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51.  Active contractility at E-cadherin junctions and its implications for cell extrusion in cancer 
Cell Cycle  2015;14(3):315-322.
Cellular contractility regulates tissue cohesion and morphogenesis. In epithelia, E-cadherin adhesion couples the contractile cortices of neighboring cells together to produce tension at junctions that can be transmitted across the epithelium in a planar fashion. We have recently demonstrated that contractility is also patterned in the apical-lateral axis within epithelial junctions. Our findings highlight the role that cytoskeletal regulation plays in controlling the levels of intra-junctional tension. Of note, dysregulation of this apicolateral pattern of tension can drive oncogenic cell extrusion. In this article, we provide a detailed description of the actomyosin cytoskeleton organization during oncogenic extrusion and discuss the implications of cell extrusion in cancer.
PMCID: PMC4353245  PMID: 25590779
actin; cell extrusion; E-Cadherin; myosin; oncogene
52.  Age‐related changes in murine myometrial transcript profile are mediated by exposure to the female sex hormones 
Aging Cell  2015;15(1):177-180.
In humans, the risk of operative first delivery increases linearly with maternal age. We previously hypothesized that prolonged, cyclical, prepregnancy exposure to estrogen and progesterone contributes to uterine aging. Here, we test this hypothesis. Myometrium was obtained from four groups of virgin mice: (i) 10‐ to 12‐week‐ and 28‐ to 30‐week‐old mice; (ii) 10‐ to 12‐week‐ and 38‐ to 40‐week‐old mice; (iii) 38‐week‐old mice that had an ovariectomy or sham operation early in life; (iv) 38‐week‐old mice that had been treated with progesterone or vehicle containing implants from 8 to 36 weeks. Transcript profiling was carried out using Affymetrix Gene ST 1.1 arrays, and data were normalized. We identified 60 differentially regulated transcripts associated with advancing age (group 1). We validated these changes in group 2 (P for overlap = 5.8 × 10−46). Early ovariectomy prevented the age‐related changes in myometrial transcript profile. Similarly, progesterone‐mediated long‐term ovarian suppression prevented the age‐related changes in myometrial transcript profile. Interferon regulatory factor 7 (Irf7) mRNA was regulated by age and hormonal exposure, and was identified as a predicted regulator of the other differentially expressed transcripts by both promoter sequence and canonical pathway activation analysis (P = 8.47 × 10−5 and P < 10−10, respectively). Immunohistochemistry demonstrated IRF7 in both mouse and human myometrium. We conclude the following: (i) Myometrial aging in mice is associated with reproducible changes in transcript profile; (ii) these changes can be prevented by interventions which inhibit cyclical changes in the female sex hormones; and (iii) IRF7 may be an important regulator of myometrial function and aging.
PMCID: PMC4717263  PMID: 26490259
steroid; myometrium; aging; labor; IRF7
53.  Neonatal Brain Tissue Classification with Morphological Adaptation and Unified Segmentation 
Measuring the distribution of brain tissue types (tissue classification) in neonates is necessary for studying typical and atypical brain development, such as that associated with preterm birth, and may provide biomarkers for neurodevelopmental outcomes. Compared with magnetic resonance images of adults, neonatal images present specific challenges that require the development of specialized, population-specific methods. This paper introduces MANTiS (Morphologically Adaptive Neonatal Tissue Segmentation), which extends the unified segmentation approach to tissue classification implemented in Statistical Parametric Mapping (SPM) software to neonates. MANTiS utilizes a combination of unified segmentation, template adaptation via morphological segmentation tools and topological filtering, to segment the neonatal brain into eight tissue classes: cortical gray matter, white matter, deep nuclear gray matter, cerebellum, brainstem, cerebrospinal fluid (CSF), hippocampus and amygdala. We evaluated the performance of MANTiS using two independent datasets. The first dataset, provided by the NeoBrainS12 challenge, consisted of coronal T2-weighted images of preterm infants (born ≤30 weeks' gestation) acquired at 30 weeks' corrected gestational age (n = 5), coronal T2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5) and axial T2-weighted images of preterm infants acquired at 40 weeks' corrected gestational age (n = 5). The second dataset, provided by the Washington University NeuroDevelopmental Research (WUNDeR) group, consisted of T2-weighted images of preterm infants (born <30 weeks' gestation) acquired shortly after birth (n = 12), preterm infants acquired at term-equivalent age (n = 12), and healthy term-born infants (born ≥38 weeks' gestation) acquired within the first 9 days of life (n = 12). For the NeoBrainS12 dataset, mean Dice scores comparing MANTiS with manual segmentations were all above 0.7, except for the cortical gray matter for coronal images acquired at 30 weeks. This demonstrates that MANTiS' performance is competitive with existing techniques. For the WUNDeR dataset, mean Dice scores comparing MANTiS with manually edited segmentations demonstrated good agreement, where all scores were above 0.75, except for the hippocampus and amygdala. The results show that MANTiS is able to segment neonatal brain tissues well, even in images that have brain abnormalities common in preterm infants. MANTiS is available for download as an SPM toolbox from
PMCID: PMC4809890  PMID: 27065840
magnetic resonance imaging; tissue classification; statistical parametric mapping; neonate; preterm birth
54.  Logistic analysis of epidemiologic studies with augmentation sampling involving re-stratification and population expansion 
Biostatistics (Oxford, England)  2014;16(1):169-178.
Epidemiologic cross-sectional, case-cohort, or case–control studies often select augmentation samples to supplement an existing (baseline) sample, primarily for the two reasons: (1) to increase the sample sizes from certain subdomains of interest that were not originally considered in the design of the baseline study and (2) to obtain samples from an extension of the target population. To address these two objectives, two-stage stratified sample designs are considered, where the stratification based on the expanded population at the second stage is not nested in the first stage strata. The sample weighting and Taylor linearization variance estimation for the two-stage stratified sample designs, involving re-stratification and population expansion, are provided for estimating population totals and logistic regression coefficients. Results from limited simulation studies and a logistic regression analysis of a study of human papillomavirus serology are provided.
PMCID: PMC4263221  PMID: 24907707
Pseudo-likelihood function; Sample weighting; Taylor linearization variance estimation; Two-stage stratified sampling
55.  Naproxen Induces Type X Collagen Expression in Human Bone-Marrow-Derived Mesenchymal Stem Cells Through the Upregulation of 5-Lipoxygenase 
Tissue Engineering. Part A  2014;21(1-2):234-245.
Several studies have shown that type X collagen (COL X), a marker of late-stage chondrocyte hypertrophy, is expressed in mesenchymal stem cells (MSCs) from osteoarthritis (OA) patients. We recently found that Naproxen, but not other nonsteroidal anti-inflammatory drugs (NSAIDs) (Ibuprofen, Celebrex, Diclofenac), can induce type X collagen gene (COL10A1) expression in bone-marrow-derived MSCs from healthy and OA donors. In this study we determined the effect of Naproxen on COL X protein expression and investigated the intracellular signaling pathways that mediate Naproxen-induced COL10A1 expression in normal and OA hMSCs. MSCs of OA patients were isolated from aspirates from the intramedullary canal of donors (50–80 years of age) undergoing hip replacement surgery for OA and were treated with or without Naproxen (100 μg/mL). Protein expression and phosphorylation were determined by immunoblotting using specific antibodies (COL X, p38 mitogen-activated protein kinase [p38], phosphorylated-p38, c-Jun N-terminal kinase [JNK], phosphorylated-JNK, extracellular signal-regulated kinase [ERK], and phosphorylated-ERK). Real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to determine the expression of COL10A1 and Runt-related transcription factor 2 gene (Runx2). Our results show that Naproxen significantly stimulated COL X protein expression after 72 h of exposure both in normal and OA hMSCs. The basal phosphorylation of mitogen-activated protein kinases (MAPKs) (ERK, JNK, and p38) in OA hMSCs was significantly higher than in normal. Naproxen significantly increased the MAPK phosphorylation in normal and OA hMSCs. NSAID cellular effects include cyclooxygenase, 5-lipoxygenase, and p38 MAPK signaling pathways. To investigate the involvement of these pathways in the Naproxen-induced COL10A1 expression, we incubated normal and OA hMSCs with Naproxen with and without inhibitors of ERK (U0126), JNK (BI-78D3), p38 (SB203580), and 5-lipoxygenase (MK-886). Our results showed that increased basal COL10A1 expression in OA hMSCs was significantly suppressed in the presence of JNK and p38 inhibitors, whereas Naproxen-induced COL10A1 expression was suppressed by 5-lipoxygenase inhibitor. This study shows that Naproxen induces COL X both at transcriptional and translational levels in normal and OA hMSCs. Elevated basal COL10A1 expression in OA hMSCs is probably through the activation of MAPK pathway and Naproxen-induced COL10A1 expression is through the increased 5-lipoxygenase signaling.
PMCID: PMC4292866  PMID: 25091567
56.  Iron Deposition Is Positively Related to Cognitive Impairment in Patients with Chronic Mild Traumatic Brain Injury: Assessment with Susceptibility Weighted Imaging 
BioMed Research International  2015;2015:470676.
Background. This study aimed to evaluate the usability of SWI in assessment of brain iron to detect cognitive dysfunction in patients with chronic mild traumatic brain injury (mTBI). Methods. 39 patients with mTBI and 37 normal controls were given the Mini-Mental State Examination (MMSE) and underwent SWI scanning at least 6 months after injury. Angle radian values were calculated with phase images. The angle radian values were compared between groups using analysis of covariance, and their association with MMSE scores was analyzed using Spearman correlations. Results. Significantly higher angle radian values (p < 0.05) were found in the head of the caudate nucleus, the lenticular nucleus, the hippocampus, the thalamus, the right substantia nigra, the red nucleus, and the splenium of the corpus callosum (SCC) in the mTBI group, compared to the control group. MMSE scores were negatively correlated with angle radian values in the right substantia nigra (r = −0.685, p < 0.001). Conclusions. Patients with chronic mTBI might have abnormally high accumulations of iron, and their MMSE scores are negatively associated with angle radian values in the right substantia nigra, suggesting a role of SWI in the assessment of cognitive impairments of these patients.
PMCID: PMC4698517  PMID: 26798636
57.  Mammal survival at the Cretaceous–Palaeogene boundary: metabolic homeostasis in prolonged tropical hibernation in tenrecs 
Free-ranging common tenrecs, Tenrec ecaudatus, from sub-tropical Madagascar, displayed long-term (nine months) hibernation which lacked any evidence of periodic interbout arousals (IBAs). IBAs are the dominant feature of the mammalian hibernation phenotype and are thought to periodically restore long-term ischaemia damage and/or metabolic imbalances (depletions and accumulations). However, the lack of IBAs in tenrecs suggests no such pathology at hibernation Tbs > 22°C. The long period of tropical hibernation that we report might explain how the ancestral placental mammal survived the global devastation that drove the dinosaurs and many other vertebrates to extinction at the Cretaceous–Palaeogene boundary following a meteorite impact. The genetics and biochemistry of IBAs are of immense interest to biomedical researchers and space exploration scientists, in the latter case, those envisioning a hibernating state in astronauts for deep space travel. Unravelling the physiological thresholds and temperature dependence of IBAs will provide new impetus to these research quests.
PMCID: PMC4213634  PMID: 25339721
mammals; hibernation; Cretaceous–Palaeogene boundary; Madagascar; Tenrec ecaudatus
58.  Thalamic inflammation after brain trauma is associated with thalamo-cortical white matter damage 
Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo.
Using [11C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17 years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage.
These findings support a link between axonal damage and persistent inflammation after brain injury.
PMCID: PMC4666189  PMID: 26627199
Microglia; Translocator protein; Positron emission tomography; Traumatic brain injury; Traumatic axonal injury; PK11195; Thalamus
59.  Determinants of acceptance of end-of-life interventions: a comparison between withdrawing life-prolonging treatment and euthanasia in Austria 
BMC Medical Ethics  2015;16:81.
End-of-life decisions remain a hotly debated issue in many European countries and the acceptance in the general population can act as an important anchor point in these discussions. Previous studies on determinants of the acceptance of end-of-life interventions in the general population have not systematically assessed whether determinants differ between withdrawal of life-prolonging treatment (WLPT) and euthanasia (EUT).
A large, representative survey of the Austrian adult population conducted in 2014 (n = 1,971) included items on WLPT and EUT. We constructed the following categorical outcome: (1) rejection of both WLPT and EUT, (2) approval of WLPT but rejection of EUT, and (3) approval of both WLPT and EUT. The influence of socio-demographics, personal experiences, and religious and socio-cultural orientations on the three levels of approval were assessed via multinomial logistic regression analysis.
Higher education and stronger socio-cultural liberal orientations increased the likelihood of approving both WLPT and EUT; personal experience with end-of-life care increased only the likelihood of approval of WLPT; and religiosity decreased approval of EUT only.
This study found evidence for both shared (education, liberalism) and different (religiosity, care experiences) determinants for the acceptance of WLPT and EUT.
PMCID: PMC4666202  PMID: 26625908
Withdrawal of life-prolonging treatment; Euthanasia; Acceptance; Determinants
60.  A randomized pilot study on the effect of niacin on pulmonary arterial pressure 
Trials  2015;16:530.
Niacin induces the release of vasodilating prostaglandins, for which receptors are present within the pulmonary arterial circulation. We hypothesized that immediate-release niacin would reduce right ventricular systolic pressure in patients with pulmonary hypertension in a randomized, double-blinded, single-dose provocation study.
We recruited inpatient subjects with a Doppler echocardiogram showing a peak tricuspid regurgitation (TR) jet velocity of 2.7 m/s or greater, and who were free of known pulmonary vascular disease. Subjects were randomized in a 1:2:2 ratio to receive a single dose of either placebo, niacin 100 mg or niacin 500 mg, respectively. TR jet velocities were measured immediately before, and 1 hour post dose, corresponding to peak niacin absorption and prostaglandin release. The primary endpoint was the change in mean TR jet velocity measured over ten successive cardiac cycles.
The baseline mean estimated right ventricular systolic pressure (RVSP) for all 49 subjects (25 male) was 51.9 ± 12.1 mm Hg. The primary endpoint of mean change in TR jet velocity was 0.016 ± 0.065 m/s in the placebo group, compared to −0.017 ± 0.065 m/s with niacin 100 mg, and −0.063 ± 0.038 m/s with niacin 500 mg (P = 0.63). The change in maximum estimated RVSP across the three drug groups was 0.2 ± 1.6 mm Hg, −1.3 ± 1.8 mm Hg and −2.2 ± 1.2 mm Hg (P = 0.62). In exploratory pairwise analysis in the high-dose niacin group (500 mg), the reduction in mean RVSP was from 50.9 ± 9.4 mm Hg to 48.7 ± 10.0 mm Hg (P = 0.09).
A single dose of immediate-release niacin (100 mg or 500 mg) had no significant effect on RVSP 1 hour post administration. A nonsignificant dose-dependent trend for a modest reduction in RVSP, most notable in the 500 mg group, was noted.
(ISRCTN number 12353191, registered April 23, 2015).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-1013-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4654874  PMID: 26590128
61.  Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative 
The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.
The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional – usually randomised – clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.
The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.
Trials can be designed using a wide array of possibilities. There is no ‘one size fits all’ solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.
PMCID: PMC4639696  PMID: 25542058
Rare cancers; Clinical trials; Randomised controlled; trials; Methodology; Frequentist; Bayesian; Multi-arm
62.  Surgical Therapy of Cervical Spine Fracture in Patients With Ankylosing Spondylitis 
Medicine  2015;94(44):e1663.
The present study aimed to explore surgical treatments and assess the effects based on the features of cervical spine fracture in patients with ankylosing spondylitis (AS) and to summarize the experiences in perioperative management. Retrospective analysis was performed in 25 AS patients with cervical spine fracture treated in our hospital from January 2011 to December 2013. The patients were divided according to fracture segments, including 4 cases at C4 to C5, 8 cases at C5 to C6, and 13 cases at C6 to C7. Among them, 12 belonged to I type, 5 to II type, and 8 to III type based on the improved classification method for AS cervical spine fracture. The Subaxial Cervical Spine Injury Classification score for these patients was 7.2 ± 1.3, and the assessment of their neurological function states showed 6 patients (24%) were in American Spinal Injury Association (ASIA) A grade, 1 (4%) in ASIA B grade, 3 (12%) in ASIA C grade, 12 (48%) in ASIA D grade, and 3 (12%) in ASIA E grade. Surgical methods contained simple anterior approach alone, posterior approach alone, and combined posterior–anterior or anterior–posterior approach. The average duration of patients’ hospital stay was 38.6 ± 37.6, and the first surgical methods were as follows: anterior approach alone on 6 cases, posterior surgery alone on 9 cases, and combined posterior–anterior or anterior–posterior approach on 10 patients. The median segments of fixation and fusion were 4.1 ± 1.4 sections. Thirteen patients developed complications. During 2 to 36 months of postoperative follow-up, 1 patient died of respiratory failure caused by pulmonary infections 2 months after leaving hospital. At the end of the follow-up, bone graft fusion was achieved in the rest of patients, and obvious looseness or migration of internal fixation was not observed. In addition, the preoperative neurological injury in 12 patients (54.5%) was also alleviated in different levels. AS cervical spine fracture, an unstable fracture, should be treated with operation, and satisfactory effects will be achieved after the individualized surgical treatment according to the improved classification method for AS cervical spine fracture.
PMCID: PMC4915866  PMID: 26554765
63.  Cationic surface modification of gold nanoparticles for enhanced cellular uptake and X-ray radiation therapy 
A challenge of X-ray radiation therapy is that high dose X-ray can damage normal cells and cause side effects. This paper describes a new nanoparticle-based method to reduce X-ray dose in radiation therapy by internalization of gold nanoparticles that are modified with cationic molecules into cancer cells. A cationic thiol molecule is synthesized and used to modify gold nanoparticles in a one-step reaction. The modified nanoparticles can penetrate cell membranes at high yield. By bring radio-sensitizing gold nanoparticles closer to nuclei where DNA is stored, the total X-ray dose needed to kill cancer cells has been reduced. The simulation of X-ray-gold nanoparticle interaction also indicates that Auger electrons contribute more than photoelectrons.
Graphical abstract
Gold nanoparticles with cationic surface modification can enhance X-ray radiation therapy by enhancing cellular uptake.
PMCID: PMC4620571  PMID: 26512323
64.  Convenient methods for ingestion of molecular hydrogen: drinking, injection, and inhalation 
Medical Gas Research  2015;5:13.
Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.
PMCID: PMC4620630  PMID: 26504515
Hydrogen water; Hydrogen-rich saline; Hydrogen gas
65.  Markers of Bone Metabolism in Patients With Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma 
Medicine  2015;94(42):e1754.
There are no studies comparing some of the most important markers, such as vitamin D, parathormone, osteocalcin, bone alkaline phosphatase, and calcium, in patients with chronic benign and malignant pancreatic diseases. Our objective was to comparatively evaluate serum markers of bone metabolism in patients with chronic pancreatitis and in those with ductal pancreatic adenocarcinoma. Sixty-three consecutive subjects were studied: 30 patients with a firm diagnosis of chronic pancreatitis and 33 having histologically confirmed pancreatic adenocarcinoma. Serum 25-hydroxyvitamin D, bone alkaline phosphatase, osteocalcin, parathormone, and calcium were determined using commercially available kits. Taking into consideration the clinical variables of all 63 patients studied, 25-hydroxyvitamin D was inversely correlated with only the body mass index (P = 0.007), whereas it was not correlated with age (P = 0.583) or fecal elastase-1 concentrations (P = 0.556). Regarding the other substances studied, parathormone was positively correlated with only the age of the patients (P = 0.015). Of the 5 substances studied, only bone alkaline phosphates were significantly different (P < 0.001) between patients with chronic pancreatitis and those with pancreatic ductal adenocarcinoma. Within the 2 groups of patients, the 23 patients with chronic pancreatitis without diabetes mellitus had serum concentrations of 25-hydroxyvitamin D significantly lower (P = 0.045) than those with chronic pancreatitis having diabetes mellitus, whereas smokers with pancreatic ductal adenocarcinoma had serum concentrations of calcium significantly higher (P < 0.001) as compared to nonsmokers. Altered bone metabolism seems to be associated with chronic diseases of the pancreas; however, the mechanism should be better elucidated.
PMCID: PMC4620801  PMID: 26496293
66.  Inflammatory Myofibroblastic Tumor of Genitourinary Tract Beyond Collecting System 
Medicine  2015;94(42):e1706.
Inflammatory myofibroblastic tumor (IMT) rarely arises in genitourinary tract especially beyond collecting system, which determines the unspecific clinic symptoms and sometimes can mimic malignancy. Therefore, IMT's diagnosis may usually be a pitfall. This case report characterizes a 35-year-old woman with a history of lower quadrant lasting pain followed by fever. Furthermore, radiologic examinations revealed that there were 2 lesions located in left adrenal area and left renalis. Owing to the anatomic complexity, the surgical resection was not complete. The pathologic diagnosis of the lesions was IMT. Adjuvant nonsteroids anti-inflammatory drugs were administrated after the operation. The symptoms were controlled finally and no further growing lesion was observed during a 1-year follow-up.
Inflammatory myofibroblastic tumor is rare in genitourinary tract beyond the collecting system. Diagnosis should be based on histopathology. Presently, the authors report this rare case with the aim to share the experience regarding differential diagnosis and therapy.
PMCID: PMC4620822  PMID: 26496281
67.  Vancomycin-induced thrombocytopaenia in a patient with severe pancreatitis 
BMJ Case Reports  2013;2013:bcr2013200830.
Vancomycin-induced thrombocytopenia is a rare side effect of a commonly used drug that may cause life-threatening disease. A 51-year-old man was treated for an episode of acute severe alcohol-induced pancreatitis complicated by development of a peripancreatic fluid collection. He developed fever of unknown origin and was treated with intravenous vancomycin and piperacillin with tazobactam. On day 6 of vancomycin therapy his platelet count dropped to 46×109/L (237×109/L on day 1 of treatment) and by day 8 of therapy platelets had fallen to a nadir of 9×109/L. The patient at this stage displayed a florid purpuric rash and haematoma formation on attempted intravenous cannulation. A clinical diagnosis of vancomycin-induced thrombocytopaenia was made and the drug withdrawn. After 3 days a significant improvement in the platelet count was noted, rising to 56 × 109/L. Immunofluorescence testing (PIFT) ruled out teicoplanin and heparin as causes of drug-induced thrombocytopenia.
PMCID: PMC3822161  PMID: 24132444
68.  Gene expression profiling of the human natural killer cell response to Fc receptor activation: unique enhancement in the presence of interleukin-12 
BMC Medical Genomics  2015;8:66.
Traditionally, the CD56dimCD16+ subset of Natural Killer (NK) cells has been thought to mediate cellular cytotoxicity with modest cytokine secretion capacity. However, studies have suggested that this subset may exert a more diverse array of immunological functions. There exists a lack of well-developed functional models to describe the behavior of activated NK cells, and the interactions between signaling pathways that facilitate effector functions are not well understood. In the present study, a combination of genome-wide microarray analyses and systems-level bioinformatics approaches were utilized to elucidate the transcriptional landscape of NK cells activated via interactions with antibody-coated targets in the presence of interleukin-12 (IL-12).
We conducted differential gene expression analysis of CD56dimCD16+ NK cells following FcR stimulation in the presence or absence of IL-12. Next, we functionally characterized gene sets according to patterns of gene expression and validated representative genes using RT-PCR. IPA was utilized for biological pathway analysis, and an enriched network of interacting genes was generated using GeneMANIA. Furthermore, PAJEK and the HITS algorithm were employed to identify important genes in the network according to betweeness centrality, hub, and authority node metrics.
Analyses revealed that CD56dimCD16+ NK cells co-stimulated via the Fc receptor (FcR) and IL-12R led to the expression of a unique set of genes, including genes encoding cytotoxicity receptors, apoptotic proteins, intracellular signaling molecules, and cytokines that may mediate enhanced cytotoxicity and interactions with other immune cells within inflammatory tissues. Network analyses identified a novel set of connected key players, BATF, IRF4, TBX21, and IFNG, within an integrated network composed of differentially expressed genes in NK cells stimulated by various conditions (immobilized IgG, IL-12, or the combination of IgG and IL-12).
These results are the first to address the global mechanisms by which NK cells mediate their biological functions when encountering antibody-coated targets within inflammatory sites. Moreover, this study has identified a set of high-priority targets for subsequent investigation into strategies to combat cancer by enhancing the anti-tumor activity of CD56dimCD16+ NK cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-015-0142-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4608307  PMID: 26470881
NK cells; CD16; Gene microarray; Interleukin-12; Interferon-gamma
69.  Lentivirus-mediated RASSF1A expression suppresses aggressive phenotypes of gastric cancer cells in vitro and in vivo 
Gene Therapy  2015;22(10):793-801.
Loss of Ras association domain family protein 1 isoform A (RASSF1A) expression is associated with the development of a variety of human cancers and the expression of carcinoembryonic antigen (CEA) frequently occurs in gastric cancer. This study investigated the effects of RASSF1A expression restoration using a hypoxia-inducible CEA promoter-driven vector on xenograft tumor growth in nude mice and on the in-vitro regulation of gastric cancer cell viability, cell cycle distribution, apoptosis, colony formation and invasion capacity. The data showed that the level of CEA mRNA and protein was much higher in gastric cancer SGC7901 cells than in a second gastric cancer cell line, MKN28, or in the MCF-10A normal epithelial breast cell line. RASSF1A expression was restored in SGC7901 cells compared with the negative control virus-infected SGC7910 cells. RASSF1A expression restoration significantly inhibited gastric cancer cell viability, colony formation and invasion capacity, but induced cell cycle arrest and apoptosis in vitro, especially under hypoxic culture conditions. At the gene level, restoration of RASSF1A expression under hypoxic culture conditions significantly suppressed matrix metalloproteinase-2 expression and prevented cyclinD1 expression. A nude mouse xenograft assay showed that the restoration of RASSF1A expression reduced gastric cancer xenograft formation and growth. In conclusion, the restoration of RASSF1A expression using a hypoxia-inducible and CEA promoter-driven vector suppressed aggressive phenotypes of gastric cancer cells in vitro and in vivo. These results suggest that LV-5HRE-CEAp-RASSF1A gene therapy may be a promising novel approach to treat advanced gastric cancer.
PMCID: PMC4598615  PMID: 26005859
70.  Electroconvulsive therapy treatment in patients with somatic symptom and related disorders 
Medically unexplained somatic complaints are highly prevalent, and lead to significant impairment and disability. The number of effective treatment modalities for somatic symptom and related disorders (SSDs) or somatoform disorders (SDs) remains limited. To date, there is no formal indication for electroconvulsive therapy (ECT) in SSD or SD. We report on the largest case series to date regarding the effectiveness of ECT in patients with SSD and SD.
A retrospective chart review of all patients treated with an index course of ECT at the Neuropsychiatric Program at the University of British Columbia Hospital from 2000 to 2010 was conducted. The primary outcomes consisted of changes in pseudoneurologic symptoms, pain symptoms, cardiopulmonary symptoms, and gastrointestinal symptoms. Complaints were examined pre- and post-ECT.
Twenty-eight participants were included in this study. Twenty-one participants received right unilateral ECT. Six received bifrontal ECT. One received bitemporal ECT. Eighteen of 21 participants reported improvement in pseudoneurologic symptoms; eleven of 14 participants reported improvement in pain symptoms; one participant reported improvement in cardiopulmonary symptoms; and one of two participants reported improvement in gastrointestinal symptoms. This paper discusses the putative mechanism of action of ECT in the treatment of SD/SSD.
This retrospective study suggests that ECT could be included as part of the existing treatment for refractory SSD and SD, particularly in refractory cases with comorbid mood disorders.
PMCID: PMC4605246  PMID: 26504388
electroconvulsive therapy; somatic symptoms; somatoform disorders
71.  Haemaphysalis longicornis Ticks as Reservoir and Vector of Severe Fever with Thrombocytopenia Syndrome Virus in China 
Emerging Infectious Diseases  2015;21(10):1770-1776.
Transstadial and transovarial virus transmission occur among ticks, and transmission to mice can occur through a tick bite.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever in East Asia caused by SFTS virus (SFTSV), a newly discovered phlebovirus. The Haemaphysalis longicornis tick has been suspected to be the vector of SFTSV. To determine whether SFTSV can be transmitted among ticks, from ticks to animals, and from animals to ticks, we conducted transmission studies between developmental stages of H. longicornis ticks and between ticks and mice. Using reverse transcription PCR, we also analyzed the prevalence of SFTSV infection among H. longicornis ticks collected from vegetation in Shandong Province, China. Our results showed a low prevalence of SFTSV among collected ticks (0.2%, 8/3,300 ticks), and we showed that ticks fed on SFTSV-infected mice could acquire the virus and transstadially and transovarially transmit it to other developmental stages of ticks. Furthermore, SFTSV-infected ticks could transmit the virus to mice during feeding. Our findings indicate ticks could serve as a vector and reservoir of SFTSV.
PMCID: PMC4593435  PMID: 26402039
bunyavirus; phlebovirus; severe fever with thrombocytopenia syndrome; severe fever with thrombocytopenia syndrome virus; SFTSV; ticks; Haemaphysalis longicornis; viruses; vector-borne infections; transmission; transstadial transmission; transovarial transmission; tickborne transmission; vector; host; larvae; nymphs; adult ticks; China
72.  Chinese Herbal Medicines Might Improve the Long-Term Clinical Outcomes in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: Results of a Decision-Analytic Markov Model  
Aims. The priority of Chinese herbal medicines (CHMs) plus conventional treatment over conventional treatment alone for acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) was documented in the 5C trial ( number: ChiCTR-TRC-07000021). The study was designed to evaluate the 10-year effectiveness of CHMs plus conventional treatment versus conventional treatment alone with decision-analytic model for ACS after PCI. Methods and Results. We constructed a decision-analytic Markov model to compare additional CHMs for 6 months plus conventional treatment versus conventional treatment alone for ACS patients after PCI. Sources of data came from 5C trial and published reports. Outcomes were expressed in terms of quality-adjusted life years (QALYs). Sensitivity analyses were performed to test the robustness of the model. The model predicted that over the 10-year horizon the survival probability was 77.49% in patients with CHMs plus conventional treatment versus 77.29% in patients with conventional treatment alone. In combination with conventional treatment, 6-month CHMs might be associated with a gained 0.20% survival probability and 0.111 accumulated QALYs, respectively. Conclusions. The model suggested that treatment with CHMs, as an adjunctive therapy, in combination with conventional treatment for 6 months might improve the long-term clinical outcome in ACS patients after PCI.
PMCID: PMC4606398  PMID: 26495019
73.  Monitoring of Fasciola Species Contamination in Water Dropwort by cox1 Mitochondrial and ITS-2 rDNA Sequencing Analysis 
Fascioliasis, a food-borne trematode zoonosis, is a disease primarily in cattle and sheep and occasionally in humans. Water dropwort (Oenanthe javanica), an aquatic perennial herb, is a common second intermediate host of Fasciola, and the fresh stems and leaves are widely used as a seasoning in the Korean diet. However, no information regarding Fasciola species contamination in water dropwort is available. Here, we collected 500 samples of water dropwort in 3 areas in Korea during February and March 2015, and the water dropwort contamination of Fasciola species was monitored by DNA sequencing analysis of the Fasciola hepatica and Fasciola gigantica specific mitochondrial cytochrome c oxidase subunit 1 (cox1) and nuclear ribosomal internal transcribed spacer 2 (ITS-2). Among the 500 samples assessed, the presence of F. hepatica cox1 and 1TS-2 markers were detected in 2 samples, and F. hepatica contamination was confirmed by sequencing analysis. The nucleotide sequences of cox1 PCR products from the 2 F. hepatica-contaminated samples were 96.5% identical to the F. hepatica cox1 sequences in GenBank, whereas F. gigantica cox1 sequences were 46.8% similar with the sequence detected from the cox1 positive samples. However, F. gigantica cox1 and ITS-2 markers were not detected by PCR in the 500 samples of water dropwort. Collectively, in this survey of the water dropwort contamination with Fasciola species, very low prevalence of F. hepatica contamination was detected in the samples.
PMCID: PMC4635834  PMID: 26537044
Fasciola species; water dropwort; cox1; ITS-2; DNA sequencing analysis
74.  ECCO2R, a french national survey 
Intensive Care Medicine Experimental  2015;3(Suppl 1):A679.
PMCID: PMC4798260

Results 51-75 (605)