25^th World Cancer Conference October 19-20, 2017 Rome, Italy

Sarah Konrad has completed her MSc in Chemistry from the Technical University of Munich (TUM) in 2014. She is now a PhD student of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) and is conducting her PhD in the Department of Gynecological Tumor Genetics (Prof. Alfons Meindl/ Dr. Juliane Ramser) at the Technische Universität München (TUM). Her project focuses on identifying and functionally characterizing new prognostic and therapyrelevant biomarkers for personalized ovarian cancer therapy.

Sporadic ovarian cancer has the highest relative mortality among gynecological cancers as approximately 75% of patients are diagnosed at an advanced stage, resulting in poor overall survival. To improve patient’s outcome targeted therapy strategies are required urgently. In search of new biomarkers for personalized therapies, we recently identified a gene encoding a specific neuronal calcium sensor (NCS). The NCS-family is known to be involved in calcium-signaling on membranes and functions as a calcium dependent molecular switch. We demonstrated that its expression, analyzed on mRNA as well as on protein level, was significantly associated with patient survival. Moreover, the putative biomarker persisted also as a significant factor for OS (p=0.008) and RFS (p=0.014) in multivariable analyses. As little is known about the involvement of the protein in cancer, we established stable knock-downs in ovarian cancer cell lines to explore the effect of its expression on cancer cell viability and migration. Most strikingly, the knock-down cells reacted significantly less sensitive to cisplatin treatment as compared to the control cells. This effect was further investigated using different cisplatin concentrations and treatment durations. The differences were reproducible and remained significant. Since platinum-based therapy represents the “gold standard” in ovarian cancer treatment, we postulate a predictive potential of our candidate to select patients that most probably benefit from platinum-based treatment from patients which will likely not have a benefit.

Hongyu Han has completed her PhD from Sun Yat-sen University Cancer Center in 2010. She was a research scientist in University of Pennsylvania and Fox

Chase Cancer Center during 2014-2016. Currently, she is a Scientist in the Department of Nutrition in Sun Yat-sen University Cancer Center. Her research interests focus on the effects and mechanisms of dietary factors and cancer development. She has published more than 10 papers in reputed journals.

Nitroso-compounds are critical dietary risk factor of liver cancer. Cancer stem cells (CSCs) play a significant role in the formation and development of cancer. To date, the action of nitroso-compounds on the induction of liver CSCs as well as the underlying mechanisms has not been defined. In the present study, we revealed that chronic N-nitroso dimethylamine (NDMA) exposure induced malignant transformation of human normal liver cells. We further showed that NDMA-induced malignant transformed liver cells exhibited CSCs properties, as evidenced by increased sphere formation capacity in serumfree- medium culture, dramatically elevated expression of liver CSCs markers and increased number of CD133+ cells, along with upregulation of TAp63α, downregulation of ΔNp63α, and activation of Sonic Hedgehog pathway. Moreover, we illustrated that suppression of Sonic Hedgehog activity inhibited NDMA-induced liver CSCs properties; over expression of TAp63α activated Sonic Hedgehog pathway and promoted liver CSCs activity, whereas down expression of TAp63α inhibited Sonic Hedgehog and suppressed liver CSCs; an opposite action of ΔNp63α on Sonic Hedgehog pathway and liver CSCs was demonstrated. Taken together, our data suggested for the first time the vital role of TP63α/Sonic Hedgehog axis in regulating NDMA-induced liver CSCs, and thus could provide new insights into the molecular mechanisms of liver carcinogenesis as well as its target intervention.

Caiyun Zhong has completed his PhD from University of California, Davis, USA in 2005 and received Diplomate of the American Board of Toxicology (DABT) in

2010. He is the Director and Professor of the Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University. He has published more than 40 papers in reputed journals and has been serving as an Editorial Board Member of journals.

Cancer stem cells (CSCs) play a crucial role in the process of cancer development. Targeting CSCs may be an effective way for adjuvant therapy to prevent the progression of cancer and prolong life. Phenethyl isothiocyanate (PEITC), the major active component from cruciferous vegetables, exhibits inspiring interventional effects in various human cancers. However, the effects of PEITC on colorectal CSCs and the underlying mechanisms remain unclear. The present study examined the inhibitory effects of PEITC on CSC-like properties in colorectal cancer spheroids. We revealed that PEITC inhibited  the spheroid formation capacity of colorectal cancer cells as well as the expression of colorectal CSCs markers, along with suppression of cell proliferation and induction of apoptosis. Moreover, we illustrated that PEITC down-regulated the activation of Wnt/β-catenin pathway, whereas up-regulation of Wnt/β-catenin diminished the inhibitory effects of PEITC on colorectal CSCs. Taken together, this study suggests that PEITC can be an effective natural compound targeting colorectal CSCs through suppression of Wnt/β-catenin pathway, and thus may be a promising agent for colorectal cancer intervention.

Denise C Arruda is graduated in Pharmacy from the Federal University of Santa Catarina in 2000. She pursued PhD in Biology Sciences from University of São Paulo (ICB-USP) with postdoctoral degree at the Experimental Oncology Unit - Discipline of Cell Biology, Federal University of São Paulo from 2008-2014. Currently, she is a professor and researcher at the Integrated Nucleus of Biotechnology at University of Mogi das Cruzes. She has published 17 papers in reputed journals, some of them in collaboration with international research groups, and received awards for poster presentation in five international meetings.

Treatment of melanoma, mainly on the metastatic stage, is a great clinical challenge because conventional chemotherapy is rather ineffective. Other strategies, including immunotherapy, have been introduced and are very encouraging. We have previously shown that peptides derived from complementarity determining regions of immunoglobulins (CDRs) display antimicrobial and antitumor activities regardless of the specificity of the antibodies they were derived from. In the present study, we show that CDR 1 from the light chain (L1) of a human IgM, mAb (HuA), specific for difucosyl human blood group A (HuA) induces necroptotic cell death in the murine melanoma cell line B16F10-Nex2 and in other murine and human tumor cell lines. HuAL1 did not exert cytotoxic effects in non-tumorigenic cell lines. Melanoma cells treated with HuAL1 showed DNA degradation, propidium iodide incorporation and abundant superoxide anion production. Moreover, peptide treatment induced mitochondrial swelling and disruption of mitochondrial cristae. All these effects were caspaseindependent and RIPK1- and MLKL-dependent, since cell death was abolished when cells were co-incubated with necrostatin or necrosulfonamide. Confocal microscopy showed that HuAL1 peptide localizes to the cell nucleus, and ELISA assay showed that it probably binds to H3 histone. We propose that necroptosis is induced after chromatin disorganization upon peptide binding to histone. Our results show, for the first time, that a peptide derived from an Ig-CDR can induce necroptotic cell death on tumor cells.

Adriana Camargo Ferrasi has completed her PhD from São Paulo State University - Institute of Biosciences and Post-doctoral studies from São Paulo State University - Botucatu Medical School. She is a Permanent Professor of the Post-Graduation Program (Stricto sensu) in Medical Biotechnology of São Paulo State University (UNESP) and Titular Professor in Paulista University (UNIP). She works in the area of molecular biology applied to cancer studies.

Meningioma is the most common tumor of the central nervous system and despite of their benign characteristic and slow growth, they frequently recur after surgical removal. Interleukin 28B seems to be involved in antiviral and antitumor immune response. Recently, IL28B rs12979860 C/T polymorphism was associated with outcome of treatment with IFNα and ribavirin in patients with Hepatitis C virus. Also, patients with CC genotype have higher chances of viral depuration than those with other genotypes. However, there are few data on this polymorphism in tumors, especially in meningioma. Thus, the aim of this study was to analyze allele and genotype frequencies of this polymorphism in patients affected by meningioma and healthy individuals (control) and to sequencing IL28b gene, searching for novel genetic variations. Sixty patients treated by UNESP Neurosurgery Service were included in this study. The Research Ethics Committee approved this study and each subject signed an informed consent form before tissue was obtained. Analysis of rs12979860 C/T polymorphism was performed by PCR-RFLP (PCR - Restriction Fragment Length Polymorphism) and the complete sequencing of the IL28B gene was performed by Sanger Sequencing Capillary Electrophoresis (Applied Biosystems™). The present study showed unpublished results that evidenced a greater frequency of TT genotype in the meningioma patients when compared to healthy individuals. Novel genetic variations (missense and silent) were detected in IL28B gene and only three have been reported in the scientific literature, but not in tumor samples. Amino acids exchanged as consequence of the missense variations are located mainly in the binding domains of IL28B protein to its receptor, reinforcing the probable importance of these alterations in protein function. These results suggest that IL28B protein and its geneticvariations may participate in the molecular mechanisms of meningioma.

Vasileios L. Tzounakas is a Post-doctoral researcher at the Department of Biology (Section of Cell Biology & Biophysics) of the National and Kapodistrian University of Athens (NKUA). He has obtained Ph.D. in Cell Biology. He has served as reviewer in international journals while his main research interests include blood transfusion biology (mainly, red blood cell storage lesion in blood products used for transfusion), erythrocyte biology in health and disease and the study of extracellular vesicles. He has expertise in evaluating the key parameters that affect storage lesion and post-transfusion performance of red blood cells and in the management of blood supplies in a way that will lead to the individualization of transfusion therapy. In this context, he has focused on the elucidation of storagelesion’s features that may serve as a donor’s signature, namely ‘the donor variation effect’.

Statement of the Problem: Red blood cells (RBCs) are the most frequently transfused blood labile product. The “Donorvariation effect”, which refers to donor-to-donor differences observed in both blood storage quality and 24h recovery, is probably a key factor in the efficiency of transfusion therapy. Donor variation effect may be associated with genetically determined features of RBCs and plasma. The aim of this study was to examine whether thedonor’s sex may independently affect the storage capacity of donated RBCs.

Methodology & Theoretical Orientation: For this purpose, 14 leukoreduced units of RBC concentrates in CPD/SAGM (7 male–7 female) were stored for 42 days at 4-6oC. Several parameters of storage quality (including hemolysis, redox status etc) were examined before and throughout the storage period. SPSS was used for statistical analysis of the results.

Findings: In-bag hemolysis, as well as osmotic and mechanical hemolysis, and intracellular calcium indexes were equally low in both groups during the whole period of storage. On the contrary, redox status markers such as total and uric acid dependent antioxidant capacity of the supernatant were significantly higher in male donors’ units (p<0.01). In the same group of donors, intracellular ROS accumulation was higher during the first two weeks of storage (p<0.05), while exogenously stimulated ROS production was higher after the middle of the storage period (797±220 vs 504±48 RFU, p<0.05).

Conclusion & Significance: Donor’s sex does not seem to affect the hemolytic parameters of the leukoreduced RBC units under storage in CPD/SAGM. Male sex is rather associated with better extracellular antioxidant activity, but worse intracellular redox status and increased susceptibility to exogenous oxidative stimuli. Sex may represent a genetic variant that affects some aspects

of the RBC storage lesion.

This study was supported by “IKY FELLOWSHIPS OF EXCELLENCE FOR POSTGRADUATESTUDIES IN GREECE – SIEMENS PROGRAM” to Vasileios Tzounakas.

Chiara Ruggirello has completed her Master’s Degree in Medical Veterinary and Pharmaceutical Biotechnologies from Parma University. She did her Master´s

thesis at the Technical University of Denmark (DTU) of Copenhagen, in Nanotechnologies. She started her PhD last October at Leipzig University at the Department of Biochemistry.

Nowadays cancer is one of the leading causes of death in Europe. Major challenges in the management of the disease are due to the lack of agents used for early diagnosis and associated with severe and often therapy-limiting side effects. Although chemotherapeutics can kill neoplastic cells, they also will induce toxicity in non-neoplastic tissues. Therefore, new approaches are necessary with the purpose of optimizing anticancer therapy. Among new experimental approaches, the magnetic particle hyperthermia has been suggested. Hyperthermia, as anticancer therapy, has been proposed since the 1970s, but it has still not established in clinical routine owing to the inability in focusing the heat only to the intended region without damaging the surrounding healthy tissue. By contrast, the so-called magnetic particle hyperthermia has the potential to address this shortcoming. Magnetic nanoparticles (NPs) may be made to accumulate exclusively in tumor tissue. Nevertheless, the only use of NPs is not enough for reducing side effects, they could in fact distribute randomly in the body, causing several adverse effects to non-neoplastic tissues. To develop directed particles, the NP have been coated with peptides, known to deliver the NP to cancer cells selectively. These magnetic NPs, when exposed to Alternating Magnetic Fields (AMF), can generate heat due to hysteresis loss. This behavior may be exploited for treating cancer, revolutionizing the existing hyperthermia procedures. Cancer cells when exposed to elevated temperatures are more sensible to chemotherapeutics and radiations, therefore, hyperthermia can also be associated to chemotherapy and radiotherapy boosting their effect.

Esma Oguz has completed his/her Bachelor of Nutrition and Dietetic from Yeditepe University and is currently enrolled in the master’s programme at the Departmant of Nutrition and Dietetic, Marmara University. He/She is also Research Assistant at the same university.

Colorectal cancer (CRC) is one of the most common types of cancer and the fourth leading cancer deaths all around the world. Many risk factors such as tobacco and alcohol consumption, over consumption of red and processed meat, age, physical activity, body weight, diet, inflammatory bowel disease, obesity and diabetes are associated with colorectal cancer. Another factor in the development of colorectal cancer is microbiota. Microbiota consist of bacteria, viruses, fungi and parasites that colonize the gastrointestinal tract from the mouth to the colon. Microbiota influences physiological functions from the maintenance of barrier homeostasis locally to metabolism, haematopoiesis, inflammation, immunity and other functions systemically. The composition of microbiota is related to various diseases such as cancer, non alcoholic fatty liver disease, obesity. Studies show that microbiota plays a role in the etiology of various types of cancer by affecting inflammation, DNA damage and apoptosis. Microbiota has a great influence on immune responses and chronic inflammation is a known risk factor for colorectal cancer. Colon mucosa is constantly exposed to intestinal microbiota and its metabolites, it has the potential of continuous low-grade inflammation with bacterial stimulation of immune responses. Gut dysbiosis is largely associated with direct hostility to colonic cancer or metabolic change. Studies show that various bacterial species include the pathogenesis of CRC. Functional different bacterial species are involved in tumor microbiology during tumorigenesis. For example, some potential pro-oncogenic pathogens such as enterotoxigenic B. Fragilis and Escherichia-Shigella may induce tumor formation. The tumor cells are located in the nucleus of the immune cells, which serve both the pro- and antitumor immunity and can be shaped by the resident microbiota even after progression to the CRC. Microbiota, immune system, and CRC are multifactorial associations that should deeply consider.

Denise C Arruda is graduated in Pharmacy from the Federal University of Santa Catarina in 2000. She pursued PhD in Biology Sciences from University of São Paulo (ICB-USP) with postdoctoral degree at the Experimental Oncology Unit - Discipline of Cell Biology, Federal University of São Paulo from 2008-2014. Currently, she is a professor and researcher at the Integrated Nucleus of Biotechnology at University of Mogi das Cruzes. She has published 17 papers in reputed journals, some of them in collaboration with international research groups, and received awards for poster presentation in five international meetings.

The Brn-2 transcription factor is related to the development of malignant melanoma, inducing cell proliferation and invasion and, consequently, the formation of metastases. The Brn-2 protein is expressed in melanocytes and overexpressed in melanoma cells. Peptides derived from the Brn-2 transcription factor could compete with the DNA binding sites, thus interfering with the development of melanoma, as well as activating the mechanisms of cell death. In the present work, the cytotoxic activities of peptides derived from the Brn-2 transcription factor were determined against murine melanoma B16F10- Nex2. Cells were treated for 24h with the peptides E12F, R18H, L13S and C9K, derived from the POU domain of the Brn-2 transcription factor. Among the peptides tested, only the R18H peptide was cytotoxic in B16F10 Nex2 cells. Moreover, a time curve was taken to evaluate the antitumor activity of R18H for 30 minutes, 1, 2, 4, 6, 12 and 24 hours. It was observed that the peptide displays antitumor activity early in the first hours of treatment, however, the cytotoxic effect increases only after 24 hours. The R18H peptide induced DNA degradation, chromatin condensation, increase of superoxide anions, phosphatidylserine translocation, activation of caspase 3 and 8, and release of extracellular cytochrome c in B16F10-Nex2 cells. These effects characterize death by apoptosis and because caspase 8 was activated we suggest that the extrinsic pathway is followed. R18H also induced membrane permeabilization in cells treated for 24 h, however, the same effect was not observed after treatment for 2 h. To determine if the membrane permeabilization effect could be due to late apoptosis or if in addition to apoptosis the R18H peptide also induced necrosis or necroptosis, we tested the peptide in the presence of necroptosis inhibitors and verified the release of LDH in the extracellular environment of treated cells. The peptide kept its cytotoxic effect in the presence of inhibitors of necroptosis and treated cells did not present LDH release in the extracellular medium. These data indicate that

membrane permeability is a late apoptosis event. It was also observed that peptide R18H showed antitumor activity in vivo. It was observed in the metastatic model that C57Bl/6 mice treated with the R18H peptide showed lower numbers of pulmonary nodules than untreated mice. The peptide was not toxic in mice at high doses, as observed in histopathological analysis of the

lung, liver, kidney, heart and spleen. These results suggest that the R18H peptide has potential to be developed as a new drug for the treatment of melanoma.

Eun-Min Kim has completed his PhD from Seoul National University College of Medicine and had worked as a Research Professor in Busan National University

College of Medicine. Currently, he is studying the mechanism of cholangiocarcinoma at Yonsei University in South Korea.

Clonorchis sinensis, the most prevalent parasite in Korea, has been reclassified as Group I bio-carcinogen for cholangiocarcinoma (CCA) in humans by IARC in 2009, C. sinensis associated cholangiocarcinoma (CCA) is still unknown. The aim of this study was to identify distinct gene expression associated with carcinogenesis of C. sinensis. In human cholangiocyte line, H69 cells were continuously exposed to N-nitroso dimethylamine (NDMA) and excretory secretory product of C. sinensis (ESP) over one year. H69 cells that were continuously exposed to ESP of C. sinensis and NDMA showed cancer-like characteristics including cell proliferation was more than 5.7 times and the proportion of cells in the G2/M phase increased up to 42% compare to non-treated H69 cells. Moreover, the expression of the cell cycle protein E2F1 and the cell proliferation related proteins, ki67, and cytokeratin 19 were more than 30-fold increased when NDMA and ESP were added together. Based on these results, whole-transcriptome sequencing was performed to compare the genome-wide gene expression patterns of H69 stimulation with NDMA and/or C. sinensis ESP with non-treated H69. A total of 1301 differentially expressed genes (DEGs) were identified, 521 of which were up-regulated and 780 were down-regulated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichments revealed that numerous DEGs belong to cancer-relevant genes, involved in cell cycles, cell proliferation, and cell adherent-relevant pathways. Among them, we focused on the P53 K-ras signaling genes and found that two genes increased and eight genes decreased from a number of their genes. This result was also confirmed by real-time PCR. In conclusion, these data suggest that the P53 and K-ras signal plays a key role in regulation of cell proliferation, which may cause cholangiocarcinoma under stimulation by ESP of C. sinensis and NDMA.

Lloyd Jenkins is a certified Naturopath and founder of the Budwig Cancer Clinic in Malaga, Southern Spain. He received authorization from Dr. Johanna Budwig in August 2000 to use her protocol for treating people with all types of cancer. He has written seven books and literally hundreds of articles on how to treat cancer and all common diseases using natural therapies. He has also been on radio talk shows and has spoken at Health Care seminars and events.

The Budwig Center approach in treating cancer is based on the research and studies of the famous German Doctor Johanna Budwig using a totally natural treatment protocol. She was a State Expert for Chemical Research on Drugs and Fats at the Dr. Kaufmann's facility in Munster, Germany. Her research has shown the tremendous effects that commercially processed fats and oils have in destroying cell membranes and lowering the voltage in the cells of our bodies, which then result in chronic and terminal disease. The cells of our body fire electrically. We are all aware of how fats clog up our veins and arteries and are the leading cause of heart attacks, but these very dangerous fats and oils are also affecting the overall health of our minds and bodies at the cellular level. Dr. Budwig discovered that when unsaturated fats have been chemically treated, their unsaturated qualities are destroyed and the field of electrons removed. Without the proper metabolism of fats in our bodies, every vital function and every organ is affected. This includes the generation of new life and new cells. Our bodies produce over 500 million new cells daily. Dr. Budwig points out that in growing new cells, there is a polarity between the electrically positive nucleus and the electrically negative cell membrane with its high unsaturated fatty acids. During cell division, the cell, and new daughter

cell must contain enough electron-rich fatty acids in the cell's surface area to divide off completely from the old cell. When this process is interrupted the body begins to die. In essence, these commercially processed fats and oils are shutting down the electrical field of the cells allowing chronic and terminal diseases to take hold of our bodies. Her most famous discovery was the use of a combination of flaxseed oil combined with Quark or Cottage cheese to restore the adequate electron activity. She also used mostly herbal, homeopathic, essential oils, sunbathing, oil massages and enemas, as well as her oil protein diet to treat and prevent cancer. In August 2000, Lloyd Jenkins visited the famous Dr. Johanna Budwig in her Cancer clinic in Stuttgart Germany. It was with deep interest that he listened to Dr. Budwig talk about her incredible health breakthrough of when she discovered the powerfully healing nature of essential fatty acids in treating cancer and all types of degenerative diseases. Lloyd received her permission to use her program in the Budwig Center Cancer clinic in Spain and has been helping people from all over the world since then to overcome cancer.

Rong Shao is currently a Professor in Department of Pharmacology, School of Medicine, Shanghai Jiao Tong University, and an adjunct Professor of Department of Biology, University of Massachusetts, Amherst. He has published more than 40 papers in top-tier journals. He has also served as an editorial board of more than thirteen peer-reviewed journals and a Reviewer of 48 journals. His research work has been supported by several US federal funding agencies including NIH (NCI), DoD, DoE and Chinese National Science Foundation.

YKL-40, also known as chitinase-3-like-1 (CHI3L1), is strikingly elevated in serum levels of patients with a variety of advanced carcinomas, including breast cancer, colorectal cancer, ovarian cancer, leukemia, lymphoma, and glioblastoma. It thus has been suggested that serum levels of YKL-40 may serve as a cancer diagnostic and prognostic biomarker. However, little is known regarding its therapeutic value of whether and how blockade of YKL 40 can inhibit cancer progression. We recently developed a mouse-derived neutralizing antibody (mAY) against YKL-40 and found that mAY targeted to bind a positively charged arginine (R) and lysine (K)-rich domain (RK-domain) proximal to its C terminus and thus interfered its binding to heparin that is essential for YKL-40 angiogenic activity. The ability of mAY to block YKL-40 angiogenesis is identical to the R or K point mutations, where alanine (A) substituted for K or R in the RK-rich domain both in cultured vascular endothelial cells and animal models xenografted with breast cancer cells MDA-MD-231. These data suggest that mAY neutralizes YKL-40 via blockade of heparin binding of the KR-rich motif, the functional domain of YKL-40, revealing the molecular mechanisms underlying neutralization of YKL-40 activity. Our findings may help pave a new avenue to develop therapeutic agents targeting YKL-40 that is highly elevated in varied cancers and chronic inflammatory diseases.

Kamran Mansouri completed his PhD at Tehran University of Medical Sciences, Iran. He is the Head of Department of Molecular Medicine at Kermanshah University of Medical Sciences, Iran. He has published more than 50 papers in reputed journals.

In cancer therapy, modulatory effects of L-arginine on various cancers remain a controversial issue. This amino acid is a substrate for different enzymes and plays a crucial role in regulating multiple metabolic and signaling pathways in both normal and cancer cells. L-arginine has a complex metabolism and its impacts on the cells are highly linked to the types and metabolism of them. Previous studies investigating the effects of L-arginine in cancer therapy have provided conflicting results. While some studies confirm that L-arginine enhances tumor growth, the others introduce L-arginine as an appropriate candidate for cancer treatment. Contradictory assertions in the case of L arginine used in cancer therapy suggest that using or depletion of this amino acid can have different result on the normal and cancer cells. So, this study attempts to reconcile these opposite notions and to revisit the thesis that L-arginine role in cancer therapy.

Manuela Boyle is an Australian Integrative Oncologist with board certification by the Institute of Integrative Medicine (USA). With over 20 years of clinical experience in Integrative Medical centres in Australia, Italy, United Kingdom and Singapore, she is a leading integrative oncology educator delivering training and mentoring to medical doctors and allied health practitioners. She is a regularly invited guest speaker at key conferences around the globe and is the published author of several peer-reviewed papers. In 2015, she was accepted as an external expert by the European Centre for Disease Prevention and Control in Stockholm, Sweden, an honorary position aimed to provide independent scientific opinions, expert advice, data and information and to maintain scientific excellence at all times through the best expertise available. She is the Director of Vingyana Integrative Oncology Clinic in Sri Lanka, a state of the art technology and residential medical centre, while maintaining her presence at her clinics in Milano, London and the Gold Coast (Australia).

Introduction & Aim: Cancer cells are better able to adapt to stress than normal cells. In cancer treatment, this adaptation results in tumor cells that develop cancer resistance to chemotherapy drugs. This event is usually the primary obstacle to successful treatment. Finding themselves in a state of high alert, cancer cells have the ability to express resistance not only to drugs they have been exposed to, but to any other noxious agent. Multi-drug resistance is a protection mechanism that can lead to failure of the conventional cancer treatment. Research shows that natural compounds can reverse drug resistance by inhibition of P-glycoprotein, inhibition of glutathione S-transferase drug detoxification system and inhibition of heat-shock proteins. There is ample evidence suggesting that selected natural compounds can produce cytotoxic effects in cancer cell through several mechanisms and that, when they are combined with chemotherapy drugs, these effects are often additive or synergistic.

Method: A review of randomized controlled trails of the mechanisms by which cancer cells, exposed to chemotherapy, have the ability to devise strategies for resistance and survival. This study involves the research of EBSCO, MEDLINE, and PubMed from 1992 to 2012 to retrieve suitable articles. Five double blind placebo controlled clinical human and animal studies were

reviewed.

Results: All the control studies conducted in large multi-centre trials, confirmed improvement in patient survival on a dose of 3 grams of PSK per day orally unless noted. 262 postoperative stomach cancer patients were randomized to receive chemotherapy or chemotherapy and PSK. The addition of PSK increased the five-year disease-free rate (from 59% to 71%) and the five year survival rate (from 60% to 73%). 462 patients with curatively resected colon cancer were randomized to receive chemotherapy or chemotherapy plus PSK. The latter combination increased the eight-year disease free rate (from about 7.8% to 28 %) and ten year survival rate (from 19% to 36%). 278 patients with stage II aT2N1 estrogen-dependent breast cancer were randomized to receive chemotherapy or chemotherapy. The administration of PSK increased the five year survival rate (from 81% to 96%). Disease-free survival also increased. 38 patients with nasopharyngeal cancer who were treated with radiotherapy, with or without chemotherapy, were randomized to receive PSK or no PSK. The addition of PSK increased survival rate (from 15 to 35 months). The PSK dose was 1 gram per day orally.

Lloyd Jenkins is a certified Naturopath and founder of the Budwig Cancer Clinic in Malaga, Southern Spain. He received authorization from Dr. Johanna Budwig in August 2000 to use her protocol for treating people with all types of cancer. He has written seven books and literally hundreds of articles on how to treat cancer and all common diseases using natural therapies. He has also been on radio talk shows and has spoken at Health Care seminars and events.

Clinics are finding that up to 90% of health problems are resolved when the microbiome of the gut is corrected resorted. The father of medicine Hippocrates said that “Your health is in your gut”. We are more bacteria than human! — 10 trillion human cells vs. 100 trillion bacteria cells. There are over 1,000 different species of commensal organisms in the GIT out of 35,000 possible. In developed parts of the world due to the diet of many processed foods we tend to suffer more from digestive issues and auto-immune diseases. Distinct Distal Gut Microbiome Diversity and Composition in Healthy Children from Bangladesh and the United States found that: The distal gut of Bangladeshi children harbored significantly greater bacterial diversity than that of U.S. children, including novel lineages from several bacterial phyla.Human gut microbiota community structures in urban and rural populations in Russia “the original microbial community structures occurred in hosts from urban populations 2.6-fold less frequently than in the rural hosts, which implies that the rural population’s microbiota community was the healthy original”. Some of the last hunter-gatherer people on earth who live an ancient, ancestral life.

Their environment hasn’t changed for 1000s of years and they have a massive exposure to ancestral microbial community. They have a vastly different microbiota compared to westernized populations. In fact, virtually no common digestive diseases such as Crohn’s, UC, Colon Cancer, Reflux, etc. found in  these parts of world that live on life natural foods.A new study by scientists at the University of California has found that contents of many bifidobacterial probiotic products differ from the ingredients listed. After testing 16 probiotic products available in local Californian stores and also online, they found only one of the products exactly matched the bifidobacterial species claims on the label. Some products had pill to pill and lot to lot variation. 35 strains from commercial products were studied. Primarily lactobacillus sp. and Bifidobacterium sp. There were studies done to evaluate the survivability of common probiotics through the GIT. Only 4 of 35 strains would survive to enter the large intestine and the survivors would have less than 50% survival. We are not aware of any other probiotic that has demonstrated the ability to fix dysbiosis. Thus, addressing the root cause of many diseases. We have worked with a lot patient going through chemotherapy, and oncologists often prohibit using probiotics but not sporebiotics. We work closely with the OncANP which is the Association of Naturopathic oncologist and they utilize the product on patients undergoing chemo to reduce the diarrhea and damage to the microbiome. It is used routinely here in the States for that purpose. We have not seen any adverse reactions thus far. We titrate the patients up as we normally do, but have had success with this application.

We found that c-Met overexpression was induced in normal breast fibroblast (NBF) by the conditioned medium (CM) of cancer cells regardless of subtypes, which made us to hypothesize that c-Met overexpression is a property of cancer associated fibroblast (CAF). Therefore, we investigated whether c-Met overexpressing NBFs contribute to tumor progression. To this end, extracellular matrix (ECM) gene expression alteration was analyzed from the NBFs transfected with c-Met overexpression plasmid using cDNA microarray since CAF constructs tumor microenvironment by ECM remodeling. In our microarray data, matrix metalloproteinase 1 (MMP1) was most up-regulated in c-Met overexpressing NBF (approximately 10-fold) compared to the control NBF. According to previous studies, MMP1 induces VEGFR2 (Vascular endothelial growth factor receptor 2) expression in endothelial cells (ECs). So, it was assumed that c-Met overexpressing NBF contributes to breast cancer angiogenesis. In our study, the CM of c-Met overexpressing NBF induced a better tube formation of endothelial cells (Hy926) than that of control. On the other hand, tube formation by c-Met overexpressing NBF CM was reduced in the presence of c-Met inhibitor. Similar results were also observed in the co culture of NBF and breast cancer cell lines (luminal A, B, Her2, and TNBC). The expression of c-Met and MMP1 was increased by the co-culture, whereas was decreased in the presence of c-Met inhibitor. Tube formation of EC was increased by the CM of the co-culture, whereas decreased by c-Met inhibitor-treated co-culture CM. Based on our results, c-Met inhibitor may be able to suppress angiogenesis in breast cancer by decreasing c-Met-induced MMP1 expression of CAFs.

Eun-Beom Lee is pursuing Master's Degree from Ajou University School of Medicine. Her major Research Interest is in mitonuclear communication in tumorigenesis and retrograde signaling in hepatoma cells.

Mitochondrial dysfunction is an important metabolic feature in human cancer. However, underlying mechanisms how mitochondrial dysfunction affects tumorigenesis remain unclear. To address the role of transcriptomic regulation by mitochondrial defects in liver cancer cells, we performed gene expression profiling for three different cell models of mitochondrial defects: cells with chemical respiratory inhibition, cells with mitochondrial DNA depletion, and liver cancer cells harboring mitochondrial defects. By comparing gene expression in the three models, we identified 10 common mitochondrial defect (CMD)–related genes that may be responsible for retrograde signaling from cancer cell mitochondria to the intracellular transcriptome. Among the CMD genes, we found that NFE2L1 is a key regulator to regulate hepatoma invasiveness. This study aims to elucidate how mitochondrial defect regulates NFE2L1 transcription. Interestingly, SNU354 and SNU423 cells showed high intracellular reactive oxygen species (ROS) levels. Exogenous treatment of H2O2 increased intracellular ROS and NFE2L1 expression in SNU387 cell harboring active mitochondria. We further selected 11 transcription factors (TFs) that could bind to promoter region of NFE2L1 by using TRANSFAC program. By monitoring NFE2L1 mRNA levels after knocking-down of the TFs, 4 TFs (USF2, STAT3, JUN and SREBP1) were identified to regulate NFE2L1 transcription. Further detailed molecular mechanisms of how mitochondrial ROS regulates NFE2L1 transcription are currently under investigation.

Young-Kyoung Lee received her PhD in Biochemistry from Ajou University School of Medicine, Suwon, Korea. She is working as a Post-Doctoral Research Fellow at Ajou University School of Medicine. For about last ten years, her research has been focused on elucidation of molecular mechanisms of mitochondrial respiratory defects which are often observed in cancer, the retrograde signaling triggered by the respiratory defect and its relevance to cancer activities.

Impaired mitochondrial oxidative phosphorylation (OXPHOS) capacity, accompanied by enhanced glycolysis, is a key metabolic feature of cancer cells, but its underlying mechanism remains unclear. Previously, we reported that human hepatoma cells that harbor OXPHOS defects exhibit high tumor cell invasiveness via elevated claudin-1 (CLN1). In the present study, we show that OXPHOS-defective hepatoma cells (SNU354 and SNU423 cell lines) exhibit reduced expression of mitochondrial ribosomal protein L13 (MRPL13), a mitochondrial ribosome (mitoribosome) subunit, suggesting a ribosomal defect. Specific mitoribosomal translation inhibition with doxycycline and chloramphenicol, or siRNA-mediated MRPL13 knockdown decreased mitochondrial protein expression, reduced the oxygen consumption rate (OCR), and increased CLN1- mediated tumor cell invasiveness in SNU387 cells, which have active mitochondria. Interestingly, we also found that exogenous lactate treatment suppressed MRPL13 expression and OCR, and induced CLN1 expression. A bioinformatics analysis of the open RNA-Seq database from The Cancer Genome Atlas Liver Hepatocellular carcinoma (TCGA-LIHC) cohort disclosed a significant negative correlation between MRPL13 and CLN1 expression. Moreover, in LIHC patients with low MRPL13 expression, two oxidative metabolic indicators, pyruvate dehydrogenase B expression and the ratio of lactate dehydrogenase (LDH) type B to LDH type A, significantly and negatively correlated with CLN1 expression. This observation implied that the combination of elevated glycolysis and deficient MRPL13 activity is negatively linked to CLN1-mediated tumor activity in LIHC. These results suggest that OXPHOS defects may be initiated and propagated by lactate-mediated mitoribosomal deficiencies and that these deficiencies are critically involved in LIHC development.

Gül ÖÄŸren has completed her Bachelor of Nutrition and Dietetic from Erciyes University and is currently enrolled in the Master programme in Department of Nutrition and Dietetic, Marmara University. She is also a Research Assistant at the same university.

Functional beverages help us to maintain healthy conditions and to provide comfort just for general nutrition. For this reason, functional beverages play a significant role in our daily lives. It has been found that functional beverages have benefits in many areas of health such as cancer prevention, healthy digestive system, immunity defenses, body weight reduction, energy and hydration, improve overall health, show antioxidant activity, improve cardiovascular health. The positive effects of functional beverages on health are explained by different mechanisms. Reduce oxidative stress and help to prevent many chronic diseases, as well as strengthen the immune system of the individual. Besides water, the best known and most commonly used functional beverages are tea, coffee and fruit juices. Functional beverages contain antioxidant bioactive compounds and different nutrient including alkaloids, anthocyanins, carotenoids, flavonoids, glucosinolates, isoflavones, phenolic acids, tannins and terpenes, vitamins (vitamin C, folate and provitamin A), minerals (potassium, calcium, magnesium) and fibers that have been associated with reduced cancer risk. Reactive oxygen species damages many tissues such as lipids, proteins, especially DNA in living organisms. Free radicals mediate oxidative damage in cancer. The biological damage that occurs in this way is called oxidative stress, and the phenolic components involved in functional beverages have a vital role in removing oxidative stress. DNA is highly susceptible to free radical damage. Modification of DNA is the most important consequence of oxidative stress, and it can become permanent via the formation of mutations and other types of genomic instability. Excessive production of reactive oxygen species and lack of adequate antioxidant components (alkaloids, anthocyanins, carotenoids, flavonoids, glucosinolates, isoflavones, phenolic acids, tannins and terpenes) in the body trigger to formation of cancer. It is thought that phytochemicals in beverages and balanced diet can be a natural treatment method to improve the individual's health condition and to prevent the development of the cancer cell with the minimal toxicity. It has been found that functional components taken with beverages contribute approximately 30% to the prevention of cancer formation in industrial countries. Functional beverages (fruit juices, vegetable juices, caffeinated beverages, dairy and soy beverages, some fermented beverages) provide sufficient quantities of antioxidant component that reduces cancer formation by preventing DNA damage and reducing oxidative stress in the body.

Veysel Akduman has completed his Bachelor of Physical Therapy and Rehabilitation from Afyon Kocatepe University and then graduated his Master’s Degree in Department of Physiotherapy and Rehabilitation, Sifa University. He is currently enrolled in the PhD programme in Department of Physical Therapy and

Rehabilitation, Marmara University, in which he is also a Research Assistant.

Breast cancer leads to physical and mental distress which is linked with increased prevalence of malignancy-related mortality among females worldwide. Survival rates for breast cancer have been improving for more than 20 years and this appears likely to continue. Therapeutic exercises as well as adjuvant treatments are important improving the quality of life and increasing survival rates in cancer patients. Exercise is recommended to minimize the side effects of chemotherapy and radiotherapy, to maximize cardio pulmonary status especially early diagnosis. Aerobic and resistance exercise are mostly performed exercises types in this population, either separately or in combination, have been shown to improve physical functioning and manage some side effects in breast cancer patients receiving chemotherapy. It has been showed that exercise program can help manage symptoms and improve physical functioning during radiation therapy. Some studies in the literature have shown that aerobic exercise in cancer patients reduces fatigue as well as increases quality of life. For many cancer patients, fatigue is a severe and limiting problem. The impairment of physical and mental performance prevents from working or carrying out regular daily activities and hence results in a substantial reduction of the quality of life. In response to fatigue, patients are usually advised to rest and down-regulate their level of daily activities. However, since inactivity induces muscular catabolism and cardiopulmonary endurance, extended rest can help perpetuate fatigue. Moreover, exercise has been proposed as a nonpharmacologic intervention for the treatment of cancer-related fatigue. An isometric exercise is one of the resistance training. One study found that three-week isometric-strength exercise program improved physical performance and reduced fatigue. In another study pointed that the effects of all forms of performed aerobic or resistance exercise, or both, with programme duration of at least six weeks should be considered. Although the exercise training is one of the necessary approach in the non-pharmacological treatment of breast cancer to reduce fatigue, there are still not enough studies in the literature. It is necessary to perform more randomized controlled studies investigating the proper exercises type and procedure to improve quality of life in breast cancer survivors.

Emel Mete graduated from Istanbul University Physiotherapy and Rehabilitation Department in 2007. She is pursuing her Master Program in Physiotherapy and

Rehabilitation Department at Marmara University. She is also a research assistant at the same department.

Cancer is defined as a class of diseases in which abnormal cells divide without control and can invade other tissues. It is a leading cause of death worldwide and accounted for 7.6 million deaths (around 13% of all deaths) in 2008. Acupuncture is one of the major treatment methods in Chinese medicine (CM). The value and safety of acupuncture are documented in the growing body of literature on acupuncture treatment for chronic pain, osteoarthritis, migraine, and the relief of procedural anxiety. In addition, acupuncture has been used to treat a range of problems associated with cancer and cancer treatments, such as hot flashes, chronic fatigue, neuropathy, nausea and vomiting, xerostomia, and dysphagia. Needle stimulation causing a typical needle sensation has been claimed to be important for reaching maximum effects on pain. Acupuncture points in the cutaneous nerve can be used to reduce pain, vomiting and nausea and to treat depression. Cancer treatment can also be used to reduce other effects such as xerostomia and sensory impairment. According to a study, acupuncture treatment was found to be effective in pain control in cancer, acupuncture alone was not better than standard drug treatment, but acupuncture

and drug therapy combination was significantly more effective than drug treatment alone. In another study, standard pain treatment with hand-foot acupuncture was compared in terms of side effects and analgesic efficacy in patients with liver cancer. Acupuncture has resulted in a longer analgesic effect without any side effects. Literature reviews indicate that acupuncture is effective in pain management and it has no side effects. On the other hand, inadequate number of randomized controlled trials and the fact that studies are performed on fewer patients and the short follow-up time lead to an inaccurate explanation of the effectiveness of acupuncture. We think that there is not enough research about acupuncture on cancer and that more randomized controlled trials are needed.

Kazunobu Baba has completed her PhD from Kwansei Gakuin University. She is a Postdoctoral Fellow of Institute for Genetic Medicine in Hokkaido University.

She has been studying the function and roles of probiotics to apply the study in prevention and treatment of cancer. She has once received Paper of the Week on

Journal of Biological Chemistry.

Lactobacillus helveticus SBT2171 (LH2171: provided by Megmilk Snow Brand Co., Ltd.) is a lactic acid bacterium that inhibits excessive immune responses. We have revealed that LH2171 shows inhibitory effects on the proliferation of BJAB, a B lymphoma cell line, through reduction of phosphorylation level of c-Jun, a critical regulator of cell proliferation. c-Jun is phosphorylated by activation of MAPKs (Mitogen-activated protein kinases)  (JNK and ERK) signaling pathway. JNK (Jun N-terminal kinases) and ERK are activated by MEK4/7 or MEK1/2 pathway, respectively. In this study, we investigated the effect of LH2171 on the proliferation of MC38, a mouse colon carcinoma cell line and HT-29, a human colorectal adenocarcinoma cell line. LH2171 inhibited the proliferation of both MC38 cells and HT-29 cells. As a result of assay for the phosphorylation of factors regulating cell growth, LH2171 inhibited phosphorylation of JNK, but not of ERK and MEK4 in MC38 cells. In addition, LH2171 induced the expression of JNK inactivating phosphatase, MKP1 and MKP1 siRNA treatment could suppress the effect of LH2171 to inhibit cell proliferation. These results indicate that the inhibitory effect of LH2171 on the proliferation of MC38 cells depends on the induction of MKP1 to inhibit JNK activity.

Fatemeh Alibeiki has been studying at Ardabil University of Medical Sciences, Iran. Currently, she is in her final year of education as a medical student. So far, she has published two papers in high-profile journals. Participating in numerous conferences and workshops is one of her interests and has done so, on a regular basis throughout the years as a student which brought her experience, extensive knowledge and so many scientific certificates. She has also associated with different groups in her university that resulted in holding several conferences and meetings.

Curcumin and its chalcone derivatives inhibit the growth of human cancer cells. It is reported that replacement of two OH groups in curcumin with less polar groups like methoxy increases its antiproliferative activity. In this study, we explored benzylidene cyclohexanone derivatives with non-polar groups, to see if they possess increased anti-cancer activity. Novel 2,6- bis benzylidene cyclohexanone analogues of curcumin were synthesized, and their inhibitory effects on gastric adenocarcinoma (AGS) and esophageal squamous cell carcinoma (KYSE30) cancer cells were studied using an MTT assay. Cell apoptosis was detected by EB/AO staining, and cell cycle was analyzed by flow cytometry. Real-time PCR was performed for gene expression analysis. All synthesized analogues were cytotoxic toward gastric and esophageal cancer cells and showed lower IC50 values than curcumin. Treatment with 2,6-Bis-(3-methoxy-4-propoxy-benzylidene)-cyclohexanone (BM2) was 17 times more toxic than curcumin after 48 h incubation. All novel compounds were more effective than curcumin in apoptosis induction and cell cycle arrest at G1 phase. These results suggest that less polar analogues of curcumin have potent cytotoxicity in vitro. However, they need to be investigated further, especially with animal tumor models, to confirm their chemotherapeutic activity in vivo.

Seung-Kye Cho is pursuing his Master’s degree in Life and Nano-pharmaceutical Sciences at Kyung Hee University. He graduated in Oriental Pharmaceutical

Science from the Kyung Hee University. He has interests in providing evidence supporting the importance of the interplay between ovarian cancer cells and

mesothelial cells, and discovering novel factors of peritoneal dissemination of ovarian cancer.

Ovarian cancer is a remarkably metastatic disease that is often characterized by widespread peritoneal dissemination. Recently, several studies have suggested that tumor microenvironment plays a significant role in ovarian cancer metastasis. However, the interaction between macrophages and mesothelial cells for ovarian cancer metastasis is unclear. We first investigated the effect of macrophages on gene expression pattern in mesothelial cells. Following treatment of mesothelial cells with conditioned medium (CM) of macrophages, we conducted a comparative analysis of global expression changes in mesothelial cells using mRNA sequencing. When compared to that in unstimulated-macrophages, 945 genes were upregulated and 777 genes were down-regulated more than 2-fold in macrophage-stimulated mesothelial cells (MSM). Among the total 1722 genes, 94 genes including WNT7B were known to be associated with the regulation of cell adhesion. Interestingly, knockdown of WNT7B using siRNA attenuated the adhesion of ovarian cancer cells to mesothelial cells. These results indicate that the enhanced levels of WNT7B in MSM may play a role in the peritoneal dissemination of ovarian cancer.

Jae-il Roh has completed his PhD from Yonsei University and continuing his research at the same laboratory. He is working in Prof. Han-Woong Lee’s lab and

interested in mouse genetics, generation of mouse models, and cancer.

Autophagy is systematically regulated by upstream factors and nutrients. Recent studies report that telomerase and hexokinase 2 (HK2) regulate autophagy through mTOR and that telomerase has the capacity to bind to the HK2 promoter. Here, we show that HK2 is a molecular bridge linking telomerase to autophagy. TERT-induced autophagy activation and its further enhancement by glucose deprivation were suppressed by HK2 inhibition in HepG2 cells. The HK2 downstream factor mTOR was responsible for TERT-induced autophagy activation under glucose deprivation, implying that TERT promotes autophagy through a HK2-mTOR pathway. TERC played a similar role as TERT, and simultaneous expression of TERT and TERC synergistically enhanced HK2 expression and autophagy. At the gene level, TERT bound to the HK2 promoter at a specific region harboring the telomerase-responsive sequence TTGGG. Mutagenesis of TERC and the TERT-responsive element on the HK2 promoter revealed that TERC is required for the binding of TERT to the HK2 promoter. We demonstrate the existence of a telomerase-HK2-mTOR-autophagy axis and suggest that inhibition of the interaction between telomerase and the HK2 promoter sensitizes cells to metabolic stress, and this pathway could be targeted for anti-cancer therapies.

Young Hwa Kim has completed all the requirements for the Doctoral Degree in Biomedical Science and expect to obtain the Ph.D. Degree Certificate at the end of February 2016, officially. She has published 8 papers, out of which she is the first author of 4 papers.

Cellular senescence has been perceived as a barrier against carcinogenesis. However, the senescence-associated secretory phenotype (SASP) of senescent cells can promote tumorigenesis. Here, we show senescent tumour cells are frequently present in the front region of collective invasion of papillary thyroid carcinoma (PTC), as well as lymphatic channels and metastatic foci of lymph nodes. In in vitro invasion analysis, senescent tumour cells exhibit high invasion ability as compared with non-senescent tumour cells through SASP expression. Collective invasion in PTC is led by senescent tumour cells characterized by generation of a C-X-C-motif ligand (CXCL)12 chemokine gradient in the front region. Furthermore, senescent cells increase the survival of cancer cells via CXCL12/CXCR4 signalling. An orthotopic xenograft in vivo model also shows higher lymphatic vessels involvement in the group co-transplanted with senescent cells and cancer cells. These findings suggest that senescent cells are actively involved in the collective invasion and metastasis of PTC.