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1.  Dissociable early attentional control mechanisms underlying cognitive and affective conflicts 
Scientific Reports  2016;6:37633.
It has been well documented that cognitive conflict is sensitive to the relative proportion of congruent and incongruent trials. However, few studies have examined whether affective conflict processing is modulated as a function of proportion congruency (PC). To address this question we recorded event-related potentials (ERP) while subjects performed both cognitive and affective face-word Stroop tasks. By varying the proportion of congruent and incongruent trials in each block, we examined the extent to which PC impacts both cognitive and affective conflict control at different temporal stages. Results showed that in the cognitive task an anteriorly localized early N2 component occurred predominantly in the low proportion congruency context, whereas in the affective task it was found to occur in the high proportion congruency one. The N2 effects across the two tasks were localized to the dorsolateral prefrontal cortex, where responses were increased in the cognitive task but decreased in the affective one. Furthermore, high proportions of congruent items produced both larger amplitude of a posteriorly localized sustained potential component and a larger behavioral Stroop effect in cognitive and affective tasks. Our findings suggest that cognitive and affective conflicts engage early dissociable attentional control mechanisms and a later common conflict response system.
doi:10.1038/srep37633
PMCID: PMC5124857  PMID: 27892513
2.  A critical role of temporoparietal junction in the integration of top-down and bottom-up attentional control 
Human brain mapping  2015;36(11):4317-4333.
Information processing can be biased toward behaviorally relevant and salient stimuli by top-down (goal-directed) and bottom-up (stimulus-driven) attentional control processes. However, the neural basis underlying the integration of these processes is not well understood. We employed functional magnetic resonance imaging and transcranial direct-current stimulation (tDCS) in humans to examine the brain mechanisms underlying the interaction between these two processes. We manipulated the cognitive load involved in top-down processing and stimulus surprise involved in bottom-up processing in a factorial design by combining a majority function task and an oddball paradigm. We found that high cognitive load and high surprise level were associated with prolonged reaction time compared to low cognitive load and low surprise level, with a synergistic interaction effect which was accompanied by a greater deactivation of bilateral temporoparietal junction (TPJ). In addition, the TPJ displayed negative functional connectivity with right middle occipital gyrus involved in bottom-up processing (modulated by the interaction effect) and the right frontal eye field (FEF) involved in top-down control. The enhanced negative functional connectivity between the TPJ and right FEF was accompanied by a larger behavioral interaction effect across subjects. Application of cathodal tDCS over the right TPJ eliminated the interaction effect. These results suggest that the TPJ plays a critical role in processing bottom-up information for top-down control of attention.
doi:10.1002/hbm.22919
PMCID: PMC4619130  PMID: 26308973
attentional control; fMRI; interaction; tDCS; temporoparietal junction
3.  Quantitative Characterization of Functional Anatomical Contributions to Cognitive Control under Uncertainty 
Journal of cognitive neuroscience  2014;26(7):1490-1506.
While much evidence indicates that reaction time increases as a function of computational load in many cognitive tasks, quantification of changes in neural activity related to increasing demand of cognitive control has rarely been attempted. In this functional magnetic resonance imaging study, we used a majority function task to quantify the effect of computational load on brain activation, reflecting the mental processes instantiated by cognitive control under conditions of uncertainty. We found that the activation of the fronto-parieto-cingulate (FPC) system as well as the deactivation of the anticorrelated default mode network varied parametrically as a function of information entropy, estimated with an information theoretic model. The current findings suggest that activity changes in the dynamic networks of the brain (especially the FPC system) track with information entropy or uncertainty, rather than only conflict or other commonly proposed targets of cognitive control.
doi:10.1162/jocn_a_00554
PMCID: PMC5070967  PMID: 24392900
Cognitive control; computational load; entropy; fMRI; information theory
4.  Prospective study of Helicobacter pylori antigens and gastric noncardia cancer risk in the Nutrition Intervention Trial cohort 
Helicobacter pylon (H. pylori) infection is the strongest known risk factor for gastric non-cardia adenocarcinoma (GNCA). We used multiplex serology to determine whether seropositivity to 15 H. pylori proteins is associated with the subsequent development of non-cardia gastric cancer in Linxian, China.
We included 448 GNCA cases and 1242 controls from two time-points within the Linxian General Population Nutrition Intervention Trial, Linxian. H. pylori multiplex seropositivity was defined as positivity to ≥4 of the 15 included antigens. Odds ratios (OR) and 95% confidence intervals were adjusted for major GNCA risk factors. Additionally, we undertook a meta-analysis combining H. pylori multiplex serology data from both timepoints.
H. pylori multiplex seropositivity was associated with a significant increase in risk of GNCA at one time-point (1985; OR: 3.44, 95% CI: 1.91, 6.19) and this association remained significant following adjustment for H. pylori or CagA ELISA seropositivity (OR: 2.92, 95% CI: 1.56, 5.47). Combining data from both timepoints in a meta-analysis H. pylori multiplex seropositivity was associated with an increased risk of GNCA, as were 6 individual antigens: GroEL, HP0305, CagA, VacA, HcpC and Omp. CagM was inversely associated with risk of GNCA.
We identified 6 individual antigens which confer an increase in risk of GNCA within this population of high H. pylori seroprevalence, as well as a single antigen which may be inversely associated with GNCA risk. We further determined that the H. pylori multiplex assay provides additional information to the conventional ELISA methods on risk of GNCA.
doi:10.1002/ijc.29543
PMCID: PMC4529753  PMID: 25845708
Helicobacter pylori; multiplex serology; gastric cancer; esophageal cancer
5.  The Capacity of Cognitive Control Estimated from a Perceptual Decision Making Task 
Scientific Reports  2016;6:34025.
Cognitive control refers to the processes that permit selection and prioritization of information processing in different cognitive domains to reach the capacity-limited conscious mind. Although previous studies have suggested that the capacity of cognitive control itself is limited, a direct quantification of this capacity has not been attempted. In this behavioral study, we manipulated the information rate of cognitive control by parametrically varying both the uncertainty of stimul measured as information entropy and the exposure time of the stimuli. We used the relationship between the participants’ response accuracy and the information rate of cognitive control (in bits per second, bps) in the model fitting to estimate the capacity of cognitive control. We found that the capacity of cognitive control was approximately 3 to 4 bps, demonstrating that cognitive control as a higher-level function has a remarkably low capacity. This quantification of the capacity of cognitive control may have significant theoretical and clinical implications.
doi:10.1038/srep34025
PMCID: PMC5034293  PMID: 27659950
6.  Autonomic and Brain Responses Associated with Empathy Deficits in Autism Spectrum Disorder 
Human brain mapping  2015;36(9):3323-3338.
Accumulating evidence suggests that autonomic signals and their cortical representations are closely linked to emotional processes, and that related abnormalities could lead to social deficits. Although socio-emotional impairments are a defining feature of autism spectrum disorder (ASD), empirical evidence directly supporting the link between autonomic, cortical, and socio-emotional abnormalities in ASD is still lacking. In this study, we examined autonomic arousal indexed by skin conductance responses (SCR), concurrent cortical responses measured by functional magnetic resonance imaging, and effective brain connectivity estimated by dynamic causal modeling, in seventeen un-medicated high-functioning adults with ASD and seventeen matched controls, while they performed an empathy-for-pain task. Compared to controls, adults with ASD showed enhanced SCR related to empathetic pain, along with increased neural activity in the anterior insular cortex, although their behavioral empathetic pain discriminability was reduced and overall SCR was decreased. ASD individuals also showed enhanced correlation between SCR and neural activities in the anterior insula. Importantly, significant group differences in effective brain connectivity were limited to greater reduction in the negative intrinsic connectivity of the anterior insular cortex in the ASD group, indicating a failure in attenuating anterior insular responses to empathetic pain. These results suggest that aberrant interoceptive precision, as indexed by abnormalities in autonomic activity and its central representations, may underlie empathy deficits in ASD.
doi:10.1002/hbm.22840
PMCID: PMC4545680  PMID: 25995134
autism spectrum disorder; autonomic nervous system; functional magnetic resonance imaging; brain connectivity; empathy; dynamic causal modelling; interoceptive inference
7.  The impact of endplate fracture on postoperative vertebral height loss and kyphotic deformity during treatment of osteoporotic vertebral compression fractures with balloon kyphoplasty 
Journal of Biomedical Research  2016;30(5):419-426.
Abstract
This retrospective study investigated the impact of endplate fracture on postoperative vertebral height loss and kyphotic deformity in 144 patients with osteoporotic vertebral compression fracture (OVCF), who received balloon kyphoplasty. Patients were divided into four groups: Group 1 had no superior endplate fracture, Group 2 had fractures on the anterior portion of the superior endplate, Group 3 had fractures on the posterior portion of the superior endplate, and Group 4 had complete superior endplate fractures. Anterior and middle vertebral body height, vertebral compression ratio, vertebral height loss rate, and kyphosis Cobb angle of each patient were measured and visual analogue scale (VAS) and Oswestry disability index (ODI) scores were recorded. The anterior vertebral height and kyphosis deformity of all groups significantly improved after the surgery, whereas substantial anterior vertebral height loss and increased Cobb angle were observed in all patients at the last follow-up. Although the vertebral height loss rate and the Cobb angle in Group 2, 3 and 4 were larger compared with Group 1 at the last follow-up, only the vertebral height loss rate in Group 4 and the increase in the Cobb angle in Group 2 and 4 were statistically different from those in Group 1. The VAS and ODI scores in all groups measured after the surgery and at the last follow-up were significantly lower compared with preoperative scores, but there was no significant difference among these groups. Balloon kyphoplasty significantly improved vertebral fracture height and kyphosis. Vertebral height loss and increased kyphotic deformity were observed in OVCF patients with endplate fractures after the surgery. Postoperative aggravation of kyphosis was observed in Group 2. Furthermore, severe vertebral height loss and increased kyphotic deformity were confirmed in Group 4 after the surgery. Our results suggested that postoperative vertebral height loss and aggravation of kyphosis may be associated with biomechanical changes in the vertebral body caused by endplate fracture. Therefore, surgery should not only restore compressed vertebral body height and correct kyphosis, but also correct the deformity of endplate to achieve an effective treatment of OVCF patients with endplate fracture.
doi:10.7555/JBR.30.20150071
PMCID: PMC5044714  PMID: 27845305
osteoporotic vertebral compression fracture; balloon kyphoplasty; endplate fracture; height loss; kyphosis
8.  A negative nontreponemal and/or specific antitreponemal IgM test does not exclude active infectious syphilis: evidence from a rabbit infectivity test 
Medicine  2016;95(31):e4520.
Abstract
Background:
The diagnostic criteria for active infectious syphilis in the clinic are important matter of controversy and debate. So far, clinicians habitually do use the negative results of the nontreponemal and/or the specific antitreponemal IgM as the evidences of disease-free or active infection-free status.
Method:
We present a case study involving a patient who was admitted to Zhongshan Hospital because of cerebral infarct. Clinical examination indicated he had a history of latent syphilis with negative nontreponemal and specific antitreponemal IgM tests. The cerebrospinal fluid sample from the patient was inoculated into seronegative New Zealand rabbit.
Results:
Motile Treponema pallidum was detected by a rabbit infectivity test in the patient's cerebrospinal fluid. This syphilis strain was confirmed by DNA subtyping form of “centers for disease control subtype/tp0548 sequence type”, and the strain type was 14d/f. Treatment with benzathine penicillin provided no apparent benefit, but treatment with aqueous crystalline penicillin G, especially recommended for neurosyphilis, led to disease regression. No evidence of cerebral infarct was observed during a 2-year follow-up period.
Conclusion:
The definitive differential diagnosis of active infectious syphilis should be reconsidered. Moreover, selecting the appropriate penicillin preparation is important because T pallidum can reside in sequestered sites. It is necessary to treat a patient with known invasion of the central nervous system with aqueous crystalline penicillin G, if previous treatment for syphilis failed and patients had some clinical neurological presentation that is otherwise unexplained, but that could represent neurosyphilis. Additional studies are needed to confirm the results in other syphilis patients.
doi:10.1097/MD.0000000000004520
PMCID: PMC4979861  PMID: 27495107
active infectious syphilis; antitreponemal IgM test; nontreponemal test; rabbit infectivity test
9.  Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers 
Background: Populations in north central China are at high risk for oesophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk.
Methods: We used the adaptive multilocus joint test to analyse 192 epigenetic genes involved in chromatin remodelling, DNA methylation and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined potential function of risk alleles using in silico and expression quantitative trait loci (eQTLs) analyses.
Results: Suggestive pathway-based associations were observed for the overall epigenetic (P-valuePATH = 0.034) and chromatin remodelling (P-valuePATH = 0.039) pathways with risk of GCA, but not GC, GNCA or ESCC. Overall, 37 different epigenetic machinery genes were associated with risk of one or more upper gastrointestinal (UGI) cancer sites (P-valueGENE < 0.05), including 14 chromatin remodelling genes whose products are involved in the regulation of HOX genes. We identified a gastric eQTL (rs12724079; rho = 0.37; P = 0.0006) which regulates mRNA expression of ASH1L. Several suggestive eQTLs were also found in oesophageal (rs10898459 in EED), gastric cardia (rs7157322 in DICER1; rs8179271 in ASH1L), and gastric non-cardia (rs1790733 in PPP1CA) tissues.
Conclusions: Results of our analyses provide limited but suggestive evidence for a role of epigenetic gene variation in the aetiology of UGI cancer.
doi:10.1093/ije/dyv050
PMCID: PMC4598798  PMID: 25921222
Epigenetics; chromatin remodelling; DNA methylation; microRNA; oesophageal squamous cell carcinoma; gastric cancer; gastric cardia; gastric non-cardia; SNP; gene-based; pathway-based
10.  Injuries sustained by earthquake relief workers: a retrospective analysis of 207 relief workers during Nepal earthquake 
Background
This study aimed to analyse the injuries sustained by rescue workers in earthquake relief efforts in high altitude areas for improving the ways of how to effectively prevent the injuries.
Methods
The clinical data of 207 relief workers from four military hospitals in Tibet, who were injured in the Tibetan disaster areas of China during ‘4.25’ Nepal earthquake rescue period, was retrospectively analyzed. The demographic features, sites of injury and causes of injury were investigated.
Results
The most frequently injured sites were the ankle-foot and hand-wrist (n = 61, 26.5 %), followed by injuries in leg-knee-calf (n = 22, 9.6 %), head-neck (4.87 %), thoracic and abdominal region (2.6 %) and lower back (3.9 %). The specific high-altitude environment increased the challenges associated with earthquake relief.
Discussion
The specific plateau environment and climate increased the burden and challenge in earthquake relief. The injury distribution data shown in this study demonstrated that effective organization and personnel protection can reduce the injury occurrences.
Conclusion
Relief workers were prone to suffering various injuries and diseases under specific high-altitude environment.
doi:10.1186/s13049-016-0286-4
PMCID: PMC4960884  PMID: 27456687
China; Earthquake; Fracture; Tibet plateau; Trauma; Rescue
11.  Body mass index and long‐term risk of death from esophageal squamous cell carcinoma in a Chinese population 
Thoracic Cancer  2016;7(4):387-392.
Abstract
Background
Studies based on Western populations have found that body mass index (BMI) is positively related to the risk of esophageal adenocarcinoma but inversely associated with esophageal squamous cell carcinoma (ESCC). Little reliable evidence exists of an association between BMI and ESCCin China, where ESCC incidence is high but BMI is low.
Methods
We evaluated the BMI‐ESCC association in a population‐based prospective study of 29 446 Chinese aged 40–69 with 27 years of follow‐up. China‐specific BMI cut‐offs (underweight < 18.5, healthy ≥ 18.5 to <24, overweight ≥ 24 to <28, and obese ≥ 28) and quartile categories were used to define BMI subgroups. Adjusted hazard ratios (HRs) and confidence intervals (CIs) for death from ESCC by BMI subgroups were calculated using Cox proportional hazards models.
Results
During a median follow‐up duration of 21.2 years (555 439 person‐years), 2436 ESCC deaths were identified. BMI was protective for death from ESCC with an HR of 0.97 (95% CI 0.95–0.99) for each unit increase in BMI. Relative to healthy weight, HRs for BMI were 1.21 (95% CI 1.02–1.43) for the underweight group and 0.87 (95% CI 0.78–0.98) for the overweight. Categorical quartile analyses found people with BMIs in the Q3 and Q4 groups had 16% and 13% reductions in the risk of ESCC, respectively. Gender‐specific analyses found that clear effects were evident in women only.
Conclusions
Higher BMI was associated with a reduced risk of ESCC in aChinese population.
doi:10.1111/1759-7714.12340
PMCID: PMC4930956  PMID: 27385979
Body mass index (BMI); Chinese population; esophageal squamous cell carcinoma (ESCC); overweight; underweight
12.  Venlafaxine treatment reduces the deficit of executive control of attention in patients with major depressive disorder 
Scientific Reports  2016;6:28028.
Attention plays an essential role in supporting other cognitive functions and behavior, and disturbance of attention is one of the most common symptoms in major depressive disorder (MDD). Although treatment with venlafaxine for MDD symptoms has been shown to reduce deficits in cognition and emotion regulation, it remains unclear whether venlafaxine improves specific attentional functions. We used the Attention Network Test to measure the attentional functions of alerting, orienting, and executive control before and after treatment with venlafaxine in patients with MDD compared to untreated healthy controls. Before treatment, the MDD group showed a selective impairment in alerting and executive control of attention, while there were no significant group differences in the orienting function. The interaction between group and session was significant for executive control, and after treatment with venlafaxine, the performance of the MDD group on executive control of attention was not significantly different from that of controls. Reported symptoms of MDD were also significantly reduced after treatment with venlafaxine. These results demonstrate that treatment with venlafaxine selectively normalizes the executive control function of attention in addition to improving clinical symptoms in MDD.
doi:10.1038/srep28028
PMCID: PMC4910055  PMID: 27306061
13.  Somatic and vicarious pain are represented by dissociable multivariate brain patterns 
eLife  null;5:e15166.
Understanding how humans represent others’ pain is critical for understanding pro-social behavior. ‘Shared experience’ theories propose common brain representations for somatic and vicarious pain, but other evidence suggests that specialized circuits are required to experience others’ suffering. Combining functional neuroimaging with multivariate pattern analyses, we identified dissociable patterns that predicted somatic (high versus low: 100%) and vicarious (high versus low: 100%) pain intensity in out-of-sample individuals. Critically, each pattern was at chance in predicting the other experience, demonstrating separate modifiability of both patterns. Somatotopy (upper versus lower limb: 93% accuracy for both conditions) was also distinct, located in somatosensory versus mentalizing-related circuits for somatic and vicarious pain, respectively. Two additional studies demonstrated the generalizability of the somatic pain pattern (which was originally developed on thermal pain) to mechanical and electrical pain, and also demonstrated the replicability of the somatic/vicarious dissociation. These findings suggest possible mechanisms underlying limitations in feeling others’ pain, and present new, more specific, brain targets for studying pain empathy.
DOI: http://dx.doi.org/10.7554/eLife.15166.001
eLife digest
The ability to experience others’ pain is a cornerstone of empathy, and binds us together in times of hardship. However, we have not yet fully understood the complex interactions in the brain that make people empathetic to others’ suffering. One possibility is that we experience others’ pain through the activation of the same brain regions as those that enable us to experience physical pain ourselves.
To test this idea, Krishnan et al. compared patterns of brain activity in human volunteers as they experienced pain (from heat being applied to their forearm or foot) or watched images of others’ hands or feet being injured. While watching these images, the volunteers were asked to try to imagine that the injuries were happening to their own bodies.
The patterns of brain activity that arose when the volunteers observed someone else in pain did not overlap with the patterns produced when the volunteers experienced pain themselves. Instead, seeing someone else in pain activated regions involved in taking another person’s perspective. This process, which is known as mentalizing, involves thinking about the other person’s thoughts, intentions and preferences. Thus within the brain, the experience of observing someone else in pain is distinct from that of experiencing physical pain in oneself.
The results presented by Krishnan et al. raise new questions about how the brain regions involved in empathy help us to relate to other people when they experience different types of pain. Future studies should explore the factors that influence our ability to adopt another’s perspective, and whether it might be possible to improve this ability.
DOI: http://dx.doi.org/10.7554/eLife.15166.002
doi:10.7554/eLife.15166
PMCID: PMC4907690  PMID: 27296895
pain; empathy; fMRI; multivariate patterns; Human
14.  Prognostic significance of discoidin domain receptor 2 (DDR2) expression in ovarian cancer 
Increasing evidence has suggested that discoidin domain receptor 2 (DDR2) plays an important role in cancer development and metastasis. However, the correlation between DDR2 expression and clinical outcome in ovarian cancer has not been investigated. In this study, DDR2 expression was examined by Real-time PCR in surgically resected ovarian cancer and normal ovary tissues. Besides, DDR2 expression was analyzed immunohistochemically in 103 ovarian cancer patients, and the correlation between DDR2 expression with clinicopathologic factors was analyzed. The result showed that DDR2 mRNA expression was upregulated in ovarian cancer tissues compared with normal ovary tissues. Statistical analysis revealed that DDR2 expression correlated with tumor stage (P = 0.008) and peritoneal metastasis (P = 0.009). Patients with high DDR2 expression showed poorer 5-year overall survival (P = 0.005), and DDR2 remained an independent prognostic marker for OS (P = 0.013) in multivariate analysis. Our results suggest that DDR2 might be closely associated with ovarian cancer progression and metastasis. Its high expression may serve as a potential prognostic biomarker in human ovarian cancer.
PMCID: PMC4931179  PMID: 27398168
DDR2; ovarian cancer; prognosis; metastasis
15.  Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome 
Machiela, Mitchell J. | Zhou, Weiyin | Karlins, Eric | Sampson, Joshua N. | Freedman, Neal D. | Yang, Qi | Hicks, Belynda | Dagnall, Casey | Hautman, Christopher | Jacobs, Kevin B. | Abnet, Christian C. | Aldrich, Melinda C. | Amos, Christopher | Amundadottir, Laufey T. | Arslan, Alan A. | Beane-Freeman, Laura E. | Berndt, Sonja I. | Black, Amanda | Blot, William J. | Bock, Cathryn H. | Bracci, Paige M. | Brinton, Louise A. | Bueno-de-Mesquita, H Bas | Burdett, Laurie | Buring, Julie E. | Butler, Mary A. | Canzian, Federico | Carreón, Tania | Chaffee, Kari G. | Chang, I-Shou | Chatterjee, Nilanjan | Chen, Chu | Chen, Constance | Chen, Kexin | Chung, Charles C. | Cook, Linda S. | Crous Bou, Marta | Cullen, Michael | Davis, Faith G. | De Vivo, Immaculata | Ding, Ti | Doherty, Jennifer | Duell, Eric J. | Epstein, Caroline G. | Fan, Jin-Hu | Figueroa, Jonine D. | Fraumeni, Joseph F. | Friedenreich, Christine M. | Fuchs, Charles S. | Gallinger, Steven | Gao, Yu-Tang | Gapstur, Susan M. | Garcia-Closas, Montserrat | Gaudet, Mia M. | Gaziano, J. Michael | Giles, Graham G. | Gillanders, Elizabeth M. | Giovannucci, Edward L. | Goldin, Lynn | Goldstein, Alisa M. | Haiman, Christopher A. | Hallmans, Goran | Hankinson, Susan E. | Harris, Curtis C. | Henriksson, Roger | Holly, Elizabeth A. | Hong, Yun-Chul | Hoover, Robert N. | Hsiung, Chao A. | Hu, Nan | Hu, Wei | Hunter, David J. | Hutchinson, Amy | Jenab, Mazda | Johansen, Christoffer | Khaw, Kay-Tee | Kim, Hee Nam | Kim, Yeul Hong | Kim, Young Tae | Klein, Alison P. | Klein, Robert | Koh, Woon-Puay | Kolonel, Laurence N. | Kooperberg, Charles | Kraft, Peter | Krogh, Vittorio | Kurtz, Robert C. | LaCroix, Andrea | Lan, Qing | Landi, Maria Teresa | Marchand, Loic Le | Li, Donghui | Liang, Xiaolin | Liao, Linda M. | Lin, Dongxin | Liu, Jianjun | Lissowska, Jolanta | Lu, Lingeng | Magliocco, Anthony M. | Malats, Nuria | Matsuo, Keitaro | McNeill, Lorna H. | McWilliams, Robert R. | Melin, Beatrice S. | Mirabello, Lisa | Moore, Lee | Olson, Sara H. | Orlow, Irene | Park, Jae Yong | Patiño-Garcia, Ana | Peplonska, Beata | Peters, Ulrike | Petersen, Gloria M. | Pooler, Loreall | Prescott, Jennifer | Prokunina-Olsson, Ludmila | Purdue, Mark P. | Qiao, You-Lin | Rajaraman, Preetha | Real, Francisco X. | Riboli, Elio | Risch, Harvey A. | Rodriguez-Santiago, Benjamin | Ruder, Avima M. | Savage, Sharon A. | Schumacher, Fredrick | Schwartz, Ann G. | Schwartz, Kendra L. | Seow, Adeline | Wendy Setiawan, Veronica | Severi, Gianluca | Shen, Hongbing | Sheng, Xin | Shin, Min-Ho | Shu, Xiao-Ou | Silverman, Debra T. | Spitz, Margaret R. | Stevens, Victoria L. | Stolzenberg-Solomon, Rachael | Stram, Daniel | Tang, Ze-Zhong | Taylor, Philip R. | Teras, Lauren R. | Tobias, Geoffrey S. | Van Den Berg, David | Visvanathan, Kala | Wacholder, Sholom | Wang, Jiu-Cun | Wang, Zhaoming | Wentzensen, Nicolas | Wheeler, William | White, Emily | Wiencke, John K. | Wolpin, Brian M. | Wong, Maria Pik | Wu, Chen | Wu, Tangchun | Wu, Xifeng | Wu, Yi-Long | Wunder, Jay S. | Xia, Lucy | Yang, Hannah P. | Yang, Pan-Chyr | Yu, Kai | Zanetti, Krista A. | Zeleniuch-Jacquotte, Anne | Zheng, Wei | Zhou, Baosen | Ziegler, Regina G. | Perez-Jurado, Luis A. | Caporaso, Neil E. | Rothman, Nathaniel | Tucker, Margaret | Dean, Michael C. | Yeager, Meredith | Chanock, Stephen J.
Nature Communications  2016;7:11843.
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk
doi:10.1038/ncomms11843
PMCID: PMC4909985  PMID: 27291797
16.  Comparison of Anterior Versus Posterior Approach in the Treatment of Thoracolumbar Fractures: A Systematic Review 
International Surgery  2015;100(6):1124-1133.
Despite extensive research on thoracolumbar fractures, controversy still exists about which approach is the most appropriate. Lack of evidence-based practice may result in patients being treated inappropriately. The objective of study was to perform a systematic review of the effectiveness of the anterior and posterior approaches in the treatment of thoracolumbar fractures. We conducted searches of PubMed and the Cochrane Library, searching for relevant trials up to August 2013 that compared anterior and posterior for the treatment of thoracolumbar fractures. The key words “anterior,” “posterior,” “thoracolumbar fracture,” “CCT,” and “RCT” were used. We assessed all included literature by using the Cochrane handbook (version 5.1). The results were expressed as the mean difference for continuous outcomes and risk difference for dichotomous outcomes, with a 95% confidence interval, using RevMan version 5.2. There were 3 randomized controlled trials and 11 clinical controlled trials included. The meta-analysis showed no significant difference between groups regarding Cobb angle, the Frankel scale, ASIA/JOA motor score, complications, and number of patients returning to work. Compared with the anterior approach, the posterior approach demonstrated superior canal decompression. In the burst fracture subgroup, operative times were significantly shorter and perioperative blood loss was less in the posterior approach group. The posterior approach is more effective for canal decompression, operative times, and perioperative blood loss. However, because of the lack of randomized controlled trials, and because of large sample size studies, heterogeneity was significant between reports. The optimal treatment for thoracolumbar fractures requires further study.
doi:10.9738/INTSURG-D-14-00135.1
PMCID: PMC4587517  PMID: 26414835
Anterior; Posterior; Thoracolumbar fracture; Systematic review
17.  Sulfasalazine inhibits inflammation and fibrogenesis in pancreas via NF-κB signaling pathway in rats with oxidative stress-induced pancreatic injury 
Background
Pathogenesis and effective therapeutics of chronic pancreatic inflammation and fibrosis remain uncertain.
Purpose
To investigate the effects of sulfasalazine (SF) on pancreatic inflammation and fibrogenesis.
Methods
Chronic pancreatic injury in rats was induced by diethyldithiocarbamate (DDC) and interfered by SF through intraperitoneal injection. The rats were divided into five groups: group N, normal control group, rats were treated with dilated water only; group DS1, rats received SF (10 mg/kg) 2 hours before DDC treatment; group DS2, rats were treated with DDC and then SF (100 mg/kg, twice a week); group DS3, rats were treated with DDC, then SF (100 mg/kg, thrice a week); and group DDC, rats were treated with DDC only. Pancreatic inflammation and fibrosis were determined by hematoxylin and eosin staining and Sirius red staining. The genes and proteins related to NF-κB pathway and fibrogenesis including NF-κB/p65, TNF-α, ICAM-1, α-SMA, and Con 1 were detected by immunohistochemical staining, reverse transcription polymerase chain reaction, and Western blotting.
Results
Rats in the DDC and DS1 groups showed the highest histological scores after DDC treatment, but the scores of DS2 and DS3 groups decreased significantly when compared with the DDC group. Sirius red staining showed collagen formation clearly in DDC and DS1 rats rather than in DS2 and DS3 rats. NF-κB/p65, ICAM-1, and α-SMA were strongly expressed in DDC and DS1 rats, while DS2 and DS3 rats showed mild to moderate expression by immunohistochemistry. Reverse transcription polymerase chain reaction showed increased levels of NF-κB/p65, ICAM-1, TNF-α, α-SMA, and Con 1 mRNA in DDC and DS1 rats in comparison to normal controls. The mRNA levels of these molecules in DS2 and DS3 rats were significantly lower than those in DS1 and DDC rats. Western blotting demonstrated that the NF-κB/p65, ICAM-1, and α-SMA expressions in pancreatic tissues of the rats of the DDC group were more clear than those of the normal control, DS2, and DS3 rats.
Conclusion
SF inhibits pancreatic inflammation and fibrogenesis via NF-κB signaling pathway.
Video abstract
doi:10.2147/DDDT.S107679
PMCID: PMC4887069  PMID: 27307705
sulfasalazine; pancreatic injury; inflammation; fibrogenesis; NF-κB
18.  Alterations in gray matter volume due to unilateral hearing loss 
Scientific Reports  2016;6:25811.
Although extensive research on neural plasticity resulting from hearing deprivation has been conducted, the direct influence of compromised audition on the auditory cortex and the potential impact of long durations of incomplete sensory stimulation on the adult cortex are still not fully understood. In this study, using voxel-based morphometry, we evaluated gray matter (GM) volume changes that may be associated with reduced hearing ability and the duration of hearing impairment in 42 unilateral hearing loss (UHL) patients with acoustic neuromas compared to 24 normal controls. We found significant GM volume increases in the somatosensory and motor systems and GM volume decreases in the auditory (i.e., Heschl’s gyrus) and visual systems (i.e., the calcarine cortex) in UHL patients. The GM volume decreases in the primary auditory cortex (i.e., superior temporal gyrus and Heschl’s gyrus) correlated with reduced hearing ability. Meanwhile, the GM volume decreases in structures involving high-level cognitive control functions (i.e., dorsolateral prefrontal cortex and anterior cingulate cortex) correlated positively with hearing loss duration. Our findings demonstrated that the severity and duration of UHL may contribute to the dissociated morphology of auditory and high-level neural structures, providing insight into the brain’s plasticity related to chronic, persistent partial sensory loss.
doi:10.1038/srep25811
PMCID: PMC4865827  PMID: 27174521
19.  Evaluation of surgical outcome of Jack vertebral dilator kyphoplasty for osteoporotic vertebral compression fracture—clinical experience of 218 cases 
Background
Osteoporotic vertebral compression fracture is a serious complication of osteoporosis. Various vertebral kyphoplasty surgeries, which have their own unique features, are commonly used for osteoporotic vertebral compression fracture. Based on the anatomic property of the thoracolumbar vertebral pedicle that its horizontal diameter is twice that of the vertical diameter, we designed Jack vertebral dilator for better restoration of the vertebral height by manipulating the mechanical force.
Methods
A total of 218 patients (236 vertebrae) with osteoporotic vertebral compression fracture were treated with Jack vertebral dilator. Surgery was successfully completed in all cases, and all the 218 patients were followed up for an average of 14.2 months (range 3 to 30 months).
Results
Bone cement leakage occurred in 12 cases, but no symptoms were reported. No other complications were noticed. The VAS scores were 8.2 ± 1.3, 1.7 ± 0.9, and 1.8 ± 0.8 and the ODI was 78.2 ± 13.3 %, 18.5 ± 7.3 %, and 20.9 ± 6.8 % before surgery and 1 week after surgery and at the final follow-up, respectively. The anterior vertebral body height was 19.3 ± 3.2, 25.1 ± 2.6, and 24.9 ± 2.6 mm and the central vertebral body height was 18.7 ± 3.0, 24.8 ± 3.0, and 24.5 ± 2.9 mm before surgery and 1 week after surgery and at the final follow-up, respectively. Cobb angle was 16.2° ± 6.6°, 8.1° ± 5.6°, and 8.5° ± 5.6° before surgery and 1 week after surgery and at the final follow-up, respectively.
Conclusions
Jack vertebral dilator kyphoplasty for osteoporotic vertebral compression fracture is safe, feasible, and effective and has the prospect of further broad application in the future.
Electronic supplementary material
The online version of this article (doi:10.1186/s13018-016-0371-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13018-016-0371-4
PMCID: PMC4852439  PMID: 27138874
Fracture; Thoracolumbar vertebra; Osteoporosis; Kyphoplasty; Jack vertebral dilator
20.  Common genetic variants related to vitamin D status are not associated with esophageal squamous cell carcinoma risk in China 
Cancer epidemiology  2015;39(2):157-159.
Background
Few studies have examined the association of common genetic variants related to vitamin D metabolism and signaling to esophageal squamous cell carcinoma(ESCC).
Methods
We evaluated the association between 12 single nucleotide polymorphisms(SNPs) in four genes related to vitamin D levels and ESCC risk using data from a genome-wide association study. Participants were recruited from the Shanxi Upper Gastrointestinal Cancer Genetics Project and the Linxian Nutrition Intervention Trials, and included 1942 ESCC cases and 2111controls. We used logistic models to estimate odds ratios(ORs) and 95% confidence intervals(CIs) for the SNP associations, after controlling for age and gender.
Results
None of the 12 evaluated SNPs in the four vitamin D-related genes were significantly associated with risk of ESCC. The strongest associations were for rs3794060(P=0.07) and rs12800438(P=0.08) in the DHCR7/NADSYN1gene. No association between vitamin D-related SNPs and risk of ESCC was observed in a genotype score analysis that included all 12 SNPs. ORs for quartiles 2, 3 and 4 of the genotype scores were 0.83 (95% CI: 0.68, 1.01), 1.02(0.85, 1.21), and 1.08 (0.89, 1.30), respectively, with no evidence for a significant monotonic trend(P=0.120).
Conclusions
Our results suggested that common genetic variants related to vitamin D levels are not associated with risk of ESCC in this Chinese population.
doi:10.1016/j.canep.2014.12.013
PMCID: PMC4382354  PMID: 25631780
vitamin D; genetic variants; esophageal squamous cell carcinoma; China
21.  Beta-Diversity Metrics of the Upper Digestive Tract Microbiome are Associated with Body Mass Index 
Obesity (Silver Spring, Md.)  2015;23(4):862-869.
Background
Studies of the fecal microbiome have implicated the gut microbiota in obesity, but few studies examined the microbial diversity at other sites. We explored the association between obesity and the upper gastrointestinal (UGI) microbial diversity.
Design/Methods
The UGI microbiome of 659 healthy Chinese adults with a measured body mass index (BMI) range of 15.0 to 35.7 was characterized using the 16S rRNA gene DNA microarray (HOMIM).
Results
In multivariate-adjusted models, alpha diversity was not associated with BMI. However, beta diversity, assessed by principal coordinate vectors generated from an unweighted unifrac distance matrix of pairwise comparisons, was associated with BMI (third and fourth vectors, p=0.0132 and p=0.0280, respectively). Moreover, beta diversity, assessed by cluster membership (3 clusters), was also associated with BMI; individuals in the first cluster (median BMI 22.35, odds ratio (OR)=0.48, 95% confidence interval (CI)=0.05–4.34) and second cluster (median BMI 22.55, OR=0.26, 95% CI=0.09–0.75) were significantly less likely to be obese (BMI ≥27.5) than those in the third cluster (median BMI 23.59).
Conclusions
A beta-diversity metric of the UGI microbiome is associated with a four-fold difference in obesity risk in this Asian population. Future studies should address whether the UGI microbiome plays a causal role in obesity.
doi:10.1002/oby.21020
PMCID: PMC4380747  PMID: 25755147
beta-diversity; body mass index; Chinese; microbiome; obesity; upper gastrointestinal tract
22.  Genetic association study identifies a functional CNV in the WWOX gene contributes to the risk of intracranial aneurysms 
Oncotarget  2016;7(13):16104-16111.
Intracranial aneurysms (IAs) accounts for 85% of hemorrhagic stroke. Genetic factors have been known to play an important role in the development of IAs. A functional CNV (CNV-67048) of human WW domain-containing oxidoreductase (WWOX), which has been identified as a tumor suppressor gene in multiple cancers, was identified to be associated with gliomas risk previously. Here, we hypothesized that the CNV-67048 could also affect susceptibility of IAs. Based on a two-stage, case− control study with a total of 976 patients of IAs and 1,200 matched healthy controls, we found the effect size for per copy deletion was 1.35 (95% CI = 1.16–1.57; Ptrend = 1.18 × 10−4). Compared with the individuals having no deletion, significantly higher risk of IAs was detected for both subjects carrying 1 copy deletion (OR = 1.24, 95% CI = 1.02–1.52) and subjects carrying 2 copy deletion (OR = 1.77, 95% CI = 1.24–2.53). Real-time PCR was used to confirm the abnormal expression of WWOX in tissues of IA patients and influence of genotypes of CNV-67048. The expression level of WWOX in IA tissues was significantly lower than that in corresponding normal tissues (P = 0.004), and the deletion genotypes of CNV-67048 have lower WWOX mRNA levels in both tumor tissues and border tissues (P < 0.01). Our data suggests that the deletion genotypes of CNV-67048 in WWOX predispose their carriers to IAs, which might be a genetic biomarker to predict risk of IAs in Chinese.
doi:10.18632/oncotarget.7546
PMCID: PMC4941300  PMID: 26910372
intracranial aneurysm; gene; SNP; risk factor; WWOX
23.  Dietary components and risk of total, cancer and cardiovascular disease mortality in the Linxian Nutrition Intervention Trials cohort in China 
Scientific Reports  2016;6:22619.
Although previous studies have shown that dietary consumption of certain food groups is associated with a lower risk of cancer, heart disease and stroke mortality in western populations, limited prospective data are available from China. We prospectively examined the association between dietary intake of different food groups at baseline and risk of total, cancer, heart disease and stroke mortality outcomes in the Linxian Nutrition Intervention Trials(NIT) cohort. In 1984–1991, 2445 subjects aged 40–69 years from the Linxian NIT cohort completed a food frequency questionnaire. Deaths from esophageal and gastric cancer, heart disease and stroke were identified through up to 26 years of follow-up. We used Cox proportional hazard models to calculate hazard ratios and 95% confidence intervals for associations between intake of groups of food items and these mortality endpoints. We concluded that higher intake of certain food groups was associated with lower risk of gastric cancer, heart disease and stroke mortality in a prospective cohort in rural China. Our findings provide additional evidence that increasing intake of grains, vegetables, beans, fruits and nuts may help reduce mortality from these diseases.
doi:10.1038/srep22619
PMCID: PMC4778051  PMID: 26939909
24.  Trends in Radical Surgical Treatment Methods for Breast Malignancies in China: A Multicenter 10-Year Retrospective Study 
The Oncologist  2015;20(9):1036-1043.
The purpose of this study was to describe Chinese trends in radical surgical modalities and influential imaging and demographic factors for breast malignancies. Rates of mastectomy in the People’s Republic of China remain elevated due to diagnosis at higher stages; however, because of increased use of diagnostic imaging, improvement of biopsy methods, and patient education, rates of less invasive lumpectomy are increasing and rates of mastectomy have decreased in China.
Background.
Incidence rates of breast cancer continue to rise in the People’s Republic of China. The purpose of this study was to describe Chinese trends in radical surgical modalities and influential imaging and demographic factors for breast malignancies.
Materials and Methods.
This study was a hospital-based, multicenter, 10-year (1999–2008), retrospective study. Descriptive statistical tests were used to illustrate information regarding radical surgical trends for the treatment of breast malignancies. Chi-square tests were used to assess effect of demographic factors in addition to imaging and pathological data on the specific surgical method.
Results.
A total of 4,211 patients were enrolled in the survey. Among them, 3,335 patients with stage 0 to stage III disease undergoing mastectomy or breast-conserving surgery (BCS) were included in the final analysis. The rate of BCS increased from 1.53% in 1999 to 11.88% in 2008. The rate of mastectomy declined over this time period, from 98.47% in 1999 to 88.12% in 2008, with increasing use of diagnostic imaging methods and pathological biopsies. A significantly greater percentage of patients with office work, high education levels, unmarried status, younger age, and early pathological stages preferred BCS compared with mastectomy.
Conclusion.
Rates of mastectomy in China remain elevated due to diagnosis at higher stages; however, because of increased use of diagnostic imaging, improvement of biopsy methods, and patient education, rates of less invasive lumpectomy are increasing and rates of mastectomy have decreased in China.
Implications for Practice:
In this study, 4,211 cases were collected from 1999 to 2008 through a multicenter retrospective study of varying geographic and socioeconomic areas to illustrate trends of surgeries in the People’s Republic of China. The correlations between demographic and tumor characteristics and among methods of surgical treatment were explored. This study shows that the rate of breast-conserving surgery (BCS) increased and the rate of mastectomy declined over this time period with increasing use of diagnostic imaging methods and pathological biopsies. Patients with office work, high education levels, unmarried status, younger age, and early pathological stages preferred BCS compared with mastectomy in China.
doi:10.1634/theoncologist.2014-0281
PMCID: PMC4571796  PMID: 26253559
Breast neoplasms; Surgical; Imaging; Diagnosis
25.  Breast Cancer Disparities: A Multicenter Comparison of Tumor Diagnosis, Characteristics, and Surgical Treatment in China and the U.S. 
The Oncologist  2015;20(9):1044-1050.
Incidence rates for breast cancer continue to rise in the People’s Republic of China. The purpose of this study was to analyze differences in characteristics of breast malignancies between China and the U.S. Chinese women were diagnosed at younger ages with higher stage and larger tumors and underwent more aggressive surgical treatment. Prospective trials should be conducted to address screening, surgical, and tumor discrepancies between China and the U.S.
Background and Objective.
Incidence of and mortality rates for breast cancer continue to rise in the People’s Republic of China. The purpose of this study was to analyze differences in characteristics of breast malignancies between China and the U.S.
Methods.
Data from 384,262 breast cancer patients registered in the U.S. Surveillance, Epidemiology, and End Results (SEER) program from 2000 to 2010 were compared with 4,211 Chinese breast cancer patients registered in a Chinese database from 1999 to 2008. Outcomes included age, race, histology, tumor and node staging, laterality, surgical treatment method, and reconstruction. The Pearson chi-square and Fisher’s exact tests were used to compare rates.
Results.
Infiltrating ductal carcinoma was the most common type of malignancy in the U.S. and China. The mean number of positive lymph nodes was higher in China (2.59 vs. 1.31, p < .001). Stage at diagnosis was higher in China (stage IIA vs. I, p < .001). Mean size of tumor at diagnosis was higher in China (32.63 vs. 21.57 mm). Mean age at diagnosis was lower in China (48.28 vs. 61.29 years, p < .001). Moreover, 2.0% of U.S. women underwent radical mastectomy compared with 12.5% in China, and 0.02% in China underwent reconstructive surgery.
Conclusion.
Chinese women were diagnosed at younger ages with higher stage and larger tumors and underwent more aggressive surgical treatment. Prospective trials should be conducted to address screening, surgical, and tumor discrepancies between China and the U.S.
Implications for Practice:
Breast cancer patients in China are diagnosed at later stages than those in America, which might contribute to different clinical management and lower 5-year survival rate. This phenomenon suggests that an earlier detection and treatment program should be widely implemented in China. By comparing the characteristics of Chinese and Chinese-American patients, we found significant differences in tumor size, lymph nodes metastasis, and age at diagnosis. These consequences indicated that patients with similar genetic backgrounds may have different prognoses due to the influence of environment and social economic determinates.
doi:10.1634/theoncologist.2014-0290
PMCID: PMC4571797  PMID: 26240131
Breast cancer; China; Disparities

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