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1.  Factors that predict lymph node status in clinical stage T1aN0M0 lung adenocarcinomas 
Background
To identify patients in whom systematic lymph node dissection would be suitable, preoperative diagnosis of the biological invasiveness of lung adenocarcinomas through the classification of these T1aN0M0 lung adenocarcinomas into several subgroups may be warranted. In this retrospective study, we sought to determine predictive factors of lymph node status in clinical stage T1aN0M0 lung adenocarcinomas.
Methods
We retrospectively reviewed the records of 273 consecutive patients undergone surgical resection of clinical stage T1aN0M0 lung adenocarcinomas at Shanghai Chest Hospital, from January 2011 to December 2012. Preoperative computed tomography findings of all 273 patients were reviewed and their tumors categorized as pure GGO, GGO with minimal solid components (<5 mm), part-solid (solid parts >5 mm), or purely solid. Relevant clinicopathologic features were investigated to identify predictors of hilar or mediastinal lymph node metastasis using univariate or multiple variable analysis.
Results
Among the 273 eligible clinical stage T1aN0M0 lung adenocarcinomas examined on thin-section CT, 103 (37.7%) were pure GGO, 118 (43.2%) GGO with minimal solid components, 13 (4.8%) part-solid (solid parts >5 mm, five GGO predominant and eight solid predominant), and 39 (14.3%) pure solid. There were 18 (6.6%) patients with lymph node metastasis. Incidence of N1 and N2 nodal involvement was 11 (6.6%) and seven (2.6%) patients, respectively. All patients with pure GGO and GGO with minimal solid components (<5 mm) tumors were pathologically staged N0. Multivariate analyses showed that the following factors significantly predicted lymph node metastasis for T1a lung adenocarcinomas: symptoms at presentation, GGO status, and abnormal carcinoembryonic antigen (CEA) titer. Multivariate analyses also showed that the following factors significantly predicted lymph node metastasis for pure solid tumors: air bronchogram sign, tumor size, symptoms at presentation, and abnormal CEA titer.
Conclusions
The patients of clinical stage T1aN0M0 lung adenocarcinomas with pure GGO and GGO with minimal solid components tumors were pathologically staged N0 and systematic lymph node dissection should be avoided. But systematic lymph node dissection should be performed for pure solid tumors or part-solid, especially in patients with CEA greater than 5 ng/mL or symptoms at presentation, because of the high possibility of lymph node involvement.
doi:10.1186/1477-7819-12-42
PMCID: PMC3945801  PMID: 24559138
Lymph node; Lung adenocarcinomas; Stage small non-small cell lung cancer
2.  The protective effects of T cell deficiency against brain injury are ischemic model-dependent in rats 
Neurochemistry international  2012;62(3):265-270.
Previous studies have reported that T cell deficiency reduced infarct sizes after transient middle cerebral artery (MCA) suture occlusion in mice. However, how reperfusion and different models affect the detrimental effects of T cells have not been studied. We investigated the effects of T cell deficiency in nude rats using two stroke models and compared their infarct sizes with those in WT rats. In the distal MCA occlusion (MCAo) model, the distal MCA was permanently occluded and the bilateral common carotid arteries (CCAs) were transiently occluded for 60 min. In the suture MCAo model, the MCA was transiently occluded for 100 min by the insertion of a monofilament suture. Our results showed that T cell deficiency resulted in about a 50% reduction in infarct size in the suture MCAo model, whereas it had no effect in the distal MCAo model, suggesting the protective effects of T cell deficiency are dependent on the ischemic model used. We further found more total T cells, CD4 T cells and CD8 T cells in the ischemic brains of WT rats in the suture MCAo model than in the distal MCAo model. In addition, we detected more CD68-expressing macrophages in the ischemic brains of WT rats than in nude rats in the suture MCAo but not the distal MCAo model. Lymphocyte reconstitution in nude rats resulted in larger infarct sizes in the suture MCAo, but not in the distal MCAo stroke model. The results of regional CBF measurement indicated a total reperfusion in the MCAo model but only a partial reperfusion in the distal MCAo model. In conclusion, the protective effects of T cell deficiency on brain injury are dependent on the ischemic model used; likely associated with different degrees of reperfusion.
doi:10.1016/j.neuint.2012.11.016
PMCID: PMC3581747  PMID: 23228347
Stroke; focal ischemia; nude rats T cells
3.  Hurdles to clear before clinical translation of ischemic postconditioning against stroke 
Translational stroke research  2013;4(1):63-70.
Ischemic postconditioning has been established for its protective effects against stroke in animal models. It is performed after post-stroke reperfusion and refers to a series of induced ischemia or a single brief one. This review article addresses major hurdles in clinical translation of ischemic postconditioning to stroke patients, including potential hazards, the lack of well-defined protective paradigms, and the paucity of deeply-understood protective mechanisms. A hormetic model, often used in toxicology to describe a dose-dependent response to a toxic agent, is suggested to study both beneficial and detrimental effects of ischemic postconditioning. Experimental strategies are discussed, including how to define the hazards of ischemic (homologous) postconditioning and the possibility of employing non-ischemic (heterologous) postconditioning to facilitate clinical translation. This review concludes that a more detailed assessment of ischemic postconditioning and studies of a broad range of heterologous postconditioning models are warranted for future clinical translation.
doi:10.1007/s12975-012-0243-0
PMCID: PMC3601799  PMID: 23524538
ischemic postconditioning; preconditioning; stroke; hormesis; clinical translation
4.  A Part-Based Probabilistic Model for Object Detection with Occlusion 
PLoS ONE  2014;9(1):e84624.
The part-based method has been a fast rising framework for object detection. It is attracting more and more attention for its detection precision and partial robustness to the occlusion. However, little research has been focused on the problem of occlusion overlapping of the part regions, which can reduce the performance of the system. This paper proposes a part-based probabilistic model and the corresponding inference algorithm for the problem of the part occlusion. The model is based on the Bayesian theory integrally and aims to be robust to the large occlusion. In the stage of the model construction, all of the parts constitute the vertex set of a fully connected graph, and a binary variable is assigned to each part to indicate its occlusion status. In addition, we introduce a penalty term to regularize the argument space of the objective function. Thus, the part detection is formulated as an optimization problem, which is divided into two alternative procedures: the outer inference and the inner inference. A stochastic tentative method is employed in the outer inference to determine the occlusion status for each part. In the inner inference, the gradient descent algorithm is employed to find the optimal positions of the parts, in term of the current occlusion status. Experiments were carried out on the Caltech database. The results demonstrated that the proposed method achieves a strong robustness to the occlusion.
doi:10.1371/journal.pone.0084624
PMCID: PMC3894947  PMID: 24465420
5.  Safety and efficacy of thoracoscopic wedge resection for elderly high-risk patients with stage I peripheral non-small-cell lung cancer 
Background
Elderly patients with severe cardiopulmonary and other system dysfunctions are unable to tolerate pulmonary lobectomy. This study aimed to evaluate the risk and efficacy of wedge resection under video-assisted thoracoscopic surgery (VATS) on elderly high-risk patients with stage I peripheral non-small-cell lung cancer (PNSCLC).
Methods
Elderly patients (≥70 years) with suspected PNSCLC were divided into high-risk group and conventional risk group. The high-risk patients confirmed in stage I by the examination of positron emission tomography computed tomography (PET-CT) and the postoperative patients in stage I PNSCLC with negative incisal margin were treated with VATS wedge resection. The conventional risk patients were treated with VATS radical resection and systematic lymphadenectomy. The clinical and pathological data were recorded. The total survival, tumor-free survival, recurrence time and style of patients were followed up.
Results
The operative time and blood loss of the VATS wedge resection group (69.4 ± 15.5 min, 52.1 ± 11.2 ml) were significantly less than those of the VATS radical resection group (128 ± 35.5 min, 217.9 ± 87.1 ml). Neither groups had postoperative death. The overall and tumor-free survival rate of the VATS wedge resection group within three years were 66.7% and 60.0%, and those of the VATS radical resection group were 93.8% and 94.1%, without significant difference (P > 0.05). The recurrence rates of the VATS wedge resection group and VATS radical resection group were 14.3% and 3.0%, without significant difference (P > 0.05).
Conclusion
It is safe, minimally invasive and meaningful to perform VATS wedge resection on the elderly high-risk patients with stage I PNSCLC.
doi:10.1186/1749-8090-8-231
PMCID: PMC3896765  PMID: 24359930
Elderly; Early lung cancer; Thoracoscope
6.  NADPH oxidase modulates MHC class II antigen presentation by B cells 
Summary
Phagocyte NADPH oxidase plays a key role in pathogen clearance via reactive oxygen species (ROS) production. Defects in oxidase function result in chronic granulomatous disease (CGD) with hallmark recurrent microbial infections and inflammation. The oxidase′s role in the adaptive immune response is not well-understood. Class II presentation of cytoplasmic and exogenous Ag to CD4+ T cells was impaired in human B cells with reduced oxidase p40phox subunit expression. Naturally arising mutations which compromise p40phox function in a CGD patient also perturbed class II Ag presentation and intracellular ROS production. Reconstitution of patient B cells with wild-type, but not a mutant, p40phox allele restored exogenous Ag presentation and intracellular ROS generation. Remarkably, class II presentation of epitopes from membrane Ag was robust in p40phox-deficient B cells. These studies reveal a role for NADPH oxidase and p40phox in skewing epitope selection and T cell recognition of self Ag.
doi:10.4049/jimmunol.1103080
PMCID: PMC3466399  PMID: 22984083
Human B cells; MHC class II presentation; NADPH oxidase
7.  Intrathoracic giant pleural lipoma: case report and review of the literature 
This report describes a giant pleural lipoma that arose from the pleura of the 7th anterior intercostal space and occupied approximately 75% of the right pleural cavity in a 49-year-old woman. The tumor was completely excised by right thoracotomy. The complete histopathological investigation showed pleural lipoma, and we made a review of literature.
doi:10.1186/1749-8090-8-196
PMCID: PMC3973812  PMID: 24120207
Intrathoracic tumor; Pleural lipoma; Imaging; Right thoracotomy surgery
8.  Four Common Vascular Endothelial Growth Factor Polymorphisms (−2578C>A, −460C>T, +936C>T, and +405G>C) in Susceptibility to Lung Cancer: A Meta-Analysis 
PLoS ONE  2013;8(10):e75123.
Background and Objective
Vascular endothelial growth factor (VEGF) is one of the key initiators and regulators of angiogenesis and it plays a vital role in the onset and development of malignancy. The association between VEGF gene polymorphisms and lung cancer risk has been extensively studied in recent years, but currently available results remain controversial or ambiguous. The aim of this meta-analysis is to investigate the associations between four common VEGF polymorphisms (i.e., −2578C>A, −460C>T, +936C>T and +405C>G) and lung cancer risk.
Methods
A comprehensive search was conducted to identify all eligible studies to estimate the association between VEGF polymorphisms and lung cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of this association.
Results
A total of 14 published case-control studies with 4,664 cases and 4,571 control subjects were identified. Our meta-analysis provides strong evidence that VEGF −2578C>A polymorphism is capable of increasing lung cancer susceptibility, especially among smokers and lung squamous cell carcinoma (SCC) patients. Additionally, for +936C>T polymorphism, increased lung cancer susceptibility was only observed among lung adenocarcinoma patients. In contrast, VEGF −460C>T polymorphism may be a protective factor among nonsmokers and SCC patients. Nevertheless, we did not find any association between +405C>G polymorphism and lung cancer risk, even when the groups were stratified by ethnicity, smoking status or histological type.
Conclusion
This meta-analysis recommends more investigations into the relationship between −2578C>A and −460C>T lung cancer risks. More detailed and well-designed studies should be conducted to identify the causal variants and the underlying mechanisms of the possible associations.
doi:10.1371/journal.pone.0075123
PMCID: PMC3788083  PMID: 24098368
9.  Altered functional brain networks in Prader–Willi syndrome 
NMR in biomedicine  2013;26(6):622-629.
Prader–Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating.
doi:10.1002/nbm.2900
PMCID: PMC3776442  PMID: 23335390
Prader; Willi syndrome; eating disorder; obesity; amplitude of low-frequency fluctuation; resting-state networks; functional MRI
10.  SOD mRNA and MDA Expression in Rectus Femoris Muscle of Rats with Different Eccentric Exercise Programs and Time Points 
PLoS ONE  2013;8(9):e73634.
Purpose
Although superoxide dismutase (SOD) and malondialdehyde (MDA) affect Delayed Onset Muscle Soreness (DOMS), their effects are unclear in rectus femoris muscles (RFM) of rats with different eccentric exercise programs and time points. The purpose of this study is to investigate the effects of the various eccentric exercise programs at different time points on the SOD mRNA expression and MDA using rat as the animal model.
Methods
248 male rats were randomly divided into 4 groups: control group (CTL, n = 8), once-only exercise group (OEG, n = 80), continuous exercise group (CEG, n = 80), and intermittent exercise group (IEG, n = 80). Each exercise group was divided into 10 subgroups that exercised 0.5 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, or 168 h. Rats were sacrificed and their SOD mRNA expression, and MDA concentrations of skeletal muscle tissue were measured.
Results
The specimen in all eccentric exercise programs showed increased RFM SOD1 mRNA expression levels at 0.5 h (P<0.05), and decreased RFM SOD3 mRNA expression at 0.5 h (P<0.05). The continuous eccentric exercise (CE) significantly enhanced muscle SOD2 mRNA level at 0.5 h (P<0.05). After once-only eccentric exercise (OE), SOD1, SOD2, and SOD3 mRNA expression significantly increased at 96 h, whereas MDA concentrations decreased at 96 h. After CE, the correlation coefficients of SOD1, SOD2, SOD3 mRNA expression levels and MDA concentrations were −0.814, −0.763, −0.845 (all P<0.05) at 12 h.
Conclusion
Regular eccentric exercise, especially CE could enhance SOD1 and SOD2 mRNA expression in acute stage and the SOD2 mRNA expression correlates to MDA concentration in vivo, which may improve the oxidative adaption ability of skeletal muscles.
doi:10.1371/journal.pone.0073634
PMCID: PMC3772806  PMID: 24058480
11.  Shear Wave Speed Measurement Using an Unfocused Ultrasound Beam 
Ultrasound in medicine & biology  2012;38(9):1646-1655.
Tissue elasticity is related to pathology and therefore has important medical applications. Radiation force from a focused ultrasound beam has been used to produce shear waves in tissues for shear wave speed and tissue elasticity measurements. The feasibility of shear wave speed measurement using radiation force for an unfocused ultrasound beam is demonstrated in this study with a linear and a curved array transducer. Consistent measurement of shear wave speed was achieved over a relatively long axial extent (z = 10-40 mm for the linear array, and z = 15-60 mm for the curved array) in 3 calibrated phantoms with different shear moduli. In vivo measurements on the biceps of a healthy volunteer show consistent increase of shear wave speed for the biceps under 0, 1, 2, and 3 kg loading. Advantages and limitations of unfocused push are discussed.
doi:10.1016/j.ultrasmedbio.2012.05.015
PMCID: PMC3413738  PMID: 22766123
Elasticity; Shear wave; Ultrasound radiation force; Unfocused
12.  Comb-push Ultrasound Shear Elastography (CUSE): A Novel Method for Two-dimensional Shear Elasticity Imaging of Soft Tissues 
IEEE transactions on medical imaging  2012;31(9):1821-1832.
Fast and accurate tissue elasticity imaging is essential in studying dynamic tissue mechanical properties. Various ultrasound shear elasticity imaging techniques have been developed in the last two decades. However, to reconstruct a full field-of-view 2D shear elasticity map, multiple data acquisitions are typically required. In this paper, a novel shear elasticity imaging technique, comb-push ultrasound shear elastography (CUSE), is introduced in which only one rapid data acquisition (less than 35 ms) is needed to reconstruct a full field-of-view 2D shear wave speed map (40 mm × 38 mm). Multiple unfocused ultrasound beams arranged in a comb pattern (comb-push) are used to generate shear waves. A directional filter is then applied upon the shear wave field to extract the left-to-right (LR) and right-to-left (RL) propagating shear waves. Local shear wave speed is recovered using a time-of-flight method based on both LR and RL waves. Finally a 2D shear wave speed map is reconstructed by combining the LR and RL speed maps. Smooth and accurate shear wave speed maps are reconstructed using the proposed CUSE method in two calibrated homogeneous phantoms with different moduli. Inclusion phantom experiments demonstrate that CUSE is capable of providing good contrast (contrast-to-noise-ratio ≥ 25 dB) between the inclusion and background without artifacts and is insensitive to inclusion positions. Safety measurements demonstrate that all regulated parameters of the ultrasound output level used in CUSE sequence are well below the FDA limits for diagnostic ultrasound.
doi:10.1109/TMI.2012.2205586
PMCID: PMC3475422  PMID: 22736690
comb-push; unfocused ultrasound beam; ultrasound elastography; acoustic radiation force; inclusion
13.  Identification of candidate genes for lung cancer somatic mutation test kits 
Genetics and Molecular Biology  2013;36(3):455-464.
Over the past three decades, mortality from lung cancer has sharply and continuously increased in China, ascending to the first cause of death among all types of cancer. The ability to identify the actual sequence of gene mutations may help doctors determine which mutations lead to precancerous lesions and which produce invasive carcinomas, especially using next-generation sequencing (NGS) technology. In this study, we analyzed the latest lung cancer data in the COSMIC database, in order to find genomic “hotspots” that are frequently mutated in human lung cancer genomes. The results revealed that the most frequently mutated lung cancer genes are EGFR, KRAS and TP53. In recent years, EGFR and KRAS lung cancer test kits have been utilized for detecting lung cancer patients, but they presented many disadvantages, as they proved to be of low sensitivity, labor-intensive and time-consuming. In this study, we constructed a more complete catalogue of lung cancer mutation events including 145 mutated genes. With the genes of this list it may be feasible to develop a NGS kit for lung cancer mutation detection.
doi:10.1590/S1415-47572013000300022
PMCID: PMC3795175  PMID: 24130455
Lung cancer; Next-generation sequencing; Somatic mutation kit; COSMIC
14.  Comparative Quantitative Analysis of Gene Expression Profiles of Glycoside Hydrolase Family 10 Xylanases in the Sheep Rumen during a Feeding Cycle 
Xylanase is a crucial hydrolytic enzyme that degrades plant polysaccharides in the rumen. To date, there is no information on the genetic composition and expression characteristics of ruminal xylanase during feeding cycles of ruminants. Here, the major xylanase of the glycoside hydrolase family 10 (GH 10) from the rumen of small-tail Han sheep was investigated during a feeding cycle. We identified 44 distinct GH 10 xylanase gene fragments at both the genomic and transcriptional levels. Comparison of their relative abundance showed that results from the evaluation of functional genes at the transcriptional level are more reliable indicators for understanding fluctuations in xylanase levels. The expression patterns of six xylanase genes, detected at all time points of the feeding cycle, were investigated; we observed a complex trend of gene expression over 24 h, revealing the dynamic expression of xylanases in the rumen. Further correlation analysis indicated that the rumen is a dynamic ecosystem where the transcript profiles of xylanase genes are closely related to ruminal conditions, especially rumen pH and bacterial population. Given the huge diversity and changing composition of enzymes over the entire rumen, this research provides valuable information for understanding the role of functional genes in the digestion of plant material.
doi:10.1128/AEM.02733-12
PMCID: PMC3568598  PMID: 23220966
15.  Video-assisted thoracoscopic surgery versus robotic-assisted thoracoscopic surgery in the surgical treatment of Masaoka stage I thymoma 
Background
The purpose of this study was to compare perioperative outcomes in patients who underwent video-assisted thoracoscopic surgery or robot-assisted thoracoscopic surgery and assess the feasibility of robotic-assisted thymectomy for the treatment of Masaoka stage I.
Methods
We evaluated the short-term outcomes of 46 patients who underwent surgery for Masaoka stage I thymoma without myasthenia gravis between January 2009 and June 2012. Of these patients, 25 received unilateral video-assisted thoracoscopic surgery (VATS group) and the rest 21 recieved unilateral robotic-assisted thoracoscopic surgery (RATS group). We evaluated the duration of surgery, amount of intraoperative blood loss, duration of chest drainage, duration of postoperative hospital stay, hospitalization costs, postoperative complications and oncological outcomes.
Results
The duration of surgery was not significantly different between the two groups. Intraoperative blood loss volumes did not differ significantly between the VATS and RATS groups (86.8 mL and 58.6 mL, respectively; P=0.168). The postoperative hospital stay was significantly shorter in the RATS group (3.7 days vs. 6.7 days; P <0.01), and the postoperative pleural drainage volume of the RATS group was significantly less than VATS group (1.1 days vs. 3.6 days; P <0.01). No patients in the RATS group needed conversion to open surgery. However, in the VATS series, one patient had conversion to an open procedure. No surgical complications were observed except that one case had pulmonary atelectasis in the RATS group and one case developed pneumonia after surgery. Use of robot is much more expensive than video. No early recurrence was observed in both groups.
Conclusions
Robotic thymectomy is feasible and safe for Masaoka stage I thymoma. RATS is equally minimally invasive as VATS and results in a shorter drainage period and reduced hospital stay compared with the VATS approach.
doi:10.1186/1477-7819-11-157
PMCID: PMC3716986  PMID: 23870330
Robotics; Thymoma; Minimally invasive surgery; Thymus
16.  Distinctive effects of T cell subsets in neuronal injury induced by co-cultured splenocytes in vitro and by in vivo stroke in mice 
Background and purpose
T cells and their subsets modulate ischemic brain injury. We studied the effects of the absence of T cell subsets on brain infarction after in vivo stroke and then used an in vitro co-culture system of splenocytes and neurons to further identify the roles of T cell subsets in neuronal death.
Methods
Stroke was induced by MCA suture occlusion in mice and infarct sizes were measured 2 days post-stroke.
Splenocytes were co-cultured with neurons, and neuronal survival was measured 3 days later.
Results
A deficiency of both T and B cells (SCID) and the paucity of CD4 or CD8 T cells equally resulted in smaller infarct sizes as measured 2 days post-stroke. Although a functional deficiency of regulatory T cells had no effect, impaired Th1 immunity reduced infarction and impaired Th2 immunity aggravated brain injury, which may be due to an inhibited and enhanced inflammatory response in mice deficient in Th1 and Th2 immunity, respectively. In the in vitro co-culture system, WT splenocytes resulted in dose-dependent neuronal death. The neurotoxicity of splenocytes from the above immunodeficient mice was consistent with their effects on stroke in vivo , except for the mice with the paucity of CD4 or CD8 T cells, which did not alter the ratio of neuronal death.
Conclusion
T cell subsets play critical roles in brain injury induced by stroke. The detrimental versus beneficial effects of Th1 cells and Th2 cells both in vivo and in vitro reveal differential therapeutic target strategies for stroke treatment.
doi:10.1161/STROKEAHA.112.656611
PMCID: PMC3506376  PMID: 22678086
cerebral ischemia; stroke; T cells; Th1; Th2
17.  Brain 3-Mercaptopyruvate Sulfurtransferase (3MST): Cellular Localization and Downregulation after Acute Stroke 
PLoS ONE  2013;8(6):e67322.
3-Mercaptopyruvate sulfurtransferase (3MST) is an important enzyme for the synthesis of hydrogen sulfide (H2S) in the brain. We present here data that indicate an exclusively localization of 3MST in astrocytes. Regional distribution of 3MST activities is even and unremarkable. Following permanent middle cerebral artery occlusion (pMCAO), 3MST was down-regulated in both the cortex and striatum, but not in the corpus collosum. It appears that the down-regulation of astrocytic 3MST persisted in the presence of astrocytic proliferation due to gliosis. Our observations indicate that 3MST is probably not responsible for the increased production of H2S following pMCAO. Therefore, cystathionine β-synthase (CBS), the alternative H2S producing enzyme in the CNS, remains as a more likely potential therapeutic target than 3MST in the treatment of acute stroke through inhibition of H2S production.
doi:10.1371/journal.pone.0067322
PMCID: PMC3689812  PMID: 23805308
18.  Using hormetic strategies to improve ischemic preconditioning and postconditioning against stroke 
Both ischemic preconditioning (IPreC) and ischemic postconditioning (IPostC) trigger endogenous neuroprotective mechanisms in cerebral ischemia. IPreC is defined as a brief ischemia that protects against a subsequent severe ischemia, while IPostC refers to a series of brief cerebral blood vessel occlusions performed at reperfusion following an ischemic event. Hormesis describes a biphasic dose-response relationship in toxicology, where a low dose of toxicant stimulates and a high dose inhibits biological responses. In general, any minor stress will stimulate a biological system to generate an adaptive response; in most cases, if not all, such an adaptive response to a minor stress is beneficial to the biological system. Proponents of hormesis suggest that this effect is independent of any models, either in vivo or in vitro, from animal, plant, fungi, yeast, to bacteria, by any measurement of end points, survival ratio or time, growth, tissue repair, life span, cognition, learning and memory. In this review, we examine whether IPreC and IPostC are actually sub-forms of hormesis and whether quantitative hormetic strategies can be used to study IPreC and IPostC. By integrating the concepts of IPreC and IPostC with hormesis, we aim to broaden the avenues leading to clinical translation of IPreC and IPostC in stroke treatment.
PMCID: PMC3669735  PMID: 23750305
Ischemic postconditioning; preconditioning; stroke; hormesis
19.  Phosphorylated MAPK/ERK1/2 may not always represent its kinase activity in a rat model of focal cerebral ischemia with or without ischemic preconditioning 
Neuroscience  2012;209:155-160.
The ERK 1/2 protein require a dual phosphorylation at conserved threonine and tyrosine residues to be fully activated under normal physiological conditions. Thus, ERK1/2 kinase activity is often defined by the quantity of phosphorylated kinase. However, this may not accurately represent its true activity under certain pathological conditions. We investigated whether ERK1/2 kinase activity is proportional to its phosphorylation state in a rat focal ischemia model with and without rapid ischemic preconditioning. We showed that phosphorylated-ERK1/2 protein levels were increased 2.6±0.07 fold, and ERK1/2 kinase activity was increased 10.6±1.9 fold in animals receiving ischemic preconditioning alone without test ischemia compared with sham group (P<0.05, n=6/group), suggesting that phosphorylated-ERK1/2 protein levels represent its kinase activity under these conditions. However, preconditioning plus test ischemia robustly blocked ERK1/2 kinase activity, while it increased phosphorylated-ERK1/2 protein levels beyond those receiving test ischemia alone, suggesting that phosphorylated-ERK1/2 protein levels were not representative of actual kinase activity in this pathological condition. In conclusion, protein phosphorylation levels of ERK1/2 do not always correspond to kinase activity, thus, measuring the true kinase activity is essential.
doi:10.1016/j.neuroscience.2012.02.005
PMCID: PMC3322316  PMID: 22366512
ischemic preconditioning; kinase activity; MAPK; ERK1/2; focal ischemia; stroke
20.  T Cells Contribute to Stroke-Induced Lymphopenia in Rats 
PLoS ONE  2013;8(3):e59602.
Stroke-induced immunodepression (SIID) results when T cell and non-T immune cells, such as B cells, NK cells and monocytes, are reduced in the peripheral blood and spleen after stroke. We investigated the hypothesis that T cells are required for the reductions in non-T cell subsets observed in SIID, and further examined a potential correlation between lymphopenia and High-mobility group protein B1 (HMGB1) release, a protein that regulates inflammation and immunodepression. Our results showed that focal ischemia resulted in similar cortical infarct sizes in both wild type (WT) Sprague Dawley (SD) rats and nude rats with a SD genetic background, which excludes the possibility of different infarct sizes affecting SIID. In addition, the numbers of CD68-positive macrophages in the ischemic brain did not differ between WT and nude rats. Numbers of total peripheral blood mononuclear cells (PBMCs) or splenocytes and lymphocyte subsets, including T cells, CD4+ or CD8+ T cells, B cells and monocytes in the blood and spleen, were decreased after stroke in WT rats. In nude rats, however, the total number of PBMCs and absolute numbers of NK cells, B cells and monocytes were increased in the peripheral blood after stroke; nude rats are athymic therefore they have few T cells present. Adoptive transfer of WT splenocytes into nude rats before stroke resulted in lymphopenia after stroke similar to WT rats. Moreover, in vitro T cell proliferation stimulated by Concanavalin A was significantly inhibited in WT rats as well as in nude rats receiving WT splenocyte adoptive transfer, suggesting that T cell function is indeed inhibited after stroke. Lastly, we demonstrated that stroke-induced lymphopenia is associated with a reduction in HMGB1 release in the peripheral blood. In conclusion, T cells are required for stroke-induced reductions in non-T immune cells and they are the most crucial lymphocytes for SIID.
doi:10.1371/journal.pone.0059602
PMCID: PMC3598760  PMID: 23555048
21.  Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of non-lymph node thoracic lesions 
Annals of Thoracic Medicine  2013;8(1):14-21.
AIMS:
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has shown excellent diagnostic capabilities for mediastinal and hilar lymphadenopathy. However, its value in thoracic non-lymph node lesions is less clear. This study was designed to assess the value of EBUS-TBNA in distinguishing malignant from benign thoracic non-lymph node lesions.
METHODS:
From October 2009 to August 2011, 552 patients underwent EBUS-TBNA under local anesthesia and with conscious sedation. We retrospectively reviewed 81 of these patients who had tracheobronchial wall-adjacent intrapulmonary or isolated mediastinal non-lymph node lesions. On-site cytological evaluation was not used. Immunohistochemistry (IHC) was performed to distinguish the origin or type of malignancy when necessary.
RESULTS:
EBUS-TBNA was performed in 68 tracheobronchial wall-adjacent intrapulmonary and 13 isolated mediastinal non-lymph node lesions. Of the 81 patients, 77 (95.1%, 60 malignancies and 17 benignancies) were diagnosed through EBUS-TBNA, including 57 primary lung cancers, 2 mediastinal tumors, 1 pulmonary metastatic adenocarcinoma, 7 inflammation, 5 tuberculosis, 3 mediastinal cysts, 1 esophageal schwannoma, and 1 focal fibrosis. There were four false-negative cases (4.9%). Of the 60 malignancies, there were 9 (15.0%) which originally had no definite histologic origin or type. Thus, IHC was performed, with 7 (77.8%) being subsequently confirmed. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in distinguishing malignant from benign lesions were 93.4% (60/64), 100% (17/17), 100% (60/60), 81.0% (17/21), and 95.1% (77/81), respectively.
CONCLUSION:
EBUS-TBNA is a safe procedure with a high sensitivity for distinguishing malignant from benign thoracic non-lymph node lesions within the reach of EBUS-TBNA, with IHC usually providing a more definitive diagnosis.
doi:10.4103/1817-1737.105714
PMCID: PMC3573552  PMID: 23439919
Endobronchial ultrasound; immunohistochemistry; lung cancer; thoracic lesion; transbronchial needle aspiration
23.  Bias Observed in Time-of-flight Shear Wave Speed Measurements Using Radiation Force of a Focused Ultrasound Beam 
Ultrasound in medicine & biology  2011;37(11):1884-1892.
Measurement of shear wave propagation speed has important clinical applications because it is related to tissue stiffness and health state. Shear waves can be generated in tissues by the radiation force of a focused ultrasound beam (push beam). Shear wave speed can be measured by tracking its propagation laterally from the push beam focus using the time-of-flight principle. This study shows that shear wave speed measurements with such methods can be transducer, depth, and lateral tracking range dependent. Three homogeneous phantoms with different stiffness were studied using curvilinear and linear array transducer. Shear wave speed measurements were made at different depths, using different aperture sizes for push, and at different lateral distance ranges from the push beam. The curvilinear transducer shows a relatively large measurement bias that is depth dependent. The possible causes of the bias and options for correction are discussed. These bias errors must be taken into account to provide accurate and precise time-of-flight shear wave speed measurements for clinical use.
doi:10.1016/j.ultrasmedbio.2011.07.012
PMCID: PMC3199321  PMID: 21924817
Shear wave speed; Liver fibrosis; Bias; ARFI
24.  The Protective Effects of Ischemic Postconditioning against Stroke: From Rapid to Delayed and Remote Postconditioning 
The author reviews the protective effects of ischemic postconditioning, a recently emerging strategy with broad implications in the search for new treatments in stroke and myocardial ischemic injury. Ischemic postconditioning, which refers to a series of brief ischemia and reperfusion cycles applied immediately at the site of the ischemic organ after reperfusion, results in reduced infarction in both cerebral and myocardial ischemia. Conventional postconditioning induced within a few minutes after reperfusion is arbitrarily defined as rapid postconditioning. In contrast, postconditioning performed hours to days after stroke is defined as delayed postconditioning. In addition, postconditioning can be mimicked using anesthetics or other pharmacological agents as stimuli to protect against ischemia/reperfusion injury or performed in a distant organ, which is known as remote postconditioning. In this article, the author discusses the conceptual origin of classical rapid ischemic postconditioning and its evolution into a term that represents a broad range of stimuli or triggers, including delayed postconditioning, pharmacological postconditioning, and remote postconditioning. Thereafter, various in vivo and in vitro models of postconditioning and its potential protective mechanisms are discussed. Since the concept of postconditioning is so closely associated with that of preconditioning and both share some common protective mechanisms, whether a combination of preconditioning and postconditioning offers greater protection than preconditioning or postconditioning alone is also discussed.
doi:10.2174/1877381801002010138
PMCID: PMC3204606  PMID: 22053169
Postconditioning; preconditioning; stroke; cerebral ischemia; focal ischemia; neuroprotection
25.  A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012 
Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs) in China. This study systematically reviewed GSDs as defined in “Nosology and Classification of genetic skeletal disorders (2010 version)” using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% (12,312 cases) of the total cases. Five groups (group 8, 12, 14, 18, 21) defined by “Nosology and Classification of genetic skeletal disorders” have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%). In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.
doi:10.1186/1750-1172-7-55
PMCID: PMC3492206  PMID: 22913777
Rare diseases; Genetic skeletal diseases; China; Bibliographic study

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