Day 1 :
Baylor College of Medicine, USA
Time : 9:30-10:10
C.Thomas Caskey, MD, FACP, FACMG, FRSC (Duke Med 62), Board Certified in Internal Medicine, Clinical and Molecular Genetics. Professor, Department of Molecular & Human Genetics-Baylor College of Medicine which he established in 1971. With Dr. Marshall Nirenberg he discovered the “universality“of the Genetic code & elucidated the mechanism of peptide chain termination. Dr. Caskey discovered 34 disease genes including the understanding of triplet repeat disorders (Fragile X & Myotonic Dystrophy). His STR identification system is internationally used by FBI, Interpol, CIA. In 1994 he became Sr. VP of Drug & Vaccine Development at Merck. Member of NAS, NAM, Royal Society of Canada.
Dr. Caskey is currently directing a program of Precision Medicine with Young Presidents Organization (YPO),Consultant to Human Longevity, and member of the Board of Metabolon. His current research focuses on the application of whole genome sequence and metabolomics of individuals for disease risk and its prevention
DNA sequencing provides a candidate list of genes/ mutations which account for an individual’s family disorder, personal disorder, and risk for medical disorders. It is not uncommon to identify DNA variants (VUS) which are difficult to interpret with regard to disease causation, since such interpretation relies heavily on disease data bases (HMGD/Clinvar/private).
The measurement of blood analytes (750 reality of 1500 detected) examines biochemical function on an individual basis. Three examples of metabolomics utility for DNA sequence interpretation will be presented. These include: 1) R/O VUS as disease causative, 2) Accurately diagnosing inborn error of metabolism both known and newly discovered, 3) identifying pathways and specific gene mutations in twin studies that were undetected by standard bioinformatics DNA based search tools.
These results have led us to utilize both metabolomics and whole genome sequence to achieve precision diagnosis and direct therapy interactions
BioSciKin Co., Ltd, USA
Time : 10:10-10:50
Dr. Dongliang Ge is President of BioSciKin Co., Ltd. and former Director of Bioinformatics at Gilead Sciences. Earlier, he was appointed as Assistant Professor at Duke University. He received his PhD of Biostatistics and Genetic Epidemiology from Chinese Academy of Medical Sciences in 2004. Dr. Ge was named by the Genome Technology as “rising stars” in 2009 and by Phacilitate as the "Top 50 Most Influential People in Big Data" in 2015. His work in the IL28B genetic variants, published in Nature in 2009, has received over 3000 citations to date. In total, his work has received over 15,000 citations.
The biopharmaceutical industry has quickly entered an era when fast evolving mutil-disciplilinary omics technologies, historical precision medicine initiatives, and disruptive bioinformatics techniques synergistically start to provide pivotal and strategic support for new drug development. Unprecedented amount of data is being generated to help discover and develop new generations of medications. Using examples, this talks covers several of the most important bioinformatic considerations in this strategy. How do we efficiently manage the massive amount of data at different levels of precision to ensure a seamless data flow? How do we annotate and present these data to make it more comprehensible and deliverable? How do we design and execute the new clinical trials more efficiently and improve the success rate? Where are we and where are we going in this new precision medicine era?
- Trak : 1 Cancer Therapeutic Approaches ; Track :2 Frontiers of Metabolomics Research
The composition of the skin lipids is unique and intriguing; (“two key words characterize the uniqueness of skin lipids: complexity and perversity” Nikolaides 1971) Elevated sebum excretion is a major factor involved in the pathophysiology of acne. The sebaceous gland synthesizes lipid species that are not found in other cells and tissues of the body. Complexity and uniqueness are characteristics of the sebaceous lipids. Δ6 desaturation, wax ester synthesis and squalene accumulation manifesting the uniqueness of sebaceous lipid metabolism. Recent studies documented the importance of these unique sebaceous lipids for normal skin functions. Genetic knockout animal models of lipid synthesis demonstrated major changes in skin pathophysiology. Skin and fur abnormalities are the common denominator once a surface lipid gene is functionally impaired. In addition essential fatty acids and their metabolites are proven to be fundamental for barrier function and involved in the pathology of eczema. Cutting edge LCMSMS has been used to dissect subtle but physiological meaningful differences in the composition of skin ceramides. These are structural components of the stratum corneum (SC) and impart essential barrier properties to this thin outer layer of the epidermis. They differ in structure and diversity from ceramides found in other body parts and tissues. Their unique chemistry is distinct since the most prevalent characteristic is that the fatty acid chain is extremely long and instead of 16-18 carbons long it could be 20-34 carbons or more. In addition, essential dietary fatty acids and their metabolites which are fundamental for barrier function, healthy or diseased skin could also be part of the skin ceramide biosynthetic pathways. Impairment of several ceramide pathways in animal models resulted in severe skin barrier defects. Variations in the ceramide species within this layer have been linked to several skin diseases in humans as atopic dermatitis. Understanding the roles of skin surface lipids is fundamental for decoding the skin physiology and homeostasis.
The lecture will educate and decode the vital role of various lipids on Skin health.
The composition of the skin lipids is unique and intriguing; (“two key words characterize the uniqueness of skin lipids: complexity and perversity” Nikolaides 1971)
Elevated sebum excretion is a major factor involved in the pathophysiology of acne.
The sebaceous gland synthesizes lipid species that are not found in other cells and tissues of the body. Complexity and uniqueness are characteristics of the sebaceous lipids. Δ6 desaturation, wax ester synthesis and squalene accumulation manifesting the uniqueness of sebaceous lipid metabolism.
Recent studies documented the importance of these unique sebaceous lipids for normal skin functions. Genetic knockout animal models of lipid synthesis demonstrated major changes in skin pathophysiology. Skin and fur abnormalities are the common denominator once a surface lipid gene is functionally impaired.
In addition essential fatty acids and their metabolites are proven to be fundamental for barrier function and involved in the pathology of eczema.
Cutting edge LCMSMS has been used to dissect subtle but physiological meaningful differences in the composition of skin ceramides. These are structural components of the stratum corneum (SC) and impart essential barrier properties to this thin outer layer of the epidermis. They differ in structure and diversity from ceramides found in other body parts and tissues. Their unique chemistry is distinct since the most prevalent characteristic is that the fatty acid chain is extremely long and instead of 16-18 carbons long it could be 20-34 carbons or more. In addition, essential dietary fatty acids and their metabolites which are fundamental for barrier function, healthy or diseased skin could also be part of the skin ceramide biosynthetic pathways.
Impairment of several ceramide pathways in animal models resulted in severe skin barrier defects. Variations in the ceramide species within this layer have been linked to several skin diseases in humans as atopic dermatitis.
Understanding the roles of skin surface lipids is fundamental for decoding the skin physiology and homeostasis.
Dr. Merritt completed his Ph.D. in physical chemistry at Washington University in St. Lous in 1996 with Dr. Jacob Schaefer. From 1997 to 2000, he completed post-doctoral training with Dr. Gary Drobny at the University of Washington. In 2000 he joined the staff at UT Southwestern Medical Center. In 2008, he became assistant professor (tenure track) and achieved the rank of associate professor in 2015. In August 2015, he joined the faculty of the University of Florida Department of Biochemistry and Molecular Biology. His group uses isotope methods for measuring flux through energy pathways in models of human pathologies.
The heart is an omnivorous organ, able to metabolize fattys acids (FAs), carbohydrates, and ketones to acetyl-CoA depending on their availability in the bloodstream. When the heart is subjected to overpressure due to stenosis or high blood pressure, it can hypertrophy and ultimately fail. This physical phenomena is intimately connected with a change in the substrate preference for the heart, where carbohydrate oxidation is emphasized over FA oxidation. Measuring substrate preference in the heart is tractable when nutrients positionally enriched in 13C can be supplied. Here we use a standard model of myocardial metabolism, the perfused mouse heart, to study substrate selection and the impact of providing propionate, an odd-chain fatty acid, on overall metabolism. We have found that propionate activates carbohydrate oxidation, leading to avid utilization of a hyperpolarized pyruvate tracer. Additonally, the propionate can cause a large change in pool sizes for the Krebs cycle intermediates without enforcing a change in flux as measured by O2 consumption. The propionate perfused heart should serve as an excellent model for validation of new isotopomer based methods for measuring metabolic flux.
Wayne State University School of Medicine, USA
Dr. Jing Li has obtained her PhD degree from the National University of Singapore and completed postdoctoral training at John Hopkins University. She is currently an Associate Professor at Wayne State University School of Medicine, and she also serves as the Director of Pharmacology Core at Karmanos Cancer Institute. Her research focuses on the clinical pharmacology of anticancer drugs, with emphasis on pharmacokinetics and pharmacometabolomics. She has published over50 papers in reputed journals, and has been serving as an editorial board member and reviewer for a number of journals.
Irinotecan, atopoisomerase I inhibitor, inhibits DNA replication and transcription. Irinotecanis widely used for treating various solid tumors. Its major toxicities include neutropenia, diarrhea, and steatohepatitis. This study investigatedthe metabolic changes induced by irinotecan in cancer patient and cell lines, which may provide mechanistic insights into the antitumor activity and toxicity of irinotecan.Plasma samples were collected at pretreatment, 1.5, 5.5, 28, and 48 h following 1.5-h irinotecan infusion (100 mg/m2) in 11 cancer patients. ~250 metaboliteswere quantitatively determined in patient plasma using a LC-MS/MS based targeted metabolomicsplatform. Additionally, metabolomic profiling was performed for human primary liver cells and two breast cancer cell lines (MDA-MB-231 and T47D) treated with SN-38 (an active metabolite of irinotecan) at 50 and 500 nM for 1, 6, and 24 h.Irinotecan causedtime-dependent changesofmetabolites including nucleosides, nucleobases, amino acids, acylcarnitines, andaminoadipic acid in patient plasma. SN-38 inducedtime- and concentration-dependent increases of nucleosides and nucleobases in culture medium of both human liver cells and cancer cells, while aminoadipic acid (an oxidative stress marker) was elevated in liver cell medium only.SN-38 induced formation of reactive oxygen species in liver cells but not in cancer cells.In conclusion: Elevated circulating levels of nucleosides and nucleobases seem associated with irinotecan-induced inhibition of DNA replication. Oxidative stress appears to be implicated in irinotecan toxicities especially steatohepatitis. Further studies are needed to investigate whether these circulating metabolite changes could serve as mechanistic biomarkers for predicting irinotecan efficacy and toxicity.
University of Arkansas for Medical Sciences, USA
Ping-Ching is currently an Assistant Professor of the University of Arkansas for Medical Sciences, where her research focuses on biomarker discovery using multi-omics to evaluate the biological effect of tobacco products including cigarettes and e-cigarettes smoking in the population in order to develop cancer prevention strategies. Previously as a postdoctoral researcher at the Ohio State University and her PhD from Georgetown University, she made important discoveries in the acute effects of cigarette smoking, and developed new biomarkers of tobacco smoke exposure
Smoking-related biomarkers for lung cancer and other diseases are needed to enhance early detection strategies and to provide a science base for tobacco product regulation. An untargeted metabolomics approach by ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF MS) totaling 957 assays was used in a novel experimental design where 105 current smokers smoked 2 cigarettes one hour apart. Blood was collected immediately before and after each cigarette allowing for within-subject replication. Dynamic changes of the metabolomic profiles from smokers’ four blood samples were observed and biomarkers affected by cigarette smoking were identified. Thirty-one metabolites were definitively shown to be affected by acute effect of cigarette smoking, uniquely including menthol-glucuronide, the reduction of glutamate, oleamide, and 13 glycerophospholipids. This first time identification of a menthol metabolite in smokers’ blood serves as proof-of-principle for using metabolomics to identify new tobacco-exposure biomarkers, and also provides new opportunities in studying menthol-containing tobacco products in humans. Gender and race differences also were observed. Network analysis revealed 12 molecules involved in cancer, notably inhibition of cAMP. Furthermore, boost of plasma methol metabolit was investigated in relation to smoking behavior and metabolomic profiles. It is a new smoking behavior biomarker that may provide specificity over self-reported use of menthol cigarettes by integrating different smoking measures for understanding smoking behavior and harm of menthol cigarettes. These novel tobacco-related biomarkers provide new insights to the effects of smoking which may be important in carcinogenesis but not previously linked with tobacco-related diseases
University of Groningen, Netherlands
Jingyuan Fu has completed her PhD cum laude in 2007 from University of Groningen and she is now an associate professor in the University Medical Center Groningen, the Netherlands. Fu’s research involves multi-dimensional “omics” integrative analysis towards a better understanding of the development of complex diseases, including their genetics, genomics, transcriptomics, and metabolomics. In recent years, her research has expanded to performing population-based gut microbiome analyses. These aim to unravel the host-microbe metabolic interactions and the microbiome’s role in the development of metabolic disorders
Abnormal metabolism is a precursor of cardiovascular disease (CVD). Emerging evidence supports a link between the gut microbiome and the development of metabolic syndrome and CVD. However, we know little about the functional connection between host-microbe metabolism and need interdisciplinary integrative analyses to understand their complex metabolic interaction.
Over the past few years we have built up LifeLines-DEEP, a multi-omics biobank that is part of LifeLines, the large population cohort study in the northern Netherlands. LifeLines-DEEP consists of 1,500 individuals (42% males, age range 18-81 years), from which dietary, genetic, gut flora and metabolic profiles have been generated. To determine an individual’s metabolic risk of developing CVD, we measured 33 serum metabolic biomarkers using a nuclear magnetic resonance (NMR) platform; the biomarkers included various lipoprotein particles, fatty acids, amino acids and glycolysis-related metabolites. We report association to 48 bacterial metabolic pathways, which were derived from metagenomics shotgun sequencing data. In particular, our data showed that microbial energy metabolism and various biosynthesis pathways - leading to the production of pyruvate, amino acids, vitamins, short-chain fatty acids and polyunsaturated fatty acids - might impact CVD risk. Our current study also presents an integrative analysis and provides a deeper insight into the complex diet-microbe-host dialogue in metabolism and inflammation that are relevant to CVD development. This knowledge can help pave the way towards the development of therapies to modulate the microbial metabolism and help prevent CVD.
Dr. Ikram-ul-Haq (SI) has completed his Postdoc from Cornell University, New York, USA, and Ph.D. in Industrial Microbiology from University of the Punjab, Lahore, Pakistan. He has been the Dean, Faculty of Science and Technology and founding Director of Institute of Industrial Biotechnology, GC University, Lahore. He has successfully completed 11 Projects sponsored by Pakistan Science Foundation, Pakistan Atomic Energy Commission, HEC, GCU & Ministry of Science and Technology while 4 Projects are in process sponsored by MoST, PSF and Pakistan Academy of Sciences. He has published more than 300 papers in journals of international repute and has been serving as an editorial board member of reputed Journals
The growing demands of bioenergy has led to the emphasis on novel cellulases to improve efficiency of biodegradation process of plant biomass. Therefore, a thermostable cellulolytic gene (CenC) with 3,675 bp was cloned from Clostridium thermocellum and over-expressed in Escherichia coli strain BL21 CodonPlus. It was attested that CenC belongs to glycoside hydrolase family 9 (GH9) with four binding domains, a processive endoglucanase. CenC was purified to homogeneity, producing a single band on SDS-PAGE corresponding to 137.11 kDa, by purification steps of heat treatment combined with ion-exchange chromatography. Purified enzyme displayed optimal activity at pH 6.0 and 70°C. CenC had a half-life of 24 min at 74°C, was stable upto 2 h at 60°C and over a pH range of 5.5-7.5. Enzyme showed high affinity towards various substrates and processively released cellobiose from cellulosic substrates. It efficiently hydrolyzed carboxymethyl cellulose (30 U/mg), β-glucan Barley (94 U/mg); also showed activity towards p-nitrophenyl-β-D-cellobioside (18 U/mg), birchwood xylan (19 U/mg), beechwood xylan (17.5 U/mg), avicel (9 U/mg), whatman filter paper (11 U/mg) and laminarin (3.3 U/mg). CenC exhibited Km, Vmax, Kcat, Vmax Km-1 and Kcat Km-1 of 7.14 mM, 52.4 µmol mg-1min-1, 632.85 s-1, 7.34 min-1 and 88.63, respectively used CMC as substrate.Recombinant CenC saccharified pretreated wheat straw and bagasse to 5.12% and 7.31%, respectively at pH 7.0 and 45°C after 2 h incubation. Its thermostability, high catalytic efficiency and independence of inhibitors make CenC enzyme an appropriate candidate for industrial applications and cost-effective saccharification process.
Third Military Medical University, China
Erlong Zhang has completed his PhD at the age of 28 years from Third Military Medical University. He is mainly studying the relationship between hypoxia and metabolism and has published three papers in reputed journals.
As a hallmark of cancer, metabolic reprogramming is recognized as new diagnostic tools and therapeutic targets of cancer. Enhanced glycolysis and mitochondrial dysfunction is the main character for cancer metabolism. Recently, agents that inhibited cancer glycolytic process and improved mitochondria were greatly developed and revealed good prospect for cancer therapy. However, current drugs targeting cancer energy metabolism showed relatively low selectivity and sensitivity and some side effects. Therefore, to clarify the metabolic changes after interrupting metabolic processes could provide comprehensive interpretation for metabolic adaption and clues for improving these therapeutic agents. Here, with normal brain cells HEB as control, we observed the metabolomic changes in U87-MG glioma cells after treatment with glycolysis inhibitor, 2-deoxy-D-glucose (2-DG) and ATPase inhibitor, oligomycin, to analyze the effects of both drugs. Firstly, the results showed that U87-MG cells showed distinguished metabolic characters, with highly increased glycolysis and amino acid and lipid metabolism. Upon 2-DG treatment, U87-MG cells showed metabolic tendency to tyrosine and valine metabolism. However, TCA cycle, glutamate and nucleic acid metabolism were obviously increased in HEB cells. This result suggested that apart from the glycolysis process, amino acid metabolism also played important roles for glioblatoma (GBM) development. After oligomycin treatment, with no significant observed in U87-MG cells, HEB cells exhibited enhanced lipid metabolism and glucose and amino acid metabolism inhibition. This implied that mitochondrial aerobic oxidation showed minor role in U87-MG cells than that in HEB cells. Our study proved that glycolysis played more important function in GBM cells than TCA cycle. However, the appropriate clinical therapeutic strategy and the specific target at metabolism for GBM therapy remain to be studied.
National Dairy Research Institute, India
Khan Farheen Badrealam has completed her PhD from Aligarh Muslim University and is currently employed as Research Associate at National Dairy Research Institute. She has published more than 8 papers in reputed journals so far and has many awards and honours to her credits.
Heat stress is a major stressor, which affects animal’s performance substantially and molecular basis coherent with the ability of Bos Indicus to survive and adapt to heat stress. Reckoning with these, the present study was planned to examine the complex serum proteome alterations in Indian zebu cattle following heat stress and normothermia applying isobaric Tags for Relative and Absolute Quantification (iTRAQ) proteomics approaches. The data of the present study suggests that out of the total 144 proteins identified, 53 proteins were differentially expressed after 4 h of heat stress (23 proteins upregulated and 30 proteins downregulated), whereas 48 (23 proteins upregulated whereas 25 downregulated) and 51 (18 proteins upregulated whereas 33 downregulated) proteins were differentially expressed after 24 and 48h of recovery period respectively. Intriguingly, this is the seminal report investigating the differential proteome profile of Sahiwal serum samples in response to heat stress. The identified proteins were subjected to analysis for their prospective involvement in various biological, cellular and molecular processes including thermoregulatory mechanism thereof. The high confidence dataset generated herein may plausibly foster identification of prospective biomarkers related to heat stress in Indian zebu cattle; nonetheless, the findings of the present study significantly advances our understanding of the physiological aspects of heat stress induced responses in Sahiwal cattle