Day 2 :
Keynote Forum
Soma Ghosh
Food and Drug Administration, USA
Keynote: Regulatory considerations for In Vitro diagnostics in oncology
Biography:
Soma Ghosh continued her training in Molecular Biology at the National Institutes of Health (NIH/NICHD), Bethesda, MD, where her work dealt with the mechanisms that regulate cellular DNA replication during animal development; after completing her Doctoral degree from the School of Life Sciences at Jawaharlal Nehru University, New Delhi, India. Her focus then shifted to development of sequencing-based assays to support clinical decision making in cancer therapy and management, an area she pursed as a Molecular Geneticist at the Sidney Kimmel Comprehensive Cancer Center in Johns Hopkins Medical Institute. Currently, she is a Regulatory Scientist at the FDA where she is actively involved in the review and approval of companion diagnostic devices.
Abstract:
Advancements and innovation in the development of in vitro diagnostic (IVD) devices are important for the success of personalized medicine. At FDA, the development of targeted therapies and the associated diagnostics have been a priority since the first companion diagnostic and corresponding drug were approved in 1998. Since this time, there has been a dramatic increase in biomarker-targeted drug development programs. In 2013, approximately 45% of new drug approvals were for targeted therapies, and there are currently upwards of 25 approved companion diagnostic devices. When a device is considered for marketing authorization, FDA relies upon valid scientific evidence to determine whether there is reasonable assurance that a device is safe and effective for its intended use. During my presentation, I will provide an overview of the regulatory framework for IVDs and discuss validation considerations for IVDs. In addition, I will highlight challenges and strategies related to the use of diagnostics in biomarker-driven clinical trials, and I will summarize recent FDA approvals of diagnostic devices for cancer therapeutics.
Keynote Forum
David I Smith
Mayo Clinic, USA
Keynote: Mate-Pair Sequencing (MP-Seq) as a powerful clinical tool for the management of cancer patients
Biography:
David I Smith completed his PhD from the University of Wisconsin in Madison and then did his Post-doctoral studies at the University of California in Irvine. Since 1996, he has been a Professor at the Mayo Clinic in the Department of Laboratory Medicine and Pathology. He is also the Chairman of the Technology Assessment Group for the Center for Individualized Medicine at the Mayo Clinic. His laboratory studies include the common fragile sites and the role that these regions of instability play in the development of cancer. His group also studies the different ways that HPV can contribute to the development of different cancers. He has published over 200 papers in reputed journals and serves on the Editorial Board of a number of journals.
Abstract:
Advances in DNA sequencing based upon massively parallel sequencing (Next Generation Sequencing- NGS) have dramatically increased sequence output. The Illumina sequencing platform is now capable of producing billions of simultaneous DNA sequences and this facilitates a number of different ways of characterizing nucleic acids. The most powerful use of NGS is for whole genome sequencing (WGS), but there are a number of limitations of utilizing WGS for the management of cancer patients, including the total cost and difficulties in interpreting the resulting data. A powerful alternative to WGS is the construction of mate-pair libraries and the sequencing of libraries of DNA fragments that were originally kilobases apart. We have been utilizing MP-Seq to characterize oropharyngeal squamous cell carcinomas (OPSCC) which are cancers that are increasingly caused by human papillomavirus. We will describe how MP-Seq can characterize the physical status of HPV in HPV-positive OPSCCs and the clinical significance of this characterization. This work has demonstrated that HPV plays different roles in the development of OPSCCs and many of these are quite distinct from HPVs role in the development of cervical cancer. In addition, MP-Seq can characterize genomic changes in each cancer and these can be used to develop cancer-specific markers, which can be used to monitor an individual patient response to therapy. Thus, MP-Seq could be a powerful and yet affordable tool that can be used as a clinical tool for the management of cancer patients.
Keynote Forum
John Michael Sauer
University of Arizona College of Medicine, USA
Keynote: The predictive safety testing consortium: Qualification of translational safety biomarkers for use in drug development
Biography:
John Michael Sauer is a Toxicologist by training with over 20 years of experience in drug discovery and development. He has been responsible for leading multiple functional areas across several pharmaceutical companies. He received his Doctorate degree in Pharmacology and Toxicology from The University of Arizona. Currently, he is working as the Program Officer of Biomarker Programs and the Executive Director of the Predictive Safety Testing Consortium at the Critical Path Institute, as well as an Adjunct Research Professor in the Department of Pharmacology at the University of Arizona, College of Medicine.
Abstract:
The use of novel safety biomarkers in clinical trials has the potential to profoundly impact the ability of drug development innovators and health authorities to evaluate and improve patient safety. Many of the biomarkers currently being used to evaluate clinical safety suffer from a lack of sensitivity or specificity for detecting drug induced organ injury. Therefore, several groups including the Critical Path Institute’s Predictive Safety Testing Consortium (PSTC) have been working towards the regulatory qualification of novel safety biomarkers with the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) to gain scientific and regulatory endorsement of these biomarkers. However, these efforts have been hampered by the lack of well-defined scientific and regulatory expectations or evidentiary criteria. Therefore, the objective of this presentation is to discuss and align the expectations for qualification of novel safety biomarkers to be applied during drug development. Furthermore, the general approach to the regulatory qualification of translational safety biomarker will be discussed using several case studies focusing on safety biomarkers.
Keynote Forum
Nikolai V Ivanov
Philip Morris International Research & Development, Switzerland
Keynote: Pre-clinical and clinical studies in COPD and cardiovascular areas and the role of biomarkers
Biography:
Nikolai V Ivanov currently holds the position of Manager of the Research Technologies Department at Philip Morris International R&D Innovation Cube, Philip Morris Products S A in Neuchatel, Switzerland. In this role, he is responsible for setting the strategic direction of the department and leading genome sequencing, gene expression, proteomics, high performance computing and quality management systems projects. He received his MSc in Mathematics and Computer Science in 2001 and his PhD in Biochemistry in 2002 from Emory University (Atlanta, USA). In 2015, he was awarded a title of Privat Docent by the University of Neuchatel (Switzerland). He has published more than 40 manuscripts primarily in the area of Systems Toxicology.
Abstract:
Cigarette smoking causes serious diseases including chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD). ApoE-deficient mice are prone to developing premature atherosclerosis and emphysema making it an ideal model in which both pathologies can be assessed simultaneously. We evaluated the effects of cigarette smoke (CS) from a cigarette (3R4F) and aerosol from tobacco heating system 2.2 (THS2.2), a candidate modified risk tobacco product. ApoE-/- mice were exposed for up to eight months to the test aerosol for three hours/day, five days/week to a target nicotine concentration of 30 µg/l. After two months of exposure to CS, cessation and switching groups were further exposed for up to six months to fresh air, or THS2.2, respectively. Multiple markers of disease progression were investigated including atherosclerotic plaque formation, pulmonary inflammation, pulmonary function and lung emphysema. Exposure to CS induced time-dependent molecular, physiological and inflammatory pulmonary responses in ApoE-/- mice consistent with emphysematous changes. Significant changes in the lung transcriptome and proteome of ApoE-/- mice were observed in response to CS-exposure compared to sham-exposed mice. Smoking cessation and switching to THS2.2 resulted in lower activation levels compared to continuous exposure to CS. Both, smoking cessation and switching to the THS2.2 halted the rate of disease development as assessed by histopathological and molecular endpoints. At the same time, a clinical study reported as part of a global clinical program for THS was designed to demonstrate sustained exposure reduction to selected HPHCs and to provide first insight on changes in clinical risk endpoints (CREs) in smokers pre-dominantly using tobacco sticks menthol variant (mTHS) for five days in confinement followed by an ambulatory period of 85 days, compared to subjects continuing to smoke menthol cigarettes (mCC) and those who abstained from smoking. Biomarkers of exposure (BoExp) to 16 HPHCs and nicotine were measured to provide an assessment of human uptake of a set of representative toxicants contained in tobacco products. Selected CREs associated with cardiovascular and respiratory diseases and genotoxicity as well as subjective effects to investigate mTHS acceptance compared to mCC were assessed.
Keynote Forum
Lowe Leroy
Lancaster University, UK
Keynote: Tackling heterogeneity in advanced cancers with personalized combination therapeutics
Biography:
Leroy J Lowe is the President and Cofounder of Getting to Know Cancer, a Canadian Non-Profit Organisation that is focused on the advancement of cancer research. His PhD is from Lancaster University in the UK and he is the Key Architect of the Halifax Project (2011-2015), a global initiative that involved more than 350 cancer researchers in 31 countries. He is currently focused on the Broadspec Clinical Trials, a multi-institution case-series that will encompass prophylactic trials for myelodysplastic syndrome patients who are at high risk of developing acute myeloid leukemia and therapeutic trials for patients with advanced-stage ovarian cancer, pancreatic ductal adenocarcinoma or glioblastoma multiforme.
Abstract:
Tackling heterogenity in advanced cancers will require personalized therapeutic protocols customized for an array of molecular targets unique to each patient. However, many existing therapies are highly toxic and approved for only a limited subset of cancers, so the range of therapeutic combinations for a given cancer is often limited. Recently, a multinational taskforce of 180 researchers collaborated to put forward a design for a broad-spectrum therapeutic approach to prevent high-risk cancers, treat refractory cancers and prevent disease relapse. In doing so, they identified a great number of natural health products and re-purposed pharmaceuticals that could be used in conjunction with existing standard of care to reach many targets simultaneously. The approach leverages our understanding of the molecular biology of the hallmarks of cancer and combines it with the principles of precision medicine and network pharmacology. The goal now is to use genomic and proteomic information to provide physicians with complementary, low-toxicity protocols that can be developed dynamically, individualized, and then used to support cancer patients who are already undergoing traditional modes of treatment. Several challenges exist, but clinical trials are now being initiated to validate key assumptions. It will necessitate concurrently administered combinations of many agents using metronomic dosing regimens specifically designed and managed to ensure patient safety. This is a logical next step forward in personalized cancer therapeutics and it will help us take advantage of next generation sequencing information. The future will most certainly make use of broad-spectrum protocols to enhance anti-cancer synergies and improve patient outcomes.
- Biomarkers | Cancer Biomarkers | Novel Approaches to Cancer Therapeutics | Molecular Biomarkers | Biomarkers for Immuno-Oncology | Biomarkers in Clinical Research & Development | Biomarkers and Drug Discovery | Cancer Metastasis | Cancer screening & Diagnostics Session | Tumor & Cancer Immunology | Biomarkers and Pathology| Biomarkers for Disorders
Session Introduction
Wenzheng Zhang
Albany Medical College, USA
Title: Water channel AQP5 is a potential novel biomarker of diabetic nephropathy
Biography:
Wenzheng Zhang completed his PhD from MD Anderson Cancer Center, University of Teaxs Health Science Center at Houston in 1998. He performed his Post-doctoral studies at Howard Hughes Medical Institute in Baylor College of Medicine. His current work is focused on kidney fibrosis, renal progenitor cells and biomarkers in the context of diabetic nephropathy and polycystic kidney disease. He has published nearly 50 papers in highly reputed journals and served in over 10 NIH study sections in the past three years.
Abstract:
Diabetic nephropathy (DN) is the most common single cause of end-stage renal disease and one of the most significant long-term complications associated with diabetes in the US. Currently, there are no ideal biomarkers for DN. Water channel AQP5 is critical for the generation of saliva, tears and pulmonary secretions. It has little or no expression in normal mouse and human kidneys. We have reported that AQP5 is up-regulated in kidney biopsies from patients with DN. To investigate, if urinary AQP5 serves as a new potential biomarker of DN, we used an AQP5-specific enzyme-linked immunosorbent assay kit and measured serum and urinary AQP5 first in a cohort consisting of normal controls (n=26) and patients with diabetes mellitus (n=25) or diabetic nephropathy (n=33) and then in a validation cohort possessing normal controls (n=10), patients with diabetes mellitus (n=10) or diabetic nephropathy (n=14), and patients with chronic kidney disease of unknown etiology (n=10). We employed various statistical methods including Pearson's correlation coefficient, ANOVA, receiver operator curve and multiple logistic regression to analyze the data. Our results show that urinary AQP5/creatinine 1) is significantly higher in DN than in other two groups, and in DN stage V than in DN stage III; 2) correlates with serum creatinine, urinary albumin and multiple other known risk factors of the disease; and 3) improves the clinical models in distinguishing DN from normal controls and diabetic mellitus. Hence, urinary AQP5/creatinine may possess diagnostic and prognostic values as a biomarker of DN.
A-Lien Lu-Chang
University of Maryland, USA
Title: SIRT1 and Chk1 inhibition as novel therapeutic strategies in melanoma
Biography:
A-Lien Lu-Chang has completed her PhD from the University of North Carolina at Chapel Hill and has done her Post-doctoral studies from Duke University, School of Medicine with Paul Modrich (Nobel laureate in Chemistry in 2015). She is working as the Professor of Biochemistry and Molecular Biology at University of Maryland Medical School and a Member of University of Maryland Greenebaum Comprehensive Cancer Center. She has published more than 63 peer-reviewed papers in reputed journals, holds a patent, and has been serving as an Eeditorial Board Member for four journals. Her laboratory is currently studying the interplays among DNA repair, DNA replication, cell cycle checkpoint, transcription and chromatin remodeling. She investigates the impact of their co-ordination on telomere integrity and carcinogensis. Her team’s work highlights potential targets that can be exploited clinically for cancer therapies.
Abstract:
Melanoma is the deadliest form of skin cancer. Mutational activation of the protein kinase BRAF accompanied by loss of the tumor suppressor PTEN is the most common cause of melanomagenesis. Targeted therapy against BRAF mutation represents one of the most significant advances in the treatment of melanoma. However, response to BRAF inhibitor (BRAFi) PLX4032 (vemurafenib) is not durable because many patients acquire drug resistance. Thus, therapies that can overcome resistance to the drug are urgently needed. We have demonstrated that a specific inhibitor of protein deacetylase SIRT1 (SIRT1i) and BRAFi synergistically reduces the viability of melanoma cells and SIRT1i slows melanoma tumor growth in mouse xenografts. Cell cycle checkpoints are very promising targets for anticancer therapies because they control cancer cell responses to chemotherapy and radiation. Currently, Chk1 inhibitors (Chk1i) are being tested clinically for several cancers. Our novel findings show that a specific Chk1i significantly decrease cell proliferation, but even more impressively, triggers PLX4032-resistant melanoma cells regaining the sensitivity to the drug. We hypothesize that SIRT1i and Chk1i will augment the potency of BRAFi against melanoma. The use of combinatorial therapies will improve the outcomes and curtail the resistance to BRAFi in melanoma. Our work holds promise for finding novel targets for anti-cancer therapies and will provide new therapy options for melanoma patients.
Biography:
Sherry A Bradford has attended undergraduate school at SUNY at Buffalo and has done her PhD in Biochemistry from the University of Buffalo. During her clinical laboratory vocation, she was solicited by the Chief of Surgery at Millard Fillmore Hospital, Buffalo, NY, to direct the Surgical Research Laboratory. She was awarded for Excellence in Research by the American Federation for Clinical Research, and for the Excellence in Research – SUNY at Buffalo. Currently, she sits on the Editorial Board of many reputed national and international journals and has authored and co-authored a number of scientific peer-reviewed manuscripts. She is also a member of many professional organizations including: International Metabolic Cancer Group, AACR, ASCO and GLIFCA.
Abstract:
Despite significant increases in the numbers of persons surviving cancer, there yet exists a vast rift in the number who dies each year despite treatment. It remains a challenging disease to treat, in part, due to the heterogeneity of the malady. It is widely accepted that virtually all cancers are highly heterogeneous and that subpopulations of cells within a single tumor can exhibit distinct genomic, protein and metabolic divergent profiles. These profound and complex profiles develop into and result in an individualistic shrewd and capricious phenotype leaving an imprint, established and ascribed to that specific tumor. Furthermore, tumor cells experience a range of microenvironmental cues, which would in turn, translate into a range of phenotypic manifestations, contributing to morphologically dissimilar cellular lineages and tissues, within the tumor milieu. Thus, interactions of tumor cells with their microenvironment mutually shape tumor behavior and phenotype. Likewise, plasticity of tumor cell phenotypes would necessarily also influence the apoptotic and autophagic responses. The clinical relevance is that this disparate and divergent heterogenicity contributes significantly to the efficacy of drug therapy and therefore imparts considerable inter-individual variation in pharmacotherapy and clinical response to a myriad of agents. Accordingly, this tumor intra-/inter- incongruence in breast cancer patients, underscores the necessity to personalize therapeutic regimens favoring more personalized patient care throughout monitoring disease progression, relapse and remission states. Our lab briefly delineates a reliable in-vitro test that employs a more scientific and logical approach to identify drug(s) and drug combinations that may be efficacious against a specific patient’s tumor in-vivo. The patient’s own tumor mass is fully disaggregated and as such, all cells (microenvironment) that compose the tumor are subjected to cytotoxic/cytolytic agents. The end-point is cell death which correlates to clinical outcomes of progression-free and overall survival in cancer patients. In summary, our studies do validate that in-vitro testing does qualify as a tool that can assist and guide oncologists to the most efficacious therapy(s) for their patients but also further demonstrates the necessity to individualize chemotherapeutic regimes. Nonetheless a randomized controlled clinical trial must be designed to further correlate and validate our studies and to fully appreciate the impact of in-vitro chemoresistance and sensitivity testing on cancer recurrence and survival rates.
Tamaki Ikuse
Juntendo University Graduate School of Medicine, Japan
Title: Key molecules associated with the development of nodular gastritis due to Helicobacter pylori infection in children
Biography:
Tamaki Ikuse has completed his MD and PhD from Juntendo University Graduate School of Medicine. He is working as an Assistant Professor in the Department of Pediatric and Adolescent Medicine, Juntendo University Graduate School of Medicine and also acts as a Visiting Assistant Professor in the Department of Pediatrics, University of Maryland School of Medicine. He has published more than 10 papers in reputed journals.
Abstract:
Background: Chronic Helicobacter pylori (H. pylori) infection in children induces lymphoid hyperplasia called nodular gastritis (NG). The aim of this study was to evaluate gene expression in pediatric antral mucosa with NG by microarray analysis to identify molecules closely associated with NG when compared to NG-negative pediatric and adult tissue with H. pylori infection.
Methods: Eight pediatric and six adult H. pylori-infected patients, as well as six pediatric and six adult uninfected patients were evaluated. All infected adults had atrophic gastritis (AG). Nodular gastritis was observed in the antrum of all eight pediatric patients and in the corpus of three patients. Adult and uninfected patients were free of NG. Total RNA was purified from gastric biopsies and microarray analysis was performed to compare gene expression between groups. The three infected children with NG in both the antrum and corpus were excluded from analysis of corpus samples.
Results: The total number of genes significantly up- or down-regulated (fold changes>3, P<0.01) compared to uninfected controls varied widely with 72 in pediatric antrum, 45 in pediatric corpus, 104 in adult antrum and 77 in adult corpus. Nineteen genes had significantly altered expression in the antrum of NG tissue compared to NG-negative pediatric corpus tissue and adult AG tissue. Although many molecules known as regulators of lymphoid follicle development were not predominantly upregulated in the NG mucosa, the CD20 B cell specific differentiation antigen demonstrated the most pronounced increase.
Conclusions: CD20 over expression may play an important role in developing lymphoid follicle enlargement and NG.
Xichun Sun
Virginia Commonwealth University, USA
Title: Cancer metastasis: Enactment of the script for human reproductive drama
Biography:
Xichun Sun is a practicing Surgical Pathologist and Cytopathologist. He graduated from Medical School in China. He completed his PhD, Post-doctoral and Residency Training and Fellowships in the USA. His current research interest centers on cancer diagnosis, carcinogenesis and cancer metastasis. He is the author of one monograph and has proposed a new theory on cancer metastasis.
Abstract:
In parallel to the appearance of primordial germ cells during early embryogenesis, the cancer reproductive saga starts with the separation of metastasis initiating cells (MICs) from cancer initiating cells when the primary cancer is still in its infancy. Prime MICs embark on a journey to the host bone marrow where they undergo further development and regulation. Migrating MICs are guided by the same CXCR4/CYCL12 axis as used in the migration of primordial germ cells to the genital ridge. Like the ovary, the host bone marrow features immune privileges, coolness, hypoxia and acidity which are essential for stemness maintenance and regulation. Opportune activation of the MICs via fusion with bone marrow stem cells triggers a frenzy of cellular proliferation and sets them on the move again. This scenario is akin to oocyte fertilization in the Fallopian tube and its subsequent journey towards the decidum. Just as the human reproductive process is plagued with undesirable outcomes so is the cancer metastasis highly inefficient. The climax of the cancer metastatic drama (colonization) is reached when proliferating MIC clusters attempt to settle down on decidum-like premetastatic sites. Successfully colonized clusters blossom into overt macrometastases only after the execution of sophisticated immunomodulation, angiogenesis and vascular remodeling. Similarly, the implanted blastomere needs to orchestrate these feats before flourishing into a new life. What is more, the cancer reproductive drama seems to be directed by a primordial hypothalamus-pituitary-gonad axis. Pursuing this reproductive trail could lead to new frontiers and breakthroughs in cancer research and therapeutics.
Michael A Tainsky
Wayne State University School of Medicine, USA
Title: Paraneoplastic antigens as biomarkers for surveillance and prediction of recurrence in ovarian cancer
Biography:
Dr. Michael A Tainsky is associated with Wayne State University, USA and his research interest in Molecular genetic mechanisms by which normal cells become malignant, Pathway analysis of gene expression changes leading to cellular immortalization, Development of novel cancer diagnostic tests for early detection of cancer in the form of a complex blood test.
Abstract:
Routine disease monitoring of ovarian cancer patients is generally recommended by gynecologic oncologists for women from high-risk families and for ovarian cancer patients during after the completion of primary surgery and first-line chemotherapeutic treatments. The recurrence is determined by measuring the level of serum CA125, one of the most extensively used tumor biomarkers in standard clinical practice for disease surveillance. Numerous studies have shown the role of tumor autoantibodies as biomarkers for ovarian cancer diagnosis and its recurrence. These autoantibodies to tumor associated antigens (TAAs) arise due to the generation of humoral immune response before evidence of clinical symptoms in cancer patients. Previously we showed that three biomarker panel predicted ovarian cancer recurrence at a median lead time of 9.07 months with 94.7% sensitivity, 86.7% specificity, and 93.3% accuracy, in a cohort of ovarian cancer patients where normalization of CA125 had occurred after the surgery and completion of chemotherapy. One of those biomarkers was a peptide epitope from a known paraneoplastic antigen, HARS. Paraneoplastic antigens can elicit a humoral immune response in cancer patients as these antigens are expressed in the cells of nervous system and tumor. The appearance of these onconeural antibodies in ovarian cancer patients leads to the development of various neurological disorders called paraneoplastic syndromes, particularly dermatomyositis or polymyositis but can precede the occurrence of dermatomyositis or polymyositis. Although the clinical implication of these onconeural antibodies as biomarkers for early diagnosis of ovarian cancer has been reported in many case studies, the usefulness of these antibodies has yet to be evaluated in monitoring disease status in ovarian cancer patients after cytoreductive surgery and chemotherapy treatments. In the present study, we evaluated the role of a panel of three recombinant paraneoplastic antigens, HARS, CDR2 and Ro52 in combination with three of our previous biomarkers in predicting recurrence in new and independent cohort of ovarian cancer patient population in which most of the patients had no elevation in CA125 level months before their clinical recurrence. Our results indicate that autoantibodies to HARS, Ro52 and CDR2 and 5H6 antigens predicted ovarian cancer recurrence 5.03 months before the clinical or symptomatic relapse in 21 ovarian cancer patients with a sensitivity of 90.5% when CA125 levels were below the standard cutoff (35 U/ml).
Vanessa Bellat
Weill Cornell Medicine, USA
Title: Nanofibers with unique adaptive and invasive properties for enhanced tumoral retention and anticancer drug delivery
Biography:
Vanessa Bellat received her PhD in Chemistry from the University of Burgundy in France in 2012. After completing her degree, she joined Welience, the private valorization subsidiary of the University of Burgundy, and oversaw the development of a new technological platform called “NanoCare”, which was devoted to the toxicological analysis of nanoparticles. In 2014, she moved to New York and became a member of the Molecular Imaging Innovations Institute (MI3) in Weill Cornell Medicine where she is currently working as a Post-doctoral fellow. Her work focuses on the development of nanomedicine for cancer drug delivery.
Abstract:
A drug delivery system that can cross multiple biological barriers, penetrate solid tumors, and prevent nonspecific body accumulation is in demand for precision treatment. We introduce a smart self-assembling peptide nanofiber that can overcome these challenges by using an approach that combined shape-controlled tumoral uptake, chargeassisted tissue penetration, and enzyme-induced retention approach to improve the delivery efficacy of anticancer agents. The nanofiber displays a high aspect ratio to promote tumoral delivery. Multimodal imaging studies reveal the tumor infiltration, invasion, and saturation properties of the nanofibers. In situ activation by tumorassociated proteases structurally transforms the fibers into networks that are more than ten times larger, leading to a weeks-long local retention. Specific examples are given on delivering aldoxorubicin, proceeding as a novel treatment for triple negative breast cancer. The drug-loaded nanofibers release the active metabolites under the acidic tumor microenvironment and display an enhanced antitumor efficacy with minimal host toxicity in immunodeficiency mice bearing tumor explants compared to the free drug and the liposomal formulation.
Porunelloor A Mathew
University of North Texas Health Science Center, USA
Title: CS1 (CD319) is an effective immunotherapeutic target for multiple myeloma
Biography:
Porunelloor A Mathewcompleted his PhD from University of Pune, India and postdoctoral studies at University of Medicine and Dentistry of New Jersey and UT Southwestern Medical Center, Dallas. Dr. Mathew, Associate Professor at UNT Health Science Center, Fort Worth, is a world-renowned Cancer Immunologist who identified and cloned human NK cell receptors, 2B4 (CD244), CS1 (CD319) and LLT1. Research in his laboratory showed that anti-CS1 antibody activates NK cell cytotoxicity against various cancer cells. Research in Dr. Mathew’s group has lead to the development of novel NK cell based immunotherapy for cancer. He has published over 60 papers in reputed journals and serving as an editorial board member of repute.
Abstract:
Multiple Myeloma (MM) is a cancer of the plasma cells and is fatal without treatment due to anemia, renal failure, hypercalcemia, and bone destruction. Natural killer (NK) cells, a component of the innate immune system, function against infection and cancer. Identification and characterization of NK cell receptors lead to a better understanding of the molecular basis of Natural Killer cell recognition and activation by cancer cells. NK cell functions are regulated by a delicate balance between signaling through activating receptors and inhibitory receptors. We have identified and characterized CS1(CD319, SLAMF7, CRACC) as an NK cell receptor activating its function through homophilic interactions. A monoclonal antibody against CS1 induced both Natural cytotoxicity and ADCC (Antibody-dependent cell-mediated cytotoxicity) by NK cells. CS1 is overexpressed on MM cells and anti-CS1 mAb enhance the killing of MM by NK cells. Elotuzamab (Empliciti) isa humanized monoclonal antibody against CS1, and has been aproved as a breakthrough drug against MM. During clinical trails, Empliciti in combination with chemotherapeutic drugs showed more effective than antibody treatment alone. However, the underlying mechanism for this is not known. We hypothesize that chemotherapeutic drugs induce the expression of CS1 on MM cells making them more susceptible to NK mediated killing. To investigate this property, MM cells were incubated with various combinations of chemotherapy and immunotherapy drugs in order to observe any change in surface expression of CS1. Our results indicate that treatment with anti-CS1 in combination with lenalidomideor doxorubicin and dexamethasone increased the cell surface expression of CS1. Thus enhancing the expression of molecular targets for NK cells is an effective strategy for immunotherapy ofcancer.
Hajime Orita
Shizuoka Hospital-Juntendo University, Japan
Title: The efficacy of Gasdermin gene family for tumor marker in colorectal cancer
Biography:
Hajime Orita graduated and completed Surgical Training from Juntendo University, School of Medicine in Japan. Currently, he is working as Associate Professor of Dept. of Upper GI and especially Laparoscopic Surgery. He has done his Post-doctoral studies and received the Adjunct Associate Professor position from Johns Hopkins University School of Medicine. He has published more than 10 papers in reputed journals and has been serving as an Editorial Board Member of repute.
Abstract:
Gasdermin (Gsdm) family was originally identified as a candidate causative gene for mouse hair follicles, recombination-induced mutation 3 (Rim3). It has four human homologs; A, B, C, and D. All Gsdm family members are located in amplicons; genomic regions often amplified during cancer development, and are considered to be involved in the regulation of epithelial apoptosis. Gsdm A is mainly expressed in the upper gastrointestinal tract. In contrast, Gsdm D is expressed in the colorectal tract. In this study, we researched those expressions in colorectal cancer and evaluated them for tumor marker, comparing between those expression and clinical pathological status. We analyzed expressions of Gsdm A and D, using thirty colorectal cancer cases which were surgically treated at our institution 2013(Stage I; 10 cases Stage II; 10 cases and Stage III; 10cases. Then retrospective analysis of the connection, between Gsdm expression and clinic-pathological data was done. GsdmA is not expressed in normal colorectal epithelium, but is overexpressed and gradually-rising in carcinoma, meanwhile, GsdmD showed precisely the opposite results. The results of the expression analysis suggest that GsdmA and GsdmD works parallel, and relate to clinical stage.
Kai Fu
Johns Hopkins University, USA
Title: Sam68 regulates colon tumorigenesis by genotoxic stress-induced NF-kB activation
Biography:
Kai Fu has completed his PhD from the University of Science and Technology of China. He started his Post-doctoral training in the Department of Biochemistry and Molecular Biology at Johns Hopkins Bloomberg School of Public Health since 2012.
Abstract:
Nuclear factor kappa B (NF-κB) is a transcription factor that controls genes for cell survival and NF-κB signaling has emerged as one of the most important mediators of the cellular response to genotoxic stresses. Genotoxic agents trigger a ‘nuclear-to-cytoplasmic’ NF-κB activation signaling pathway; however, the early events controlling the initiation of the signaling pathway is poorly understood. Our data demonstrate that Src-associated-substrate-during-mitosis-of-68 kDa/KH domain containing, RNA binding, signal transduction associated 1 (Sam68/ KHDRBS1) plays a key role in genotoxic stress-initiated NF-κB signaling pathway. Sam68 directly binds to Poly (ADP-ribose) polymerase 1 (PARP1) and regulates PARP1 enzymatic activity in vitro. Sam68 deficiency abolishes DNA damage-stimulated polymers of ADP-ribose (PAR) production and the PAR-dependent NF-κB transactivation of anti-apoptotic genes. Sam68 null cells are hypersensitive to genotoxicity caused by genotoxic agents. Up-regulated Sam68 coincides with elevated PAR production and NF-κB activation in human and mouse colon cancer. Interference with Sam68 protein sensitizes human colon cancer cells to genotoxic stress-induced apoptosis and the hypersensitivity is abolished by ectopic expression of constitutively activated NF-κB. Further, genetic deletion of Sam68 substantially alleviates colon tumor burden in mice model. Taken together, our findings reveal a novel function of Sam68 in the genotoxic stress-initiated nuclear signaling, which is critical for colon tumorigenesis.
Biography:
Tijen Atacag is associated with Near East University, Turkey.
Abstract:
Many cancer patients are in a hypercoagulable state. The association between thrombocytosis and the presence of an underlying solid tumor has long been recognized, prompting investigation of the role of platelets in disease progression. The pathogenesis of the hypercoagulable state of malignancy involves the interplay of multiple variables. Thrombotic episodes may precede the diagnosis of malignancy by months or years. In gynecologic cancers, pre-operative elevations in platelet counts have been described for endometrial, vulvar and cervical cancer and studies suggest that thrombocytosis may be an independent poor prognostic factor in locally advanced cervical carcinomas. The recent studies indicate that platelets are actively involved in tumour growth and metastasis, especially in ovarian cancer. Ovarian cancer is the deadliest gynecologic malignancy. Early detection decreases the mortality. But, because of the anatomic location within the peritoneal cavity, ovarian cancer may be very advanced or even distantly metastatic before a patient experiences symptoms. Further, these symptoms are often initially vague and non-specific, and may mimic a variety of benign conditions. Platelet count is an easy and cheap parameter. It can be done everywhere. Thrombocytosis can help us in the differential diagnosis of adnexal masses especially if combined with CA-125. The aim of this present paper is to emphasize that thrombocytosis when combined with CA-125 can be used as an early detection parameter in the diagnostic evaluation of suspicious pelvic masses.
Biography:
Dr. Manikonda Prakash Rao, a self-made Healthcare specialist, excellence in Mucus related respiratory Health, Hyderabad, Telangana has completed his Master’s Degree, International Law and Legal Studies, and was a Gold Medalist in International law and Constitutional law. He presented papers at various international Medical conferences. So far he participated in about 20 conferences including All India Institute of Medical Sciences, New Delhi for Geriatric conferences, WAO of US for conferences in immunology and allergy etc. He was also made the Chairperson at Multi disciplinary healthcare conferences organized by All India Institute of Medical Sciences, New Delhi in the year 2014 and 2016. Recently he presented papers at Indo global health summit and expo at Hyderabad and other summits on Throat and Lung cancers – prevention and Management through exercise interventions.
Abstract:
Background: The objective of the paper is to create awareness among people about alternative and complimentary methods to protect themselves from various respiratory diseases including Throat and Lung cancers. The diseases cause the following changes in Airways.1) Inflammation: Acute inflammation is a defense process whereas chronic inflammation is a diseases process. 2) Hyper secretion of mucus:Chronic mucus hyper secretion is a potential risk factor for an accelerated loss of lung function. The thick viscous mucus in the lungs will be conducive to pathogens. Currently available medicines and methods are not able to meet the needs of the sufferers. Continued inflammation and mucus hyper secretion may significantly contribute to transformation of normal cells into cancer cells i.e. the scope for series of mutations may get increased. 3) Bronchospasm: is an additional factor in asthma patients.
Methods: Exercise is a potent medication in history. It can be used as a tool to manage various respiratory diseases including throat and lung cancers. a) Cleaning Upper airway passages, mouth, nose and pharynx, the primary sites of colonization of pathogens and the sinuses, the way stations to the brain. These exercises should be practiced with hypertonic solution i.e., a solution having greater osmotic pressure than that of cells or body fluids and draws water out of cells thus inducing plasmolysis.b)Physical, aerobic and yogic exercises: help in strengthening the Inspiratory and Expiratory muscles.
Conclusions: Any mucus related respiratory health problem commences from upper airway passages and spread to tracheo bronchial tree as they constitute only one path way. The mucociliary clearance mechanism becomes defunct when excess and sticky mucus forms. Once the upper airway passages are cleaned of it, the defunct cilia become active and ciliate mucus towards mouth and it can be pushed out easily. The upper airway passages and the bronchial airways get cleaned from excess and sticky mucus. The diseases originating from its pathway come under control. The exercises are based on the concept “ Once the offending factor, excess mucus is removed, the origin of it, Inflammation gets resolved “ As a result of management of the above two factors, the gene damaging effect may get reduced i.e., the scope for series of mutations on genes may get reduced.
- Biomarker Discovery | Radiation Oncology| Cancer Clinical Trials | Cancer Diagnostics & Diagnostic Market | Targeted Cancer Therapy | Verification & Validation | Personalized Medicine and Data Analysis | Cancer Research | Clinical Research | Clinical Trials| Translational Biomarkers & Diagnostics
Session Introduction
Yelizaveta (Lisa) Torosyan
Food and Drug Administration, USA
Title: In silico approach to biomarker discovery and precision medicine applications pertaining to medical devices
Biography:
Yelizaveta (Lisa) Torosyan is an interdisciplinary MD/PhD Scientist with clinical background and extensive biomedical expertise including translational research with potential health care applications. She is currently working at the Center for Devices and Radiological Health, Food and Drug Administration (CDRH/FDA) and her research involves in silico synthesis of epidemiologic and genetic evidence for discovery of biomarkers indicative of device performance.
Abstract:
Translational research involving pharmacoepidemiologic and pharmacogenetic applications is critically important for enabling access to safe and effective medical products. The ongoing efforts for predictive evaluation of real-world performance of medical devices at the Division of Epidemiology at the Center for Devices and Radiological Health include development of an in silico framework that is based on re-utilization of pre-existing epidemiologic and genetic data and that is aimed to identify candidate biomarkers indicative of device performance. The current presentation will share experience from a number of projects on the discovery of device-related biomarkers guided by epidemiologic evidence. As an example, a retrospective analysis of discharges from the Nationwide Inpatient Sample from Agency for Healthcare Research and Quality (NIS/AHRQ) will be presented as a preliminary step for the discovery of candidate SNPs using Personalized Medicine Research Project data on hip arthroplasty outcomes from Marshfield Clinic Research Institute (PMRP/MCRI). The presentation will also include use of causal analytics approaches (ingenuity pathway analysis) for exploring functional plausibility of the identified candidate SNPs indicative of periprosthetic osteolysis in the sex/race-stratified subpopulations with hip arthroplasty. As a result, the presentation will render new in silico approaches that reutilize pre-existing (genetic and epidemiologic) data and that thus can augment the evidentiary needs for development of cost/time-efficient precision medicine applications.
Peter Schulz-Knappe
Protagen AG, Germany
Title: Serum biomarkers in cancer patients treated with checkpoint inhibitors
Biography:
Peter Schulz-Knappe is working as MD and Cell Biologist by training. He is a Board Member of biotech companies and serves as CSO since 1997. His scientific passion for the last 25 years has been in the discovery, validation and development of protein biomarkers from blood. His main research topics are: proteomics, peptidomics, biomarkers, autoantibodies, protein microarrays, IVD-development. He has published and co-authored over 100 peer reviewed papers. In addition, he is inventor of > 20 patents and patent families on peptides, biomarkers, and analytical procedures.
Abstract:
Autoantibodies (AAB) targeting self-antigens can be found in two clinically and immunologically opposing diseases, autoimmune diseases and cancer. While in autoimmune diseases, the immune system is hyperactivated against self-antigens, many tumors suppress the anti-tumor immune response. Therapeutic cancer vaccines are designed to generate an antigen-specific tumor response in cancer. To further augment the immune response, combination therapies of therapeutic vaccines with checkpoint inhibitors such as ipilimumab are currently tested in clinical studies. Ipilimumab is an antibody that blocks the immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). However, treatment with ipilimumab is associated with immune-related adverse events (irAEs). We investigated AAB profiles in cancer patients treated with therapeutic vaccines, ipilumumab, and combination therapy. Serum samples from cancer patients treated with therapeutic vaccines and/or ipiliumab therapy were tested for the presence of serum autoantibodies. Candidate antigens comprise immune-related and cancer signaling pathway proteins, autoimmune disease antigens and tumor-associated antigens. Samples were collected prior to treatment (T0 samples), at three and six month. In total, 87 AABs were found significantly different in patients with irAEs and those without irAEs. AABs associated with irAEs were also associated with overall survival. Analysis of pathways revealed that AABs predicting irAEs target cancer, cell cycle, cell adhesion and apoptosis pathways. We also found elevated levels of AABs in patients who do not experience irAEs. These AABs target proteins involved in inflammatory, adaptive and cellular immune response pathways or represent autoimmune disease antigens. Further studies in larger sample sets are needed to confirm these findings.
Tao Lu
Indiana University School of Medicine, USA
Title: AlphaLISA high throughput screen discovers a novel small-molecule inhibitor to target protein arginine methyltransferase 5 in pancreatic and colorectal cancers
Biography:
Tao Lu is a tenure-track Assistant Professor and Principle Investigator at Department of Pharmacology and Toxicology, and a member of Simon Cancer Center at Indiana University School of Medicine. She obtained her PhD degree from University of Toledo, School of Medicine, and finished her Post-doctoral training with the world renowned scientist Dr. George Stark at Cleveland Clinic, Ohio. Her research focuses on the discovery of novel regulators of NF-kB, particularly, on the epigenetic regulation of NF-kB and its role in cancer therapeutics. She won multiple awards at international scientific meetings. She has published near 50 papers with 2 being highlighted by F1000 Prime. She currently holds 2 provisional patents regarding NF-kB regulation and serves as the board member of 5 scientific journals.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggests that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher antitumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.
Tomoaki Ito
Shizuoka Hospital-Juntendo University, Japan
Title: Detection of gene mutations in gastric cancer tissues by sequencing panel
Biography:
Dr. Tomoaki Ito was received the M.D. in 2000 and the Ph.D.in medical science from Juntendo University, Tokyo, Japan. and postdoctoral studies from Stanford University School of Medicine. He is an assistant professor of Department of Surgery, Juntendo Shizuoka Hospital, Juntendo University School of Medicine, Shizuoka, Japan. His reseach interest includes Oncology and Cancer Biomarker.
Abstract:
Companion diagnostics provide information of the effective use of a drug or biological product to help physicians to decide appropriate treatment to the patients. Especially, in cancer field, new technologies such as next generation sequencing, are used to identify nucleotide mutation in the genome of biopsy tissue.
Cancer Panel analysis (Illumina) provides pre-designed, optimized oligonucleotide probes for sequencing mutational hotspots in > 35 kilobases (kb) of target genomic sequence. Forty-eight genes are targeted with 212 amplicons in a highly multiplexed, single-tube reaction.
We performed mutation analysis of the fresh Gastric cancertissues from 4 patients by Cancer Panel analysis using next generation sequencer (MiSeq). We found three hotspots mutations from two patients by comparison with normal tissues, and those mutations would be correlated with their clinical information.
Also, Cancer Panel analysis was successful for same tissues which were fixed by 5% of formalin within one day. Nucleic acid transition appeared in samples fixed for more than 3 days, but such error was not detected for samples fixed within a day. These results would be useful to establish guidelines of tissue fixation for protocols of DNA analysis.
Victor Frenkel
University of Maryland School of Medicine, USA
Title: Focused ultrasound enhanced delivery in solid tumors
Biography:
Victor Frenkel completed his PhD in 1999 at the Technion, Israel Institute of Technology. After a Post-doctoral Fellowship at the University of Maryland Biotechnology Istitute, he was a Staff Scientist at the National Institutes of Health Clinical Center, and Associate Professor of Biomedical Engineering at Catholic University in Washington, DC. He is currently working as an Associate Professor and Director of Translational Focused Ultrasound Research at the Department of Diagnostic Radiology and Nuclear Medicine at the University of Maryland School of Medicine. He has published more than 100 peer-reviewed original research articles, invited reviews, editorials, books and book chapters and conference abstracts.
Abstract:
One of the main impediments to succesful treatment of solid tumors is the inability to obtain sufficient and uniform delivery of therapeutic agents. This is due in part to unique characteristics of the tumor micro-environment, which include abnormalities in the tumor vasculature (such as leaky and tortuous vessels) and a dense and heterogenous extracellular matrix. The presence of these factors can result in deficiencies in transvascular and interstitial transport, respectively, which will ultimately affect the bioavailability and efficacy of administered therapeutics. We have shown how non-invasive and nondestructive, focused ultrasound (FUS) exposures provided in pulsed mode (pFUS) can enhance the delivery of therapeutic agents of various formulations in solid tumor models, including small molecules, antibodies, liposomes, nanoparticles and DNA. Studies were carried out using state of the art, image-guided FUS devices. Enhanced delivery was observed when employing both systemic and local injection, where therapeutic studies demonstrated significant improvements in tumor growth inhibition and survival. Mechanistic studies carried out to support these results showed increase in the effective pore size of the extracellular space, disruption of fibrillar collagen, increased hydraulic conductivity and lower interstitial fluid pressure of the tumor tissue. Preliminary studies were also carried out on the potential of the pFUS exposures on the metastatic process.
Alexander M Buko
Human Metabolome Technologies, USA
Title: Clinical plasma biomarker development for Major Depressive Disorder (MDD
Biography:
Alexander M Buko received his PhD in 1980 from the University of Virginia under Professor Donald F Hunt. He went onto work at the Bureau of Biologics and Biophysics (Today called CBER) for four years then moved to Abbott Labs for 18 years as a distinguished research fellow. From 2002 to 2012, he was Sr. Director of Translational Medicine at Biogen Idec. Currently, he is the Vice President of Business and Product Development for HMT-America (Human Metabolome Technologies).
Abstract:
Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of low mood, independent of life experience. It is often accompanied by low self-esteem, loss of interest in normally enjoyable activities, low energy and pain without a clear cause. Major depressive disorder affected approximately 216 million people (3% of the world's population) in 2015 and is the leading cause of disability in the US for ages 15 to 44. MDD affects more than 15 million American adults, or about 6.7 percent of the US population aged 18 and older in a given year. The American Psychiatric Association added "major depressive disorder" to the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980. The diagnosis of major depressive disorder can be based on the person's reported experiences and a mental status examination. There is currently no laboratory or blood test for major depression. Two of the most common examinations are the CES-D and HAMD-17 scores. While the specificity of these scores can be close to 100%, the sensitivity can be as low as 40%, i.e., when the score diagnoses MDD, it can do so very well, however, more than half of the patients with MDD can be missed. Using metabolomics, HMT, in collaboration with Dr. Noriyuki Kawamura of the Gyokikai Medical Corporation we identified a plasma metabolite, phosphoethanolamine or PEA, that was consistently low in patients with clinically diagnosed MDD. PEA measured by it has over 90% sensitivity and specificity, but in conjunction with a clinical score can achieve close to 100% sensitivity and specificity for MDD. Low levels of PEA distinguish MDD from other forms of mental disorders such as schizophrenia, bipolar disorder or other anxieties. Early studies also suggest successful treatment where MSS, PEA levels are restored to normal. Multi-center large clinical studies in the US, Japan, Europe and in China are currently ongoing to validate the diagnostic utility of PEA for MDD patients. The talk will provide a walk-through the development process of PEA for MDD from early discovery to large scale clinical validation, from CE-MS discovery measurements to a recently released beta version clinical assay kit designed for large scale clinical measurements at independent laboratories.
Melvin L DePamphilis
National Institute for Child Health & Human Development, USA
Title: Aberrant genome duplication as both a cause and a cure for cancer
Biography:
Melvin L DePamphilis received his PhD in Biochemistry from the University of Wisconsin, with Post-doctoral work in enzyme mechanisms at UW and tumor virus DNA replication at Stanford University Medical School. He is currently working as a Senior Research Scientist at the National Institutes of Health. Prior to that, he was a Professor in the Department of Biological Chemistry at Harvard Medical School, and then a Lab Chief at the Roche Institute of Molecular Biology. His professional career is focused on genome duplication in animal viruses, cells, and preimplantation embryos. He has published 147 research papers, 55 reviews, and 10 books.
Abstract:
Most cancers result from the accumulation of genetic mutations that occur during proliferation of the cells that give rise to and maintain tissues. Cancer driver mutations initiate carcinogenesis, but genome destabilizing mutations promote aneuploidy, which contributes to tumor heterogeneity, drug resistance, and treatment failure. Aneuploidy results from missegregation of chromatids during mitosis, which is promoted by aberrant genome duplication in the form of unscheduled endoreplication. At least 35 genes are essential to prevent endoreplication during mitosis and cytokinesis. Fourteen of these genes have been shown to prevent aneuploidy and tumors in mice. Thus, reducing expression of a gene essential to prevent endoreplication during cell proliferation facilitates the rise of cancer. Conversely, induction of aneuploidy can also prevent tumor formation. During mammalian development, pluripotent stem cells give rise to all cell lineages, but when they mislocate to ectopic sites, pluripotent stem cells act as cancer stem cells by producing germ cell tumors. Geminin is one of seven proteins that are essential to prevent DNA re-replication dependent apoptosis during cell proliferation. Although geminin is essential in cells derived from various human cancers, geminin is not essential in normal cells-with one exception. Geminin is essential to prevent DNA re-replication dependent apoptosis in pluripotent embryonic stem cells. Therefore Geminin is a potential chemotherapeutic target in the treatment of germ cell neoplasia, as well as any cancer whose origin depends on a pluripotent progenitor cell.
Daniel M Krainak & Robert Ochs
Food and Drug Administration, USA
Title: FDA/CDRH perspectives on imaging biomarkers: Technical performance and analytical validation
Biography:
Daniel Krainak obtained his PhD in Biomedical Engineering from Northwestern University and completed a Post-doctoral fellowship at CDRH investigating diffusion tensor imaging. He has been a reviewer in the division of Radiological Health since 2012 with an emphasis on magnetic resonance imaging technologies. He participated in the review of radiological devices, imaging biomarkers, and radiological imaging in therapeutic product clinical trials.
Abstract:
The Center for Devices and Radiological Health has responsibility for radiological device pre-market reviews and participates in biomarker qualification review teams for imaging biomarkers through the Medical Device Development Tools program (CDRH) and the Biomarker Qualification Program (CDER). CDRH’s perspective on the evidentiary approach to quantitative imaging devices and imaging biomarkers will be presented. A regulatory perspective on the interaction between claims and analytical validation expectations will be explored for radiological imaging devices. Combinations of technical performance assessments including combinations of physical phantoms, digital reference objects and in vivo imaging may be used to approach analytical validation of imaging devices. Differing evidentiary expectations will be presented with examples. Research within CDRH continues to refine and expand the available methods for assessing the performance of quantitative imaging biomarkers.
Janio Szklaruk
UT MD Anderson Cancer Center, USA
Title: Hepatocellular carcinoma 2017: MR and MSCT imaging
Biography:
Janio Szklaruk has completed his PhD in Physical Chemistry from the State University of New York at Stony Brook NY and his MD degree from the University of Pennsylvania School of Medicine. He completed his Residency in Diagnostic Radiology at Thomas Jefferson University Hospital in Philadelphia. He is the Director of Abdominal Imaging MR at MD Anderson Cancer Center. He is also the Co-Chief, ad interim, of the Abdominal Imaging Section in the Radiology Department at MD Anderson Cancer Center. He has published more than 60 papers and presented multiple talks at international conferences.
Abstract:
Worldwide, hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death with over 500,000 new cases occurring per year. Some of the risk factors associated with HCC include hepatitis B and C, cirrhosis, alcoholic liver disease and aflatoxin exposure. Multislice-computed tomography (MSCT) and magnetic resonance imaging (MRI) are commonly used in the diagnosis, staging, and surveillance of these patients. The purpose of this presentation is to demonstrate a step-wise approach to the radiological evaluation of patients suspected with HCC. The presentation will discuss the importance of the optimum imaging protocol and the common. The new LIRADS criteria for the diagnosis of HCC and the application of Gd-EOB-DTPA to the management of HCC will be presented. Relevant imaging information to provide appropriate staging for HCC will be presented. Following the treatment of HCC, the detection of recurrent disease also depends on imaging findings. The imaging patterns that distinguish post-treatment changes versus recurrent disease will be presented. The goals of this presentation are for the participants to (i) to learn the importance of optimum imaging protocols, (ii) to become familiar with the imaging features of HCC, (iii) to recognize the imaging patterns of recurrence following treatment.
Satoshi Tokuda
Shizuoka Hospital-Juntendo University, Japan
Title: The study of the markers of mood disorder with gastrointestinal cancer patients
Biography:
Satoshi Tokuda graduated from Juntendo University School of Medicine in Japan in 2012. From 2012-2014, he was a Junior Resident at Juntendo Shizuoka Hospital, Shizuoka, Japan; near the Mt Fuji. He has been a GI Surgeon at Juntendo Shizuoka Hospital from October, 2014, until now.
Abstract:
Introduction: The number of the patients of major depressive and bipolar disorders are increasing. Cancer and depression have a close relationship; about 16% of all cancer patients are diagnosed with it. In this study, we selected two genes as potential markers of the mood disorder and checked the amount of the gene expression in gastrointestinal cancer patients at several points.
Materials & Methods: Three patients who were diagnosed with gastrointestinal cancer were selected and we gathered blood samples. They had no medical examination of psychiatric disorder. The timings of sample collection were before operation, post-operative day 1 and almost seven days after the surgery. We gathered blood in PAXgene RNA tube. After extracting RNA, we measured the expression of two genes by Real-time PCR. All patients of this study signed written informed consent forms.
Results: We compared the gene expressions of before operation and post-operative day 1 and confirmed the reduction of the prevalence of mood disorder in three patients after surgery.
Discussion: Before an operation, the patients must have a lot of stress and after their surgery they experience relief from the stress. This study suggests that we can confirm the mood changes with numeric data. If we grasp the mood disorder in the early period of cancer patients, we can help the patients with early intervention of mental side. The optimal outcome is to increase the cases and use the markers in clinical application. Add to that, we will gather saliva specimens and measure the gene expressions as well. The reason is that we can get the patient’s saliva easily and utilize in various situations; e.g. disaster and little children.
Conclusion: The marker of the mood disorder is suggested by colon cancer patients.
Martin Tobi
Central Michigan University College of Medicine, USA
Title: Clinical constellation of the utility of the p87 biomarker for cancer
Biography:
Martin Tobi completed his MB ChB (MD equivalent) from the University of Cape Town Medical School, South Africa, clinically trained in Jerusalem and Chicago, and Post-graduate Training at the NCI, NIH, Bethesda Maryland. He was the Chief of Gastroenterology at the Philadelphia VAMC and Faculty at the University of Pennsylvania Perelman School of Medicine. He currently is at the Saginaw VAMC working as Clinical Professor of Gastroenterology at CMUCOM and has an active laboratory at the Detroit VAMC. He has more than 80 articles in peer-reviewed publications and served on Editorial Boards, organized conferences and participated in study sections.
Abstract:
The p87 biomarker is recognized by an anti-adenoma murine monoclonal antibody (Mab), tailored for early detection of colorectal neoplasia in colonic effluent. The Mab functions for immuno-blotting, ELISA and immunohistochemistry (IHC). It recognizes an epitope on a 87 kDa 10% N-linked glycoprotein. It is constitutively expressed but at a low level in the human GIT. The cell of origin appears to be the paneth cell, a component of the innate immune system. Expression is increased in normal-appearing colonic mucosa comensurate to risk of colorectal cancer (CRC). It is found in tissues from all colon genetic syndromes and is increased in the stool of patients at increased risk for CRC. It is postulated to be the human analogue of the modifier of min (MOM). In the human, it increases with age but disproportionately increased in younger patients rectal mucosa mirroring the current epidemiologic trend. It can be differentially expressed in the serum of patients with cancer which suggests that it may have diagnostic utility for serum bank samples. It has prognostic capability in IHC for pancreatic cancer (adenocarcinoma and IPMN); gastric adenocarcinoma and CRC. Prospectively, it has been shown to have 52% sensitivity and 91% specificity in lung and 67% with 90% respectively in pancreatic cancer patients, diagnosing patients two years before the cancer was clinically diagnosed. Thus, the p87 biomarker therefore covers a gamut of most common cancers possibly giving most cancer victims a chance at early diagnosis in order to bring cancer therapy to bear at a earlier cancer stage.
Padmanabhan Balasundaram
National Institute of Mental Health and Neuro Sciences, India
Title: Identification of phenanthridinone based inhibitors of BRD2-BD2 bromodomain by structure-based drug discovery approach
Biography:
B Padmanabhan is working as a Professor and Head of the Department of Biophysics, NIMHANS, Bangalore, India. He is a Structural Biologist and has more than 22 years of work experience blended with industry and academic careers. He has worked in various international organizations including Mitsubishi Chemical Corporation, ERATO-JST, RIKEN in Japan, the University of Washington, Seattle, USA, Laurus Lab Pvt. Ltd., Hyderabad, India. His group is now focusing on structure-based drug discovery on the protein targets associated with neurological disorders including Parkinson’s disease (PD), ALS and glioma. He earned his PhD in Biophysics and Protein Crystallography from All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Abstract:
Epigenetics, through the modulation of genetic information, involve a fundamental life process, such as cell-proliferation, cell development and decision between cell survival and cell death. Alteration of epigenetic function, which causes abnormal cellular functions, can lead to the development of cancer, neurodegeneration, autoimmune/inflammatory diseases, metabolic diseases and viral infections. Hence, the epigenetic targets are of great importance to discover new drug molecules for various major diseases. One of the epigenetic ‘reader’ proteins, bromodomain containing proteins recognized acetylated-lysine histones (H3 and H4) and non-histones, such as the tumor suppressor, p53. The BET family nuclear proteins possess two tandem bromodomains (BD1 and BD2) and a conserved extra-terminal domain. The BRD2 protein, a BET family member, recognizes mono-acetylated and di-acetylated histones through N- and C-terminal bromodomains. The BRD2 protein are reported to possess potential role in the pathogenesis of cancer, defects in embryonic stem cell differentiation, seizures and neurodegenerative disorders. Drug discovery of small molecule inhibitors targeting BRD2/BRD4 are in the pipeline, and some of them are already in clinical trials for the treatment of cancer. We have recently discovered compounds, by structure-based drug design method, which significantly inhibit the second bromodomain, BD2 of BRD2. The crystal structures of the BRD2-BD2 inhibitor complexes were determined at atomic resolution by using the X-ray diffraction data collected on the beamline, BM14 at ESRF, France. The drug discovery process such as in-silico screening, co-crystal structure determination, binding study and cell-based assay of the BRD2-BD2 complex will be discussed.
Vishwajeet Rohil
Vallabhbhai Patel Chest Institute, India
Title: Anticancer activity of polyphenolic acetates mediated by calreticulin transacetylase in lung cancer
Biography:
V Rohil has obtained his MBBS degree from University College of Medical Sciences, Delhi and MD in Biochemistry from V P Chest Institute and has joined the Department of Clinical Biochemistry, V P C I, University of Delhi in 2001 as Assistant Professor, after doing Senior Residency at Maulana Azad Medical College, New Delhi. He has more than 24 years of Professional experience in the medical profession out of which 16 years of experience he has got in Teaching, Diagnostics and Research in the field of Biochemistry, Clinical Biochemistry and Molecular Biology. He is Supervisor and In-charge of the Clinical Biochemistry Autoanalyzer Laboratory for patient care at the Viswanathan Chest Hospital at V P C I and he is actively involved in Research and Teaching and guiding Post-graduate MD and PhD Students. He was selected as Govt. of India Expert, Medical Faculty under Govt. of India assistance programme by Ministry of External Affairs on special deputation to work at the Dept. of Biochemistry at B P K I H S, Dharan, Nepal and taught Medical graduates and Post-graduates for three years in an integrated setup, thereby he has acquired skills in structured interactive session [SIS], laboratory exercises [LABEX], problem based learning [PBL], multi-system seminars [MSS] with integrated teaching along with newer improved assessment techniques like OSPE [Objective structured practical examination], MCQ, Item analysis, SAQ, MEQ etc.
Abstract:
Background: Cancer is a group of diseases involving abnormal cell growth, occasionally having metastasis. This underlying genetic disease is initiated either by mutation or epigenetics. We are targeting lung carcinoma, most common cause of cancer-related death in men and women. Our new drug discovery is targeted on Calreticulin Transacetylase (CRTAase). We intend to treat lung cancer in-vivo and in-vitro by inducing hyperacetylation and upregulating the expression of genes important in tumor suppression. The polyphenolic acetates in combination with HDAC inhibitors are known to promote hyperacetylation, leading to apoptosis in lung cancer cells.
Aim: To determine the anticancer activity of 7, 8-Diacetoxy-4-Methyl Coumarin (DAMC), Polyphenolic acetate targeting acetylated histone interaction.
Methodology: DAMC showed anticancer activity both in-vitro and in-vivo. The hyperacetylation activity of DAMC on CRTAase induced epigenetic modulations were observed in A549 cells, as well as mice with Ehrlich ascites tumor (EAT) cells. The in-vitro and in-vivo data was validated by the apoptosis. Additionally specific target based anticancer property of DAMC was evaluated using microarray and RTPCR prior and after demethylation.
Results: In A549 cells, highest transfection efficiency was obtained after 72 hrs. Significant increase (p<0.01) in expression of H3 (2.67±0.02) and H4 2.755±0.016) was observed in DAMC treated CRTAase gene transfected A549 cells as compared to non-transfected A549 cells treated with DAMC (2.14±0.023) and (2.161±0.011) respectively. High apoptotic index was observed in The EAT cells in-vivo as well as in A549 cells in-vitro. RNA having RIN (RNA Integrity) values between 8.5 and 9.8 on electropherogram were subjected to microarray and RTPCR. A549 cells treated with DAMC and Valproic acid (VA) were suggestive of synergistic upregulation of tumor suppressor genes viz. ING4, TCF21, MFSD2A, FHIT and metalloproteinase inhibitor 3 i.e.TIMP3 and downregulating the oncogene Skp2.
Conclusion: The in-vivo as well as in-vitro findings suggest that DAMC and VA can potentiate the apoptotic pathway via CRTAase and thus can be a very promising anticancer drug candidate. In further ongoing studies we are screening more drugs targeting similar/more molecular targets and extending correlation with clinical applications.
Weiming Xia
Boston University School of Medicine, U
Title: Combination of mass spectrometry-ELISA platforms for Alzheimer blood biomarkers
Biography:
Weiming Xia received his PhD degree from the University of Texas Medical School at Houston in 1994. He pursued his Post-doctoral training in Dennis Selkoe’s laboratory and became Assistant Professor at Harvard Medical School in 1999. Currently he is working as an Acting Associate Director of Research at GRECC, Bedford VA Hospital affiliated with Boston University School of Medicine. He has published over 110 original research articles and edited a book. His research focuses on the molecular mechanisms responsible for Alzheimer pathogenesis and biomarkers, and on exploration of therapeutic interventions.
Abstract:
Two pathological hallmarks of Alzheimer’s disease (AD) are Tau-containing neurofibrillary tangles and amyloid β protein (Aβ)-containing neuritic plaques. Due to the heterogeneity and multifactorial nature of AD, a single biomarker for diagnosis of AD has not been identified. In this study, we have collected peripheral blood mononuclear cells (PBMC) and plasma from AD patients and cognitive normal subjects. We have converted PBMC to induced pluripotent stem cell (iPSC) lines, and we have further differentiated iPSC into human 3D neurons. At autopsy, AD pathology was confirmed in brains of patients from whom we derived blood, iPSC and 3D neurons. Quantitation of Aβ and Tau by ELISA illustrated much higher levels of Aβ and phosphorylated Tau at residues Thr 181 and Thr 231 in brain tissue from superior and inferior frontal cortex area, compared to those from cerebellum region. Liquid chromatography/mass spectrometry was used to analyze plasma, iPSC, 3D neurons and post-mortem brain tissue labelled with isobaric mass tags for relative protein quantification. Our study revealed compartmental segregation as well as association of differentially expressed proteins between AD and control subjects. We found that the levels of Tau and neurofilament light and medium polypeptides were increased in 3D neurons derived from AD patients. Analysis of plasma samples also allows us to separate AD patients from healthy subjects. In conclusion, we present a unique platform to discover proteins linked to AD as candidate biomarkers.
- Biomarkers & its Diseases| Cancer Cell Biology | Cancer Drugs | Precision Medicine & Cancer Therapy | Functional Genomics and Cytogenetic Biomarkers | Omics Technologies in Biomarkers Discovery and Validation | Techniques to Maximize Biomarker Identification | Biomarkers and Pharmacology
Session Introduction
Hem D Shukla
University of Maryland, USA
Title: Oxidative stress induced NRF2 regulation in BxPC-3 pancreatic cancer cells and identification of therapeutic targets
Biography:
Hem D Shukla is a Research Scientist in the Department of Pharmaceutical Sciences at University of Maryland and adjunct Professor of Genomics in Notre Dame of Maryland University. He has also worked as Research Faculty in Department of Biology at Johns Hopkins University. He has worked on proteomic analysis of oxidative stress response in BxPC-3 pancreatic cell lines and identification of biomarkers for early detection of pancreatic cancer. He has worked on “The Nrf2 mediated antioxidant defense against oxidative stress in pancreatic cancer cell lines and targets for therapeutic intervention”. He has shown elevated level of Nrf2 transcriptional factor in pancreatic cancer cell lines under oxidative stress, which is phosphorylated by protein kinase C and affects phosphatidylinositol 3-kinase and MAP kinase pathways. After phosphorylation, Nrf2 translocates to the nucleus, binds AREs and transactivates detoxifying enzymes and antioxidant enzymes, such as glutathione S-transferase, and superoxide dismutase. The IPA analysis has suggested a potential role of Nrf2 under oxidative stress conditions. His research interests are: proteomic analysis of oxidative stress response in BxPC-3 pancreatic cell lines, identification of biomarkers for pancreatic cancer and Nrf2 mediated antioxidant defense against oxidative stress in pancreatic cancer cell lines.
Abstract:
Pancreatic cancer is one of the most aggressive human malignancies and ninth leading cause of cancer death in the world. Estimated new cases and deaths from pancreatic cancer in 2013 in the United States would be 45,220 and deaths 38,460. Most patients diagnosed with pancreatic cancer die within 6 months, and only 4% survive 5 years after diagnosis. Pancreatic cancer is characterized by colossal local invasion and early metastatic growth to the liver and regional lymph nodes. Expression of Nrf2 was up-regulated in oxidatively stressed BxPC-3 cell line and ductal adenocarcinomas. Furthermore, the BxPC-3 cell line responds to stress signals and resist chemotherapeutic interventions and have shown drug resistance. The Nrf2 has also been implicated in proliferation in certain pancreatic adenocarcinomas. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2. We have also identified the presence of a number of gene products involved in integrin signaling pathways. The comparative proteomic analysis using Protein Center and Ingenuity Pathway Analysis have shown the activation of DNA repair pathway genes like RAD50, ApeX, damage-specific DNA binding protein, which have the capability to repair DNA damage. The activation of NRF2 transcriptional factor and its phosphorylation in BxPC-3 treated cells shows that it may bind to the DNA at the location of the Antioxidant Response Element (ARE) or also called hARE (Human Antioxidant Response Element), which is the master regulator of the total antioxidant defense system. The proteomic data have also shown the activation of INT-ILK-PT3K-ILKAP-AKT and Cav-1-GRB2-SOS-cRas-Raf-MEK cascades. These results may have some promise in therapeutic intervention in the treatment of pancreatic cancer adenocarcinoma.
Praveen Sonkusre
CSIR - Institute of Microbial Technology, India
Title: Specificity of biogenic selenium nanoparticles for prostate cancer chemoprevention with reduced risk of toxicity
Biography:
Dr. Praveen Sonkusre has completed his Ph.D. from CSIR - Institute of Microbial Technology, Sector 39A, Chandigarh, India and currently working in the same institute as Research Associate. He has published 4 research articles in the early stage of his scientific career and is a part of one patent (filed).
Abstract:
Selenium deficiency is associated with many physiological disorders including the high risk of cancer. The rehabilitation of selenium with different selenium supplements, however, fails due to their low therapeutic index. Therefore, it is advantageous to have a less toxic form of selenium for supplementation with potentially high anticancer activity. In this study, selenium nanoparticles were synthesized biologically by Bacillus licheniformisJS2, and a method was developed for extraction and purification of intracellular nanoparticles. Characterization of extracted nanoparticles with various biochemical, microscopic and spectroscopic techniques suggested that these 110 nm sized particles are composed of selenium and capped with a few functional groups that provide steric stability to them. These neutral charged, non-agglomerating selenium nanoparticles at a concentration as low as 2 µg Se/ml were inducing reactive oxygen species (ROS) mediated necroptosis in PC-3 cells by gaining cellular internalization without causing any significant toxicity to human peripheral blood mononuclear cells and RBCs. Real-time qPCR analysis showed increased expression of necroptosis associated tumor necrotic factor (TNF) and interferon regulatory factor 1 (IRF1). An increased expression of the RIP1 protein was also observed at the translational level upon SeNP treatment. Moreover, the cell viability was significantly increased in the presence of necroptosis inhibitor, Necrostatin-1. Furthermore, histopathological analysis showed the subsequent oral administrations of ten times higher concentration of these endotoxin free selenium nanoparticles in C3H/HeJ mice (50 mg Se/kg of body weight), induce significantly lower toxicity compared to the L-selenomethionine (5 mg Se/kg). Data suggest that these biogenic SeNP could be the safest form of selenium supplementation with potentially high anticanceractivity.
Saganuwan Alhaji
University of Agriculture, Nigeria
Title: Derivation of a unique body surface area (BSA) formula for calculation of relatively safe doses of dog and human anticancer drugs
Biography:
Saganuwan Alhaji Saganuwan is working as an Associate Professor of Pharmacology, former HOD, Registration/Time Table Officer, College of Veterinary Medicine, University of Agriculture, Makurdi, Nigeria, Fellow, Institute of Industrial Administration, Licensed Member of Veterinary Council of Nigeria, Honorary Member, Nigeria Institute of Food Science and Technology, Member of Science and Technology Forum, Member of Institute of Research and Development Network, Editorial Board Member to many local and international journals of high repute. He received DVM degree in Veterinary Medicine, MSc in Pharmacology and PhD in Pharmacology from Usmanu Danfodiyo University, Sokoto, Nigeria. He received also PGD in Statistics and PGDE in Science Education from University of Agriculture, Makurdi, Nigeria. He received Medical International Noble Award in 2012. His areas of research interest are Pharmacology, Toxicology, Oncology and Medicinal Chemistry. Presently he teaches, carries out research and supervises undergraduate and graduate students of University of Agriculture, Makurdi, Nigeria. He has over 230 citations with 60 publications in local and international journals of high repute. He has presented conference papers in USA, UK, India, Spain, Japan, China, Cyprus, Australia and Nigeria.
Abstract:
The safety of anticancer dosing has become a serious concern due to high incidence of life-threatening toxicity signs. More so, dogs are used as models of research for human cancers. As such, a uniform body surface area (BSA) formula is developed for human and dogs with a view to having low safe effective therapeutic doses of anticancers.. The derived formula (BSA=BW0.528×H0.528×K) was used to calculate BSAs of greyhound, toy, companion, terrier, hunting and working dogs, yielded low doses of dacarbazine, asparaginase, streptozotocin, dactinomycin, epirubicine and prednisolone. Hunting and working dogs have high body weight, BMI and BSAs similar to that of human and may be prone to obesity and obesity associated diseases. Whereas BSAs and doses of anticancer agents of light and relatively tall dogs are relatively higher in comparison with that of short and light dogs. Greyhounds have higher BSA in comparison with toys, companions and terriers. Working breeds of dog: treeing walker coon haired (65.0 kg), great swiss mountain dog (59.0 kg), longhaired St bernard (55.0 kg), french mastiff (50.0 kg) and female komondor (59.0 kg) have same BSA values with humans weighing 51.3, 46.7, 44.8, 44.0 and 43.0 kg, respectively. Calculated exponent (0.528) may be the common relationship between basal metabolism of dog and human.
Biography:
Mr. Kamaju Suryahari and Ms. Sreevallika Immadi is working with Clinical Trials company for the past 3 years. Both are involved in active participation in running the company. The Basic profile related company is to provide Diagnostic tests in lower cost which help rural Indian Population. The Primary aim of the company is to promote low cost Biomarker Investigations for Rural Indian Population. Where they not able to afford for corporate pricing of the Bio Marker Investigations. Mr. Kamaju Suryahari is having almost 14 years of experience in Oncology Trials and well versed in Solid Tumor Test Based Investigations Related Studies. Ms. Immadi Sreevallika is having almost 2 years experience related to Oncology Therapeutic Area BasedStudies.
Abstract:
Non-interventional, retrospective & anonymized data base study on breast tumors for markers predictive of risk of recurrence: This is a non-interventional, anonym zed and retrospective research study. It does not involve enrollment of patients/administration of drugs. The study uses left over FEPE tumor blocks remaining after routine diagnosis for the patient is over. IHC/RTPCR based tests will be done on these blocks. Each patient will be de-identified with a unique code, by the hospital. No contact between patient and researcher at any point of time, thus study will have no side effects on the health of the patient. Main aim the study To carry out a non -intervenaial, retrospective & anonymized study on 2000 breast cancer tumors to assess biomarkers for :
i) Prediction of risk of cancer recurrence
ii) Usefulness of chemo/radio therapy
iii) Overall effective cancer treatment planning.
Benefits :
1) Patients will avoid excessive therapy/ side effects & enjoy improved quality of life & save resources.
2) Medical oncologists can prescribe most effective therapy and targeted drugs .
Cancer and Recurrence:
*ASCO report: 1M new cancer cases in India per year. 12 Million Breast cancer survivors in US. In India 2.4M breast cancer cases.
*Cancer recurrence is the most feared aspect of cancer as it is responsible for the Morbidity and mortality associated with the disease.
*Current means to predict risk of recurrence are limited. Treatment can be planned optimally if recurrence information is available.
Mission: To develop novel diagnostic tests for prediction of risk of recurrence for ALL cancers, first focus on breast cancer.
Clinical Trials Company Established in Year 2015. Currently the company is working with leading Medical Oncologists in India. Involving the Clinical Trials as well as the Molecular testing and Bio Marker Investigations. Most of the Trials involved in Medical Oncology related areas such as (Breast Cancer, Metastatic Colorectal Cancer, Head & Neck Cancer and other Lymphomas.
Mirjana Maletic-Savatic
Baylor College of Medicine, USA
Title: Biomarker of adult human neurogenesis enables studies of aging and depression
Biography:
Mirjana Maletic-Savatic is a Board-Certified Neurologist and a Physician/Scientist interested in the interactions between genes and environment, particularly those that affect learning and memory. The new concepts and analytic algorithms she and her team have developed at the bench have the potential to change the standard of clinical care, ultimately leading to improved diagnosis, prognosis and individualized treatment of our patients. She is the Recipient of numerous awards and has published extensively in top-tier journals.
Abstract:
The discovery of adult neurogenesis has opened a new era in modern neurobiology: the brain, after all, has the capacity to regenerate. In the mammalian brain, new neurons are continuously formed in the hippocampus, the center for learning and memory. In animal models, newborn neurons are important for cognition, mood and stress regulation. In humans, it is estimated that about 700 new neurons are integrated daily into the hippocampus, but their functional importance is not known because of the lack of a live and non-invasive measure. Based on a series of experiments using magnetic resonance spectroscopy (MRS), we identified a fatty acid-related metabolite that is highly enriched in neuroprogenitors and visible at 1.28 ppm on the resonance spectrum. To enable detection of the neuroprogenitors in the human brain, we developed an analytical algorithm that allows automated and objective quantitation of the 1.28 ppm spectroscopic signal obtained by 3T MRS. Using this method, we can distinguish neurogenic and non-neurogenic areas in the human brain. Further, we discovered that the neurogenic signal is associated with age and depression. Strikingly, in medication-resistant depressed individuals, electroconvulsive treatment provokes a two-fold signal increase–a leading indicator that predicts subsequent hippocampal plasticity and clinical outcome. Overall, we now have the means to study neurogenesis in the live human brain and provide new insights on the role of this process in human brain function, dysfunction and treatment response. Moreover, this method may be used to trace activated and/or stem cells transplanted into the human brain, already in clinical trials for stroke and multiple sclerosis.
Biography:
Erin Sharkawy has completed her Bachelor’s degree of Science (Biochemistry) in 2012, Diploma of Medical Tests–Biochemistry Analysis in 2013, Master’s degree in Biochemistry from Cairo University of Science. She is a Member of Presedential Leadership Programme. She is currently waiting to publish three papers on cancer researches. She has also worked as a Bio-Analytical Chemist and Medical Representative, but now she works as a Demonstrator and Molecular Biologist at National Cancer Institute. She has participated in Summer Training courses at NCI of Basics of Cancer and Molecular Biology.
Abstract:
Hepatitis C virus (HCV) is a single stranded RNA virus, of the Flaviviridae family. It is the main cause of chronic HCV diseases like fibrosis, cirrhosis, HCC and end stage liver disease. Worldwide, about 71 millions of individuals have HCC resulting from HCV chronic infection with about 790 thousands annual deaths. A major cause of high mortality rate due to HCC is the lack of early diagnostic resources. There is a great need for a sensitive, specific and non-invasive diagnostic marker to detect HCC in the earlier stages. We studied four protein markers in serum (SAA2, KNG1, PON1 and GAL3) that were significantly elevated in HCV-related HCC patients in previous study in our lab using C-MS/MS screening analysis and separated by SDS-PAGE gel electrophoresis. Estimation of protein concentrations were done in 52 patients infected with HCV-free HCC, 51 with HCV-related HCC in addition to 40 healthy participants as a control group. Analyses of protein concentrations were performed using sandwich ELISA technique. From the studied biomarkers, SAA2 provided the highest diagnostic accuracy (AUC=0.925) for HCC patients at (p<0.001). Morever, the diagnostic accuracy increased slightly when we used the panel of SAA2 with AFP, together with AUC=0.946, for HCC patients. SAA2 may have a considerable use in early detection of HCC in both normal population and high-risk patients.
Nina Mezu-Nwaba
Food and Drug Administration, USA
Title: Current regulatory trends and applicability of biomarkers in drugs, biologics and devices: A US FDA Outlook
Biography:
Nina Mezu-Nwaba is working as a Captain with the United States Public Health Service and a Senior Compliance Officer in the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration. She has over 20 years of clinical, retail, and regulatory experience, with expert knowledge in OB/GYN, Gastroenterology, Surgical and Urology products. She has been with the FDA for 17 years and has held positions at the Office of Generic Drugs, the Center for Drug Evaluation and Research, CDRH Office of Device Evaluation, and CDRH Office of Surveillance and Biometrics. She obtained her Doctor of Pharmacy from the University of Maryland at Baltimore, a Master’s in Biomedical Science from Georgetown University and a Master’s in Public Health from the John Hopkins Bloomberg School of Public Health. She has represented the FDA in Berlin, Puerto Rico, and the US as the Liaison for International Standards Committees. She actively participates in community health outreach, mentoring, as well as international humanitarian missions. She seeks to bridge gaps in health-disparities through voluntary service with the Commissioned Corps, Health and Human Services, MI Foundation in Nigeria, Rotary Club and serving the USPHS in Indian Health Reservations and other US locations.
Abstract:
The US Food and Drug Administration (FDA) defines a biomarker as “a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.” The increasing worldwide trend in the utilization of biomarkers has shown to be a significant element in the field of healthcare. Biomarkers have been integrated as measuring outcomes in the regulation of drugs, devices and biologics. Biomarkers in drug and medical device development provide information concerning detection of disease states in early stages as well as efficacious treatment options. For example, non-specific biomarkers such as WBC, D-dimers, C-reactive protein and criteria to diagnose sepsis have also played a part in therapy. In a recent study, biomarkers were utilized for a mice model of retinopathy of prematurity to ultimately benefit premature neonates in the early detection of this disorder. Based on the current trend, biomarkers offer an optimistic, yet challenging perspective on the future of its incorporation into personalized medicine. Clinicians can potentially measure and identify positive and negative responses to therapies benefitting both providers and patients. However, there have been several challenges in application of biomarkers due to lack of regulations in developing these biomarkers. In order to address these challenges, the FDA developed the Biomarker Qualification Program to establish the regulatory framework in biomarker evaluation and acceptance. As part of this program the FDA is working together with external stakeholders to develop a list of qualified biomarkers that can be applied in development of any drug, biologic or medical device. With more regulations put in place to assess and verify a biomarker’s value, the integration of biomarkers will continue to expand our understanding of human health.
Mangilal Agarwal
Indiana University, USA
Title: Biomarkers of hypoglycemia in human breath and sensor development
Biography:
Mangilal Agarwal received his MS (2002) and PhD (2004) in Engineering from Louisiana Tech University (Ruston, LA). After his PhD, he was a Post-doctoral Research Associate at Louisiana Tech’s Institute for Micromanufacturing, which was followed by an appointment as Research Assistant Professor there. He joined IUPUI in 2009 as the Associate Director for Research Development in the Office of the Vice Chancellor for Research. He is currently working as Associate Professor of Mechanical Engineering and Director of Integrated Nanosystems Development Institute (INDI) at Indiana University-Purdue University Indianapolis (IUPUI) and directs the development of interdisciplinary research and education initiatives.
Abstract:
It is well recognized that trained canines can identify hypoglycemic lows in patients with type 1 diabetes (T1D) from smell alone. In order to build a noninvasive breath sensor to mimic canines’ ability to detect hypoglycemia in breath, we’ve collected breath samples from people with T1D and at the same time we’ve been developing cross-selective polymer and nanoparticle-based sensors for constructing a nanosensor array. Gas chromatography/mass spectrometry (GC/MS) was used to detect volatile organic compounds (VOCs) in the breath samples, and the GC/MS results were then aggregated and subsequently analyzed using statistical models to identify the specific panel of VOC biomarkers co-related to hypoglycemia. The analysis shows that from the panel of seven identified biomarkers one can detect hypoglycemia in breath with 91% sensitivity and 84% specificity (cross-validated results). Concurrently, we have been developing polymer and nanoparticle-based resistive sensors that can differentiate VOCs specific to the types of VOCs identified by results from the first summer. We have shown how poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP)-based sensors can have increased sensitivity and cross-selectivity by modifying specific sensors in an array to increase or decrease both adsorption and transduction efficiency for specific classes of VOCs including alcohols (detector response can be varied by 200%) and ketones (response changes of up to 89%).
Mohammad Obaidul Hoque
Johns Hopkins University, USA
Title: Stem cell factors and markers: Biomarkers for bladder cancer detection and target therapy
Biography:
Mohammad Obaidul Hoque is working as an Associate Professor of Otolaryngology-Head and Neck Surgery, Urology and Oncology at Johns Hopkins University School of Medicine. He completed Dental and Oral Surgery Training at the Dhaka Dental College, Dhaka University, Bangladesh. He then moved to Japan for the completion of PhD degree, where he also completed Advanced Clinical Training in Oral and Maxillofacial Surgery and Oncology. After training in Japan, he worked in the Head and Neck Cancer Research Division as a Post-doctoral Fellow under the mentorship of David Sidransky. He joined as a Faculty Member in 2006 in the Department of Otolaryngology-Head and Neck Surgery. His research interests includes: a) understanding the molecular biologic basis of head and neck, lung and genitourinary cancer b) developing and validating genetic and epigenetic approaches for early cancer diagnosis, cancer risk assessment and cancer prognosis and c) identifying molecular alterations due to environmental exposures such as active smoking, passive smoking and arsenic.
Abstract:
Bladder cancer (BCa) is classified as non-muscle-invasive BC (NMIBC) or muscle-invasive BC (MIBC). Because the recurrence and mortality rates of BCa are high, suitable biomarkers for early detection and targeted therapy are needed. Cancer stem cells (CSCs) have been shown to contribute to tumorigenesis and therapeutic resistance. In a recent study we found that CSC factors can be detected in the urine of BCa patients with high sensitivity and specificity and targeting CSC pathways elicits a long-lasting therapeutic response by limiting CSC expansion following chemotherapy and EGFR inhibition in BCa.
Ismael Obaidi
Conway Institute, Ireland
Title: Dysregulation of apoptosis-regulating miRNA by curcumin sensitizes kidney cancer cells to TRAIL induced apoptosis
Biography:
Obaidi I is currently a final year PhD Student at the Conway Institute, School of Biomolecular and Biomedical Sciences, UCD, Ireland. He is also a Pharmacist, and has an MSc in Pharmacology and Toxicology, from the School of Medicine, University of Babylon, Iraq. He has more than eight published papers/abstracts. He is currently a Member of the International Cell Death Society.
Abstract:
Renal cancer is the ninth most common cancer in the world. In 2012 there were 337,860 newly diagnosed renal cancer cases worldwide, with 121,629 cases in Europe alone. In 2013, the number of deaths in the USA due to renal cancer was 13,680 out of 65,150 total cancer deaths (21%) cancer cases. Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults, responsible for approximately 95% of cases. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), is a trimeric ligand, which binds to death receptors. Upon incorporation with DR4 (TRAIL-R1) and/or DR5 (TRAIL-R2), it activates the death inducing signaling cascade (DISC) in which fas associated death domain (FADD) recruits and activates the initiator procaspase 8 to active caspase 8, which in turn, amplifies the death signal by cleaving and activating many caspases including procaspase 3. Micro-RNAs (miRNAs) are a class of a highly conserved, small (~19-25 nucleotides) non protein-coding RNA. They silence gene expression by the induction of mRNA degradation or translational inhibition. Following the exposure of cancerous human renal cells (ACHN) to 25 µM curcumin for 24h, an miRNA screening test was performed for an estimated number of 84 apoptosis-regulating miRNA. The results revealed that let-7C was significantly upregulated. Several bio-informatic tools were used to identify let-7C gene targets. The results of the search revealed that genes regulating cell cycle phases and those controlling tumor metabolism are the primary targets of let-7C. Inhibition of let-7C using antagomirs was associated with the abbrogation of curcumin effects on cell cycle and cancer cell metabolism.
Hediye Nese Cinar
Food and Drug Administration, USA
Title: Organelle genome polymorphisms: A molecular epidemiology tool for differentiation of cyclospora cayetanensis isolates during foodborne outbreaks
Biography:
Hediye Nese Cinar has completed her MD degree from Dokuz Eylul University in Turkey. After completing her Post-doctoral studies at University of California Santa Cruz she joined Food and Drug Administration as a Research Fellow. She works as a Staff Scientist/ Research Biologist at FDA.
Abstract:
Cyclospora cayetanensis is a coccidian apicomplexan parasite causing large outbreaks in different countries, including the US. The surveillance data collected by the CDC between 1996-2015 indicated that C. cayetanensis is the second most common cause of illness and outbreaks in the U.S. associated with imported foods regulated by FDA. Cyclosporiasis outbreak investigations are limited by the absence of molecular epidemiological tools for tracebacks. Due to difficulties in the recovery of the oocysts from produce and clinical samples, the unculturable nature of the organism, and limitations in efficient DNA extraction, until recently very little C. cayetanensis genomic information was available. In different apicomplexan parasites, multicopy organellar DNA such as mitochondrial and apicoplast genomes have been used for detection and molecular epidemiology analysis. We developed genomic workflows to obtain complete mitochondrial and apicoplast genome sequences from contaminated foods and clinical samples, for differentiation of C. cayetanensis isolates. The 6274 bp C. cayetanensis mitochondrial genome was amplified by PCR in four overlapping amplicons from genomic DNA extracted directly from cilantro spiked with oocysts, and from clinical stool samples. DNA sequence libraries of pooled amplicons were prepared using the Ovation Ultralow System library kit (NuGEN technologies) and sequenced using MiSeq. To obtain larger apicoplast genomes (34 kb), oocysts were purified from clinical stool samples. Genomic DNA was extracted from purified oocysts, NGS libraries were prepared using the Ovation Ultralow System library kit and sequenced using Miseq. Sequence reads were assembled using CLC Genomics WorkBench, and Geneious programs, to map to a reference C. cayetanensis mitochondria or apicoplast genome. The PCR amplification combined with NGS sequencing approach allowed us to sequence complete mitochondrial genomes directly from produce samples seeded with C. cayetanensis oocysts, and from stool samples. We were able to obtain whole apicoplast sequences from purified oocysts isolated from clinical stool samples. SNP profiles of both mitochondria and apicoplast genomes exhibited discriminatory power based on geographical metadata. C. cayetanensis isolates from different states grouped together in an evolutionary tree, suggesting that genomic analyses of mitochondria and apicoplast sequences may help to link outbreak cases to the source. The described approaches will facilitate the application of genomics tools to epidemiologically link C. cayetanensis identified in clinical and food samples during outbreak investigations.
Shyam Mohapatra
University of Soiuth Florida, USA
Title: Nanotechnology platform for personalized cancer treatment
Biography:
Shyam Mohapatra is a distinguished USF Health Professor, Director of the Division of Translational Medicine (Internal Medicine) and Associate Dean of Graduate Programs at the College of Pharmacy in the University of South Florida. He also directs the USF Center for Research and Education in Nanobio-Engineering and is a Research Career Scientist at the James A Haley VA Hospital in Tampa. He has published over 200 papers and holds over 30 US and foreign patents. He is a Fellow of the AAAAI, NAI, AIMBE and AAAS and a 2014 Inductee of the Florida Inventors Hall of Fame.
Abstract:
Considerable technological success has been achieved in this burgeoning field of nanomedicine, but there remain substantial challenges, from this becoming a new paradigm in modern and evolving human needs for diagnostics and therapeutics. These include the complexities and heterogeneity of biology of chronic diseases, an incomplete understanding of nano–bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This presentation will highlight the progress, challenges and opportunities in nanomedicine and discuss novel engineering approaches that capitalize on our growing understanding of biology and nano–bio interactions. Advances in knowledge of tumor microenvironment and the realization that the use of cancer cell cultures in 2D-monolayer format for anticancer drug discovery are responsible for the high attrition rate of drugs in clinical trials have led to use of 3D cell culture platforms that closely mimic in vivo tumors. Herein, we review the difference between 2D and 3D cultures and provide use of various nanotechnology platforms that are used not only to explicate the development of novel drug candidates that target tumor microenvironment, but also facilitate in personalizing cancer treatment.
Wassil Nowicky
Ukrainian Anti-Cancer Institute, Austria
Title: Angiogenic properties of NSC-70 (UKRAIN/NSC-631570)
Biography:
WassilNowicky obtained Diploma and is the Director of “NowickyPharma” and President of the Ukrainian Anti-Cancer Institute (Vienna, Austria). He has finished his study at the Radiotechnical Faculty of the Technical University of Lviv (Ukraine) with the end of 1955 with graduation to “Diplomingeniueur” in 1960 which title was nostrificated in Austria in 1975. He is the inventor of the anti-cancer preparation on basis of celandine alkaloids “NSC-631570”.
Abstract:
Another important feature of NSC-631570 is the inhibition of the formation of the new blood vessels supplying a tumor. Due to these antiangiogenic properties NSC-631570 administered before surgery brings about better demarcation of the tumor from surrounding tissue and the tumor encapsulation. This alleviates the surgical removal of tumors what has been confirmed in breast cancer studies [67, 71, 103-106, 140]. In tests in vitro, NSC-631570 inhibited in a dose-dependent manner the proliferation of human endothelial cells without exerting cytotoxic effect. The angiogenesis inhibition was observed on the capillary formation model [134]. This inhibition of the neoangiogenesis prevents the metastasis formation as well.
The length of the total capillary tubes after the incubation with NSC-631570 in given concentrations. 1 – HUVEC were incubated with NSC-631570 for 4 h. 2 – HUVEC were preincubated with NSC-631570 for 4h and then incubated for 2 h in fresh medium without NSC-631570. HUVEC – human umbilical vein endothelial cells
Dan Yan
Emory University, USA
Title: MERTK promotes resistance to irreversible EGFR TKIs in NSCLCs expressing wildtype EGFR
Biography:
Dan Yan received her MD and PhD degrees from Tongji Medical College in China. She has published 22 research papers in journals including Science Translational Medicine, Proceedings of the National Academy of Sciences (PNAS), and Journal of Biochemistry. She has reviewed multiple journals and is an Editorial Board Member for Results in Immunology and Gavin Journal of Blood. She joined the Emory Faculty in 2015 as a newly appointed Instructor focusing on characterization of roles for MERTK in non-small cell lung cancer (NSCLC) with an emphasis on identification of other pathways that cooperate with MERTK to promote tumorigenesis.
Abstract:
Lung cancer is the leading cause of cancer-related death with poor survival rates worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and 60% of these have wild-type EGFR (wtEGFR) overexpression, which portends a poor prognosis. However, agents targeting EGFR have limited utility in preclinical models with wtEGFR overexpression. Our laboratory previously identified MERTK receptor tyrosine kinase as a potential therapeutic target in NSCLC and developed MRX-2843, a novel MERTK-selective small molecule inhibitor with favorable properties for clinical translation. MRX-2843 mediated potent anti-tumor effects in the wtEGFR-expressing A549 NSCLC line in vitro and in vivo. In addition, we screened a library of 378 kinase inhibitors in various development stages and identified favorable interactions between MRX-2843 and multiple irreversible EGFR TKIs, including CO-1686 and Osimertinib/AZD-9291. Synergistic inhibition of cell expansion was observed in a spectrum of wtEGFR-expressing NSCLC cell lines. Further, we found that wtEGFR and MERTK were frequently co-expressed and co-immunoprecipitated from NSCLC cell lysates. Mechanistically, combined treatment with CO-1686 and MRX-2843 inhibited MERTK and EGFR phosphorylation and downstream PI3K-AKT and MAPK-ERK signaling. In contrast, MERTK, EGFR, and downstream signaling were not efficiently inhibited in response to treatment with single agents. Furthermore, tumor size was reduced in response to treatment with combination therapy relative to single agent treatments in a wtEGFR-expressing xenograft model. Taken together, our data provide rationale for combined treatment with MRX-2843 and an irreversible EGFR inhibitor as a novel strategy for treatment of NSCLC with wtEGFR overexpression.
Biography:
Bhuvarahamurthy V has gained his research and teaching experience at prestigious institutions including Harvard Medical School (Boston, USA), Weizmann Institute of Science (Israel), and Humboldt University (Berlin, Germany). His research areas are Cancer Genetics, Metabolic Disorder, Cardiovascular and Neurobiology. He is skilled in assay development, cell culture, molecular biology, biochemistry, KO mouse model creation and human genetics and genomics. He has excellent skills in teaching, presentation, collaboration and working in a team. He also has experience of working in a supervisory role (experiment planning and oversee the plan execution), highly inquisitive, creative, resourceful and a fast learner. Due to vast knowledge in research field, he gained experience in writing validation protocols for biotech, medical devices and managing the protocol to completion.
Abstract:
Despite recent advances in pancreatic islet isolation techniques and changes in the regimen of immunosuppressive drugs, between 50-70% of islet cells are lost to hypoxic cell death within the first 10 to 14 days after isolation and subsequent transplantation. Islet survival must be increased, during the ischemic period between isolation and revascularization if islet transplantation is to succeed as a preferred treatment modality. The present study directly addresses the problem of isolated and transplanted islet survival. The use of exogenous growth factors has decreased the period required for islet revascularization, potentially reducing the total time of ischemia, however the resultant blood vessels surround but do not penetrate the islets sufficiently to prevent prolonged ischemia and central islet cell death. Therefore, it must be recognized that revascularization is only part of the islet survival equation in islet transplants. Cytoglobin (CYGB) is a recently discovered intracellular oxygen binding protein inducible in islet beta cells during hypoxia. Transfection of islet cells with CYGB DNA induces the production of CYGB and increases islet survival and preserves insulin secretion in cultured and immunoisolated islets, and significantly reduces the generation of toxic reactive oxygen species (ROS). Our results also suggest that the increased survival of islets by the overexpression of CYGB promotes increased vascular density in transplanted islets and surrounding immunoisolation chambers. This result is of prime interest as CYGB induces VEGF either directly or indirectly as a consequence of enhanced islet survival. The hypothesis examined by the present study is that the induction of cytoglobin will increase islet survival in isolated islets and islet transplants, thereby reducing the number of islets required to prevent the reoccurrence of diabetes in the recipient. World population contains a significant percentage of diabetic patients or those at risk to develop diabetes from aging and diet, and from pancreatitis or pancreatic malignancy. The present study will provide new information relevant to the prevention of diabetes in those patients.
Aurora Esquela Kerscher
Eastern Virginia Medical School, USA
Title: Human MicroRNA miR-888 cluster is a novel oncogenic network in the prostate involved in cancer progression pathways
Biography:
Aurora Esquela-Kerscher completed her MS in Biotechnology and PhD in Biochemistry, Cellular and Molecular Biology at the Johns Hopkins University School of Medicine. She conducted a Post-doctoral Fellowship in Frank Slack’s laboratory at Yale University where she began her studies on the role of microRNAs during development and disease. She is currently working as an Associate Professor in the Department of Microbiology and Molecular Cell Biology and Member of the Leroy T Canoles Jr. Cancer Research Center at Eastern Virginia Medical School in Norfolk, Virginia. Her lab aims to develop novel diagnostic and therapeutic targets for aggressive forms of prostate cancer.
Abstract:
Prostate cancer (PCa) is the 2nd leading cause of cancer-related male deaths in the US. Clinicians lack effective clinical options for advanced disease and metastatic PCa remains incurable and lethal. MicroRNAs (miRNAs) are often dysregulated in human PCa. It is poorly understood how these small non-coding RNAs function in the prostate to promote cancer progression. In a screen for miRNAs correlating with advanced disease, we found miR-888 was enriched in aggressive, castration-resistant human PCa cell lines and in tumors from PCa patients. This miRNA was elevated in an innovative prostatic fluid biomarker source called expressed prostatic secretions in urine (EPS urine) from PCa patients with high-grade disease. We postulated that miR-888 plays an oncogenic role in the prostate. Indeed, we noted miR-888 promoted prostate cell proliferation, migration and colony formation in vitro. miR-888 belongs to a genomic cluster of seven miRNAs (miR-892c, -890, -888, -892a, -892b, -891b, -891a) located on chromosome Xq27.3 and lies within HPCX1 (hereditary PCa, X-linked 1), a region associated with hereditary PCa. miR-888 cluster members were similarly elevated in aggressive PC3 cell lines and enriched in EPS urine exosomes from high-grade PCa patients. Our in vitro assays indicated that this cluster modulated prostate cell growth, migration, invasion, and ability to grow in soft agar. miR-888 and miR-891a were validated as bona fide pro-oncogenic factors and accelerated prostate tumorigenesis in mice. We are testing if miR-888 cluster inactivation using antimir reagents blocks disease progression in animal models. This work will lead to effective clinical tools for aggressive PCa.
James O McNamara
The University of Iowa, USA
Title: Bacterial nucleases as signal-amplifying biomarkers for infectious disease diagnostics
Biography:
James McNamara had studied Chemical Engineering at the University of Virginia (BS in 1992), Neurobiology at Duke University (PhD in 2003) and then completed a Post-doc at Duke University where he developed RNA based therapeutic approaches for cancer. He joined the Department of Internal Medicine at the University of Iowa in 2007. His research is focused on developing rapid clinical diagnostic assays for bacterial infectious diseases based on selective detection of pathogen-derived nuclease activities.
Abstract:
Rapid and sensitive methods are currently needed for the detection of many important bacterial pathogens. The diversity of nucleases and their presence in all living organisms make them an attractive class of biomarkers for such applications. Moreover, in contrast to most biomarkers, the enzymatic activity of nucleases can be used for signal amplification in assays that detect them. An important advantage of this approach is that it is not subject to the background that results from the non-specific adherence of exogenous enzymes (e.g., HRP-coupled antibodies binding to ELISA plates). We have developed various rapid and ultrasensitive assays that detect target bacterial species with quenched fluorescent oligonucleotide substrates that are selectively digested (and thereby activated) by their nucleases. The author will discuss applications that have been developed with this platform, including rapid culture-independent detection of 1) urinary tract infections via detection of endonuclease I (of E. coli) and 2) S. aureus bacteremia via detection of micrococcal nuclease.
Umashanger Thayasivam
Rowan University , USA
Title: Proteomics-based biomarker discovery through data mining
Biography:
Umashanger Thayasivam has completed his PhD from the University of Georgia in 2009. He is currently working as an Associate Professor of Statistics at Rowan University, Mathematics Department. His interdisciplinary research spans diverse areas including data mining, robust estimation and network security. He collaborated with Biomarker Discovery Center at Rowan School of Osteopathic Medicine and optimizing and verifying the utility of autoantibody biomarkers for early diagnosis. He has published several papers in reputed journals and conference proceeedings. He has been PI/co-PI for several internal and external grants. He won the Best Research Paper Award for his work on robust estimation (GSTF 2017).
Abstract:
Analyzing biomarkers is a rapidly emerging study that helps answering a wide range of biological questions. Modern biology has experienced an increasing use of data mining techniques for large scale and complex biomarker analysis. There is an urgent need to identify biomarkers that can accurately detect and diagnose rare diseases. One of its greatest potentials is, the development of criteria that allow us to diagnose a disease or to classify patients according to their risk for a clinical outcome of interest. Metabolite profiling data and omics data in general, pose several statistical challenges for classification and prediction. Metabolomics, like most ‘omics’ technologies, suffer from the problem of having huge quantities of data without the ability to efficiently process them and gain valuable knowledge. Random Forest (RF) technique, which includes an ensemble of decision trees and incorporates feature selections and interactions naturally within the learning process, is a popular choice for omics data. Recent work in computational biology has shown an increased use of random forest, owing to its unique advantages in dealing with small sample. The focus of this presentation is two-fold. First, to provide an overview of data mining in particlulur Random Forest (RF) technique in biomarker discovery, including feature selection. Second, to briefly introduce application by presenting results from different biomarker studies.