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1.  Mutation of POC1B in a severe syndromic retinal ciliopathy 
Human mutation  2014;35(10):1153-1162.
We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease. Targeted NGS for excluding mutations in known LCA and JBTS genes, homozygosity mapping and whole-exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with non-syndromic cone-rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe polycystic kidney disease.
PMCID: PMC4425427  PMID: 25044745
POC1B; LCA; Joubert syndrome; ciliopathy; zebrafish
2.  Articular cartilage of the knee 3 years after ACL reconstruction 
Acta Orthopaedica  2015;86(5):605-610.
Background and purpose
T1ρ or T2 relaxation imaging has been increasingly used to evaluate the cartilage of the knee. We investigated the cartilage of ACL-reconstructed knees 3 years after surgery using T2 relaxation times.
Patients and methods
10 patients with a clinically successful unilateral ACL reconstruction were examined 3 years after surgery. Multiple-TE fast-spin echo sagittal images of both knees were acquired using a 3T MRI scanner for T2 mapping of the tibiofemoral cartilage. T2 values of the superficial and deep zones of the tibiofemoral cartilage were analyzed in sub-compartmental areas and compared between the ACL-reconstructed and uninjured contralateral knees.
Higher T2 values were observed in 1 or more sub-compartmental areas of each ACL-reconstructed knee compared to the uninjured contralateral side. Most of the T2 increases were observed at the superficial zones of the cartilage, especially at the medial compartment. At the medial compartment of the ACL-reconstructed knee, the T2 values of the femoral and tibial cartilage were increased by 3–81% compared to the uninjured contralateral side, at the superficial zones of the weight-bearing areas. T2 values in the superficial zone of the central medial femoral condyle differed between the 2 groups (p = 0.002).
The articular cartilage of ACL-reconstructed knees, although clinically satisfactory, had higher T2 values in the superficial zone of the central medial femoral condyle than in the uninjured contralateral side 3 years after surgery. Further studies are warranted to determine whether these patients would undergo cartilage degeneration over time.
PMCID: PMC4564784  PMID: 25854533
3.  Stepping in the direction of the fall: the next foot placement can be predicted from current upper body state in steady-state walking 
Biology Letters  2014;10(9):20140405.
During human walking, perturbations to the upper body can be partly corrected by placing the foot appropriately on the next step. Here, we infer aspects of such foot placement dynamics using step-to-step variability over hundreds of steps of steady-state walking data. In particular, we infer dependence of the ‘next’ foot position on upper body state at different phases during the ‘current’ step. We show that a linear function of the hip position and velocity state (approximating the body center of mass state) during mid-stance explains over 80% of the next lateral foot position variance, consistent with (but not proving) lateral stabilization using foot placement. This linear function implies that a rightward pelvic deviation during a left stance results in a larger step width and smaller step length than average on the next foot placement. The absolute position on the treadmill does not add significant information about the next foot relative to current stance foot over that already available in the pelvis position and velocity. Such walking dynamics inference with steady-state data may allow diagnostics of stability and inform biomimetic exoskeleton or robot design.
PMCID: PMC4190959  PMID: 25252834
biomechanics; foot placement; walking; stability; control; dynamics
4.  Changes in cardiovascular health score and atherosclerosis progression in middle-aged and older persons in China: a cohort study 
BMJ Open  2015;5(8):e007547.
The American Heart Association (AHA) proposed a definition of 4 cardiovascular health behaviours and 3 health factors. On the basis of the 7 metrics, the cardiovascular health score (CHS) was used to estimate individual-level changes in cardiovascular health status. The aim of this study was to investigate whether changes in CHS (⊿CHS) at different time-points are associated with atherosclerosis progression in middle-aged and older persons.
Prospective cohort study in China.
We defined 8 groups (≤−4, −3, −2, −1, 0, 1, 2 and ≥3) according to ⊿CHS. The impact of ⊿CHS on the change of brachial–ankle pulse wave velocity (⊿baPWV) and atherosclerosis progression was analysed.
A total of 3951 individuals met the inclusion criteria (≥40 years old; no history of stroke, transient ischaemic attack or myocardial infarction) and had complete information.
⊿baPWV decreased gradually (126.46±355.91, 78.4±343.81, 69.6±316.27, 49.59±287.57, 57.07±261.17, 40.45±264.27, 37.45±283.26 and 21.66±264.17 cm/s, respectively) with increasing ⊿CHS (p for trend<0.05). Multivariate linear regression analysis suggested a negative relationship between these 2 variables, which persisted after adjustment for other risk factors. Each increase in CHS was associated with a reduced baPWV for 15.22 cm/s (B value −15.22, p<0.001).
⊿CHS were negatively related to ⊿baPWV, which proved to be an independent predictor of the progression of atherosclerosis in middle-aged and older persons.
Trial registration number
Kailuan study (ChiCTR-TNC-11001489).
PMCID: PMC4554904  PMID: 26310397
5.  Transplantation of induced pluripotent stem cell-derived renal stem cells improved acute kidney injury 
Cell & Bioscience  2015;5:45.
Acute kidney injury (AKI) is a severe disease with high morbidity and mortality. Methods that promote repair of the injured kidney have been extensively investigated. Cell-based therapy with mesenchymal stem cells or renal progenitor cells (RPCs) resident in the kidney has appeared to be an effective strategy for the treatment of AKI. Embryonic stem cells or induced pluripotent stem cells (iPSCs) are also utilized for AKI recovery. However, the therapeutic effect of iPSC-derived RPCs for AKI has yet to be determined.
In this study, we induced iPSCs differentiation into RPCs using a nephrogenic cocktail of factors combined with the renal epithelial cell growth medium. We then established the rat ischemia–reperfusion injury (IR) model and transplanted the iPSC-derived RPCs into the injured rats in combination with the hydrogel. Next, we examined the renal function-related markers and renal histology to assess the therapeutic effect of the injected cells. Moreover, we investigated the mechanism by which iPSC-derived RPCs affect AKI caused by IR.
We showed that the differentiation efficiency of iPSCs to RPCs increased when cultured with renal epithelial cell growth medium after stimulation with a nephrogenic cocktail of factors. The transplantation of iPSC-derived RPCs decreased the levels of biomarkers indicative of renal injury and attenuated the necrosis and apoptosis of renal tissues, but resulted in the up-regulation of renal tubules formation, cell proliferation, and the expression of pro-renal factors.
Our results revealed that iPSC-derived RPCs can protect AKI rat from renal function impairment and severe tubular injury by up-regulating the renal tubules formation, promoting cell proliferation, reducing apoptosis, and regulating the microenvironment in the injured kidney.
Electronic supplementary material
The online version of this article (doi:10.1186/s13578-015-0040-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4541730  PMID: 26294957
Acute kidney injury; iPSC-derived RPCs; Renal ischemia–reperfusion injury; Hydrogel
6.  Role of Neurexin-1β and Neuroligin-1 in Cognitive Dysfunction After Subarachnoid Hemorrhage in Rats 
Supplemental Digital Content is available in the text.
Background and Purpose—
Neurexin-1β and neuroligin-1 play an important role in the formation, maintenance, and regulation of synaptic structures. This study is to estimate the potential role of neurexin-1β and neuroligin-1 in subarachnoid hemorrhage (SAH)-induced cognitive dysfunction.
In vivo, 228 Sprague–Dawley rats were used. An experimental SAH model was induced by single blood injection to prechiasmatic cistern. Primary cultured hippocampal neurons were exposed to oxyhemoglobin to mimic SAH in vitro. Specific small interfering RNAs and expression plasmids for neurexin-1β and neuroligin-1 were exploited both in vivo and in vitro. Western blot, immunofluorescence, immunoprecipitation, neurological scoring, and Morris water maze were performed to evaluate the mechanism of neurexin-1β and neuroligin-1, as well as neurological outcome.
Both in vivo and in vitro experiments showed SAH-induced decrease in the expressions of neurexin-1β and neuroligin-1 and the interaction between neurexin-1β and neuroligin-1 in neurons. In addition, the interaction between neurexin-1β and neuroligin-1 was reduced by their knockdown and increased by their overexpression. The formation of excitatory synapses was inhibited by oxyhemoglobin treatment, which was significantly ameliorated by overexpression of neurexin-1β and neuroligin-1 and aggravated by the knockdown of neurexin-1β and neuroligin-1. More importantly, neurexin-1β and neuroligin-1 overexpression ameliorated SAH-induced cognitive dysfunction, whereas neurexin-1β and neuroligin-1 knockdown induced an opposite effect.
Enhancing the expressions of neurexin-1β and neuroligin-1 could promote the interaction between them and the formation of excitatory synapses, which is helpful to improve cognitive dysfunction after SAH. Neurexin-1β and neuroligin-1 might be good targets for improving cognitive function after SAH.
PMCID: PMC4542569  PMID: 26219651
neurexin-Ibeta; neuroligin 1; stroke; subarachnoid hemorrhage; synapses
7.  Inconsistencies Exist in National Estimates of Eye Care Services Utilization in the United States 
Journal of Ophthalmology  2015;2015:435606.
Background. There are limited research and substantial uncertainty about the level of eye care utilization in the United States. Objectives. Our study estimated eye care utilization using, to our knowledge, every known nationally representative, publicly available database with information on office-based optometry or ophthalmology services. Research Design. We analyzed the following national databases to estimate eye care utilization: the Medical Expenditure Panel Survey (MEPS), National Health Interview Survey (NHIS), Joint Canada/US Survey of Health (JCUSH), Behavioral Risk Factor Surveillance System (BRFSS), and the National Ambulatory Medical Care Survey (NAMCS). Subjects. US adults aged 18 and older. Measures. Self-reported utilization of eye care services. Results. The weighted number of adults seeing or talking with any eye doctor ranges from 87.9 million to 99.5 million, and the number of visits annually ranges from 72.9 million to 142.6 million. There were an estimated 17.2 million optometry visits and 55.8 million ophthalmology visits. Conclusions. The definitions and estimates of eye care services vary widely across national databases, leading to substantial differences in national estimates of eye care utilization.
PMCID: PMC4546761  PMID: 26346484
8.  IGF-1 regulates the SIRT1-p53 pathway in cellular senescence 
Aging cell  2014;13(4):669-678.
Cellular senescence, which is known to halt proliferation of aged and stressed cells, plays a key role against cancer development, and is also closely associated with organismal aging. While increased IGF signaling induces cell proliferation, survival and cancer progression, disrupted insulin-like growth factor (IGF) signaling is known to enhance longevity concomitantly with delay in aging processes. The molecular mechanisms involved in the regulation of aging by IGF signaling and whether IGF regulates cellular senescence are still poorly understood. In this study, we demonstrate that IGF-1 exerts a dual function in promoting cell proliferation as well as cellular senescence. While acute IGF-1 exposure promotes cell proliferation and is opposed by p53, prolonged IGF-1 treatment induces premature cellular senescence in a p53-dependent manner. We show that prolonged IGF-1 treatment inhibits SIRT1 deacetylase activity, resulting in increased p53 acetylation as well as p53 stabilization and activation, thus leading to premature cellular senescence. In addition, either expression of SIRT1 or inhibition of p53 prevented IGF-1-induced premature cellular senescence. Together, these findings suggest that p53 acts as a molecular switch in monitoring IGF-1-induced proliferation and premature senescence, and suggest a possible molecular connection involving IGF-1-SIRT1-p53 signaling in cellular senescence and aging.
PMCID: PMC4118446  PMID: 25070626
IGF-1; SIRT1; p53; senescence; aging
10.  Testis-Specific Lactate Dehydrogenase (LDH-C4) in Skeletal Muscle Enhances a Pika’s Sprint-Running Capacity in Hypoxic Environment 
LDH-C4 is a lactate dehydrogenase that catalyzes the conversion of pyruvate to lactate. In mammals, ldh-c was originally thought to be expressed only in testis and spermatozoa. Plateau pika (Ochotona curzoniae), which belongs to the genus Ochotona of the Ochotonidea family, is a hypoxia tolerant mammal living 3000–5000 m above sea level on the Qinghai-Tibet Plateau, an environment which is strongly hypoxic. Ldh-c is expressed not only in testis and sperm but also in somatic tissues of plateau pika. In this study, the effects of N-propyl oxamate and N-isopropyl oxamate on LDH isozyme kinetics were compared to screens for a selective inhibitor of LDH-C4. To reveal the role and physiological mechanism of LDH-C4 in skeletal muscle of plateau pika, we investigated the effect of N-isopropyl oxamate on the pika exercise tolerance as well as the physiological mechanism. Our results show that Ki of N-propyl oxamate and N-isopropyl oxamate for LDH-A4, LDH-B4, and LDH-C4 were 0.094 mmol/L and 0.462 mmol/L, 0.119 mmol/L and 0.248 mmol/L, and 0.015 mmol/L and 0.013 mmol/L, respectively. N-isopropyl oxamate is a powerful selective inhibitor of plateau pika LDH-C4. In our exercise tolerance experiment, groups treated with inhibitors had significantly lower swimming times than the uninhibited control group. The inhibition rates of LDH, LD, and ATP were 37.12%, 66.27%, and 32.42%, respectively. Our results suggested that ldh-c is expressed in the skeletal muscle of plateau pika, and at least 32.42% of ATP in the skeletal muscle is catalyzed by LDH-C4 by anaerobic glycolysis. This suggests that pika has reduced dependence on oxygen and enhanced adaptation to hypoxic environment due to increased anaerobic glycolysis by LDH-C4 in skeletal muscle. LDH-C4 in plateau pika plays the crucial role in anaerobic glycolysis and generates ATP rapidly since this is the role of LDH-A4 in most species on plain land, which provide evidence that the native humans and animals in Qinghai-Tibet plateau can adapt to the hypoxia environment.
PMCID: PMC4555275  PMID: 26262630
testis-specific lactate dehydrogenase C (LDH-C4); hypoxia; Qinghai-Tibet Plateau; plateau pika (Ochotona curzoniae); skeletal muscle
11.  The Different Sensitive Behaviors of a Hydrogen-Bond Acidic Polymer-Coated SAW Sensor for Chemical Warfare Agents and Their Simulants 
Sensors (Basel, Switzerland)  2015;15(8):18302-18314.
A linear hydrogen-bond acidic (HBA) linear functionalized polymer (PLF), was deposited onto a bare surface acoustic wave (SAW) device to fabricate a chemical sensor. Real-time responses of the sensor to a series of compounds including sarin (GB), dimethyl methylphosphonate (DMMP), mustard gas (HD), chloroethyl ethyl sulphide (2-CEES), 1,5-dichloropentane (DCP) and some organic solvents were studied. The results show that the sensor is highly sensitive to GB and DMMP, and has low sensitivity to HD and DCP, as expected. However, the sensor possesses an unexpected high sensitivity toward 2-CEES. This good sensing performance can’t be solely or mainly attributed to the dipole-dipole interaction since the sensor is not sensitive to some high polarity solvents. We believe the lone pair electrons around the sulphur atom of 2-CEES provide an electron-rich site, which facilitates the formation of hydrogen bonding between PLF and 2-CEES. On the contrary, the electron cloud on the sulphur atom of the HD molecule is offset or depleted by its two neighbouring strong electron-withdrawing groups, hence, hydrogen bonding can hardly be formed.
PMCID: PMC4570322  PMID: 26225975
hydrogen-bond acidic polymer; chemical sensor; SAW
12.  Crinone Gel for Luteal Phase Support in Frozen-Thawed Embryo Transfer Cycles: A Prospective Randomized Clinical Trial in the Chinese Population 
PLoS ONE  2015;10(7):e0133027.
To compare Crinone vaginal progesterone gel with intramuscularly injected progesterone for luteal phase support in progesterone-supplemented frozen-thawed embryo transfer (FET) cycles, a randomized prospective study of patients qualified for FET was conducted between September 2010 and January 2013 at a hospital in Shanghai, China. From the day of transformation into secretory phase endometrium (day 0), Crinone vaginal gel (90 mg/d) was administered to patients in the Gel Group, while progesterone (40 mg/d) was injected intramuscularly in patients in the Inj Group (n = 750 per group). All patients received oral dydrogesterone (20 mg/d) and estradiol valerate (4–8 mg/d). Day 3 embryos with the highest pre-frozen scores were transferred to patients in the two groups and the clinical outcomes compared. This study comprised 1,500 cycles (750 in each group). Twenty-nine cycles in the Gel Group and 24 in the Inj Group were withdrawn. There were no significant differences between groups in age, endometrial thickness, endometrial preparation time or number of embryos transferred. No significant differences were observed between the Gel Group and Inj Group in the rates of live birth (32.6% vs. 31.7%, P = 0.71), clinical pregnancy (40.1% vs. 40.6%, P = 0.831), implantation (25.8% vs. 25.3%, P = 0.772), abortion (16.3% vs. 18.3%, P = 0.514) or ectopic pregnancy (2.8% vs. 4.4%, P = 0.288). Multivariate logistic regression analysis revealed that the odds ratios (95% confidence intervals) for the rates of live birth, clinical pregnancy, abortion and ectopic pregnancy (Gel Group relative to Inj Group) were 1.036 (0.829–1.295), 0.971 (0.785–1.200), 0.919 (0.595–1.420) and 0.649 (0.261–1.614), respectively. Our study revealed that using Crinone vaginal gel in FET cycles achieved similar pregnancy outcomes to intramuscular progesterone, indicating that vaginal gel is a viable alternative to intramuscular injection.
Trial Registration
Chinese Clinical Trial Registry ChiCTR-TRC-14004565
PMCID: PMC4519178  PMID: 26222435
13.  Overexpression of Class III β-tubulin, Sox2, and nuclear Survivin is predictive of taxane resistance in patients with stage III ovarian epithelial cancer 
BMC Cancer  2015;15:536.
Class III β-tubulin, Sox2, and Survivin play important roles in tumor survival and proliferation. However, the association of these three factors with clinicopathological characteristics, chemoresistance, and survival in patients with ovarian cancer remains controversial.
We investigated the predictive value and correlation among the expression levels of Class III β-tubulin, Sox2, and Survivin in 110 patients with stage III ovarian epithelial cancer, including 58 patients who received taxane-based chemotherapy and 52 patients who received non-taxane-based chemotherapy. Expression of these three factors was immunohistochemically examined in 110 ovarian tumor tissues obtained from patients before chemotherapy.
The positive expression rates for Class III β-tubulin, Sox2, and Survivin in ovarian tumor tissues were 59.09 %, 61.82 % and 52.73 %, respectively. The expression of nuclear Survivin and Class III β-tubulin was consistent with that of Sox2 (p = 0.005 and 0.020, respectively). Positive expression of Class III β-tubulin, Sox2, and nuclear Survivin was significantly associated with chemoresistance to taxane-based chemotherapy (p = 0.006, 0.007, and 0.009, respectively), but not to non-taxane-based chemotherapy. Additionally, overexpression of Class III β-tubulin, Sox2, and nuclear Survivin predicted poor progression-free survival in patients receiving taxane-based chemotherapy (p = 0.032, 0.005, and 0.004, respectively).
These findings suggest that overexpression of Class III β-tubulin, Sox2, and nuclear Survivin might be predictive of taxane resistance and poor progression-free survival in patients with stage III ovarian epithelial cancer. Expression of these three factors may show positive correlations in these patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1553-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4511538  PMID: 26198101
Ovarian cancer; Class III β-tubulin; Sox2; Survivin; Taxane; Resistance; Survival
14.  Effects of stem cell transplantation on cognitive decline in animal models of Alzheimer’s disease: A systematic review and meta-analysis 
Scientific Reports  2015;5:12134.
Alzheimer’s disease (AD), an irreversible progressive neurodegenerative disease, causes characteristic cognitive impairment, and no curative treatments are currently available. Stem cell transplantation offers a powerful tool for the treatment of AD. We conducted a systematic review and meta-analysis of data from controlled studies to study the impact of stem cell biology and experimental design on learning and memory function following stem cell transplantation in animal models of AD. A total of 58 eligible controlled studies were included by searching PubMed, EMBASE, and Web of Science up to April 13, 2015. Meta-analysis showed that stem cell transplantation could promote both learning and memory recovery. Stratified meta-analysis was used to explore the influence of the potential factors on the estimated effect size, and meta-regression analyses were undertaken to explore the sources of heterogeneity for learning and memory function. Publication bias was assessed using funnel plots and Egger’s test. The present review reinforces the evidence supporting stem cell transplantation in experimental AD. However, it highlights areas that require well-designed and well-reported animal studies.
PMCID: PMC4498325  PMID: 26159750
15.  Morphologic and Hemodynamic Analysis in the Patients with Multiple Intracranial Aneurysms: Ruptured versus Unruptured 
PLoS ONE  2015;10(7):e0132494.
Background and Purpose
The authors evaluated the impact of morphologic and hemodynamic factors on multiple intracranial aneurysms and aimed to identify which parameters can be reliable indexes as one aneurysm ruptured, and the others did not.
Between June 2011 and May 2014, 69 patients harboring multiple intracranial aneurysms (69 ruptured and 86 unruptured) were analyzed from 3D-digital subtraction angiography (DSA) images and computational fluid dynamics (CFD). Morphologic and hemodynamic parameters were evaluated for significance with respect to rupture. Receiver operating characteristic (ROC) analysis identified area under the curve (AUC) and optimal thresholds separating ruptured from unruptured intracranial aneurysms for each parameter. Significant parameters were examined by binary logistic regression analysis to identify independent discriminators.
Nine morphologic (size, neck width, surface area, volume, diameter of parent arteries, aspect ratio, size ratio, lateral/bifurcation type and regular/irregular type) and 6 hemodynamic (WSSmean, WSSmin, OSI, LSA, flow stability and flow complexity) parameters achieved statistical significance (p<0.05). Six morphologic (size, surface area, volume, aspect ratio, size ratio and regular/irregular type) and five hemodynamic (WSSmean, WSSmin, LSA, flow stability and flow complexity) parameters had high AUC values (AUC>0.7). By binary logistic regression analysis, large aspect ratio and low WSSmean were the independently significant rupture factors (AUC, 0.924; 95% CI, 0.883–0.965).
Large aspect ratio and low WSSmean were independently associated with the rupture status of multiple intracranial aneurysms.
PMCID: PMC4492509  PMID: 26147995
16.  Biological Characteristics of Human-Urine-Derived Stem Cells: Potential for Cell-Based Therapy in Neurology 
Tissue Engineering. Part A  2014;20(13-14):1794-1806.
Stem cells in human urine have gained attention in recent years; however, urine-derived stem cells (USCs) are far from being well elucidated. In this study, we compared the biological characteristics of USCs with adipose-derived stem cells (ASCs) and investigated whether USCs could serve as a potential cell source for neural tissue engineering. USCs were isolated from voided urine with a modified culture medium. Through a series of experiments, we examined the growth rate, surface antigens, and differentiation potential of USCs, and compared them with ASCs. USCs showed robust proliferation ability. After serial propagation, USCs retained normal karyotypes. Cell surface antigen expression of USCs was similar to ASCs. With lineage-specific induction factors, USCs could differentiate toward the osteogenic, chondrogenic, adipogenic, and neurogenic lineages. To assess the ability of USCs to survive, differentiate, and migrate, they were seeded onto hydrogel scaffold and transplanted into rat brain. The results showed that USCs were able to survive in the lesion site, migrate to other areas, and express proteins that were associated with neural phenotypes. The results of our study demonstrate that USCs possess similar biological characteristics with ASCs and have multilineage differentiation potential. Moreover USCs can differentiate to neuron-like cells in rat brain. The present study shows that USCs are a promising cell source for tissue engineering and regenerative medicine.
PMCID: PMC4086681  PMID: 24387670
17.  Analysis of lung tumor initiation and progression in transgenic mice for Cre-inducible overexpression of Cul4A gene 
Thoracic Cancer  2015;6(4):480-487.
Lung cancer is the leading cause of morbidity and death worldwide. Although the available lung cancer animal models have been informative and further propel our understanding of human lung cancer, they still do not fully recapitulate the complexities of human lung cancer. The pathogenesis of lung cancer remains highly elusive because of its aggressive biologic nature and considerable heterogeneity, compared to other cancers. The association of Cul4A amplification with aggressive tumor growth and poor prognosis has been suggested. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied.
Viral delivery approaches have been used extensively to model cancer in mouse models. In our experiments, we used Cre-recombinase induced overexpression of the Cul4A gene in transgenic mice to study the role of Cul4A on lung tumor initiation and progression and have developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A.
Here we show that the use of a recombinant adenovirus expressing Cre-recombinase (“AdenoCre”) to induce Cul4A overexpression in the lungs of mice allows controls of the timing and multiplicity of tumor initiation. Following our mouse models, we are able to study the potential role of Cul4A in the development and progression in pulmonary adenocarcinoma as well.
Our findings indicate that Cul4A is oncogenic in vivo, and this mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.
PMCID: PMC4511328  PMID: 26273405
AdenoCre; Cre; Cul4A; lung cancer; mouse models
18.  Effects of continuous fascia iliaca compartment blocks for postoperative analgesia in patients with hip fracture 
Orthopedic surgery patients often experience severe postoperative pain, and effective analgesia is essential. In this study, the authors compared continuous fascia iliaca compartment block with patient-controlled intravenous analgesia using fentanyl postoperatively in patients with hip fractures. Changes in pain scores as well as delirium and postoperative nausea and vomiting were evaluated.
Effective analgesia is essential for the postoperative care of orthopedic patients.
To evaluate the efficacy of continuous fascia iliaca compartment block (FIB) as postoperative analgesia after hip fracture surgery, and to compare FIB with patient-controlled intravenous analgesia (PCIA) using fentanyl for 48 h postoperatively.
Patients with hip fractures who were scheduled for open reduction and internal fixation surgery using the antirotation proximal femoral nail technique were randomly assigned to the FIB or PCIA groups. Postoperative pain was assessed using a numeral rating scale at 2 h, 4 h, 6 h, 12 h, 24 h and 48 h after analgesia was started. Delirium, postoperative nausea and vomiting (PONV), and pruritus were also monitored.
Patients in the FIB group reported less pain than those in the PCIA group (P=0.039, d=−0.3). The change in pain scores over time was similar between the two groups. There were six patients with PONV and five patients with pruritus in the PCIA group, while no PONV or pruritus was noticed in the FIB group (P=0.013). Ten (19.6%) patients in the FIB group and three (5.7%) patients in the PCIA group developed postoperative delirium (P=0.032, d=0.77).
Continuous FIB is a safe and effective technique for postoperative analgesia after hip fracture surgery, making it an option for pain management in elderly patients with hip fractures.
PMCID: PMC4532207  PMID: 26125194
Hip fracture; Iliaca compartment block; Patient-controlled intravenous analgesia
19.  Clinical and Angioarchitectural Risk Factors Associated with Intracranial Hemorrhage in Dural Arteriovenous Fistulas: A Single-Center Retrospective Study 
PLoS ONE  2015;10(6):e0131235.
To investigate which clinical and angioarchitectural features were associated with the occurrence of intracranial hemorrhage in patients with intracranial dural arteriovenous fistulas (DAVFs).
Materials and Methods
We retrospectively reviewed the clinical and angioarchitectural features of 236 consecutive patients diagnosed with DAVF in our department from April 2009 to November 2013. Two groups of patients, with or without intracranial hemorrhage as clinical presentation at the initial diagnosis, were analysed to identify the differences in clinical and angioarchitectural features in univariate analysis. A multivariate logistic regression model was also developed to assess the independent contribution of the potential risk factors. Associations were considered significant for p<0.05.
Fifty-six patients (23.7%) presented with intracranial hemorrhage at the initial diagnosis of DAVF. In univariate analysis, male patients (p = 0.002), patients with medical history of smoking (p<0.001) or alcohol consumption (p = 0.022), and DAVFs located at the tentorium (p = 0.010), frontalbasal (p = 0.007), foramen magnum (p = 0.043) or cerebral convexity (p<0.001) were associated with an increased risk of intracranial hemorrhage. A higher risk of hemorrhagic occurrence was also observed in DAVFs with superficial cortical venous drainage (p<0.001), deep venous drainage (p = 0.003), occluded venous sinus (p<0.032), or higher Borden type (p<0.001). A multivariate logistic regression model showed that intracranial hemorrhage in patients with DAVFs was correlated with higher Borden classification (OR 5.880; 95% CI, 3.370–10.257; p<0.001).
Venous drainage pattern was the only independent risk factor of intracranial hemorrhage in our patients with intracranial DAVF. The other potential risk factors may be confounding factors in predicting intracranial hemorrhage.
PMCID: PMC4488263  PMID: 26120845
20.  Pattern Visualization of Human Connectome Data 
The human brain is a complex network with countless connected neurons, and can be described as a “connectome”. Existing studies on analyzing human connectome data are primarily focused on characterizing the brain networks with a small number of easily computable measures that may be inadequate for revealing complex relationship between brain function and its structural substrate. To facilitate large-scale connectomic analysis, in this paper, we propose a powerful and flexible volume rendering scheme to effectively visualize and interactively explore thousands of network measures in the context of brain anatomy, and to aid pattern discovery. We demonstrate the effectiveness of the proposed scheme by applying it to a real connectome data set.
PMCID: PMC4469287  PMID: 26090521
21.  Population genetic structure of Oryza sativa in East and Southeast Asia and the discovery of elite alleles for grain traits 
Scientific Reports  2015;5:11254.
We investigated the nuclear simple sequence repeat (SSR) genotypes of 532 rice (Oryza sativa L.) accessions collected from East and Southeast Asia and detected abundant genetic diversity within the population. We identified 6 subpopulations and found a tendency towards directional evolution in O. sativa from low to high latitudes, with levels of linkage disequilibrium (LD) in the 6 subpopulations ranging from 10 to 30 cM. We then investigated the phenotypic data for grain length, grain width, grain thickness and 1,000-grain weight over 4 years. Using a genome-wide association analysis, we identified 17 marker-trait associations involving 14 SSR markers on 12 chromosome arms, and 8 of the 17 associations were novel. The elite alleles were mined based on the phenotypic effects of the detected quantitative trait loci (QTLs). These elite alleles could be used to improve target traits through optimal cross designs, with the expected results obtained by pyramiding or substituting the elite alleles per QTL (independent of possible epistatic effects). Together, these results provide an in-depth understanding of the genetic diversity pattern among rice-grain traits across a broad geographic scale, which has potential use in future research work, including studies related to germplasm conservation and molecular breeding by design.
PMCID: PMC4462027  PMID: 26059752
22.  Image-guided percutaneous renal cryoablation for stage 1 renal cell carcinoma with high surgical risk 
This study was undertaken to evaluate the feasibility, safety, and therapeutic effects of percutaneous renal cryoablation under local anesthesia with conscious sedation for patients who have unresectable stage 1 (T1NoMo) renal cell carcinoma (RCC) in high surgical risk.
Eighteen patients who were not candidates for surgery underwent primary cryosurgery guided by gray-scale ultrasound. Contrast-enhanced ultrasonography (CEUS) and contrast-enhanced computed tomography (CT) were performed to evaluate treatment at completion.
The mean follow-up period was 26.8 months (range, 12–56 months). All tumors were biopsied before cryosurgery. Seventeen tumors remained free of enhancement during follow-up period. No major complications associated with cryoablation procedures were found though two instances of subcapsular hematomas, one of retroperitoneal errhysis and one of nausea, were seen after cryoablation. One patient had a local recurrence of tumor and received additional cryoablation. Local tumor control rate was 100 % of T1NoMo tumors including the recurrence case who underwent additional cryoablation.
Percutaneous cryoablation can be recommended as a feasible, safe, and promising therapy for the treatment of renal tumor, especially those unresectable stage 1 RCC, with a low risk of complications.
PMCID: PMC4468960  PMID: 26059547
Cryoablation; Renal cell carcinoma; Local anesthesia
23.  Effect of dietary supplementation of Bacillus subtilis B10 on biochemical and molecular parameters in the serum and liver of high-fat diet-induced obese mice* #  
While a high-fat diet (HFD) is assumed to be related to fat-mediated oxidative stress decreasing antioxidant enzyme activity, probiotics are believed to have positive effects on the regulation of HFD-induced obesity as well as lipid metabolism, energy homeostasis, and anti-oxidation. Because Bacillus subtilis B10 has beneficial effects on the abnormal lipid metabolism and the oxidative stress in HFD-induced obese mice, ICR mice were randomly assigned into an HFD group and the HFD was supplemented with 0.1% (w/w) Bacillus subtilis B10 (HFD+B10 group). Thereafter, 30-d treatments were run, and then hepatic lipid level and antioxidant status were measured. The expression of genes related to lipid metabolism and oxidative stress in the liver was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR). We found that HFD-induced obese mice treated with B10 showed a decrease in weight gain, serum glucose activity as well as hepatic triglyceride (TG), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) activities. In addition, the gene expressions of antioxidant genes, glutathione reductase (GR), xanthine oxidase (XO), heat-shock protein 90 (Hsp90), and lipid synthesis gene 3β-hydroxysteroid-∆24 reductase (DHCR24) in the HFD+B10 group were down-regulated, suggesting alleviation of oxidative stress, while the lipolysis gene 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), energy metabolism gene peroxisome proliferator-activated receptor α (PPARα) and the gene encoding tumor-suppressor protein p53 were up-regulated. The regulatory and positive effect of dietary supplementation of probiotic B10 suggests that it has a beneficial effect on the homeostasis of the lipid metabolism and on alleviating oxidative stress in HFD-induced obese mice.
PMCID: PMC4471600  PMID: 26055910
Bacillus subtilis; High-fat diet; Oxidative stress; Lipid metabolism
24.  Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia 
Angiogenic biomarkers, including soluble fms-like tyrosine kinase 1 (sFlt1), are thought to be predictors of preeclampsia onset; however, improvement is needed before a widespread diagnostic test can be utilized. Here we describe the development and use of diagnostic monoclonal antibodies specific to the two main splice variants of sFlt1, sFlt1-1 and sFlt1-14. These antibodies were selected for their sensitivity and specificity to their respective sFlt1 isoform in a capture ELISA format. Data from this pilot study suggest that sFlt1-1 may be more predictive of preeclampsia than total sFlt1. It may be possible to improve current diagnostic platforms if more specific antibodies are utilized.
PMCID: PMC4490453  PMID: 26042465
preeclampsia; soluble fms-like tyrosine kinase 1 (sFlt1); splice variants; isoforms; monoclonal antibody (mAb); diagnostic
25.  Biological conduits combining bone marrow mesenchymal stem cells and extracellular matrix to treat long-segment sciatic nerve defects 
Neural Regeneration Research  2015;10(6):965-971.
The transplantation of polylactic glycolic acid conduits combining bone marrow mesenchymal stem cells and extracellular matrix gel for the repair of sciatic nerve injury is effective in some respects, but few data comparing the biomechanical factors related to the sciatic nerve are available. In the present study, rabbit models of 10-mm sciatic nerve defects were prepared. The rabbit models were repaired with autologous nerve, a polylactic glycolic acid conduit + bone marrow mesenchymal stem cells, or a polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel. After 24 weeks, mechanical testing was performed to determine the stress relaxation and creep parameters. Following sciatic nerve injury, the magnitudes of the stress decrease and strain increase at 7,200 seconds were largest in the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel group, followed by the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells group, and then the autologous nerve group. Hematoxylin-eosin staining demonstrated that compared with the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells group and the autologous nerve group, a more complete sciatic nerve regeneration was found, including good myelination, regularly arranged nerve fibers, and a completely degraded and resorbed conduit, in the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel group. These results indicate that bridging 10-mm sciatic nerve defects with a polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel construct increases the stress relaxation under a constant strain, reducing anastomotic tension. Large elongations under a constant physiological load can limit the anastomotic opening and shift, which is beneficial for the regeneration and functional reconstruction of sciatic nerve. Better regeneration was found with the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells + extracellular matrix gel grafts than with the polylactic glycolic acid conduit + bone marrow mesenchymal stem cells grafts and the autologous nerve grafts.
PMCID: PMC4498360  PMID: 26199615
nerve regeneration; peripheral nerve injury; rabbits; sciatic nerve injury; autologous nerve repair; polylactic glycolic acid conduit; extracellular matrix gel; grafting; stress relaxation; creep; viscoelasticity; histomorphology; electrophysiology; neural regeneration

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