Safety of a non-viral plasmid-encoding dual isoforms of hepatocyte growth factor in critical limb ischemia patients: a phase I study

Henry, T D,Hirsch, A T,Goldman, J,Wang, Y L,Lips, D L,McMillan, W D,Duval, S,Biggs, T A,Keo, H H Macmillan Publishers Limited 2011 Gene therapy Vol.18 No.8

We aimed to evaluate in a phase I dose-escalation study, the safety of intramuscular injections of a novel non-viral plasmid DNA expressing two isoforms of human hepatocyte growth factor (HGF) (VM202) in patients with critical limb ischemia (CLI). In total, 12 patients with CLI and unsuitable for revascularization were consecutively assigned to increasing doses (2 to 16 mg) of VM202 administered into the ischemic calf muscle at days 1 and 15. Patients were evaluated for safety and tolerability, changes in ankle- and toe brachial index (ABI and TBI), and pain severity score using a visual analog scale (VAS) throughout a 12-month follow-up period. Median age was 72 years and 53% of the patients were male. VM202 was safe and well tolerated with no death during the 12-month follow-up. Median ABI and TBI significantly increased from 0.35 to 0.52 (P=0.005) and from 0.15 to 0.24 (P=0.01) at 12 months follow-up. Median VAS decreased from 57.5 to 16.0 mm at 6 months follow-up (P=0.03). In this first human clinical trial, VM202, which expresses two isoforms of human HGF, appear to be safe and well tolerated with encouraging clinical results and thus supports the performance of a phase II randomized controlled trial.

Sustainable hydrogen production from water using tandem dye-sensitized photoelectrochemical cells

Sherman Benjamin D.,McMillan Nelli Klinova,Willinger Debora,Leem Gyu 나노기술연구협의회 2021 Nano Convergence Vol.8 No.7

If generated from water using renewable energy, hydrogen could serve as a carbon-zero, environmentally benign fuel to meet the needs of modern society. Photoelectrochemical cells integrate the absorption and conversion of solar energy and chemical catalysis for the generation of high value products. Tandem photoelectrochemical devices have demonstrated impressive solar-to-hydrogen conversion efficiencies but have not become economically relevant due to high production cost. Dye-sensitized solar cells, those based on a monolayer of molecular dye adsorbed to a high surface area, optically transparent semiconductor electrode, offer a possible route to realizing tandem photochemical systems for H 2 production by water photolysis with lower overall material and processing costs. This review addresses the design and materials important to the development of tandem dye-sensitized photoelectrochemical cells for solar H 2 production and highlights current published reports detailing systems capable of spontaneous H 2 formation from water using only dye-sensitized interfaces for light capture.

Pedestrian level wind speeds in downtown Auckland

P.J. Richards,G.D. Mallinson,D. McMillan,Y.F. Li 한국풍공학회 2002 Wind and Structures, An International Journal (WAS Vol.5 No.2

Pedestrian level wind speeds in downtown Auckland

Richards, P.J.,Mallinson, G.D.,McMillan, D.,Li, Y.F. Techno-Press 2002 Wind and Structures, An International Journal (WAS Vol.5 No.2

Predictions of the pedestrian level wind speeds for the downtown area of Auckland that have been obtained by wind tunnel and computational fluid dynamic (CFD) modelling are presented. The wind tunnel method involves the observation of erosion patterns as the wind speed is progressively increased. The computational solutions are mean flow calculations, which were obtained by using the finite volume code PHOENICS and the $k-{\varepsilon}$ turbulence model. The results for a variety of wind directions are compared, and it is observed that while the patterns are similar there are noticeable differences. A possible explanation for these differences arises because the tunnel prediction technique is sensitivity to gust wind speeds while the CFD method predicts mean wind speeds. It is shown that in many cases the computational model indicates high mean wind speeds near the corner of a building while the erosion patterns are consistent with eddies being shed from the edge of the building and swept downstream.

Temporalis muscle as a disc replacement in the temporomandibular joint of sheep

윤중호(Jung Ho Yoon),Gerard M Thyne,Neil H Luyk,Malcolm D Mcmillan 대한구강악안면외과학회 1992 대한구강악안면외과학회지 Vol.18 No.3

저자는 양에서 측두하악관절원판 절제후 측두근피판을 이의 대체물로서 삽입한 후 2주, 4주, 12주 및 24주째의 변화를 병리조직학적으로 관찰한 바, 측두근피판이 초기에는 무혈관성 괴사를 보이다가 점차 관절강 내에서 소실되어 결국 관절와와 하악과두가 밀접하게 집적 접촉함을 관찰할 수 있었다. 한편 측두근피판을 관절측방조직에 봉합한 수술 대조군에서는 4, 12, 24주째 군에서 모두 근피판이 생존하였고 일부는 섬유성 조직으로 잔존 하였다. 관절와와 하악과두의 표층은 초기에 소실되었다가 시간이 경과하면서 원래의 조직으로 재형성되었다. 본 실험 결과, 양에 있어서의 측두하악관절강에 삽입한 측두근피판은 저작기능 부하(압력)에 지탱할 수 없었으며 관절강 내에 원판과 같은 대체물이 없어도 하악과두나 관절와가 재형성 됨을 보여 주었다. Temporalis muscle flaps were evaluated in sheep. Flaps placed as interpositional material following meniscectomy were examined at 2, 4, 12 and 24 weeks. Histological evaluation of these muscle flaps showed avascular necrosis, subsequent displacement and loss of tissue from the joint in operative controls were examined at 4, 12 and 24 weeks. This muscle remained viable while undergoing fibrous replacement. The surface layers of the condyle and fossa were initially lost, but he tissues were reformed loading within the joint. Despite the lack of interpositional material the condyle and fossa can remodel.

Computational discovery of pathway-level genetic vulnerabilities in non-small-cell lung cancer

Young, Jonathan H.,Peyton, Michael,Seok Kim, Hyun,McMillan, Elizabeth,Minna, John D.,White, Michael A.,Marcotte, Edward M. Oxford University Press 2016 Bioinformatics Vol.32 No.9

<P><B>Motivation:</B> Novel approaches are needed for discovery of targeted therapies for non-small-cell lung cancer (NSCLC) that are specific to certain patients. Whole genome RNAi screening of lung cancer cell lines provides an ideal source for determining candidate drug targets.</P><P><B>Results:</B> Unsupervised learning algorithms uncovered patterns of differential vulnerability across lung cancer cell lines to loss of functionally related genes. Such genetic vulnerabilities represent candidate targets for therapy and are found to be involved in splicing, translation and protein folding. In particular, many NSCLC cell lines were especially sensitive to the loss of components of the LSm2-8 protein complex or the CCT/TRiC chaperonin. Different vulnerabilities were also found for different cell line subgroups. Furthermore, the predicted vulnerability of a single adenocarcinoma cell line to loss of the Wnt pathway was experimentally validated with screening of small-molecule Wnt inhibitors against an extensive cell line panel.</P><P><B>Availability and implementation:</B> The clustering algorithm is implemented in Python and is freely available at https://bitbucket.org/youngjh/nsclc_paper.</P><P><B>Contact:</B>marcotte@icmb.utexas.edu or jon.young@utexas.edu</P><P><B>Supplementary information:</B>Supplementary data are available at <I>Bioinformatics</I> online.</P>

Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle

Scheffler, T. L.,Scheffler, J. M.,Park, S.,Kasten, S. C.,Wu, Y.,McMillan, R. P.,Hulver, M. W.,Frisard, M. I.,Gerrard, D. E. American Physiological Society 2014 American journal of physiology. Cell physiology Vol.306 No.4

<P>An inverse relationship between skeletal muscle fiber cross-sectional area (CSA) and oxidative capacity suggests that muscle fibers hypertrophy at the expense of oxidative capacity. Therefore, our objective was to utilize pigs possessing mutations associated with increased oxidative capacity [AMP-activated protein kinase (AMPKγ<SUB>3</SUB><SUP>R200Q</SUP>)] or fiber hypertrophy [ryanodine receptor 1 (RyR1<SUP>R615C</SUP>)] to determine if these events occur in parallel. Longissimus muscle was collected from wild-type (control), AMPKγ<SUB>3</SUB><SUP>R200Q</SUP>, RyR1<SUP>R615C</SUP>, and AMPKγ<SUB>3</SUB><SUP>R200Q</SUP>-RyR1<SUP>R615C</SUP> pigs. Regardless of AMPK genotype, RyR<SUP>R615C</SUP> increased fiber CSA by 35%. In contrast, AMPKγ<SUB>3</SUB><SUP>R200Q</SUP> pig muscle exhibited greater citrate synthase and β-hydroxyacyl CoA dehydrogenase activity. Isolated mitochondria from AMPKγ<SUB>3</SUB><SUP>R200Q</SUP> muscle had greater maximal, ADP-stimulated oxygen consumption rate. Additionally, AMPKγ<SUB>3</SUB><SUP>R200Q</SUP> muscle contained more (∼50%) of the mitochondrial proteins succinate dehydrogenase and cytochrome <I>c</I> oxidase and more mitochondrial DNA. Surprisingly, RyR1<SUP>R615C</SUP> increased mitochondrial proteins and DNA, but this was not associated with improved oxidative capacity, suggesting that altered energy metabolism in RyR1<SUP>R615C</SUP> muscle influences mitochondrial proliferation and protein turnover. Thus pigs that possess both AMPKγ3<SUP>R200Q</SUP> and RyR<SUP>R615C</SUP> exhibit increased muscle fiber CSA as well as greater oxidative capacity. Together, our findings support the notion that hypertrophy and enhanced oxidative capacity can occur simultaneously in skeletal muscle and suggest that the signaling mechanisms controlling these events are independently regulated.</P>