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1.  A modified bicanalicular intubation procedure to repair canalicular lacerations using silicone tubes 
Liang, X | Lin, Y | Wang, Z | Lin, L | Zeng, S | Liu, Z | Li, N | Wang, Z | Liu, Y
Eye  2012;26(12):1542-1547.
Purpose
To explore a modified technique for silicone intubation for the repair of canalicular lacerations.
Methods
The surgery was performed on 35 eyes in 35 adult patients from October 2007 to September 2009. Using a modified soft probe, silicone tubes were inserted through the lacrimal punctum and left in the bicanaliculi for 3–10 months.
Results
The surgery was performed successfully in all cases. The tubes were removed after 3–10 months (mean 5.3±1.8 months). The mean follow-up time after tube removal was 13.8 months (range, 6–22 months). Lower punctum splitting occurred in one case (2.86%) after the surgery. No other complications associated with the silicone tubes occurred. All the tubes were removed successfully without any difficulty. No iatrogenic injuries occurred during tube removal.
Conclusions
The modified bicanalicular intubation procedure described here is an effective and atraumatic procedure for the management of canalicular lacerations in adults, and it is associated with fewer complications than the traditional sutures of canalicular lacerations.
doi:10.1038/eye.2012.212
PMCID: PMC3522846  PMID: 23060024
modified; canalicular laceration; tube intubation
2.  Aldosterone deficiency prevents high-fat-feeding-induced hyperglycaemia and adipocyte dysfunction in mice 
Diabetologia  2013;56(4):901-910.
Aims/hypothesis
Obesity is associated with aldosterone excess, hypertension and the metabolic syndrome, but the relative contribution of aldosterone to obesity-related complications is debated. We previously demonstrated that aldosterone impairs insulin secretion, and that genetic aldosterone deficiency increases glucose-stimulated insulin secretion in vivo. We hypothesised that elimination of endogenous aldosterone would prevent obesity-induced insulin resistance and hyperglycaemia.
Methods
Wild-type and aldosterone synthase-deficient (As−/−) mice were fed a high-fat (HF) or normal chow diet for 12 weeks. We assessed insulin sensitivity and insulin secretion using clamp methodology and circulating plasma adipokines, and examined adipose tissue via histology.
Results
HF diet induced weight gain similarly in the two groups, but As−/− mice were protected from blood glucose elevation. HF diet impaired insulin sensitivity similarly in As−/− and wild-type mice, assessed by hyperinsulinaemic–euglycaemic clamps. Fasting and glucose-stimulated insulin were higher in HF-fed As−/− mice than in wild-type controls. Although there was no difference in insulin sensitivity during HF feeding in As−/− mice compared with wild-type controls, fat mass, adipocyte size and adiponectin increased, while adipose macrophage infiltration decreased. HF feeding significantly increased hepatic steatosis and triacylglycerol content in wild-type mice, which was attenuated in aldosterone-deficient mice.
Conclusions/interpretation
These studies demonstrate that obesity induces insulin resistance independently of aldosterone and adipose tissue inflammation, and suggest a novel role for aldosterone in promoting obesity-induced beta cell dysfunction, hepatic steatosis and adipose tissue inflammation.
doi:10.1007/s00125-012-2814-8
PMCID: PMC3593801  PMID: 23314847
Adiponectin; Aldosterone; Aldosterone synthase; Diabetes; Fatty liver; Insulin; Insulin resistance; Insulin secretion; Renin-angiotensin-aldosterone system
3.  Expression of Trk A receptors in the mammalian inner ear 
Hearing research  2004;187(0):1-11.
Tyrosine kinase receptors, including Trk A, Trk B and Trk C, participate in many different biological processes that are regulated by neurotrophic factors. Nerve growth factor (NGF)-triggered Trk A signaling is involved in growth, survival and differentiation of neurons in the central nervous system and in neural crest-derived cells. Trk A, Trk B and Trk C expression has been reported in the rat ventral cochlear nucleus. In the present study, we explored the immunocytochemical distribution of Trk A in the rodent inner ear. Rat and mouse cochleae were immunolabeled with a rabbit anti-Trk A polyclonal antibody (Chemicon) that has no reported cross-reactivity with Trk B and Trk C. In embryonic day 16 mice, no Trk A immunolabeling could be detected in the developing neuroepithelium. At postnatal day 6, weak Trk A labeling could be observed in both inner and outer hair cells. At postnatal day 12, enhanced punctate Trk A immunoexpression was present in hair cells. In adult mice and rats, intense Trk A labeling was observed in outer and inner hair cell bodies, in supporting cell bodies throughout the cochlea, and in spiral ganglion neurons. Trk A was not observed in stria vascularis, hair cell stereocilia, nor in the Trk B- and Trk C-rich cerebellum. This distribution pattern of Trk A suggests that its ligand, NGF, exerts significant trophic effects in the rodent inner ear.
PMCID: PMC3964775  PMID: 14698082
4.  NITRIC OXIDE DELIVERY VIA A PERMEABLE BALLOON CATHETER INHIBITS NEOINTIMAL GROWTH AFTER ARTERIAL INJURY 
The Journal of surgical research  2012;180(1):35-42.
Background
Neointimal hyperplasia limits the longevity of vascular interventions. Nitric oxide (NO) is well known to inhibit neointimal hyperplasia. However, delivery of NO to the vasculature is challenging. Our study aims to evaluate the efficacy of delivering NO to the site of injury using a permeable balloon catheter. Our hypothesis is that ultra-short duration of NO delivery using a permeable balloon catheter will inhibit neointimal hyperplasia.
Materials and Methods
10-week-old male Sprague-Dawley rats underwent carotid artery balloon injury. Groups included: 1) control, 2) injury, 3) injury + periadventitial NO, and 4) injury + endoluminal NO via permeable balloon catheter. The catheter was inflated to 5 atmospheres of pressure for 5 minutes. Arteries were harvested 2 weeks following injury. Morphometric assessment for neointimal hyperplasia and immunhistochemical staining for inflammatory markers were performed.
Results
Injury increased neointimal hyperplasia compared to control (intima/media area [I/M] ratio 1.07 vs. 0.11, respectively, p<0.001). Periadventitial delivery of NO reduced the I/M area ratio compared to injury alone (55% decrease, p<0.001). Endoluminal delivery of NO also reduced the I/M area ratio compared to injury alone (65% decrease; p<0.001). Both endoluminal and periadventitial NO affected the I/M ratio by reducing the intimal area (64% and 46%, respectively, p<0.001) whereas neither affected the medial area. Periadventital NO delivery increased lumen area (p<0.05), whereas endoluminal NO delivery increased circumference (p<0.05). Periadventitial NO delivery inhibited macrophage intimal infiltration compared to injury alone (p<0.05).
Conclusion
These data demonstrate that short duration endoluminal NO delivery via permeable balloon catheters inhibits neointimal hyperplasia following arterial interventions. Endoluminal delivery of NO could become a focus for future clinical interventions.
doi:10.1016/j.jss.2012.10.048
PMCID: PMC3578007  PMID: 23164361
Neointimal Hyperplasia; Restenosis; Nitric Oxide; Adventitia; Media; Intima; Inflammation; Macrophage; Endoluminal
5.  PSGL-1/selectin and ICAM-1/CD18 interactions are involved in macrophage-induced drug resistance in myeloma 
Leukemia  2012;27(3):702-710.
Chemoresistance is the major obstacle in multiple myeloma (MM) management. We previously showed that macrophages protect myeloma cells, on a cell contact basis, from melphalan or dexamethasone-induced apoptosis in vitro. In this study, we found that macrophage-mediated myeloma drug resistance was also seen with purified macrophages from myeloma patients’ bone marrow (BM) in vitro and was confirmed in vivo using the human myeloma-SCID (severe combined immunodeficient) mouse model. By profiling differentially regulated and paired plasma membrane protein genes, we showed that PSGL-1 (P-selectin glycoprotein ligand-1)/selectins and ICAM-1/CD18 played an important role in macrophage-mediated myeloma cell drug resistance, as blocking antibodies against these molecules or genetic knockdown of PSGL-1 or ICAM-1 in myeloma cells repressed macrophages’ ability to protect myeloma cells. Interaction of macrophages and myeloma cells via these molecules activated Src and Erk1/2 kinases and c-myc pathways and suppressed caspase activation induced by chemotherapy drugs. Thus, our study sheds new light on the mechanism of drug resistance in MM and provides novel targets for improving the efficacy of chemotherapy in patients.
doi:10.1038/leu.2012.272
PMCID: PMC3652581  PMID: 22996336
macrophage; multidrug resistance; multiple myeloma; PSGL-1
6.  Survivin is essential for fertile egg production and female fertility in mice 
Cell Death & Disease  2014;5(3):e1154-.
Survivin is the smallest member of the inhibitor of apoptosis protein (IAP) family and acts as a bifunctional protein involved in mitosis regulation and apoptosis inhibition. To identify the physiological role of Survivin in female reproduction, we selectively disrupted Survivin expression in oocytes and granulosa cells (GCs), two major cell types in the ovary, by two different Cre-Loxp conditional knockout systems, and found that both led to defective female fertility. Survivin deletion in oocytes did not affect oocyte growth, viability and ovulation, but caused tetraploid egg production and thus female infertility. Further exploration revealed that Survivin was essential for regulating proper meiotic spindle organization, spindle assembly checkpoint activity, timely metaphase-to-anaphase transition and cytokinesis. Mutant mice with Survivin depleted in GCs showed reduced ovulation and subfertility, caused by defective follicular growth, increased follicular atresia and impaired luteinization. These findings suggest that Survivin has an important role in regulating folliculogenesis and oogenesis in the adult mouse ovary.
doi:10.1038/cddis.2014.126
PMCID: PMC3973204  PMID: 24675472
folliculogenesis; apoptosis; granulosa cell; meiosis; oocyte; Survivin
7.  SKLB-163, a new benzothiazole-2-thiol derivative, exhibits potent anticancer activity by affecting RhoGDI/JNK-1 signaling pathway 
Peng, X | Xie, G | Wang, Z | Lin, H | Zhou, T | Xiang, P | Jiang, Y | Yang, S | Wei, Y | Yu, L | Zhao, Y
Cell Death & Disease  2014;5(3):e1143-.
Small-molecule inhibitors are an attractive therapeutic approach for most types of human cancers. SKLB-163, a novel benzothiazole-2-thiol derivative, was developed via computer-aided drug design and de novo synthesis. MTT assay showed it had potent anti-proliferative activity on various human cancer cells. Treatment of cancer cells with SKLB-163 induced obvious apoptosis and inhibited proliferation in vitro. SKLB-163 administered p.o. showed a marked antitumor activity in vivo. Proteomic techniques were employed to identify possible drug target proteins. The data showed molecular mechanism of action might be involved in downregulation of RhoGDI, which finally contributed to increased apoptosis and inhibited proliferation. These findings provided the potential value of SKLB-163 as a novel candidate antitumor drug.
doi:10.1038/cddis.2014.107
PMCID: PMC3973246  PMID: 24675461
benzothiazole-2-thiol derivative; cancer; RhoGDI; apoptosis; proliferation
8.  Pancreatic Castleman’s Disease: Studies of Three Cases And A Cumulative Review of the Literature 
The Indian Journal of Surgery  2012;75(1):34-38.
Castleman’s disease (CD) is a relatively rare and benign disorder. Pancreatic localization of CD is even more rare and is usually indistinguishable from pancreatic neoplasms. We report three cases of CD in which pancreas was all involved. One located in the tail of the pancreas, who accepted distal pancreatectomy, and the others in the head accepted enucleation. In addition, we review current data on its pathogenesis, imaging findings, diagnosis, differential diagnosis, and treatment.
doi:10.1007/s12262-012-0495-7
PMCID: PMC3585527  PMID: 24426381
Castleman’s disease; Pancreas
9.  Cannabinoid receptor 1 suppresses transient receptor potential vanilloid 1-induced inflammatory responses to corneal injury 
Cellular signalling  2012;25(2):501-511.
Cannabinoid receptor type 1 (CB1)-induced suppression of transient receptor potential vanilloid type 1 (TRPV1) activation provides a therapeutic option to reduce inflammation and pain in different animal disease models through mechanisms involving dampening of TRPV1 activation and signaling events. As we found in both mouse corneal epithelium and human corneal epithelial cells (HCEC) that there is CB1 and TRPV1 expression colocalization based on overlap of coimmunostaining, we determined in mouse corneal wound healing models and in human corneal epithelial cells (HCEC) if they interact with one another to reduce TRPV1-induced inflammatory and scarring responses. Corneal epithelial debridement elicited in vivo a more rapid wound healing response in wildtype (WT) than in CB1−/− mice suggesting functional interaction between CB1 and TRPV1. CB1 activation by injury is tenable based on the identification in mouse corneas of 2-arachidonylglycerol (2-AG) with tandem LC–MS/MS, a selective endocannabinoid CB1 ligand. Suppression of corneal TRPV1 activation by CB1 is indicated since following alkali burning, CB1 activation with WIN55,212-2 (WIN) reduced immune cell stromal infiltration and scarring. Western blot analysis of coimmunoprecipitates identified protein–protein interaction between CB1 and TRPV1. Other immunocomplexes were also identified containing transforming growth factor kinase 1 (TAK1), TRPV1 and CB1. CB1 siRNA gene silencing prevented suppression by WIN of TRPV1-induced TAK1–JNK1 signaling. WIN reduced TRPV1-induced Ca2+ transients in fura2-loaded HCEC whereas pertussis toxin (PTX) preincubation obviated suppression by WIN of such rises caused by capsaicin (CAP). Whole cell patch clamp analysis of HCEC showed that WIN blocked subsequent CAP-induced increases in nonselective outward currents. Taken together, CB1 activation by injury-induced release of endocannabinoids such as 2-AG downregulates TRPV1 mediated inflammation and corneal opacification. Such suppression occurs through protein–protein interaction between TRPV1 and CB1 leading to declines in TRPV1 phosphorylation status. CB1 activation of the GTP binding protein, Gi/o contributes to CB1 mediated TRPV1 dephosphorylation leading to TRPV1 desensitization, declines in TRPV1-induced increases in currents and pro-inflammatory signaling events.
doi:10.1016/j.cellsig.2012.10.015
PMCID: PMC3607947  PMID: 23142606
Human corneal epithelial cells (HCEC); Currents; Cannabinoid receptor subtype 1 (CB1); Transient receptor potential vanilloid type 1 (TRPV1); Inflammation; Small interfering RNA (siRNA) gene silencing
10.  A Serine-Substituted P450 Catalyzes Highly Efficient Carbene Transfer to Olefins In Vivo 
Nature chemical biology  2013;9(8):485-487.
Genetically encoded catalysts for non-natural chemical reactions will open new routes to sustainable production of chemicals. We designed a unique serine-heme ligated cytochrome “P411” that catalyzes efficient and selective carbene transfers from diazoesters to olefins in intact Escherichia coli cells. The mutation C400S in cytochrome P450BM3 gives a signature ferrous-CO Soret peak at 411 nm, abolishes monooxygenation activity, raises the resting state FeIII/II reduction potential, and significantly improves NAD(P)H-driven cyclopropanation activity.
doi:10.1038/nchembio.1278
PMCID: PMC3720782  PMID: 23792734
11.  HMGB1–LPS complex promotes transformation of osteoarthritis synovial fibroblasts to a rheumatoid arthritis synovial fibroblast-like phenotype 
Qin, Y | Chen, Y | Wang, W | Wang, Z | Tang, G | Zhang, P | He, Z | Liu, Y | Dai, S-M | Shen, Q
Cell Death & Disease  2014;5(2):e1077-.
It is generally believed that some inflammatory antigens can recognize Toll-like receptors on synovial fibroblasts (SFs) and then activate downstream signals, leading to the formation of RASFs and inducing rheumatoid arthritis (RA). The objective of the current work was to study on the hypothesis that outer PAMP (LPS) binds to the inner DAMP (HMGB1) and becomes a complex that recognizes TLRs/RAGE on SFs, thus initiating a signaling cascade that leads to the secretion of inflammatory cytokines and chemokines, production of tissue-destructive enzymes, and formation of RASFs, finally resulting in RA. Osteoarthritis synovial fibroblasts (OASFs) were co-cultured with HMGB1–LPS complex in vitro for five generations to induce the transformation of human SFs to RA-like SFs (tOASFs). Then, changes of tOASFs in cell cycle and apoptosis–autophagy balance were investigated in vitro, and the pathogenicity of tOASFs was evaluated in a SCID mouse model in vivo. In vitro cell cycle analysis showed more tOASFs passing through the G1/S checkpoint and moving to S or G2 phase. Flow cytometry and confocal microscopy showed that apoptosis was reduced and autophagy was enhanced significantly in tOASFs as compared with those in OASFs. The expression of certain receptors and adhesion molecules in tOASFs was upregulated. In vivo experiments showed that tOASFs attached to, invaded, and degraded the co-implanted cartilage. In addition, histochemistry showed excessive proliferation of tOASFs and the expression of matrix metalloproteinases (MMPs). Based on the above findings, we conclude that HMGB1–LPS complex could promote the formation of RASFs.
doi:10.1038/cddis.2014.48
PMCID: PMC3944262  PMID: 24556692
rheumatoid arthritis synovial fibroblast; HMGB1; autophagy
12.  Takayasu arteritis: imaging spectrum at multidetector CT angiography 
The British Journal of Radiology  2012;85(1020):e1282-e1292.
Takayasu arteritis is a chronic, idiopathic, inflammatory disease that primarily affects large vessels, such as the aorta and its major branches and the pulmonary and coronary arteries. The non-specific inflammation of involved vessels usually leads to concentric wall thickening, fibrosis and thrombus formation. Diseased arteries become stenotic or occluded, undergo vascular remodelling or develop aneurysms. According to the involvement of arteries, six types of Takayasu arteritis are documented. The purpose of this pictorial review is to illustrate the various multidetector CT angiography appearances of Takayasu arteritis and to discuss the differential diagnosis.
doi:10.1259/bjr/25536451
PMCID: PMC3611735  PMID: 23175494
13.  Induction of necrotic cell death by oxidative stress in retinal pigment epithelial cells 
Cell Death & Disease  2013;4(12):e965-.
Age-related macular degeneration (AMD) is a degenerative disease of the retina and the leading cause of blindness in the elderly. Retinal pigment epithelial (RPE) cell death and the resultant photoreceptor apoptosis are characteristic of late-stage dry AMD, especially geographic atrophy (GA). Although oxidative stress and inflammation have been associated with GA, the nature and underlying mechanism for RPE cell death remains controversial, which hinders the development of targeted therapy for dry AMD. The purpose of this study is to systematically dissect the mechanism of RPE cell death induced by oxidative stress. Our results show that characteristic features of apoptosis, including DNA fragmentation, caspase 3 activation, chromatin condensation and apoptotic body formation, were not observed during RPE cell death induced by either hydrogen peroxide or tert-Butyl hydroperoxide. Instead, this kind of cell death can be prevented by RIP kinase inhibitors necrostatins but not caspase inhibitor z-VAD, suggesting necrotic feature of RPE cell death. Moreover, ATP depletion, receptor interacting protein kinase 3 (RIPK3) aggregation, nuclear and plasma membrane leakage and breakdown, which are the cardinal features of necrosis, were observed in RPE cells upon oxidative stress. Silencing of RIPK3, a key protein in necrosis, largely prevented oxidative stress-induced RPE death. The necrotic nature of RPE death is consistent with the release of nuclear protein high mobility group protein B1 into the cytoplasm and cell medium, which induces the expression of inflammatory gene TNFα in healthy RPE and THP-1 cells. Interestingly, features of pyroptosis or autophagy were not observed in oxidative stress-treated RPE cells. Our results unequivocally show that necrosis, but not apoptosis, is a major type of cell death in RPE cells in response to oxidative stress. This suggests that preventing oxidative stress-induced necrotic RPE death may be a viable approach for late-stage dry AMD.
doi:10.1038/cddis.2013.478
PMCID: PMC3877549  PMID: 24336085
cell death; RIPK3; RPE cell; oxidative stress; AMD
14.  Characterization and Application of a Nose-Only Exposure Chamber for Inhalation Delivery of Liposomal Drugs and Nucleic Acids to Mice 
Abstract
Background
A small nose-only exposure chamber was evaluated for inhalation delivery of drug carrier systems (DCSs) to mice for the treatment of lung cancer. The chamber then was used for inhalation delivery of an anticancer drug, antisense oligonucleotides (ASO), and small interfering RNA (siRNA) directly to the cancerous lungs of mice.
Methods
The uniformity of particle delivery across the ports of the exposure chamber and stability of the DCS (liposomes) during continuous aerosolization by a Collison nebulizer were examined. The mean produced particle size by number was approximately 130 nm, and the mass median diameter was approximately 270 nm. The system was then used to deliver DCS containing doxorubicin (DOX) and ASO or siRNA targeted to multidrug resistance-associated protein 1 (MRP1) mRNA as suppressors of cancer cell resistance. The retention of the drug in the lungs and the effect on tumor size were compared after inhalation delivery and intravenous injection in a nu/nu mouse model of lung cancer.
Results
The aerosol mass across the four inhalation ports had a coefficient of variation of less than 12%, and approximately 1.4% of the nebulized mass was available for inhalation at each port. The mean size of 130 nm of liposomal DCS did not change significantly during continuous 60-min aerosolization. For inhalation delivery of DCS with DOX+ASO/siRNA, the amount of drugs available for inhalation was lower compared with intravenous injection of DOX; however, the observed lung dose and the retention time were significantly higher. The delivery of DOX+ASO/siRNA via inhalation resulted in tumor volume reduction of more than 90%, whereas only about 40% reduction was achieved after intravenous injection of DOX.
Conclusions
The investigated exposure system is suitable for inhalation delivery of complex DCS, and its use to deliver DCS containing anticancer drugs and resistance suppressors via inhalation offered a superior method for lung cancer treatment in mice compared with intravenous injections.
doi:10.1089/jamp.2011-0966
PMCID: PMC3889495  PMID: 23530772
lung cancer; inhalation; exposure; nose-only chamber; drug carrier systems; liposomes; pump and nonpump resistance
15.  Using Computational and Mechanical Models to Study Animal Locomotion 
Recent advances in computational methods have made realistic large-scale simulations of animal locomotion possible. This has resulted in numerous mathematical and computational studies of animal movement through fluids and over substrates with the purpose of better understanding organisms’ performance and improving the design of vehicles moving through air and water and on land. This work has also motivated the development of improved numerical methods and modeling techniques for animal locomotion that is characterized by the interactions of fluids, substrates, and structures. Despite the large body of recent work in this area, the application of mathematical and numerical methods to improve our understanding of organisms in the context of their environment and physiology has remained relatively unexplored. Nature has evolved a wide variety of fascinating mechanisms of locomotion that exploit the properties of complex materials and fluids, but only recently are the mathematical, computational, and robotic tools available to rigorously compare the relative advantages and disadvantages of different methods of locomotion in variable environments. Similarly, advances in computational physiology have only recently allowed investigators to explore how changes at the molecular, cellular, and tissue levels might lead to changes in performance at the organismal level. In this article, we highlight recent examples of how computational, mathematical, and experimental tools can be combined to ultimately answer the questions posed in one of the grand challenges in organismal biology: “Integrating living and physical systems.”
doi:10.1093/icb/ics115
PMCID: PMC3475976  PMID: 22988026
16.  A meta-analysis of lymph node metastasis rate for patients with thoracic oesophageal cancer and its implication in delineation of clinical target volume for radiation therapy 
Ding, X | Zhang, J | Li, B | Wang, Z | Huang, W | Zhou, T | Wei, Y | Li, H
The British Journal of Radiology  2012;85(1019):e1110-e1119.
Objectives
The objective of this study was to pool the lymph node metastasis rate (LNMR) in patients with thoracic oesophageal cancer (TOC) and to determine which node level should be included when undergoing radiation therapy.
Methods
Qualified studies were identified on Medline, Embase, CBM and the Cochrane Library through to the end of April 2011. Pooled estimates of LNMR were obtained through a random-effect model. Possible effect modifiers which might lead to the statistical heterogeneity were identified through meta-regression, and further subgroup analyses of factors influencing LNMR were performed.
Results
45 observational studies with a total of 18 415 patients were included in the meta-analysis. The pooled estimates of LNMR in upper, middle and lower TOC were 30.7%, 16.8% and 11.0% cervical, 42.0%, 21.1% and 10.5% upper mediastinal, 12.9%, 28.1% and 19.6% middle mediastinal, 2.6%, 7.8% and 23.0% lower mediastinal, and 9%, 21.4% and 39.9% abdominal, respectively. Lymph node metastasis most frequently happened to paratracheal, paraoesophageal, perigastric 106recR and station 7. The most obvious difference (≥15%) of LNMR between two-field and three-field lymphatic dissection occurred in cervical, paratracheal, 106recR and 108.
Conclusions
Through the meta-analysis, more useful information was obtained about clinical target volume (CTV) delineation of TOC patients treated with radiotherapy. However, our study is predominantly a description of squamous carcinoma and the results may not be valid for adenocarcinoma.
doi:10.1259/bjr/12500248
PMCID: PMC3500810  PMID: 22700258
17.  Amyloid-β1–42 oligomer accelerates senescence in adult hippocampal neural stem/progenitor cells via formylpeptide receptor 2 
Cell Death & Disease  2013;4(11):e924-.
The failure of adult hippocampal neurogenesis is increasingly considered as an important factor in the pathological correlates for memory decline in Alzheimer's disease (AD). Loss of adult-born neurons and abnormalities of neural stem/progenitor cells (NSPCs) within the dentate gyrus (DG) of adult hippocampus might contribute to this process. In this study, we showed that amyloid-β1–42 (Aβ42) oligomer triggers senescent phenotype of NSPCs in vitro. Oligomerized Aβ42 induced the production of senescence-associated biomarkers p16 and senescence-associated β-galactosidase (SA-β-gal) in adult mouse hippocampal NSPCs, as well as inhibited cells proliferation and differentiation. In the DG of amyloid precursor protein/presenilin1 (APP/PS1) transgenic mice, the number of senescent NSPCs was significantly increased and senescence-associated protein p16 was upregulated. Formylpeptide receptor 2 (FPR2), one of Aβ42 functional receptors, may be involved in NSPCs senescence. The FPR2 antagonist WRW4 significantly inhibited NSPCs senescence induced by Aβ42. In addition, the activation of p38 mitogen-activated protein kinase (MAPK) in response to the accumulation of reactive oxygen species (ROS) was involved in NSPCs senescence induced by Aβ42. WRW4 inhibited the accumulation of ROS and the activation of p38 MAPK in NSPCs. Our data suggest that Aβ42 accelerates NSPCs senescence via FPR2-dependent activation of its downstream ROS-p38 MAPK signaling, which limits the function of NSPCs and contributes to failure of neurogenesis. This is the first demonstration of NSPCs senescence response to Aβ42.
doi:10.1038/cddis.2013.437
PMCID: PMC3847315  PMID: 24263098
Aβ42; adult hippocampal neural stem/progenitor cells; senescence; FPR2; ROS; p38 MAPK
18.  The HECTD3 E3 ubiquitin ligase facilitates cancer cell survival by promoting K63-linked polyubiquitination of caspase-8 
Li, Y | Kong, Y | Zhou, Z | Chen, H | Wang, Z | Hsieh, Y-C | Zhao, D | Zhi, X | Huang, J | Zhang, J | Li, H | Chen, C
Cell Death & Disease  2013;4(11):e935-.
Apoptosis resistance is a hurdle for cancer treatment. HECTD3, a new E3 ubiquitin ligase, interacts with caspase-8 death effector domains and ubiquitinates caspase-8 with K63-linked polyubiquitin chains that do not target caspase-8 for degradation but decrease the caspase-8 activation. HECTD3 depletion can sensitize cancer cells to extrinsic apoptotic stimuli. In addition, HECTD3 inhibits TNF-related apoptosis-inducing ligand (TRAIL)-induced caspase-8 cleavage in an E3 ligase activity-dependent manner. Mutation of the caspase-8 ubiquitination site at K215 abolishes the HECTD3 protection from TRAIL-induced cleavage. Finally, HECTD3 is frequently overexpressed in breast carcinomas. These findings suggest that caspase-8 ubiquitination by HECTD3 confers cancer cell survival.
doi:10.1038/cddis.2013.464
PMCID: PMC3847339  PMID: 24287696
ubiquitination; apoptosis; breast cancer; HECTD3; caspase-8
19.  Reactivation of p53 by Novel MDM2 Inhibitors: Implications for Pancreatic Cancer Therapy 
Current cancer drug targets  2010;10(3):319-331.
The present study is the first to show in pancreatic cancer (PC) the growth inhibition and apoptosis by novel MDM2 inhibitors (MI-319 & 219) through reactivation of p53 pathway. Our results highlight two new secondary targets of MDM2 inhibitor ‘SIRT1’ and Ku70. SIRT1 has a role in ageing and cancer and is known to regulate p53 signaling through acetylation. Ku70 is a key component of non-homologous end joining machinery in the DNA damage pathway and is known to regulate apoptosis by blocking Bax entry into mitochondria. Given the growth inhibition and apoptosis by MI-219, MI-319 was accompanied by increase in levels of p53 along with p21WAF1 and the proapoptotic Puma. SiRNA against p21WAF1 abrogated the growth inhibition of PC cells confirming p21WAF1 as a key player downstream of activated p53. Immunoprecipitation-western blot analysis revealed reduced association of MDM2-p53 interaction in drug exposed PC cells. In combination studies, the inhibitors synergistically augmented anti-tumor effects of therapeutic drug gemcitabine both in terms of cell growth inhibition as well as apoptosis. Surface plasmon resonance studies confirmed strong binding between MI-319 and Ku70 (KD 170 nM). Western blot revealed suppression of SIRT1 and Ku70 with simultaneous upregulation of acetyl-p53 (Lys379) and Bax. Co-Immunoprecipitation studies confirmed that MI-319 could disrupt Ku70-Bax and SIRT1-Bax interaction. Further, using wt-p53 xenograft of Capan-2, we found that oral administration of MI-319 at 300 mg/kg for 14 days resulted in significant tumor growth inhibition without any observed toxicity to the animals. No tumor inhibition was found in mut-p53 BxPC-3 xenografts. In light of our results, the inhibitors of MDM2 warrant clinical investigation as new agents for PC treatment.
PMCID: PMC3809102  PMID: 20370686
MDM2 and p53; Small molecule inhibitors; cell cycle arrest; apoptosis; pancreatic cancer
20.  Stimulated mast cells promote maturation of myocardial microvascular endothelial cell neovessels by modulating the angiopoietin-Tie-2 signaling pathway 
Angiopoietin (Ang)-1 and Ang-2 interact in angiogenesis to activate the Tie-2 receptor, which may be involved in new vessel maturation and regression. Mast cells (MCs) are also involved in formation of new blood vessels and angiogenesis. The present study was designed to test whether MCs can mediate angiogenesis in myocardial microvascular endothelial cells (MMVECs). Using a rat MMVEC and MC co-culture system, we observed that Ang-1 protein levels were very low even though its mRNA levels were increased by MCs. Interestingly, MCs were able to enhance migration, proliferation, and capillary-like tube formation, which were associated with suppressed Ang-2 protein expression, but not Tie-2 expression levels. These MCs induced effects that could be reversed by either tryptase inhibitor [N-tosyl-L-lysine chloromethyl ketone (TLCK)] or chymase inhibitor (N-tosyl-L-phenylalanyl chloromethyl ketone), with TLCK showing greater effects. In conclusion, our data indicated that MCs can interrupt neovessel maturation via suppression of the Ang-2/Tie-2 signaling pathway.
doi:10.1590/1414-431X20132873
PMCID: PMC3854333  PMID: 24270910
Myocardial microvascular endothelial cells; Mast cell; Angiogenesis; Angiopoietin; Tie-2
21.  Which should be the routine cross-sectional reconstruction mode in spectral CT imaging: monochromatic or polychromatic? 
The British Journal of Radiology  2012;85(1018):e887-e890.
Objective
To provide evidence for the selection of an optimal cross-sectional reconstruction mode in spectral CT imaging of the abdomen, we compared the monochromatic images with polychromatic images.
Methods
Three phase-enhanced CT scans of the abdomen were recorded using the spectral imaging technique on 100 patients. Images were reconstructed using two modes: polychromatic and 70 keV monochromatic. The following variables were then compared: contrast-to-noise ratio (CNR) of the liver, spleen, gallbladder, kidney and pancreas, and the noise. Paired t-tests were used to compare differences between the two sets of images. Three experienced doctors graded the quality of the images with a five-point scale. The image quality scores were compared with a non-parametric rank sum test.
Results
Compared with polychromatic images, the 70 keV monochromatic mode images yielded significantly greater tissue-to-fat CNR and lower noise (p<0.001 for all comparisons). The image quality of the 70 keV monochromatic mode showed significantly better results than the polychromatic mode (p<0.001).
Conclusions
In abdominal spectral CT imaging, 70 keV monochromatic mode reconstruction images were better than those reconstructed using the polychromatic mode. The monochromatic mode may become the routine reconstruction mode for cross-sectional images.
doi:10.1259/bjr/27844842
PMCID: PMC3474011  PMID: 22723512
22.  Interconnections in Superior Temporal Cortex Revealed by Musicogenic Seizure Propagation 
Journal of neurology  2012;259(10):2251-2254.
doi:10.1007/s00415-012-6556-9
PMCID: PMC3632445  PMID: 23010942
Epilepsy; Seizure; Intracranial electrodes; Epilepsy surgery; Epileptogenic zone; Cortical localization
23.  Deregulation of let-7e in epithelial ovarian cancer promotes the development of resistance to cisplatin 
Cai, J | Yang, C | Yang, Q | Ding, H | Jia, J | Guo, J | Wang, J | Wang, Z
Oncogenesis  2013;2(10):e75-.
Drug resistance remains a major clinical obstacle to successful treatment in ovarian cancer patients, and the evidence of microRNAs involvement in drug resistance has been emerging recently. In this report, we investigated the role of let-7e in the development of cisplatin-resistant ovarian cancer. On the cellular level, let-7e expression was significantly reduced in cisplatin-resistant human epithelial ovarian cancer (EOC) cell line A2780/CP compared with parental A2780 cell and decreased in a concentration-dependent manner in A2780, SKOV3 and ES2 cells treated with cisplatin. Overexpression of let-7e by transfection of agomir could resensitize A2780/CP and reduce the expression of cisplatin-resistant-related proteins enhancer of zeste 2 (EZH2) and cyclin D1 (CCND1), whereas let-7e inhibitors increased resistance to cisplatin in parental A2780 cells. Quantitative methylation-specific PCR analysis showed hypermethylation of the CpG island adjacent to let-7e in A2780/CP cells, and demethylation treatment with 5-aza-CdR or transfection of pYr-let-7e-shRNA plasmid containing unmethylated let-7e DNA sequence could restore let-7e expression and partly reduce the chemoresistance. In addition, cisplatin combined with let-7e agomirs inhibited the growth of A2780/CP xenograft more effectively than cisplatin alone. Diminished expression of EZH2 and CCND1 and higher cisplatin concentrations in tumor tissue of mice subjected to administration of let-7e agomirs in addition to cisplatin were revealed by immunohistochemistry and atomic absorption spectroscopy, respectively. Taken together, our findings suggest that let-7e may act as a promising therapeutic target for improvement of the sensibility to cisplatin in EOC.
doi:10.1038/oncsis.2013.39
PMCID: PMC3816216  PMID: 24100610
let-7e; cisplatin; epithelial ovarian cancer; methylation; agomir
24.  Gpr97 is essential for the follicular versus marginal zone B-lymphocyte fate decision 
Cell Death & Disease  2013;4(10):e853-.
Gpr97 is an orphan adhesion GPCR and is highly conserved among species. Up to now, its physiological function remains largely unknown. Here, we show that Gpr97 deficiency results in an extensive reduction in B220+ lymphocytes in mice. More intensive analyses reveal an expanded marginal zone but a decreased follicular B-cell population in Gpr97−/−spleen, which displays disorganized architecture characterized by diffuse, irregular B-cell areas and the absence of discrete perifollicular marginal and mantle zones. In vivo functional studies reveal that the mutant mice could generate antibody responses to T cell-dependent and independent antigens, albeit enhanced response to the former and weakened response to the latter. By screening for the molecular events involved in the observed phenotypes, we found that lambda 5 expression is downregulated and its upstream inhibitor Aiolos is increased in the spleen of mutant mice, accompanied by significantly enhanced phosphorylation and nuclear translocation of cAMP response element-binding protein. Interestingly, increased constitutive Nf-κb p50/p65 expression and activity were observed in Gpr97−/− spleen, implicating a crucial role of Gpr97 in regulating Nf-κb activity. These findings uncover a novel biological function of Gpr97 in regulating B-cell development, implying Gpr97 as a potential therapeutic target for treatment of immunological disorders.
doi:10.1038/cddis.2013.346
PMCID: PMC3824656  PMID: 24113187
Gpr97; knockout mice; B lymphopoiesis; follicular B cells; lambda 5 gene
25.  Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment 
Sui, X | Chen, R | Wang, Z | Huang, Z | Kong, N | Zhang, M | Han, W | Lou, F | Yang, J | Zhang, Q | Wang, X | He, C | Pan, H
Cell Death & Disease  2013;4(10):e838-.
Induction of cell death and inhibition of cell survival are the main principles of cancer therapy. Resistance to chemotherapeutic agents is a major problem in oncology, which limits the effectiveness of anticancer drugs. A variety of factors contribute to drug resistance, including host factors, specific genetic or epigenetic alterations in the cancer cells and so on. Although various mechanisms by which cancer cells become resistant to anticancer drugs in the microenvironment have been well elucidated, how to circumvent this resistance to improve anticancer efficacy remains to be defined. Autophagy, an important homeostatic cellular recycling mechanism, is now emerging as a crucial player in response to metabolic and therapeutic stresses, which attempts to maintain/restore metabolic homeostasis through the catabolic lysis of excessive or unnecessary proteins and injured or aged organelles. Recently, several studies have shown that autophagy constitutes a potential target for cancer therapy and the induction of autophagy in response to therapeutics can be viewed as having a prodeath or a prosurvival role, which contributes to the anticancer efficacy of these drugs as well as drug resistance. Thus, understanding the novel function of autophagy may allow us to develop a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in the treatment of cancer patients.
doi:10.1038/cddis.2013.350
PMCID: PMC3824660  PMID: 24113172
autophagy; chemotherapy resistance; cancer; therapy

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