INTEGRATION OF BIOMEDICAL IMAGING AND TRANSLATIONAL APPROACHES FOR MANAGEMENT OF HEAD AND NECK CANCER

The aim of the clinical component of this work was to determine whether the currently available clinical imaging tools can be integrated with radiotherapy (RT) platforms for monitoring and adaptation of radiation dose, prediction of tumor response and disease outcomes, and characterization of patterns of failure and normal tissue toxicity in head and neck cancer (HNC) patients with potentially curable tumors. In Aim 1, we showed that the currently available clinical imaging modalities can be successfully used to adapt RT dose based-on dynamic tumor response, predict oncologic disease outcomes, characterize RT-induced toxicity, and identify the patterns of disease failure. We used anatomical MRIs for the RT dose adaptation purpose. Our findings showed that after proper standardization of the immobilization and image acquisition techniques, we can achieve high geometric accuracy. These images can then be used to monitor the shrinkage of tumors during RT and optimize the clinical target volumes accordingly. Our results also showed that this MR-guided dose adaptation technique has a dosimetric advantage over the standard of care and was associated with a reduction in normal tissue doses that translated into a reduction of the odds of long-term RT-induced toxicity. In the second aim, we used quantitative MRIs to determine its benefit for prediction of oncologic outcomes and characterization of RT-induced normal tissue toxicity. Our findings showed that delta changes of apparent diffusion coefficient parameters derived from diffusion-weighted images at mid-RT can be used to predict local recurrence and recurrence free-survival. We also showed that Ktrans and Ve vascular parameters derived from dynamic contrast-enhanced MRIs can characterize the mandibular areas of osteoradionecrosis. In the final clinical aim, we used CT images of recurrence and baseline CT planning images to develop a methodology and workflow that involves the application of deformable image registration software as a tool to standardize image co-registration in addition to granular combined geometric- and dosimetric-based failure characterization to correctly attribute sites and causes of locoregional failure. We then successfully applied this methodology to identify the patterns of failure following postoperative and definitive IMRT in HNC patients. Using this methodology, we showed that most recurrences occurred in the central high dose regions for patients treated with definitive IMRT compared with mainly non-central high dose recurrences after postoperative IMRT. We also correlated recurrences with pretreatment FDG-PET and identified that most of the central high dose recurrences originated in an area that would be covered by a 10-mm margin on the volume of 50% of the maximum FDG uptake. In the translational component of this work, we integrated radiomic features derived from pre-RT CT images with whole-genome measurements using TCGA and TCIA data. Our results demonstrated a statistically significant associations between radiomic features characterizing different tumor phenotypes and different genomic features. These findings represent a promising potential towards non-invasively tract genomic changes in the tumor during treatment and use this information to adapt treatment accordingly. In the final project of this dissertation, we developed a high-throughput approach to identify effective systemic agents against aggressive head and neck tumors with poor prognosis like anaplastic thyroid cancer. We successfully identified three candidate drugs and performed extensive in vitro and in vivo validation using orthotopic and PDX models. Among these drugs, HDAC inhibitor and LBH-589 showed the most effective tumor growth inhibition that can be used in future clinical trials

Efficient and Privacy-Preserving Ride Sharing Organization for Transferable and Non-Transferable Services

Ride-sharing allows multiple persons to share their trips together in one vehicle instead of using multiple vehicles. This can reduce the number of vehicles in the street, which consequently can reduce air pollution, traffic congestion and transportation cost. However, a ride-sharing organization requires passengers to report sensitive location information about their trips to a trip organizing server (TOS) which creates a serious privacy issue. In addition, existing ride-sharing schemes are non-flexible, i.e., they require a driver and a rider to have exactly the same trip to share a ride. Moreover, they are non-scalable, i.e., inefficient if applied to large geographic areas. In this paper, we propose two efficient privacy-preserving ride-sharing organization schemes for Non-transferable Ride-sharing Services (NRS) and Transferable Ride-sharing Services (TRS). In the NRS scheme, a rider can share a ride from its source to destination with only one driver whereas, in TRS scheme, a rider can transfer between multiple drivers while en route until he reaches his destination. In both schemes, the ride-sharing area is divided into a number of small geographic areas, called cells, and each cell has a unique identifier. Each driver/rider should encrypt his trip's data and send an encrypted ride-sharing offer/request to the TOS. In NRS scheme, Bloom filters are used to compactly represent the trip information before encryption. Then, the TOS can measure the similarity between the encrypted trips data to organize shared rides without revealing either the users' identities or the location information. In TRS scheme, drivers report their encrypted routes, an then the TOS builds an encrypted directed graph that is passed to a modified version of Dijkstra's shortest path algorithm to search for an optimal path of rides that can achieve a set of preferences defined by the riders

産卵鶏卵巣の自然免疫システムにおけるサイトカインと抗菌ペプチドの役割に関する研究

広島大学(Hiroshima University)博士(学術)Doctor of Philosophydoctora

METSIM Modelling of Selenium Recovery on Lignin Using Bio-sorption

Selenium is an important mineral for plants and living organisms; trace amounts are needed for our everyday function. However, when large amounts are consumed, it becomes really dangerous with adverse health effects; as a result of this, its removal has been the focus of many studies over the past decades. Selenium is found in most sulfide ores since they both share similar chemical attrib-utes, such as atomic radius. The mining and refining industries release the most amounts of selenium which are present in their wastewater in most cases. Current conventional methods of recycling selenium include pyrometal-lurgical and hydrometallurgical processes, which are often costly, environmentally unfriendly and potentially hazardous. Therefore, researchers have turned towards the study of biomass-based ad-sorbents, also known as biosorbents, for applications in selenium recovery and recycling. Biosorp-tion was the process of choice for reasons such as its operating cost, its recovery rates and reusa-bility In the research presented in the thesis herein, lignin which is a major component in plants was used to adsorb selenium from selenium monochloride (Se2Cl2) using METSIM as the simulation soft-ware of choice due to its versatility and flexibility to control numerous parameters, add new com-ponents and perform mass and heat balances. Lignin was the only component that was added, and the thermodynamic data was found via some research articles where it was plotted in excel and en-tered in METSIM. Further data analysis revealed that the adsorption rate of selenium (Se) on lignin progressed via the pseudo-second order rate model. Adsorption isotherm model studies indicate that the adsorption of Se by lignin followed the Freundlich adsorption isotherm. Calculated energy levels of activation by Se suggest that adsorption progresses due to chemisorption in nature. Thermodynamic studies re-veal that lignin adsorption of Se is exothermic in nature and that the increasing temperature reduces the efficiency of the adsorption process. A recovery rate of 99.4% was achieved for Se2Cl2 at 25 °C temperature and 0.39M HCl. To fur-ther prove that this model is functional, the two other known chloride forms of selenium, SeCl2 and SeCl4 were tested; selenium recovery rate from SeCl2 and SeCl4 was 45% and 40%, respectively

Production, Expression And Characterization Of A Heat-Stable Organic Solvent Tolerant Lipase From Bacillus Sp, Strain 42

Ninety two bacterial strains were isolated from oil palm effluent from Bangi,Selangor; Kluang, Johor; Alor Gajah hot spring (up to 54 OC) Melaka and Slim River hot spring (up to 9I0C) Perak. An enrichment culture technique was used to isolate bacteria utilizing olive oil as a substrate. Cultures were incubated at 60°C to select for the thermophilic bacteria. Eight isolates showed lipolytic activity on tributyrin and triolein agar plates. In order to screen for highest lipase producer, six production media were used. Isolate 42 was observed to produce the highest level (0.059 Ulml) after 72h. Its crude lipase retained its full activity when preincubated at 70°C for 30 min. It also showed high stability in several organic solvents (25% vlv). Furthermore, its activity was enhanced in benzene, hexane and hexadecane while, completely inhibited by butanol. Isolate 42 was identified as Bacillus sp. Strain 42 using 16s rDNA. The nucleotide sequence deposited at GenBank under accession number AY 7631 18. Further optimization studies were done in order to determine the best lipase production condition. lnoculum size of 3% proved to be the best for lipase production, with an optimum temperature of 50°C when, grown under shaking condition of 150 rpm. A combination of tryptone and yeast extract was the best nitrogen source. Lipase production was stimulated by olive oil. The lipase gene was amplified by polymerase chain reaction using consensus primers based on multiple aligned sequences of thermophilic genes from other thermophilic Bacillus species. Nucleotide sequence comparison shared high homology with the thermostable genes in Geobacillus sp., Bacillus stearothermophilus and Bacillus thermoleovorans. Nucleotide sequence deposited at GenBank under accession number AY 787835. The amplified gene was successfully cloned using a pQE-30 UA expression vector and induced by IPTG at the optimum concentration of 0.75 mM. The recombinant lipase was facilitated by the fusion of 6-histidine and this allowed a one-step purification of the lipase enzyme using Ni-NTA affinity chromatography. The histidine-tagged lipase was purified 6-fold with a yield of 21.7%. Purified lipase migrated as a single band with a molecular mass of -43 KDa on SDS-PAGE. The purified lipase showed high activity at 70°C with its optimum at pH 8.0. The enzyme was stable over a broad range of pH from 6.0 to 10.0. It also showed high stability with half-lives of 315 min at 60°C, 120 min at 65OC, and 45 min at 70°C. Preincubation enzyme activity was stimulated with Na+, K' and ca2+. While, zn2+, ~ n ' + and Fe *+ at high concentration (10 mM) were greatly inhibitory. Protease inhibitors Bestatin and pepstatin stimulated the lipase activity while, phenylmethylsulfonyl fluoride (PMSF) completely inhibited the lipase activity. Tween 80 (0.1%) enhanced the lipase activity while higher concentration ( I %) dramatically decreased the lipase activity. The activity of preincubated enzyme in heptanol (log P 2.4) and octanol (log P 2.9) was slightly enhanced while, remains very stable with other organic solvents tested. Solvents such as ethylbenzene (log P 3.1) and dodecane (log P 6.6) reduced the lipase activity up to 35% and 38%, respectively. The highest specificity was observed towards tricaprylin (CtJ, followed by tricaprin (Clo). Its hydrolyzed all the natural oils tested, with highest hydrolysis rate on olive oil