs in Breast Cancer Cells/Explants. She also availed fellowships like Young- and Women-Scientist. During her PhD program, she received training in Endocrinology from CSIR-CDRI.
We present fi rst report on novel and previously reported chromosomal mosaicism and genetic copy number variation in histopathologically characterized medulloblastoma (MB) in North Indian cases using array based comparative genomic hybridization (CNV-targeted; CytoScan 750K Array). In fi rst case, the results revealed gain mosaic (CN state=2.91)/gains (CN=3.00) at Ch: 1q and Loss Mosaic (CN=1.22) at Ch: 1p, Ch: 2 q37.1-37.3 (CN=1.50), Ch: 4 q28.1-35.2 (CN=1.18) and Ch: 8 q22.3-24.13 (CN=1.73). Importantly, Loss of HHIP gene at 4q31.21, suggests it to be SHH Type of MB. In second case, gain mosaic of 17 q (CN=3.00), 16p (CN=2.23) 12 (CN=2.48; Gain at 3 regions) 2p (CN=2.91)7 (CN=3.00) and 1q (CN=2.91) and loss mosaic of 17 p (CN=1.61), 16q (CN=1.27) 13 (CN=1.61) 11 (CN=1.56), 10 (CN=1.27 and Loss at 10q), 8 (CN=1.67), 2q (CN=1.62) was observed. Additionally, amplifi cation at MYCN at 2p24.3, CDK6 at 7q21.2, GLI1 at 12q13.3, Loss of MYC at 8q24.2, IRS2 at 13q34, Tp53 in 17p31.1, SUFU at 10q24.32, PAX6 at 11p13, SFRP1 at 8p11.21 classify this case into SHH group of MB. Gain of 17q, 7 and 1q and Loss of 17p, 16q, 11p, 10q and 8 have been previously reported, however gains in Ch: 16p, 12, 7, 2p, 1q and X, as well as losses of Ch: 20, 13q, 11, 10, 8, 4q and 2q were the novelty. Th e results validate the previously reported as well as novel alterations in onco- and tumor-suppressor genes and classify both the samples as SHH type of MB.
New York Medical College, USA
Title: High prevalence of human papillomavirus type 16 (HPV-16) in breast cancer with chrysotile asbestos in more than 90% of over 500 mammograms of human breast cancer indicated potential involvement of HPV-16 in other cancers and found them in adenocarcinoma of the esophagus, stomach, colon& prostate gland but not in the pancreas: future treatment & prevention of HPV-16 infected cancers should include safe effective treatment or prevention of HPV-16 & asbestos with average vitamin D3 400 I.U.
Time : 14:25-14:45
Yoshiaki Omura received both Oncology Residency Training and a Doctor of Science Degree through research on Pharmaco-Electro Physiology of Single Cardiac Cells in vivo and in vitro from Columbia University. He has published over 250 articles and 7 books. He is Executive Editor of Integrative Oncology & Editorial Board Member of Journal of Clinical Trials in Cardiology, etc. Using his new diagnostic method, which received U.S. patent, he can non-invasively and rapidly measure many neurotransmitters, other chemicals, asbestos, viruses, and bacteria. He developed a non-invasive, quick diagnostic methods of malignancies, as well as a method of evaluating the effects of any treatment.
Our latest study with over 500 cases of published breast cancer mammogram analysis indicated in more than 90% Human Breast Cancers had HPV-16 & Chrysotile Asbestos with a relatively smooth outline. Less than 5% had HPV-18 & Tremolite Asbestos, in which the outline of tumor was sawtooth-like, zigzag and irregular. Because of this high incident of involvement of HPV-16 in breast cancer, the author investigated which cancers of other organs may have HPV-16 infection with Chrysotile asbestos. Th e following cancer tissues were found to have HPV-16 infection with Chrysotile Asbestos: 1) Adenocarcinoma of tongue; 2) Adenocarcinoma of Esophagus (Squamous Cell Carcinoma did not have any one of HPV-16, -18, &-33); 3) Adenocarcinoma of Lung (Small Cell Carcinoma, Squamous Cell Carcinoma, and Large Cell Carcinoma did not have HPV-16, -18 &-33); 4) Adenocarcinoma of Stomach (but Scirrhous Carcinoma of Stomach and Signet Ring Cell Carcinoma of Stomach did not have HPV-16, -18 &-33); 5) Adenocarcinoma of Colon6) Adenocarcinoma of Prostate Gland, but Adenocarcinoma of Pancreas did not have HPV-16,-18 or -33, but had Coxsackie Virus B. HPV-18 or HPV-33 were not found in other types of cancers of the same organs but all kinds of cancer examined had Chrysotile Asbestos with less than 5% of Breast Cancers. Th us safe & eff ective treatment or prevention of these cancers should also control HPV-16 & Asbestos along with a few benefi cial optimal doses of mutually compatible supplements including Vitamin D3, average 400 I.U. for average adult cancer patients.
University of Erciyes, Turkey
Title: Prognostic signifi cance of two dimensional agnor evaluation in local advanced rectal cancer with treated chemo radiotherapy
Time : 14:45-15:05
Nalan Imamoglu has completed her PhD from Erciyes University, Medical Faculty, Department of Medical Biology in Turkey. Her present occupation is Assoc. Prof. Dr. Her scientifi c interests are cytogenetics, tumour/cancer biology and genetics and genotoxicity. She is a member of Society of Medical Biology and Genetics and Society of Medical Genetics. She has published about 20 papers in reputed journals.
The aim of this study is to reveal the prognostic importance of Argilophilic Nucleolus Organizer Region (AgNOR) proteins on the patients with stage II-III rectal cancer with chemoradiotherapy. Silver staining technic was applied to the 3 μm section collected from the parafi n blocked tissues on 30 rectal cancer patients who treated with 5-FU based chemotherapy and 50, 4 Gy (1,8 Gy/day, 28 fractions) external beam radiotherapy to the pelvic lymph nodes and tumor bed, b etween May 2003 – June 2006 at University of Erciyes, M.K. Dedeman Oncolgy Hospital. Th e microscopic displays of the cells were transferred in to the computer medium via video camera. AgNOR area/Total Nucleus area (NORa/TNa) values were found. Th e facts are analysed in terms of locoregional recurrence (LRR), disease free survival (DFS) and overall survival (OS). Th e statistical analysis was accomplished by SPSS 15.0 package programme. OS and DFS in the high NORa/TNa (>9.02) patients were 52.21 months and 39.41 months, respectively. OS and DFS in the low NORa/TNa (<9.02) patients were 100.69 mounths and 98.38 mounths, respectively. A statistically signifi cant diff erence was found between high NORa/TNa patients and low NORa/TNa patients (p=0.001) and the prognosis in the high NORa/TNa patients was worse (p<0.05). In terms of OS and DFS, a statistically signifi cant negative correlation was found with value of NORa/TNa in the correlations tests (p=0.001). Additionally, there was a statistically signifi cant correlation found between NORa/TNa and LRR (p=0.020). As a result, we suggested that two-dimensional AgNOR evaluation may be a safe and usable parameter for prognosis and indicator of cell proliferation instead of AgNOR dots.
University of Antwerp, Belgium
Title: Heart transplantation in patients with prior malignancy: A systematic review from a cardiologic viewpoint
Time : 15:05-15:25
Wilhelm P. Mistiaen graduated as MD at the University of Antwerp in 1984. In 1994, he completed a surgical training and registered as surgeon. He completed his first PhDin 1999 and a second one in 2009 at the same university. Currently, he is lecturer and associate professor of Anatomy and of Pathology at the University of Antwerp / Artesis-Plantijn University College.The focus of interest is complications after aortic valve replacement. Another focus is heart disease in patients with (prior) malignancy. Several manuscripts appeared on these topics. He is a regular reviewer for the European Journal of Cancer Prevention.
A history of malignancy can be considered as a contraindication for heart transplantation in patients with end-stage heart failure. A systematic search of the available literature about this theme resulted in some older case reports (n=3) and small series. More recent series are larger (n=10), have a specific design or rely on nationwide databases (n=2). All reports are retrospective in nature. Entirely pediatric series are excluded. The preoperative profile of the patients include demographics, time interval between malignancy and transplantation (if available), indication of transplantation and co-morbid conditions. Postoperative results include hospital mortality, long-term survival, recurrence of malignancy, infection and rejection rate. Findings: 1) Ten to 27% of cancer survivors suffer from chemotherapy-related cardiomyopathy. Moreover, two series show that the number of surviving cancer patients, needing transplantation is increasing; chemotherapy related end-stage heart failure almost doubled as indication for transplantationbetween the periods 2000-2004and 2004-2008. 2) Hospital mortality varied between 0-10% in small series and seems comparable to patients without malignancy. 3) The same is true for 5-year survival, being 55-75%. The disease free interval between malignancy and transplantation has an important effect on postoperative survival and on recurrence rate of cancer: 5-year survival decreases from 80% to 55% if the interval decreases from 5 to 1 year.Recurrencerate of cancer increases from 6% to 63%. Although the published series are not comparable, it can be concluded that transplantation in patients with prior malignancy can be justified when the interval between malignancy and transplantation exceeds 5 years.
Time : 15:25-15:45
Ping Xie is an Associate Professor in Rutgers Cancer Institute of New Jersey. Research in Dr. Xie’s laboratory focuses on understanding molecular mechanisms of immune regulation and cancer pathogenesis.
B cell neoplasms comprise >50% of blood cancers. However, many types of B cell malignancies remain incurable. Identification and validation of novel genetic risk factors and oncogenic signaling pathways are imperative for the development of new therapeutic strategies. We and others recently identified TRAF3, a cytoplasmic adaptor protein, as a novel tumor suppressor gene in B lymphocytes. We found that TRAF3 inactivation results in prolonged survival of mature B cells, which eventually leads to spontaneous development of B lymphomas in mice. Corroborating our findings, TRAF3 deletions and mutations frequently occur in human B cell chronic lymphocytic leukemia, non-Hodgkin lymphoma (such as splenic marginal zone lymphoma and mantle cell lymphoma), multiple myeloma, and Waldenström’s macroglobulinemia. In this context, we have been investigating TRAF3 signaling mechanisms in B cells, and are developing new therapeutic strategies to target TRAF3 downstream signaling pathways in B cell neoplasms. Here I will present and discuss our new translational data that demonstrate the therapeutic potential of targeting TRAF3 downstream signaling pathways in B lymphoma and multiple myeloma. Grant support: This study was supported by the Department of Defense grant W81XWH-13-1-0242, the National Institutes of Health grant CA158402, and the Cancer Institute of New Jersey through Grant Number P30CA072720 from the National Cancer Institute.
M-C. Dieu-Nosjean has first studied the biology and migratory capacity of human dendritic cells. Her work has gained insights to several inflammatory diseases including skin pathologies. More recently, she studied the immune microenvironment of lung tumors, and contributed to the characterization of tertiary lymphoid structures in cancer patients. During her career, she has authored more than 50 peer-reviewed reports and 4 patents. Dr. M-C. Dieu-Nosjean is Associate-Editor for Frontiers in Immunology. She is a member of the French Society of Immunology.
It is well established that a high level of infiltration of memory T cells withTh1 or cytotoxic orientation correlates with long-term survival in most human cancers. However, a key question remains: where does the activation of tumor-specific T cells take place? We recently described, tumor-associated lymph node-like entities termed “tertiary lymphoid structures” (TLS) in primary and metastatic lung cancers. TLS exhibit a structural organization that is reminiscent of secondary lymphoid organs. Lung tumor-associated TLS present a specific chemo-attractant signature associated with T cell infiltration. High endothelial venules selectively co-localize with TLS suggesting that TLS provide a key hub for the recruitment of peripheral blood immune cells into the tumor. We demonstrated that TLS are critical for the local coordination and polarization of protective immunity.Moreover, the presence of mature DC is required to license the positive prognostic value of tumor-infiltrating CD8+ T cells suggesting that TLS may imprint the behavior of intra-tumoralCD8+ T cells. NSCLC-associated TLS are also composed of a B-cell follicle where somatic hypermutation and class switch recombination machineries are activated.We showed that the density of follicular B cells is associated with a favorable clinical outcome, and correlates with the density of plasma cells. These data strongly suggest that TLS play a protective role against tumors by promoting an humoral immune response in lung cancer patients. In conclusion, TLS presenceis accompanied by profoundlocal modifications and systemic effects, as TLShave an impact on the tumor micro-architecture, immune microenvironment, and ultimately, cancer patient survival.
René Rachou Research Centre, Oswaldo Cruz Foundation, Brazil
Time : 16:20-16:40
Lídia Maria de Andrade is a dentist, MSc in Nuclear Sciences and PhD in Health Sciences at René Rachou Research Centre, Brazil, with an internship in cell dynamics and non-invasive functional images at Radboud UMC, The Netherlands. She was Head of Radiology Technology Department at José do RosárioVellano University, wrote the book chapter Calcium signaling and the cancer cell growth in: Calcium signaling: cellular biochemistry and physiology and has published 16 papers in reputed journals and received Honorable Mention during the Third Week of Knowledge for having stood out among the best papers presented at Federal University of Minas Gerais, Brazil.
Conventional cancer therapies have been shown lower overall survival especially to treat epithelial tumors which has encouraged researchers worldwide to search for new approaches that could be able to improve chemotherapy eff ects as well as radiotherapy. In this scenario the main challenge is to fi nd one method with higher selectivity to tumor cells rather than normal tissues avoiding severe sequels. Th is lecture will address the role of nucleoplasmic calcium as a potential new therapeutically cancer targeting to impair tumor cell proliferation and migration. Our research group already demonstrated that nuclear calcium buff ering decreases tumor hepatic cell proliferation in vitro as well as in vivo through mitosis blocking even as the asparaginyl endo peptidase legumain expression reduction. Recently, we found the action of nuclear calcium buff ering in the prevention of a disintegrin and metalloproteinase (ADAM-17) and epidermal growth factor receptor (EGFR) overexpression induced by ionizing radiation on human squamous cell carcinoma. Moreover, association of nuclear calcium buff ering and X-rays is able to decrease survival fractions in 90%. Likewise, proliferation rate also decreased under nuclear calcium buff ering in squamous cell carcinoma, without alteration on non-tumorigenic cells.In addition to these subjects, attendees of this lecture will be familiarized with the importance of calcium signaling patterns to cellular physiology and the proposal of nucleoplasmic calcium as a promising new targeting to epithelial cancer even as an adjuvant method to improve the benefi cial radiotherapy eff ects.
Bose Institute, India
Title: Animal toxicology and treatment of cancer patients by a novel anticancer formulation with methylglyoxal as lead compound
Time : 16:40-17:00
Manju Ray is an Indian scientist in Molecular Enzymology and Cancer Biochemistry. She has done notable work in the development of anticancer drug and understanding of differentiation process of cells. Her interests cover tumor biochemistry and molecular enzymology.
The anticancer eff ect of methylglyoxal has been known for a long time. But relatively recent work has shown that it acts exclusively against malignant cellular mitochondrial complex I and GAPDH to elicit its anticancer eff ect. With the primary objective to treat cancer patients by methylglyoxal its toxicity was assessed at fi rst by administering through three diff erent routes to four diff erent species of animals. Having found that methylglyoxal is potentially safe for human consumption and able to destroy cancer cells in vivo a methylglyoxal-based anticancer formulation was administered orally to diverse groups of cancer patients with the due permission from regulatory authorities. Th e patients were divided in three study groups. In fi rst group (14 months, January 2000-February 2001) 24 patients were recruited and complete remission was observed for 11 patients and partial remission for 5 patients. In the second group (60 months, October 2000-September 2005) 46 patients were recruited and complete remission was observed for 18 patients and partial remission for 18 patients. In the third group (42 months, May 2005-October 2008) of the 23 patients complete remission was observed for 11 patients and partial remission for 7 patients. Th e treatment was found to be especially eff ective for adenocarcinoma of urinary bladder, breast, uterus, esophageal and gastrointestinal tract cancer. Several vital biochemical, radiological and other parameters were tested in patients who received treatment for a long time to assess the possible long term toxicity of methylglyoxal treatment, if any, and the results implicated no toxicity as per the parameter studied. All the results showed great promise of methylglyoxal treatment and demands further improvisation the methylglyoxal based therapeutics.
Korea University College of Pharmacy, Korea
Time : 17:00-17:20
Soon Hong Yuk has completed his PhD at the age of 26 years from Korea Advanced Institute of Science and Technology (KAIST) in 1987 and Postdoctoral studies from University of Utah Department of Pharmaceutics and Pharmaceutical Chemistry in 1989. He is currently a Professor in College of Pharmacy at Korea University. He has published more than 110 papers in reputed journals. His current research interests are nanotechnology-based drug delivery system for cheomotherapeutic drugs and protein drugs.
The formation of nanoparticles (NPs) with a core/shell structure was demonstrated through temperature-induced phase transitions in the melt state of a Pluronic/poly ethylene oxide (PEG)/paclitaxel (PTX) mixture. Liquid PEG (molecular weight: 400) was used as a PTX solubilizer, and the polymer that encapsulated the PTX was composed of Pluronic F-68. For the preparation of Pluronic NPs for docetaxel (DTX), a liquid soybean oil/Tween 80 mixture was used as the solubilizer instead of PEG in a temperature-induced phase transition. Th e Pluronic NPs delivering PTX or DTX showed an improved antitumor effi cacy compared with a Cremophor EL-based PTX formulation and a Tween 80/ethanol-based DTX formulation (Taxotere®). NPs with multi-core structure has been designed based on the incorporation of NPs through the lipid bilayer membrane during the fusion process of vesicles and characterized as delivery vehicles for chemotherapy. Th e improvement on DTXloaded Pluronic NPs was made using the fusion process of vesicles and the new type of DTX formulation was prepared in the aqueous media. We then evaluated the nanoparticle drug release, therapeutic effi cacy, and in vivo biodistribution for tumor targeting using a non-invasive live animal imaging technology. Finally, the antitumor effi cacy of NPs with various core/shell structure was evaluated by measuring changes of tumor volumes in tumor-bearing mice.
ONGA-NAKAMA Medical Association Onga Hospital, Japan
Time : 17:20-17:40
Taketoshi Suehiro has completed his MD (1989) and PhD (2000) from Kyushu University. He did the clinical training and research of the liver transplantation in Mount Sinai Hospital, New York from 1993 to 1996. He is Assistant Director of Onga-Nakama Medical Association Onga Hospital. His specialty is wide with digestive organ surgery, endoscope, infectious disease, nutrition and so on. He has published more than 70 papers in surgical journals and has been serving as an Editorial Board Member of Hepato-Gastroenterology Journal.
Hepatocellular carcinoma (HCC) oft en occurs in the chronic liver disease and cirrhosis and the resectability of a tumor is limited by the diminished functional reserve of the cirrhotic liver. For these cirrhotic patients, liver transplantation (LTx) is the only potentially curative treatment options for HCC. Milan criteria is a gold selection criteria for HCC patients in LTx. However, a major question is whether tumor size and number are only determinants for recurrence or not. I am going to show not only tumor factors expressing malignant potentials but also host factors such as immune suppression closely related to recurrence. In the recent reports, explant pathology clearly showed signifi cant rates of under- and over-estimated cases before LTx. In addition, signifi cant number of patients, who did not meet the Milan criteria, were reported to survive. Up to now, tumor size, vascular invasion and poorly diff erentiated histology are well-known risk factors for recurrence. Exclusion of poorly diff erentiated HCC by preoperative tumor biopsy was reported to bring a better survival. Several tumor biological indicators such as microsatellite markers were reported as predictive indicators of recurrence. Detection of micrometastasis in bone marrow or circulating tumor cells using such as AFP and telomerase mRNA suggested the possibility to predict recurrence. In my series of living donor LTx, a multivariate analysis revealed des-gamma-prothrombin (DCP) of over 300 mAU/ml and tumor size of over 5cm were independent prognostic factors. HCC recurrence aft er LTx is not determined by only tumor size or number. An order-made criterion should be urgently established using updating molecular biological methods.