Publications by authors named "Hansoo Kim"

36 Publications

Health Technology Assessment in Australia: The Pharmaceutical Benefits Advisory Committee and Medical Services Advisory Committee.

Value Health Reg Issues 2021 Jan 8;24:6-11. Epub 2021 Jan 8.

Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, Australia.

Health technology assessment (HTA) was introduced in Australia for the reimbursement of pharmaceuticals in 1992 and in the following years for procedures, diagnostic tests, and devices. The Australian health system is largely funded by the government. The Pharmaceutical Benefits Scheme is a national list of prescription pharmaceuticals for which the patient pays a small copayment. HTA submissions to the Pharmaceutical Benefits Scheme are assessed by the Pharmaceutical Benefits Advisory Committee. The Medical Benefits Scheme provides ambulatory medical services and HTA submissions are assessed by the Medical Services Advisory Committee. This article describes the processes of reimbursement in Australia as well as the special case of codependent technologies (eg, diagnostic test and a therapeutic drug) where a combined Medical Services Advisory Committee and Pharmaceutical Benefits Advisory Committee application is required. There are many future challenges for HTA in Australia, with growing pressure to provide early access to promising treatments and high cost personalized medicines looming on the horizon. However, Australia is well placed to deal with these issues as the early adoption of HTA and coexistence between industry, academia and the payer has proven to be a fertile environment for developing capacity to undertake and evaluate HTA.
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http://dx.doi.org/10.1016/j.vhri.2020.09.001DOI Listing
January 2021

The Potential for Early Health Economic Modelling in Health Technology Assessment and Reimbursement DecisionMaking Comment on "Problems and Promises of Health Technologies: The Role of Early Health Economic Modeling".

Int J Health Policy Manag 2020 Feb 5. Epub 2020 Feb 5.

School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Grutters et al recently investigated the role of early health economic modelling of health technologies by undertaking a secondary analysis of health economic modelling assessments performed by their group. Our commentary offers a broad perspective on the potential utility of early health economic modelling to inform health technology assessment (HTA) and decision-making around reimbursement of new health technologies. Further we provide several examples to compliment Grutters and colleagues' observations.
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http://dx.doi.org/10.15171/ijhpm.2020.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947661PMC
February 2020

Cost-effectiveness and financial risks associated with immune checkpoint inhibitor therapy.

Br J Clin Pharmacol 2020 09 18;86(9):1703-1710. Epub 2020 Jun 18.

Centre for Health Economics Research and Evaluation, University of Technology Sydney, Sydney, Australia.

The reimbursement of immune checkpoint inhibitors is challenging. Funding these technologies involves the careful balance between awarding innovation and ensuring affordability as increases in drug spending compete directly with other health care and social expenditure. This narrative review examines the recommendations of 2 health technology assessment agencies-the Australian Pharmaceutical Benefits Advisory Committee and the British National Institute of Clinical Excellence-to determine the factors that contribute to the approval and rejection of immune checkpoint inhibitors as well as the use of manage entry schemes and risk management strategies to control expenditure. Reimbursement decisions from 6 immune checkpoint inhibitor drugs (ipilimumab, pembrolizumab, nivolumab, durvalumab, atezolizumab, avelumab) covering 10 different cancers were examined. The extrapolation of survival beyond the clinical trial and lack of head-to-head evidence are some of the main issues relating to cost effectiveness. Payers managed financial risks using different mechanisms such as risk share agreements and financial caps. This review of the reimbursement decisions and subsequent financial impact in Australia and the UK suggests budgets for immune checkpoint inhibitor therapy have been well managed so far. Through risk agreements and managed entry programmes, the example of immune checkpoint inhibitor therapies illustrates that industry and payers can effectively collaborate to ensure that innovative, but expensive, drugs can be made readily available to patients.
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http://dx.doi.org/10.1111/bcp.14337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444763PMC
September 2020

Health Technology Assessment Challenges in Oncology: 20 Years of Value in Health.

Value Health 2019 05;22(5):593-600

Monash University, Melbourne, Victoria, Australia.

Background: Oncology treatments have changed from chemotherapies to targeted therapies and more recently immuno-oncology. This has posed special challenges in the field of health technology assessment (HTA): capturing quality of life (QOL) associated with toxicity due to chemotherapy, crossover upon progression in targeted therapy trials, and survival extrapolation for immuno-oncology drugs.

Objectives: To showcase 20 years of Value in Health (ViH) publications in oncology.

Methods: A review was undertaken of oncology articles published in ViH from May 1998 to August 2018. Full-length articles published in ViH with the keywords "oncology," "cancer," "h(a)ematology," and "malignancy" were included for review. Conference abstracts were excluded.

Results: Four major themes were identified: (1) QOL and the development of multiple functional assessment of cancer therapy tools and mapping instruments; (2) analysis of clinical evidence using indirect comparisons, network analyses, and adjustment for crossovers; (3) modeling, Markov models, partitioned survival models, and extrapolation methods; and (4) financial implications and how to deal with uncertainty, introduction of conditional reimbursement, managed entry, and risk share agreements.

Discussion: This review article highlights the important role ViH has played in disseminating HTA research in oncology. A few key issues loom on the horizon: precision medicine, further development and practical application of new QOL measures, methods for translating clinical evidence, and exploration of modeling techniques. For a better understanding of the complex interplay between access and financial risk management, ViH will no doubt continue to promote pioneering research in HTA and oncology.
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http://dx.doi.org/10.1016/j.jval.2019.01.001DOI Listing
May 2019

A real world example of coverage with evidence development in Australia - ipilimumab for the treatment of metastatic melanoma.

J Pharm Policy Pract 2018 13;11. Epub 2018 Feb 13.

Bristol-Myers Squib, Level 2/4 Nexus Court, Mulgrave, VIC 3170 Australia.

Background: Australian Government subsidisation of ipilimumab for the treatment of patients with metastatic melanoma was conditional on the sponsor entering a 'managed entry scheme' to assess the 2-year overall survival rate in metastatic melanoma patients who received ipilimumab in the first year of Pharmaceutical Benefits Scheme listing.

Methods: All unresectable stage IIIc / IV metastatic melanoma patients treated with at least one dose of ipilimumab therapy in Australia from the PBS listing date to a time point 12 months later (i.e. from 1-Aug-2013 to 31-Jul-2014) were invited to participate. Overall survival at 2 years post treatment initiation was measured, with Cox regression analysis used to examine the relationship between survival and patient baseline characteristics.

Results: The evaluable population (910 patients) was on average 63.3 years old, male (70.1%) and treated in a public hospital (64.4%) in an urban area (76.5%). The majority of patients were treatment naïve (63.3%), did not have brain metastases (71.1%), and were classified as ECOG performance status 0 or 1 (90.4%). The 2 year overall survival rate was conservatively calculated to be at least 23.9% and potentially as high as 34.2%. A significant difference in overall survival at 2 years was demonstrated across the categories of ECOG performance status ( < 0.0001), M-status ( = 0.0005) and treatment status ( = 0.0114). No statistical difference in survival rate was observed when examining brain metastases vs no brain metastases ( = 0.2622), treatment at private vs public hospitals ( = 0.7601) nor treatment in the urban vs rural setting ( = 0.5048).

Conclusions: The 2 year overall survival rate for all patients receiving PBS subsidised ipilimumab in Australia from the first year Pharmaceutical Benefits Scheme cohort is estimated to be between 23.9% and 34.2%, which is higher than the 23.5% observed in the key ipilimumab registrational trial. Results and learnings from the ipilimumab 'managed entry scheme' illustrate that early access with the promise of future evidence to confirm a medicine's cost-effectiveness can work, but needs to be carefully considered, constructed and managed.
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http://dx.doi.org/10.1186/s40545-018-0131-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810048PMC
February 2018

Mobility of Amphidinium carterae Hulburt measured by high-frequency ultrasound.

J Acoust Soc Am 2017 04;141(4):EL395

Laboratory of Algal Technology for Biofuel and Applications, Peking University Shenzhen Graduate School, School of Environment and Energy, Shenzhen 518055, Guangdong, China

The over-growth of phytoplankton causes harmful algal blooms (HABs) in marine ecological environments. Mobility measurement is important in understanding the action of HABs. In this study, the mobility of Amphidinium carterae Hulburt (A. carterae) was investigated using high-frequency ultrasound in the laboratory. Mobility in response to light was illustrated with M-mode images reconstructed from echoed signals. This study suggests that mobility of the swimming speed of A. carterae in response to light can be measured and calculated with M-mode images through high-frequency ultrasound. This finding may be helpful in understanding the fundamental behavior of HABs.
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http://dx.doi.org/10.1121/1.4980007DOI Listing
April 2017

A Cost-Effectiveness Analysis of Nivolumab Compared with Ipilimumab for the Treatment of BRAF Wild-Type Advanced Melanoma in Australia.

Value Health 2016 Dec;19(8):1009-1015

Melbourne EpiCentre, Royal Melbourne Hospital, and the University of Melbourne, Parkville, Victoria, Australia.

Purpose: The aim of this study was to evaluate the cost-effectiveness of nivolumab versus ipilimumab for the treatment of previously untreated patients with BRAF-advanced melanoma (BRAF-AM) from an Australian health system perspective.

Methods: A state-transition Markov model was constructed to simulate the progress of Australian patients with BRAF-AM. The model had a 10-year time horizon with outcomes discounted at 5% annually. For the nivolumab group, risks of progression and death were based on those observed in the nivolumab arm of a phase III trial (nivolumab vs. dacarbazine). Progression-free survival and overall survival were extrapolated using parametric survival modeling with a log-logistic distribution. In the absence of head-to-head evidence, overall survival and progression-free survival for ipilimumab were estimated on the basis of an indirect comparison using published data. Costs of managing AM were estimated from a survey of Australian clinicians. The cost of ipilimumab was based on the reimbursement price in Australia. The cost of nivolumab was based on expected reimbursement prices in Australia. Quality-of-life data were obtained within the trial using the EuroQol five-dimensional questionnaire.

Results: Compared with ipilimumab, nivolumab therapy over 10 years was estimated to yield 1.58 life-years and 1.30 quality-adjusted life-years per person, at a (discounted) net cost of US $39,039 per person. The incremental cost-effectiveness ratios for nivolumab compared with ipilimumab were US $25,101 per year of life saved and $30,475 per quality-adjusted life-year saved.

Conclusions: Nivolumab is a cost-effective means of preventing downstream mortality and morbidity in patients with AM compared with ipilimumab in the Australian setting.
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http://dx.doi.org/10.1016/j.jval.2016.05.013DOI Listing
December 2016

SIMS of transfer ribonucleic acid molecules encapsulated between free-standing graphene sheets.

Biointerphases 2016 Jun 1;11(2):02A324. Epub 2016 Jun 1.

Department of Chemistry, Texas A&M University, College Station, Texas 77843-3144.

In this study, the authors used cluster-secondary ion mass spectrometry method to investigate the preserved transfer ribonucleic acid (tRNA) encapsulated between two free-standing graphene sheets. Single impacts of 50 keV C60 (2+) projectiles generated the emission of tRNA fragment ions in the transmission direction for mass selection and detection in a time-of-flight mass spectrometer. Ribonucleic acid (RNA) is extremely unstable and prone to rapid enzymatic degradation by ribonucleases. Employing graphene to isolate RNA from the environment, the authors prevent the aforementioned process. Encapsulation was achieved by drop casting a solution of tRNA, prepared using deuterated water, onto one graphene sheet and covering it with another. The event-by-event bombardment/detection mode allowed us to use colocalization analysis method to characterize the tRNA and its immediate environment. The authors found that upon drying, tRNA agglomerated into nanostructures ∼60 nm in diameter via formation and subsequent drying of aqua cells. The tRNA nanoagglomerates had a density of ∼42 structures per μm(2) with coverage of ∼12% of the surface area. In addition, trace amounts of water remained mostly around the tRNA nanoagglomerates, probably in the form of hydration.
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http://dx.doi.org/10.1116/1.4942879DOI Listing
June 2016

From Regulatory Approval to Subsidized Patient Access in the Asia-Pacific Region: A Comparison of Systems Across Australia, China, Japan, Korea, New Zealand, Taiwan, and Thailand.

Value Health Reg Issues 2015 May 16;6:40-45. Epub 2015 May 16.

Bristol Myers Squibb Australia, Mulgrave, Victoria, Australia.

Objectives: To compare processes and timings of regulatory and subsidized access systems for medicines across seven jurisdictions within the Asia-Pacific region.

Methods: A questionnaire was developed focusing on regulatory and health technology assessment-based subsidized access processes and timings in each of the seven surveyant's jurisdictions.

Results: Australia and Thailand are the only two jurisdictions that formally allow the subsidized access evaluation process to be conducted in parallel with the regulatory evaluation process. Australian, Japanese, Korean, New Zealand, and Taiwanese systems afford broad coverage, whereas Chinese and Thai systems provide limited coverage for medicines under patent. Subsidized access systems for all jurisdictions except Thailand have an associated patient co-payment for each medicine/prescription. The biggest disparity across the study group relates to time from regulatory submission to subsidized access of patented medicines-ranging from just over 1 year (Japan) to a minimum of 5 years (China).

Conclusions: There is consistency across the seven jurisdictions studied in relation to regulatory and subsidized patient access processes-that is, regulatory approval is required before subsidized access review; subsidized access coverage is broad; and the cost of medicine subsidization is offset, in part, by patient co-payments. Although local differences will always exist in relation to budget and pricing negotiation, there may be efficiencies that can be applied across systems to improve time to subsidized access. Closer understanding of regulatory and subsidized access systems can lead to best-practice sharing and, ultimately, timely access and better health outcomes for patients.
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http://dx.doi.org/10.1016/j.vhri.2015.03.013DOI Listing
May 2015

PAD-MAC: primary user activity-aware distributed MAC for multi-channel cognitive radio networks.

Sensors (Basel) 2015 Mar 30;15(4):7658-90. Epub 2015 Mar 30.

Department of Electronics and Radio Engineering, College of Electronics and Information, Kyung Hee University, Deogyeong-daero, Giheung-gu, Yongin-si, Gyeonggi-do 446-701, Suwon, Korea.

Cognitive radio (CR) has emerged as a promising technology to solve problems related to spectrum scarcity and provides a ubiquitous wireless access environment. CR-enabled secondary users (SUs) exploit spectrum white spaces opportunistically and immediately vacate the acquired licensed channels as primary users (PUs) arrive. Accessing the licensed channels without the prior knowledge of PU traffic patterns causes severe throughput degradation due to excessive channel switching and PU-to-SU collisions. Therefore, it is significantly important to design a PU activity-aware medium access control (MAC) protocol for cognitive radio networks (CRNs). In this paper, we first propose a licensed channel usage pattern identification scheme, based on a two-state Markov model, and then estimate the future idle slots using previous observations of the channels. Furthermore, based on these past observations, we compute the rank of each available licensed channel that gives SU transmission success assessment during the estimated idle slot. Secondly, we propose a PU activity-aware distributed MAC (PAD-MAC) protocol for heterogeneous multi-channel CRNs that selects the best channel for each SU to enhance its throughput. PAD-MAC controls SU activities by allowing them to exploit the licensed channels only for the duration of estimated idle slots and enables predictive and fast channel switching. To evaluate the performance of the proposed PAD-MAC, we compare it with the distributed QoS-aware MAC (QC-MAC) and listen-before-talk MAC schemes. Extensive numerical results show the significant improvements of the PAD-MAC in terms of the SU throughput, SU channel switching rate and PU-to-SU collision rate.
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http://dx.doi.org/10.3390/s150407658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431221PMC
March 2015

Low-salinity-induced surface sound channel in the western sea of Jeju Island during summer.

J Acoust Soc Am 2015 Mar;137(3):1576-85

Department of Mechanical Engineering Education, Andong National University, 1375 Gyeongdong-ro, Andong-si, Gyeongsangbuk-do 760-749, Republic of Korea.

Surface salinity in the western sea of Jeju Island in Korea becomes low due to the inflow of the Chinese coastal waters during summer. One of the characteristics of low salinity water is the formation of a surface sound channel (SSC) due to the decrease in sound speed by salinity. However, a quantitative analysis between low salinity water and SSC has not been fully investigated yet. In this paper, a temperature-salinity (T-S) gradient diagram is introduced in order to assess SSC formation and its acoustic characteristics are also investigated through a case study of low salinity waters. Maximum angles of limiting rays were less than 4.6° and low frequency cutoffs were higher than 2.0 kHz for the SSCs formed in low salinity water. When the salinity gradients were large (>0.5 psu/m), a SSC was formed more efficiently than other cases whose salinity gradients were small. On the other hand, a SSC was not formed in spite of highly positive salinity gradients when the amount of temperature gradients was negatively high enough (<-0.5 °C/m). However, the acoustic energy transfer in the surface ducts was dependent on frequency and position of source.
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http://dx.doi.org/10.1121/1.4913812DOI Listing
March 2015

Brittle intermetallic compound makes ultrastrong low-density steel with large ductility.

Nature 2015 Feb;518(7537):77-9

Graduate Institute of Ferrous Technology, POSTECH, Pohang 790-784, South Korea.

Although steel has been the workhorse of the automotive industry since the 1920s, the share by weight of steel and iron in an average light vehicle is now gradually decreasing, from 68.1 per cent in 1995 to 60.1 per cent in 2011 (refs 1, 2). This has been driven by the low strength-to-weight ratio (specific strength) of iron and steel, and the desire to improve such mechanical properties with other materials. Recently, high-aluminium low-density steels have been actively studied as a means of increasing the specific strength of an alloy by reducing its density. But with increasing aluminium content a problem is encountered: brittle intermetallic compounds can form in the resulting alloys, leading to poor ductility. Here we show that an FeAl-type brittle but hard intermetallic compound (B2) can be effectively used as a strengthening second phase in high-aluminium low-density steel, while alleviating its harmful effect on ductility by controlling its morphology and dispersion. The specific tensile strength and ductility of the developed steel improve on those of the lightest and strongest metallic materials known, titanium alloys. We found that alloying of nickel catalyses the precipitation of nanometre-sized B2 particles in the face-centred cubic matrix of high-aluminium low-density steel during heat treatment of cold-rolled sheet steel. Our results demonstrate how intermetallic compounds can be harnessed in the alloy design of lightweight steels for structural applications and others.
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http://dx.doi.org/10.1038/nature14144DOI Listing
February 2015

The effects of mouth opening on changes in the thickness of deep cervical flexors in normal adults.

J Phys Ther Sci 2015 Jan 9;27(1):239-41. Epub 2015 Jan 9.

Department of CAM & Naturopathy, DaeJeon Institute of Science and Technology, Republic of Korea.

[Purpose] The purpose of this study was to identify changes in the thickness of the deep cervical flexors (DCFs) according to the degree of mouth opening (MO) in normal adults. [Subjects] The study's subjects were 50 normal adults (30 men, 20 women). [Methods] Ultrasound was used to obtain images of muscles, and the NIH ImageJ software was used to measure the thickness of each muscle. [Results] An increase in MO resulted in a corresponding increase in the thickness of the DCFs, and in isometric exercises (IEs), the thickness of the DCFs further increased during MO. [Conclusion] During MO, the thickness of the DCFs increased. This may be due to correlations between mandibular movements and DCFs. Therefore, the results are likely to be utilized as new clinical research data.
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http://dx.doi.org/10.1589/jpts.27.239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305572PMC
January 2015

Hypervelocity nanoparticle impacts on free-standing graphene: a sui generis mode of sputtering.

J Chem Phys 2015 Jan;142(4):044308

Department of Chemistry, Texas A&M University, College Station, Texas 77843-3144, USA.

The study of the interaction of hypervelocity nano-particles with a 2D material and ultra-thin targets (single layer graphene, multi-layer graphene, and amorphous carbon foils) has been performed using mass selected gold nano-particles produced from a liquid metal ion source. During these impacts, a large number of atoms are ejected from the graphene, corresponding to a hole of ∼60 nm(2). Additionally, for the first time, secondary ions have been observed simultaneously in both the transmission and reflection direction (with respect to the path of the projectile) from a 2D target. The ejected area is much larger than that predicted by molecular dynamic simulations and a large ionization rate is observed. The mass distribution and characteristics of the emitted secondary ions are presented and offer an insight into the process to produce the large hole observed in the graphene.
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http://dx.doi.org/10.1063/1.4906343DOI Listing
January 2015

Photoinduced membrane damage of E. coli and S. aureus by the photosensitizer-antimicrobial peptide conjugate eosin-(KLAKLAK)2.

PLoS One 2014 7;9(3):e91220. Epub 2014 Mar 7.

Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas, United States of America.

Background/objectives: Upon irradiation with visible light, the photosensitizer-peptide conjugate eosin-(KLAKLAK)2 kills a broad spectrum of bacteria without damaging human cells. Eosin-(KLAKLAK)2 therefore represents an interesting lead compound for the treatment of local infection by photodynamic bacterial inactivation. The mechanisms of cellular killing by eosin-(KLAKLAK)2, however, remain unclear and this lack of knowledge hampers the development of optimized therapeutic agents. Herein, we investigate the localization of eosin-(KLAKLAK)2 in bacteria prior to light treatment and examine the molecular basis for the photodynamic activity of this conjugate.

Methodology/principal Findings: By employing photooxidation of 3,3-diaminobenzidine (DAB), (scanning) transmission electron microscopy ((S)TEM), and energy dispersive X-ray spectroscopy (EDS) methodologies, eosin-(KLAKLAK)2 is visualized at the surface of E. coli and S. aureus prior to photodynamic irradiation. Subsequent irradiation leads to severe membrane damage. Consistent with these observations, eosin-(KLAKLAK)2 binds to liposomes of bacterial lipid composition and causes liposomal leakage upon irradiation. The eosin moiety of the conjugate mediates bacterial killing and lipid bilayer leakage by generating the reactive oxygen species singlet oxygen and superoxide. In contrast, the (KLAKLAK)2 moiety targets the photosensitizer to bacterial lipid bilayers. In addition, while (KLAKLAK)2 does not disrupt intact liposomes, the peptide accelerates the leakage of photo-oxidized liposomes.

Conclusions/significance: Together, our results suggest that (KLAKLAK)2 promotes the binding of eosin Y to bacteria cell walls and lipid bilayers. Subsequent light irradiation results in membrane damage from the production of both Type I & II photodynamic products. Membrane damage by oxidation is then further aggravated by the (KLAKLAK)2 moiety and membrane lysis is accelerated by the peptide. These results therefore establish how photosensitizer and peptide act in synergy to achieve bacterial photo-inactivation. Learning how to exploit and optimize this synergy should lead to the development of future bacterial photoinactivation agents that are effective at low concentrations and at low light doses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091220PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946741PMC
February 2015

Ginsenoside Rb1 is transformed into Rd and Rh2 by Microbacterium trichothecenolyticum.

J Microbiol Biotechnol 2013 Dec;23(12):1802-5

Medical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.

Ginsenosides are the most important ingredient of ginseng and are known to possess many pharmacological and biological effects. Rb1, a major protopanaxadiol ginsenoside, is the most abundant ginsenoside in Panax ginseng C.A Meyer and can be hydrolyzed into more pharmaceutically potent minor ginsenosides. To identify a microorganism that is capable of converting Rb1 into other ginsenosides, we screened 12 Microbacterium spp., and M. trichothecenolyticum was identified as a likely candidate. M. trichothecenolyticum converted Rb1 into Rd and then into Rh2 based on TLC and HPLC analyses of reaction products. This biotransformation method can be easily applied for mass production of Rd and Rh2 by using Rb1.
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http://dx.doi.org/10.4014/jmb.1307.07049DOI Listing
December 2013

Overview of methods for comparing the efficacies of drugs in the absence of head-to-head clinical trial data.

Br J Clin Pharmacol 2014 Jan;77(1):116-21

Melbourne EpiCentre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Parkville, VIC, 3010, Australia.

In most therapeutic areas, multiple drug options are increasingly becoming available, but there is often a lack of evidence from head-to-head clinical trials that allows for direct comparison of the efficacy and/or safety of one drug vs. another. This review provides an introduction to, and overview of, common methods used for comparing drugs in the absence of head-to-head clinical trial evidence. Naïve direct comparisons are in most instances inappropriate and should only be used for exploratory purposes and when no other options are possible. Adjusted indirect comparisons are currently the most commonly accepted method and use links through one or more common comparators. Mixed treatment comparisons (MTCs) use Bayesian statistical models to incorporate all available data for a drug, even data that are not relevant to the comparator drug. MTCs reduce uncertainty but have not yet been widely accepted by researchers, nor drug regulatory and reimbursement authorities. All indirect analyses are based on the same underlying assumption as meta-analyses, namely that the study populations in the trials being compared are similar.
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http://dx.doi.org/10.1111/bcp.12150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895352PMC
January 2014

Fe-Al-Mn-C lightweight structural alloys: a review on the microstructures and mechanical properties.

Sci Technol Adv Mater 2013 Feb 12;14(1):014205. Epub 2013 Mar 12.

Graduate Institute of Ferrous Technology (GIFT) and CAAM, POSTECH San 31, Hyoja-dong, Pohang, Gyungbuk 790-784, Republic of Korea.

Adding a large amount of light elements such as aluminum to steels is not a new concept recalling that several Fe-Al-Mn-C alloys were patented in 1950s for replacement of nickel or chromium in corrosion resistance steels. However, the so-called lightweight steels or low-density steels were revisited recently, which is driven by demands from the industry where steel has served as a major structural material. Strengthening without loss of ductility has been a triumph in steel research, but lowering the density of steel by mixing with light elements will be another prospect that may support the competitiveness against emerging alternatives such as magnesium alloys. In this paper, we review recent studies on lightweight steels, emphasizing the concept of alloy design for microstructures and mechanical properties. The influence of alloying elements on the phase constituents, mechanical properties and the change of density is critically reviewed. Deformation mechanisms of various lightweight steels are discussed as well. This paper provides a reason why the success of lightweight steels is strongly dependent on scientific achievements even though alloy development is closely related to industrial applications. Finally, we summarize some of the main directions for future investigations necessary for vitalizing this field of interest.
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http://dx.doi.org/10.1088/1468-6996/14/1/014205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5090571PMC
February 2013

Non-quantum electronic responses of zinc oxide nanomaterials.

Nanotechnology 2013 Mar 28;24(11):115701. Epub 2013 Feb 28.

Microscopy and Imaging Center, Texas A&M, College Station, TX 77843, USA.

The influence of the high surface-to-volume ratio of ZnO nanomaterials, whose sizes are large enough to exclude the quantum effect, on electronic properties was investigated by spatially resolved valence electron energy loss spectroscopy. ZnO nanowires, nanoplates, and nanotubes with different sizes were fabricated and characterized. Both the reduced volume and the increased surface area of the large ZnO nanomaterials were found to be able to modify electronic properties significantly. Hence, a nanoplate and a nanotube with very small volumes show unique energy loss functions and dielectric functions different from those of bulk ZnO at all the probe points. On the other hand, a nanowire with a relatively large diameter (70 nm) has electronic properties similar to those of bulk ZnO at the center. However, they are dissimilar at the edge of the nanowire due to the component of surface parallel to the electron path and the reduced interaction volume. Moreover, some interband transitions shift positions and bulk plasmons change oscillator strength depending upon the size of the volume and the geometry of the surface. These empirical results demonstrate that semiconducting nanomaterials larger than the exciton Bohr radius can still behave differently from bulk materials due to the high ratio between surface area and volume.
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http://dx.doi.org/10.1088/0957-4484/24/11/115701DOI Listing
March 2013

Overview of pharmacoeconomic modelling methods.

Br J Clin Pharmacol 2013 Apr;75(4):944-50

Melbourne EpiCentre, Department of Medicine (Royal Melbourne Hospital), The University of Melbourne, Melbourne, Victoria, Australia.

In the current climate of burgeoning health care costs, pharmacoeconomics is becoming increasingly important, but knowledge about pharmacoeconomic methods is limited among most clinicians. This review provides an introduction to, and overview of, common methods used in pharmacoeconomic modelling: decision analysis, Markov modelling, discounting and uncertainty analyses via Monte Carlo simulation. It will conclude with a suggested approach to reading and appraising published pharmacoeconomic analyses.
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http://dx.doi.org/10.1111/j.1365-2125.2012.04421.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612711PMC
April 2013

Vesicular monoamine transporter 2 and dopamine transporter are molecular targets of Pitx3 in the ventral midbrain dopamine neurons.

J Neurochem 2009 Dec 24;111(5):1202-12. Epub 2009 Sep 24.

Molecular Neurobiology Laboratory, McLean Hospital and Harvard Medical School, Belmont, MA, USA.

Midbrain dopamine (mDA) neurons play critical roles in the regulation of voluntary movement and their dysfunction is associated with Parkinson's disease. Pitx3 has been implicated in the proper development of mDA neurons in the substantia nigra pars compacta, which are selectively lost in Parkinson's disease. However, the basic mechanisms underlying its role in mDA neuron development and/or survival are poorly understood. Toward this goal, we sought to identify downstream target genes of Pitx3 by comparing gene expression profiles in mDA neurons of wild-type and Pitx3-deficient aphakia mice. This global gene expression analysis revealed many potential target genes of Pitx3; in particular, the expression of vesicular monoamine transporter 2 and dopamine transporter, responsible for dopamine storage and reuptake, respectively, is greatly reduced in mDA neurons by Pitx3 ablation. In addition, gain-of-function analyses and chromatin immunoprecipitation strongly indicate that Pitx3 may directly activate transcription of vesicular monoamine transporter 2 and dopamine transporter genes, critically contributing to neurotransmission and/or survival of mDA neurons. As the two genes have been known to be regulated by Nurr1, another key dopaminergic transcription factor, we propose that Pitx3 and Nurr1 may coordinately regulate mDA specification and survival, at least in part, through a merging and overlapping downstream pathway.
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http://dx.doi.org/10.1111/j.1471-4159.2009.06404.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896488PMC
December 2009

Biophysical characterization of the iron in mitochondria from Atm1p-depleted Saccharomyces cerevisiae.

Biochemistry 2009 Oct;48(40):9556-68

Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, USA.

Atm1p is an ABC transporter localized in the mitochondrial inner membrane; it functions to export an unknown species into the cytosol and is involved in cellular iron metabolism. Depletion or deletion of Atm1p causes Fe accumulation in mitochondria and a defect in cytosolic Fe/S cluster assembly but reportedly not a defect in mitochondrial Fe/S cluster assembly. In this study the nature of the accumulated Fe was examined using Mossbauer spectroscopy, EPR, electronic absorption spectroscopy, X-ray absorption spectroscopy, and electron microscopy. The Fe that accumulated in aerobically grown cells was in the form of iron(III) phosphate nanoparticles similar to that which accumulates in yeast frataxin Yfh1p-deleted or yeast ferredoxin Yah1p-depleted cells. Relative to WT mitochondria, Fe/S cluster and heme levels in Atm1p-depleted mitochondria from aerobic cells were significantly diminished. Atm1p depletion also caused a buildup of nonheme Fe(II) ions in the mitochondria and an increase in oxidative damage. Atm1p-depleted mitochondria isolated from anaerobically grown cells exhibited WT levels of Fe/S clusters and hemes, and they did not hyperaccumulate Fe. Atm1p-depleted cells lacked Leu1p activity, regardless of whether they were grown aerobically or anaerobically. These results indicate that Atm1p does not participate in mitochondrial Fe/S cluster assembly and that the species exported by Atm1p is required for cytosolic Fe/S cluster assembly. The Fe/S cluster defect and the Fe-accumulation phenotype, resulting from the depletion of Atm1p in aerobic cells (but not in anaerobic cells), may be secondary effects that are observed only when cells are exposed to oxygen during growth. Reactive oxygen species generated under these conditions might degrade iron-sulfur clusters and lower heme levels in the organelle.
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http://dx.doi.org/10.1021/bi901110nDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758324PMC
October 2009

Activation of autophagy during glutamate-induced HT22 cell death.

Biochem Biophys Res Commun 2009 Oct 6;388(2):339-44. Epub 2009 Aug 6.

Medical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.

Recent evidence suggests that autophagy plays a role in oxidative injury-induced cell death. Here we examined whether glutamate-mediated oxidative toxicity induces autophagy in murine hippocampal HT22 cells and if autophagy induction affects the molecular events associated with cell death. Markers for autophagy induction including LC3 conversion, suppression of mTOR pathway, and GFP-LC3 dot formation were enhanced by glutamate treatment. By contrast, autophagy inhibition blocked glutamate-induced LC3 conversion and consequently reduced cell death. Activation of ERK1/2, a hallmark of glutamate-induced cytotoxicity, was also decreased by autophagy inhibition. Interestingly, autophagy inhibition also affected the expression of chaperones including Hsp60 and Hsp70, which are differentially regulated during HT22 cell death. Conversely, knock-down of Hsp60 greatly decreased LC3 conversion. Together these results suggest that glutamate-induced cytotoxicity involves autophagic cell death and chaperones may play a role in this process.
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http://dx.doi.org/10.1016/j.bbrc.2009.08.007DOI Listing
October 2009

Modifications in electronic properties of polystyrene methacrylic acid by neutralization and fast electrons.

Authors:
Hansoo Kim

J Phys Chem B 2009 Jul;113(28):9359-63

Microscopy and Imaging Center, Texas A&M, College Station, TX 77843, USA.

In this study an ionomer, an ion-containing polymer, was investigated at various degrees of neutralization and irradiated by fast electrons to see the effects on its properties by an electron-microscope-electron-spectroscopy system. It was found that electronic and chemical structures of the polymer can be changed dramatically by neutralization and irradiation. The modifications by neutralization may be attributed to reversible cross-linking and resultant vulnerability due to residual strain while those by irradiation to irreversible cross-linking and scission. The combination of neutralization and irradiation can change the chemistry of the polymer rapidly but in a controllable manner. It can also manipulate the size of the band gap and the type of interband transition along with the degree of the modifications. Since the modifications can be induced in a nanoscale area by convergent electrons the results of the current study may lead to utilizing an ionomer for nanotechnology.
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http://dx.doi.org/10.1021/jp901045dDOI Listing
July 2009

Simple and fast annealing synthesis of titanium dioxide nanostructures and morphology transformation during annealing processes.

Nanotechnology 2009 Mar 17;20(10):105608. Epub 2009 Feb 17.

Department of Mechanical Engineering, Texas A&M University, College Station, TX 77843, USA.

Wire- and belt-like single-crystalline titanium dioxide nanostructures were synthesized by using a simple thermal annealing method, which has often been avoided for the synthesis of metal oxide nanostructures from high melting point metals such as Ti. The synthesis method requires neither high reaction temperature nor complicated reaction processes, and can be used for producing dense nanomaterials with relatively short reaction time at temperatures much lower than the melting point of titanium and titanium dioxide. Key synthesis factors including the choice of eutectic catalyst, growth temperature, and annealing time were systematically investigated. The synthesis reaction was promoted by a copper eutectic catalyst, producing long nanostructures with short reaction times. For example, it was observed that only 30 min of annealing time at 850 degrees C was enough to produce densely grown approximately 10 microm long nanowires with diameters of approximately 100 nm, and longer reaction time brought about morphology changes from wires to belts as well as producing longer nanostructures up to approximately 30 microm. The nanostructures have the crystalline rutile structure along the [Formula: see text] growth direction. Finally, our simple and effective method for the synthesis of TiO2 nanostructures could be utilized for growing other metal oxide nanowires from high melting temperature metals.
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http://dx.doi.org/10.1088/0957-4484/20/10/105608DOI Listing
March 2009

Band-gap modification in a nanoscale region of polyethylene by fast electrons.

Authors:
Hansoo Kim

Chemphyschem 2009 Feb;10(2):442-7

Microscopy and Imaging Center, Texas A&M, College Station, Texas 77843, USA.

Drastic change: A nanoscale spot of polyethylene (PE) can change its electrical properties dramatically after exposure to fast electrons-from a representative insulator, via a semiconductor, to a hopping conductor (see picture). These modifications of the chemical and energy-band structures of PE are extremely localized, thus opening a new way to use this conventional polymer in nanotechnology. Herein, a nanoscale area on a polyethylene film is investigated by an electron-microscope-electron-spectroscopy system after exposure to various doses of fast electrons. Therefore, modifications in its physical and chemical properties and the spatial size of a beam-affected area are measured. The results show that the modifications of PE by electrons are significant enough to rebuild the chemical and energy-band structures. Hydrogen is removed through scission while pi bonds are formed by cross-linking between main chains. These changes cause the energy band of PE to show dramatic variation from a wide to a narrow (down to approximately 0.8 eV) band-gap. At the highest dose (10(10) C m(-2)) used herein, an illuminated area of PE becomes quite similar in properties to graphitic amorphous carbon. On the other hand, the size of the beam-affected area is as small as roughly 50 nm in diameter. Since the extent of the modifications can be tailored in a controllable way by the dose, these findings may be fundamental for the utilization of a conventional polymer in nanotechnology.
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http://dx.doi.org/10.1002/cphc.200800618DOI Listing
February 2009

Long-term clinical outcome of helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma is comparable to that of h. pylori-positive lymphoma.

J Clin Gastroenterol 2009 Apr;43(4):312-7

Seoul National University Hospital Healthcare System, Yeoksam-dong, Gangnam-gu, Yongon-Dong, Chongno-Gu, Seoul, Republic of Korea.

Goals And Background: Little is still known regarding the clinical features and prognosis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma without Helicobacter pylori (H. pylori) infection.

Study: From January 1996 to April 2006, a total of 185 patients with gastric MALT lymphoma were enrolled at Seoul National University Hospital. To assess the differences in clinical characteristics and long-term outcomes between H. pylori-negative (n=29, 15.7%) and H. pylori-positive (n=156, 84.3%) cases, we compared these 2 types of lymphoma.

Results: The overall median follow-up period was 39 months. There were no significant differences between the 2 groups in terms of age, macroscopic phenotype, or histologic grade. H. pylori-negative group showed male predominancy (72.4%) and higher percentage of proximal stomach location (62.1%). Although H. pylori-negative lymphomas were more frequently presented as advanced disease (stage IIE or IV, 37.9%), no significant differences in both the overall complete response and overall survival rates were observed between the 2 groups.

Conclusions: Our results suggest that H. pylori-negative gastric MALT lymphoma shows a favorable long-term outcome, which is comparable to that of H. pylori-positive lymphoma.
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http://dx.doi.org/10.1097/MCG.0b013e31816a48f8DOI Listing
April 2009

Controlled modifications in electronic and chemical structures of a nanoscale region of polystyrene by fast electrons.

Authors:
Hansoo Kim

J Phys Chem B 2008 Oct 11;112(40):12579-84. Epub 2008 Sep 11.

Micriscopy and Imaging Center, Texas A&M, College Station, TX 77843, USA.

In this study the effect of electron irradiation on properties of a nanosized area of polystyrene was investigated at various doses by an electron-microscope-electron-spectroscopy system. Therefore, changes in electronic and chemical properties by the exposure were monitored from local areas of the conventional polymer using electron energy loss spectroscopy. Also, their spatial extension was measured by a high angle annular dark field detector. From the study it was found that a nanoscale region of polystyrene can modify its electronic and chemical structures dramatically by the irradiation, and the degree of modifications can be tailored by the electron dose. These results may suggest a way of utilizing conventional polymers in nanotechnology.
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http://dx.doi.org/10.1021/jp8024655DOI Listing
October 2008

EPR and Mössbauer spectroscopy of intact mitochondria isolated from Yah1p-depleted Saccharomyces cerevisiae.

Biochemistry 2008 Sep 22;47(37):9888-99. Epub 2008 Aug 22.

Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, USA.

Yah1p, an [Fe 2S 2]-containing ferredoxin located in the matrix of Saccharomyces cerevisiae mitochondria, functions in the synthesis of Fe/S clusters and heme a prosthetic groups. EPR, Mossbauer spectroscopy, and electron microscopy were used to characterize the Fe that accumulates in Yah1p-depleted isolated intact mitochondria. Gal- YAH1 cells were grown in standard rich media (YPD and YPGal) under O 2 or argon atmospheres. Mitochondria were isolated anaerobically, then prepared in the as-isolated redox state, the dithionite-treated state, and the O 2-treated state. The absence of strong EPR signals from Fe/S clusters when Yah1p was depleted confirms that Yah1p is required in Fe/S cluster assembly. Yah1p-depleted mitochondria, grown with O 2 bubbling through the media, accumulated excess Fe (up to 10 mM) that was present as 2-4 nm diameter ferric nanoparticles, similar to those observed in mitochondria from yfh1Delta cells. These particles yielded a broad isotropic EPR signal centered around g = 2, characteristic of superparamagnetic relaxation. Treatment with dithionite caused Fe (3+) ions of the nanoparticles to become reduced and largely exported from the mitochondria. Fe did not accumulate in mitochondria isolated from cells grown under Ar; a significant portion of the Fe in these organelles was in the high-spin Fe (2+) state. This suggests that the O 2 used during growth of Gal- YAH1 cells is responsible, either directly or indirectly, for Fe accumulation and for oxidizing Fe (2+) --> Fe (3+) prior to aggregation. Models are proposed in which the accumulation of ferric nanoparticles is caused either by the absence of a ligand that prevents such precipitation in wild-type mitochondria or by a more oxidizing environment within the mitochondria of Yah1p-depleted cells exposed to O 2. The efficacy of reducing accumulated Fe along with chelating it should be considered as a strategy for its removal in diseases involving such accumulations.
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http://dx.doi.org/10.1021/bi801047qDOI Listing
September 2008

Quantitative correlation between promoter methylation and messenger RNA levels of the reduced folate carrier.

BMC Cancer 2008 May 1;8:124. Epub 2008 May 1.

Department of Pediatrics and Molecular Pharmacology (R,Y,, R,G,), The Albert Einstein College of Medicine, The Children's Hospital at Montefiore, Bronx, NY 10461, USA.

Background: Methotrexate (MTX) uptake is mediated by the reduced folate carrier (RFC). Defective drug uptake in association with decreased RFC expression is a common mechanism of MTX resistance in many tumor types. Heavy promoter methylation was previously identified as a basis for the complete silencing of RFC in MDA-MB-231 breast cancer cells, its role and prevalence in RFC transcription regulation are, however, not widely studied.

Methods: In the current study, RFC promoter methylation was assessed using methylation specific PCR in a panel of malignant cell lines (n = 8), including MDA-MB-231, and M805, a MTX resistant cell line directly established from the specimen of a patient with malignant fibrohistocytoma, whom received multiple doses of MTX. A quantitative approach of real-time PCR for measuring the extent of RFC promoter methylation was developed, and was validated by direct bisulfite genomic sequencing. RFC mRNA levels were determined by quantitative real-time RT-PCR and were related to the extent of promoter methylation in these cell lines.

Results: A partial promoter methylation and RFC mRNA down-regulation were observed in M805. Using the quantitative approach, a reverse correlation (correlation coefficient = -0.59, p < 0.05) was identified between the promoter methylation and RFC mRNA levels in this a panel of malignant cell lines.

Conclusion: This study further suggests that promoter methylation is a potential basis for MTX resistance. The quantitative correlation identified in this study implies that promoter methylation is possibly a mechanism involved in the fine regulation of RFC transcription.
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http://dx.doi.org/10.1186/1471-2407-8-124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387170PMC
May 2008