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1.  RB Maintains Quiescence and Prevents Premature Senescence through Upregulation of DNMT1 in Mesenchymal Stromal Cells 
Stem Cell Reports  2014;3(6):975-986.
Many cell therapies currently being tested are based on mesenchymal stromal cells (MSCs). However, MSCs start to enter the senescent state upon long-term expansion. The role of retinoblastoma (RB) protein in regulating MSC properties is not well studied. Here, we show that RB levels are higher in early-passage MSCs compared with late-passage MSCs. RB knockdown induces premature senescence and reduced differentiation potentials in early-passage MSCs. RB overexpression inhibits senescence and increases differentiation potentials in late-passage MSCs. Expression of DNMT1, but not DNMT3A or DNMT3B, is also higher in early-passage MSCs than in late-passage MSCs. Furthermore, DNMT1 knockdown in early-passage MSCs induces senescence and reduces differentiation potentials, whereas DNMT1 overexpression in late-passage MSCs has the opposite effect. These results demonstrate that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs. Therefore, genetic modification of RB could be a way to improve the efficiency of MSCs in clinical use.
Graphical Abstract
•RB levels are higher in early-passage MSCs than in late-passage MSCs•RB knockdown induces a premature senescence and reduces differentiation potentials•RB overexpression reverses senescence and increases differentiation potentials•RB upregulates DNMT1 to inhibit senescence and promote differentiation potentials
In this article, Hung, Kao, and colleagues show that retinoblastoma (RB) levels are higher in early-passage mesenchymal stromal cells (MSCs) than in late-passage MSCs, which serves to regulate senescence and differentiation potentials. Expression of DNMT1 is also higher in early-passage MSCs than in late-passage MSCs. This study demonstrates that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs.
PMCID: PMC4264040  PMID: 25455074
2.  Diabetes Mellitus and Risk of Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(9):e108196.
Age-related macular degeneration (AMD) is a major cause of severe vision loss in elderly people. Diabetes mellitus is a common endocrine disorder with serious consequences, and diabetic retinopathy (DR) is the main ophthalmic complication. DR and AMD are different diseases and we seek to explore the relationship between diabetes and AMD. MEDLINE, EMBASE, and the Cochrane Library were searched for potentially eligible studies. Studies based on longitudinal cohort, cross-sectional, and case-control associations, reporting evaluation data of diabetes as an independent factor for AMD were included. Reports of relative risks (RRs), hazard ratios (HRs), odds ratio (ORs), or evaluation data of diabetes as an independent factor for AMD were included. Review Manager and STATA were used for the meta-analysis. Twenty four articles involving 27 study populations were included for meta-analysis. In 7 cohort studies, diabetes was shown to be a risk factor for AMD (OR, 1.05; 95% CI, 1.00–1.14). Results of 9 cross-sectional studies revealed consistent association of diabetes with AMD (OR, 1.21; 95% CI, 1.00–1.45), especially for late AMD (OR, 1.48; 95% CI, 1.44–1.51). Similar association was also detected for AMD (OR, 1.29; 95% CI, 1.13–1.49) and late AMD (OR, 1.16; 95% CI, 1.11–1.21) in 11 case-control studies. The pooled ORs for risk of neovascular AMD (nAMD) were 1.10 (95% CI, 0.96–1.26), 1.48 (95% CI, 1.44–1.51), and 1.15 (95% CI, 1.11–1.21) from cohort, cross-sectional and case-control studies, respectively. No obvious divergence existed among different ethnic groups. Therefore, we find diabetes a risk factor for AMD, stronger for late AMD than earlier stages. However, most of the included studies only adjusted for age and sex; we thus cannot rule out confounding as a potential explanation for the association. More well-designed prospective cohort studies are still warranted to further examine the association.
PMCID: PMC4169602  PMID: 25238063
3.  Obstacles delaying the prompt deployment of piston-type mechanical cardiopulmonary resuscitation devices during emergency department resuscitation: A video-recording and time-motion study 
Resuscitation  2013;84(9):1208-1213.
The quality of cardiopulmonary resuscitation (CPR) is important to survival after cardiac arrest. Mechanical devices (MD) provide constant CPR, but their effectiveness may be affected by deployment timeliness.
To identify the timeliness of the overall and of each essential step in the deployment of a piston-type MD during emergency department (ED) resuscitation, and to identify factors associated with delayed MD deployment by video recordings.
Between December 2005 and December 2008, video clips from resuscitations with CPR sessions using a MD in the ED were reviewed using time-motion analyses. The overall deployment timeliness and the time spent on each essential step of deployment were measured.
There were 37 CPR recordings that used a MD. Deployment of MD took an average 122.6 ± 57.8 s. The 3 most time-consuming steps were: (1) setting the device (57.8 ± 38.3 s), (2) positioning the patient (33.4 ± 38.0 s), and (3) positioning the device (14.7 ± 9.5 s). Total no flow time was 89.1 ± 41.2 s (72.7% of total time) and associated with the 3 most time-consuming steps. There was no difference in the total timeliness, no-flow time, and no-flow ratio between different rescuer numbers, time of day of the resuscitation, or body size of patients.
Rescuers spent a significant amount of time on MD deployment, leading to long no-flow times. Lack of familiarity with the device and positioning strategy were associated with poor performance. Additional training in device deployment strategies are required to improve the benefits of mechanical CPR.
PMCID: PMC4023508  PMID: 23571118
Mechanical devices; Cardiopulmonary resuscitation (CPR); Video-recording; Time-motion analysis; No-flow time Quality
4.  A Novel Support Vector Machine-Based Approach for Rare Variant Detection 
PLoS ONE  2013;8(8):e71114.
Advances in next-generation sequencing technologies have enabled the identification of multiple rare single nucleotide polymorphisms involved in diseases or traits. Several strategies for identifying rare variants that contribute to disease susceptibility have recently been proposed. An important feature of many of these statistical methods is the pooling or collapsing of multiple rare single nucleotide variants to achieve a reasonably high frequency and effect. However, if the pooled rare variants are associated with the trait in different directions, then the pooling may weaken the signal, thereby reducing its statistical power. In the present paper, we propose a backward support vector machine (BSVM)-based variant selection procedure to identify informative disease-associated rare variants. In the selection procedure, the rare variants are weighted and collapsed according to their positive or negative associations with the disease, which may be associated with common variants and rare variants with protective, deleterious, or neutral effects. This nonparametric variant selection procedure is able to account for confounding factors and can also be adopted in other regression frameworks. The results of a simulation study and a data example show that the proposed BSVM approach is more powerful than four other approaches under the considered scenarios, while maintaining valid type I errors.
PMCID: PMC3737136  PMID: 23940698
5.  First Genome Sequence of a Burkholderia pseudomallei Isolate in China, Strain BPC006, Obtained from a Melioidosis Patient in Hainan 
Journal of Bacteriology  2012;194(23):6604-6605.
Melioidosis, caused by Burkholderia pseudomallei, is considered to be endemic to Northern Australia and Southeast Asia, with high mortality and relapse rates, regardless of powerful antibiotic therapy. Here we report the first genome sequence of Burkholderia pseudomallei strain BPC006, obtained from a melioidosis patient in Hainan, China. The genome sizes of the 2 chromosomes were determined to be 4,001,777 bp and 3,153,284 bp.
PMCID: PMC3497521  PMID: 23144371
7.  Compromised autophagy by MIR30B benefits the intracellular survival of Helicobacter pylori 
Autophagy  2012;8(7):1045-1057.
Helicobacter pylori evade immune responses and achieve persistent colonization in the stomach. However, the mechanism by which H. pylori infections persist is not clear. In this study, we showed that MIR30B is upregulated during H. pylori infection of an AGS cell line and human gastric tissues. Upregulation of MIR30B benefited bacterial replication by compromising the process of autophagy during the H. pylori infection. As a potential mechanistic explanation for this observation, we demonstrate that MIR30B directly targets ATG12 and BECN1, which are important proteins involved in autophagy. These results suggest that compromise of autophagy by MIR30B allows intracellular H. pylori to evade autophagic clearance, thereby contributing to the persistence of H. pylori infections.
PMCID: PMC3429542  PMID: 22647547
Helicobacter pylori; MIR30B; ATG12; BECN1; autophagy
8.  Risk factors in cutout of sliding hip screw in intertrochanteric fractures: an evaluation of 937 patients 
International Orthopaedics  2009;34(8):1273-1276.
The aim of this study was designed to assess the risk factors of lag-screw cutout in the treatment of intertrochanteric fracture with a dynamic hip screw (DHS). From 2003 to 2007, 1,150 patients who had acute unilateral intertrochanteric fractures of the femur were enrolled to the study. All fractures were managed by closed reduction and internal fixation with 135° DHS devices. Patient demographics, fracture patterns, reduction and fixation and perioperative course parameters were all recorded. The follow-up period was 38 months on average (range 16–60 months). Finally, 937 patients were available for evaluation of final results in which we focused on lag-screw cutout. Excluding complications not related to screw position, 64 patients (6.8%) with screw cutout were encountered, and the remaining 873 patients had uneventful union, with the average union time of 17.5 weeks (range15–24 weeks). Upon analysis with logistic regression, the tip−apex distance (TAD) was shown to be the most important predictive factor for cutout, followed by screw position, fracture pattern, reduction and patient age. In order to decrease the risk of lag-screw cutout, it is important to ensure good fracture reduction and to place the lag screw in either the middle/middle or inferior/middle position with appropriate TAD.
PMCID: PMC2989068  PMID: 19784649
9.  Comparison of articulating and static spacers regarding infection with resistant organisms in total knee arthroplasty 
Acta Orthopaedica  2011;82(4):460-464.
The result of treatment of infections involving antibiotic-resistant organisms in total knee arthroplasty (TKA) is often poor. We evaluated the efficacy of 2-stage revision in TKAs infected with resistant organisms and compared the clinical outcomes with articulating and conventional static spacers, in terms of both infection control and function.
In a prospective manner, from June 2003 to January 2007 selected patients with a TKA infected with resistant organisms were enrolled and treated with 2-stage re-implantation. The 45 patients were divided into 2 groups: group A (23 patients) implanted with the articulating spacers and group S (22 patients) implanted with static spacers. All patients followed the same antibiotic protocols and had the same re-implantation criteria. The efficacy of infection control was evaluated using re-implantation rate, recurrence rate, and overall success rate. The functional and radiographic results were interpreted with the Hospital of Special Surgery (HSS) knee score and the Insall-Salvati ratio.
With mean 40 (24–61) months of follow-up, 22 of 23 knees were re-implanted in group A and 21 of 22 were re-implanted in group S. Of these re-implanted prostheses, 1 re-infection occurred in group A and 2 occurred in group S. Range of motion after re-implantation, the final functional scores, and the satisfaction rate were better in group A. One third of the patients in group S, and none in group A, had a patella baja.
After 2-stage re-implantation of TKAs originally infected with resistant organisms, the clinical outcome was satisfactory—and similar to that reported after treatment of TKAs infected with low-virulence strains. Treatment with an articulating spacer resulted in better functional outcome and lower incidence of patella baja.
PMCID: PMC3237037  PMID: 21883049
10.  Isometric measurement of wrist-extensor power following surgical treatment of displaced lateral condylar fracture of the humerus in children 
International Orthopaedics  2007;32(5):679-684.
Muscle disability is a common sequel after fracture management. Previous research has shown divergent results concerning muscle-power recovery after bone healing. This study has investigated the muscle function of wrist extensors after lateral condylar fracture in children, as evaluated by a hand-held dynamometer and compared with sex- and age-matched children. From 1999 to 2004, 20 patients (13 boys and seven girls; mean age: 9 years and 4 months) with displaced lateral condylar fracture of the humerus were treated by open reduction and internal fixation with Kirschner wires (K-wire). The duration of K-wire fixation was 35 days and the mean follow-up time was 50 months. A total of 180 healthy age-, sex- and weight-matched children were used as control groups. A paired Student’s test was applied for the analysis of statistical significance. The range of motion of the elbow and radiographic findings were not significantly different between the injured limb and normal control groups. The maximum isometric power of wrist-extensor muscles after surgical treatment of lateral condylar fracture of the humerus in final follow-up was not statistically different from that in the normal control children. Muscle power therefore recovers to its normal status after the healing of lateral condylar fracture of the humerus in children.
PMCID: PMC2551724  PMID: 17534616

Results 1-10 (10)