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1.  Genetic variants in Fas signaling pathway genes and risk of gastric cancer 
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.
doi:10.1002/ijc.28415
PMCID: PMC3858487  PMID: 23921907
Gastric cancer; gastric cardia; gastric noncardia; Fas signaling; genetic variants; GWAS; single nucleotide polymorphisms; pathway genes
2.  Abnormal autonomic and associated brain activities during rest in autism spectrum disorder 
Brain  2014;137(1):153-171.
Autism spectrum disorders are associated with social and emotional deficits, the aetiology of which are not well understood. A growing consensus is that the autonomic nervous system serves a key role in emotional processes, by providing physiological signals essential to subjective states. We hypothesized that altered autonomic processing is related to the socio-emotional deficits in autism spectrum disorders. Here, we investigated the relationship between non-specific skin conductance response, an objective index of sympathetic neural activity, and brain fluctuations during rest in high-functioning adults with autism spectrum disorder relative to neurotypical controls. Compared with control participants, individuals with autism spectrum disorder showed less skin conductance responses overall. They also showed weaker correlations between skin conductance responses and frontal brain regions, including the anterior cingulate and anterior insular cortices. Additionally, skin conductance responses were found to have less contribution to default mode network connectivity in individuals with autism spectrum disorders relative to controls. These results suggest that autonomic processing is altered in autism spectrum disorders, which may be related to the abnormal socio-emotional behaviours that characterize this condition.
doi:10.1093/brain/awt294
PMCID: PMC3891443  PMID: 24424916
autism; autonomic nervous system; emotion; skin conductance; resting state
3.  The Neural Correlates of Anomalous Habituation to Negative Emotional Pictures in Borderline and Avoidant Personality Disorder Patients 
Objective
Extreme emotional reactivity is a defining feature of borderline personality disorder, yet the neural-behavioral mechanisms underlying this affective instability are poorly understood. One possible contributor would be diminished ability to engage the mechanism of emotional habituation. We tested this hypothesis by examining behavioral and neural correlates of habituation in borderline patients, healthy controls, and a psychopathological control group of avoidant personality disorder patients.
Method
During fMRI scan acquisition, borderline patients, healthy controls and avoidant personality disorder patients viewed novel and repeated pictures, providing valence ratings at each presentation. Statistical parametric maps of the contrasts of activation during repeat versus novel negative picture viewing were compared between groups. Psychophysiological interaction analysis was employed to examine functional connectivity differences between groups.
Results
Unlike healthy controls, neither borderline nor avoidant personality disorder participants showed increased activity in dorsal anterior cingulate cortex when viewing repeat versus novel pictures. This failure to increase dorsal anterior cingulate activity was associated with greater affective instability in borderline participants. In addition, borderline and avoidant participants showed smaller insula-amygdala connectivity increases than healthy participants and did not show habituation in ratings of the emotional intensity of the images as did healthy participants. Borderline patients differed from avoidant patients in insula-ventral anterior cingulate connectivity during habituation.
Conclusions
Borderline patients fail to habituate to negative pictures as do healthy participants and differ from both healthy controls and avoidant patients in neural activity during habituation. A failure to effectively engage emotional habituation processes may contribute to affective instability in borderline patients.
doi:10.1176/appi.ajp.2013.13070852
PMCID: PMC3947284  PMID: 24275960
borderline personality disorder; avoidant personality disorder; affective instability; fMRI; functional connectivity
4.  Noncanonical FK506-binding Protein BDBT Binds DBT to Enhance its Circadian Function and Forms Foci at Night 
Neuron  2013;80(4):10.1016/j.neuron.2013.08.004.
SUMMARY
The kinase DOUBLETIME is a master regulator of the Drosophila circadian clock, yet the mechanisms regulating its activity remain unclear. A proteomic analysis of DOUBLETIME interactors led to the identification of an unstudied protein designated CG17282. RNAi-mediated knock-down of CG17282 produced behavioral arrhythmicity and long periods, high levels of hypophosphorylated nuclear PERIOD and phosphorylated DOUBLETIME. Overexpression of DOUBLETIME in flies suppresses these phenotypes and overexpression of CG17282 in S2 cells enhances DOUBLETIME-dependent PERIOD degradation, indicating that CG17282 stimulates DOUBLETIME’s circadian function. In photoreceptors, CG17282 accumulates rhythmically in PERIOD- and DOUBLETIME-dependent cytosolic foci. Finally, structural analyses demonstrated CG17282 is a noncanonical FK506-binding protein with an inactive peptide prolyl-isomerase domain that binds DOUBLETIME and tetratricopeptide repeats that may promote assembly of larger protein complexes. We have named CG17282 Bride of Doubletime and established it as a mediator of DOUBLETIME’s effects on PERIOD, most likely in cytosolic foci that regulate PERIOD nuclear accumulation.
doi:10.1016/j.neuron.2013.08.004
PMCID: PMC3869642  PMID: 24210908
5.  Ultrasound Imaging in the Diagnosis of Benign and Suspicious Adrenal Lesions 
Background
The purpose of this study was to define the ultrasound imaging characteristics of adrenal tumors and to assess the performance of ultrasound in differentiating benign ‘leave-alone’ lesions from suspicious lesions.
Material/Methods
We enrolled 882 patients in this study. The nature of each lesion was determined by histopathology. Ultrasound finding of each lesion was compared with its corresponding histopathologic result. The final study group consisted of 911 adrenal masses in 882 patients. All images were reviewed by 2 experienced investigators in a double blind manner.
Results
There were 553 adenomas identified in the study, which constituted 60.70% of the lesions. There were 161 pheochromocytomas (17.67%), 49 myelolipomas (5.38%), 39 cysts (4.28%), 37 metastasis (4.06%), 35 ganglioneuromas (3.84%), 22 lymphomas (2.41%), and 15 cortical carcinomas (1.65%). The sensitivity, specificity, and accuracy of ultrasound-based diagnosis were 89%, 99%, and 93.9%, respectively. A positive predictive value of 90.9% and a negative predictive value of 94.2% were obtained in this study.
Conclusions
This large-sample study showed that ultrasound was a reliable method in differentiating benign ‘leave-alone’ lesions from suspicious lesions.
doi:10.12659/MSM.890800
PMCID: PMC4228948  PMID: 25363391
Adrenal Medulla; Pharmacy; Ultrasonography
6.  The association between the upper digestive tract microbiota by HOMIM and oral health in a population-based study in Linxian, China 
BMC Public Health  2014;14(1):1110.
Background
Bacteria affect oral health, but few studies have systematically examined the role of bacterial communities in oral diseases. We examined this relationship in a large population-based Chinese cancer screening cohort.
Methods
Human Oral Microbe Identification Microarrays were used to test for the presence of 272 human oral bacterial species (97 genera) in upper digestive tract (UDT) samples collected from 659 participants. Oral health was assessed using US NHANES (National Health and Nutrition Examination Survey) protocols. We assessed both dental health (total teeth missing; tooth decay; and the decayed, missing, and filled teeth (DMFT) score) and periodontal health (bleeding on probing (BoP) extent score, loss of attachment extent score, and a periodontitis summary estimate).
Results
Microbial richness, estimated by number of genera per sample, was positively correlated with BoP score (P = 0.015), but negatively correlated with tooth decay and DMFT score (P = 0.008 and 0.022 respectively). Regarding β-diversity, as estimated by the UniFrac distance matrix for pairwise differences among samples, at least one of the first three principal components of the UniFrac distance matrix was correlated with the number of missing teeth, tooth decay, DMFT, BoP, or periodontitis. Of the examined genera, Parvimonas was positively associated with BoP and periodontitis. Veillonellacease [G-1] was associated with a high DMFT score, and Filifactor and Peptostreptococcus were associated with a low DMFT score.
Conclusions
Our results suggest distinct relationships between UDT microbiota and dental and periodontal health. Poor dental health was associated with a less microbial diversity, whereas poor periodontal health was associated with more diversity and the presence of potentially pathogenic species.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-1110) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2458-14-1110
PMCID: PMC4223728  PMID: 25348940
Microbiota; Oral health; Dental caries; Periodontitis; Bleeding on probe; Attachment loss
7.  Anterior Insular Cortex and Emotional Awareness 
The Journal of comparative neurology  2013;521(15):3371-3388.
This paper reviews the foundation for a role of the human anterior insular cortex (AIC) in emotional awareness, defined as the conscious experience of emotions. We first introduce the neuroanatomical features of AIC and existing findings on emotional awareness. Using empathy, the awareness and understanding of other people’s emotional states, as a test case, we then present evidence to demonstrate: 1) AIC and anterior cingulate cortex (ACC) are commonly coactivated as revealed by a meta-analysis, 2) AIC is functionally dissociable from ACC, 3) AIC integrates stimulus-driven and top-down information, and 4) AIC is necessary for emotional awareness. We propose a model in which AIC serves two major functions: integrating bottom-up interoceptive signals with top-down predictions to generate a current awareness state and providing descending predictions to visceral systems that provide a point of reference for autonomic reflexes. We argue that AIC is critical and necessary for emotional awareness.
doi:10.1002/cne.23368
PMCID: PMC3999437  PMID: 23749500
anterior insular cortex; emotional awareness; empathy; fMRI; meta-analysis; top-down; bottom-up; predictive coding
8.  Cognitive Control and Attentional Functions 
Brain and cognition  2013;82(3):301-312.
Cognitive control is essential to flexible, goal-directed behavior under uncertainty, yet its underlying mechanisms are not clearly understood. Because attentional functions are known to allocate mental resources and prioritize the information to be processed by the brain, we propose that the attentional functions of alerting, orienting, and executive control and the interactions among them contribute to cognitive control in the service of uncertainty reduction. To test this hypothesis, we examined the relationship between cognitive control and attentional functions. We used the Majority Function Task (MFT) to manipulate uncertainty in order to evoke cognitive control along with the Revised Attention Network Test (ANT-R) to measure the efficiency and the interactions of attentional functions. A backwards, stepwise regression model revealed that performance on the MFT could be significantly predicted by attentional functions and their interactions as measured by the ANT-R. These results provide preliminary support for our theory that the attentional functions may be involved in the implementation of cognitive control as required to reduce uncertainty, though further investigation is needed.
doi:10.1016/j.bandc.2013.05.004
PMCID: PMC3722267  PMID: 23792472
attention; cognitive control; executive control; uncertainty
9.  A Nation-Wide Multicenter 10-Year (1999-2008) Retrospective Clinical Study of Endocrine Therapy for Chinese Females with Breast Cancer 
PLoS ONE  2014;9(7):e100159.
Endocrine therapy (ET) is one of the main systemic treatments for patients with breast cancer. To our knowledge, few studies have addressed the performance of ET or relevant influencing factors in cancer treatment in China. By retrospectively analyzing the clinicopathological data on breast cancer collected from representative hospitals of 7 traditional areas in China in one random month from each year between year 1999 and 2008, we found that: 1) The rate of the use of hormone receptor (HR) testing was 83.8% (3529/4211), with the estrogen receptor-positive (ER+) rate and/or the progesterone receptor-positive (PR+) rate being 67.9% (2395/3529), and the ER-PR rate being 32.1% (1134/3529). 2) Of the 1599 patients who had received ET, 999 patients (58.3%) were premenopausal while 600 (41.7%) were postmenopausal; 1598 patients received adjuvant hormonal therapy (AHT), whereas only 1 patient received palliative therapy. The medications mainly administered to patients were anti-estrogen agents (80.3% [1283/1598]), followed by AIs (15.5% [248/1598]). Of the 1598 patients receiving AHT, 1416 patients (88.6%) were positive for ER and/or PR, while 75 (4.7%) were negative for both and 108 patients (6.7%) had unknown HR status. The ratio of the use of endocrine therapy for breast cancer patients with ER+ and/or PR+ status was 60.0% (1416/2395). 3) Results from the logistic regression analysis revealed that geography, occupations, and history of chemotherapy and surgery were dependent factors affecting the application of ET in breast cancer treatment in China (P<0.001). In conclusion, the use of ET on Chinese women with breast cancer is increasingly and gradually accounted into the standardized process. Economic status, occupations, and history of chemotherapy and surgery were key factors affecting the application of ET. People residing in developed areas, engaging in mental labour, having history of chemotherapy and surgery are susceptible to accept ET.
doi:10.1371/journal.pone.0100159
PMCID: PMC4103779  PMID: 25036532
10.  Application of intraoperative frozen section examination in the management of female breast cancer in China: a nationwide, multicenter 10-year epidemiological study 
Background
Intraoperative frozen section examination (IFSE) during breast cancer surgery can partly reflect the status of surgical treatment since the surgical method used directly determines the purpose of IFSE use in disease management. This study aims to investigate the application of, changing trends in, and factors influencing IFSE in the management of female breast cancer in China.
Methods
We collected the sociodemographic and clinical data of 4,211 breast cancer patients between 1999 and 2008 and statistically analyzed these data using χ2 or Fisher’s exact tests.
Results
A total of 2,283 (54.22%) patients with breast cancer underwent IFSE. During the 10-year study period, IFSE use was associated with an increase in the number of sentinel lymph node biopsies (SLNB) and breast-conserving surgeries (BS) performed, with significant regional differences noted in this trend (P <0.05). Patients’ education, occupation, age, tumor size estimated by preoperative palpation, and the use of imaging examinations affected the purpose of IFSE use (P <0.05).
Conclusions
Our results show that the purpose of IFSE in the surgical treatment of breast cancer in China is gradually approaching that in developed countries. We believe that policymakers must address the differences in breast cancer treatment based on the socioeconomic status of patients. Lastly, the use of IFSE for determining tumor characteristics should be avoided as far as possible, and patient education and breast cancer screening programs tailored to the Chinese population should be established. Our findings may guide the formulation of breast cancer control strategies in China and other low-income countries.
doi:10.1186/1477-7819-12-225
PMCID: PMC4105393  PMID: 25034137
Application mode; Female breast cancer; Intraoperative frozen section examination; Sociodemographic factor
12.  Genetic variants in DNA repair pathway genes and risk of esophageal squamous cell carcinoma and gastric adenocarcinoma in a Chinese population 
Carcinogenesis  2013;34(7):1536-1542.
The DNA repair pathways help to maintain genomic integrity and therefore genetic variation in the pathways could affect the propensity to develop cancer. Selected germline single nucleotide polymorphisms (SNPs) in the pathways have been associated with esophageal cancer and gastric cancer (GC) but few studies have comprehensively examined the pathway genes. We aimed to investigate associations between DNA repair pathway genes and risk of esophageal squamous cell carcinoma (ESCC) and GC, using data from a genome-wide association study in a Han Chinese population where ESCC and GC are the predominant cancers. In sum, 1942 ESCC cases, 1758 GC cases and 2111 controls from the Shanxi Upper Gastrointestinal Cancer Genetics Project (discovery set) and the Linxian Nutrition Intervention Trials (replication set) were genotyped for 1675 SNPs in 170 DNA repair-related genes. Logistic regression models were applied to evaluate SNP-level associations. Gene- and pathway-level associations were determined using the resampling-based adaptive rank-truncated product approach. The DNA repair pathways overall were significantly associated with risk of ESCC (P = 6.37 × 10− 4), but not with GC (P = 0.20). The most significant gene in ESCC was CHEK2 (P = 2.00 × 10− 6) and in GC was CLK2 (P = 3.02 × 10− 4). We observed several other genes significantly associated with either ESCC (SMUG1, TDG, TP53, GTF2H3, FEN1, POLQ, HEL308, RAD54B, MPG, FANCE and BRCA1) or GC risk (MRE11A, RAD54L and POLE) (P < 0.05). We provide evidence for an association between specific genes in the DNA repair pathways and the risk of ESCC and GC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.
doi:10.1093/carcin/bgt094
PMCID: PMC3697889  PMID: 23504502
13.  Emotional bias of cognitive control in adults with childhood attention-deficit/hyperactivity disorder 
NeuroImage : Clinical  2014;5:1-9.
Affect recognition deficits found in individuals with attention-deficit/hyperactivity disorder (ADHD) across the lifespan may bias the development of cognitive control processes implicated in the pathophysiology of the disorder. This study aimed to determine the mechanism through which facial expressions influence cognitive control in young adults diagnosed with ADHD in childhood. Fourteen probands with childhood ADHD and 14 comparison subjects with no history of ADHD were scanned with functional magnetic resonance imaging while performing a face emotion go/no-go task. Event-related analyses contrasted activation and functional connectivity for cognitive control collapsed over face valence and tested for variations in activation for response execution and inhibition as a function of face valence. Probands with childhood ADHD made fewer correct responses and inhibitions overall than comparison subjects, but demonstrated comparable effects of face emotion on response execution and inhibition. The two groups showed similar frontotemporal activation for cognitive control collapsed across face valence, but differed in the functional connectivity of the right dorsolateral prefrontal cortex, with fewer interactions with the subgenual cingulate cortex, inferior frontal gyrus, and putamen in probands than in comparison subjects. Further, valence-dependent activation for response execution was seen in the amygdala, ventral striatum, subgenual cingulate cortex, and orbitofrontal cortex in comparison subjects but not in probands. The findings point to functional anomalies in limbic networks for both the valence-dependent biasing of cognitive control and the valence-independent cognitive control of face emotion processing in probands with childhood ADHD. This limbic dysfunction could impact cognitive control in emotional contexts and may contribute to the social and emotional problems associated with ADHD.
Highlights
•We tested adult probands diagnosed with ADHD in childhood and comparison subjects.•Emotional bias of cognitive control was modeled with a face emotion go/no-go task.•Probands made fewer correct responses and correct inhibitions on the go/no-go task.•Probands showed reduced prefrontal connectivity with limbic and paralimbic regions.•Probands showed no valence-dependent limbic activation for cognitive control.
doi:10.1016/j.nicl.2014.05.016
PMCID: PMC4050315  PMID: 24918067
ADHD; fMRI; Emotional bias; Prefrontal cortex; Go; No-go task; Adults
14.  Neural Basis of Emotional Decision Making in Trait Anxiety 
The Journal of Neuroscience  2013;33(47):18641-18653.
Although trait anxiety has been associated with risk decision making, whether it is related to risk per se or to the feeling of the risk, as well as the underlying neurocognitive mechanisms, remains unclear. Using a decision-making task with a manipulation of frame (i.e., written description of options as a potential gain or loss) and functional magnetic resonance imaging, we investigated the neurocognitive relationship between trait anxiety and decision making. The classic framing effect was observed: participants chose the safe option when it was described as a potential gain, but they avoided the same option when it was described as a potential loss. Most importantly, trait anxiety was positively correlated with this behavioral bias. Trait anxiety was also positively correlated with amygdala-based “emotional” system activation and its coupling with the ventromedial prefrontal cortex (vmPFC) when decisions were consistent with the framing effect, but negatively correlated with the dorsal anterior cingulate cortex (dACC)-based “analytic” system activation and its connectivity to the vmPFC when decisions ran counter to the framing effect. Our findings suggest that trait anxiety is not associated with subjective risk preference but an evaluative bias of emotional information in decision making, underpinned by a hyperactive emotional system and a hypoactive analytic system in the brain.
doi:10.1523/JNEUROSCI.1253-13.2013
PMCID: PMC3834062  PMID: 24259585
15.  Genetic variants in sex hormone metabolic pathway genes and risk of esophageal squamous cell carcinoma 
Carcinogenesis  2013;34(5):1062-1068.
In China, esophageal cancer is the fourth leading cause of cancer death where essentially all cases are histologically esophageal squamous cell carcinoma (ESCC), in contrast to esophageal adenocarcinoma in the West. Globally, ESCC is 2.4 times more common among men than women and recently it has been suggested that sex hormones may be associated with the risk of ESCC. We examined the association between genetic variants in sex hormone metabolic genes and ESCC risk in a population from north central China with high-incidence rates. A total of 1026 ESCC cases and 1452 controls were genotyped for 797 unique tag single-nucleotide polymorphisms (SNPs) in 51 sex hormone metabolic genes. SNP-, gene- and pathway-based associations with ESCC risk were evaluated using unconditional logistic regression adjusted for age, sex and geographical location and the adaptive rank truncated product (ARTP) method. Statistical significance was determined through use of permutation for pathway- and gene-based associations. No associations were observed for the overall sex hormone metabolic pathway (P = 0.14) or subpathways (androgen synthesis: P = 0.30, estrogen synthesis: P = 0.15 and estrogen removal: P = 0.19) with risk of ESCC. However, six individual genes (including SULT2B1, CYP1B1, CYP3A7, CYP3A5, SHBG and CYP11A1) were significantly associated with ESCC risk (P < 0.05). Our examination of genetic variation in the sex hormone metabolic pathway is consistent with a potential association with risk of ESCC. These positive findings warrant further evaluation in relation to ESCC risk and replication in other populations.
doi:10.1093/carcin/bgt030
PMCID: PMC3643422  PMID: 23358850
16.  Altered Regional and Circuit Resting-State Activity Associated with Unilateral Hearing Loss 
PLoS ONE  2014;9(5):e96126.
The deprivation of sensory input after hearing damage results in functional reorganization of the brain including cross-modal plasticity in the sensory cortex and changes in cognitive processing. However, it remains unclear whether partial deprivation from unilateral auditory loss (UHL) would similarly affect the neural circuitry of cognitive processes in addition to the functional organization of sensory cortex. Here, we used resting-state functional magnetic resonance imaging to investigate intrinsic activity in 34 participants with UHL from acoustic neuroma in comparison with 22 matched normal controls. In sensory regions, we found decreased regional homogeneity (ReHo) in the bilateral calcarine cortices in UHL. However, there was an increase of ReHo in the right anterior insular cortex (rAI), the key node of cognitive control network (CCN) and multimodal sensory integration, as well as in the left parahippocampal cortex (lPHC), a key node in the default mode network (DMN). Moreover, seed-based resting–state functional connectivity analysis showed an enhanced relationship between rAI and several key regions of the DMN. Meanwhile, lPHC showed more negative relationship with components in the CCN and greater positive relationship in the DMN. Such reorganizations of functional connectivity within the DMN and between the DMN and CCN were confirmed by a graph theory analysis. These results suggest that unilateral sensory input damage not only alters the activity of the sensory areas but also reshapes the regional and circuit functional organization of the cognitive control network.
doi:10.1371/journal.pone.0096126
PMCID: PMC4006821  PMID: 24788317
17.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
18.  Estrogen improves the proliferation and differentiation of hBMSCs derived from postmenopausal osteoporosis through notch signaling pathway 
Molecular and Cellular Biochemistry  2014;392(1-2):85-93.
Estrogen deficiency is the main reason of bone loss, leading to postmenopausal osteoporosis, and estrogen replacement therapy (ERT) has been demonstrated to protect bone loss efficiently. Notch signaling controls proliferation and differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). Moreover, imperfect estrogen-responsive elements (EREs) were found in the 5′-untranslated region of Notch1 and Jagged1. Thus, we examined the molecular and biological links between estrogen and the Notch signaling in postmenopausal osteoporosis in vitro. hBMSCs were obtained from healthy women and patients with postmenopausal osteoporosis. Notch signaling molecules were quantified using real-time polymerase chain reaction (real-time PCR) and Western Blot. Luciferase reporter constructs with putative EREs were transfected into hBMSCs and analyzed. hBMSCs were transduced with lentiviral vectors containing human Notch1 intracellular domain (NICD1). We also used N-[N-(3, 5-diflurophenylacetate)-l-alanyl]-(S)-phenylglycine t-butyl ester, a γ-secretase inhibitor, to suppress the Notch signaling. We found that estrogen enhanced the Notch signaling in hBMSCs by promoting the expression of Jagged1. hBMSCs cultured with estrogen resulted in the up-regulation of Notch signaling and increased proliferation and differentiation. Enhanced Notch signaling could enhance the proliferation and differentiation of hBMSCs from patients with postmenopausal osteoporosis (OP-hBMSCs). Our results demonstrated that estrogen preserved bone mass partly by activating the Notch signaling. Because long-term ERT has been associated with several side effects, the Notch signaling could be a potential target for treating postmenopausal osteoporosis.
Electronic supplementary material
The online version of this article (doi:10.1007/s11010-014-2021-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11010-014-2021-7
PMCID: PMC4053611  PMID: 24390089
Estrogen; Postmenopausal osteoporosis; HBMSCs; Notch signaling pathway; Cell proliferation; Cell differentiation
19.  Guanfacine Modulates the Influence of Emotional Cues on Prefrontal Cortex Activation for Cognitive Control 
Psychopharmacology  2012;226(2):261-271.
Rationale
Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic α2 adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established.
Objectives
This study tested the effect of the postsynaptic α2 adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex.
Methods
Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, crossover design.
Results
Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces, but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response-related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions.
Conclusions
These results provide evidence that guanfacine stimulation of postsynaptic α2 adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the α2 adrenoceptor agonist treatment of attention-deficit hyperactivity disorder (ADHD).
doi:10.1007/s00213-012-2893-8
PMCID: PMC3567242  PMID: 23086020
Guanfacine; Response execution; Response inhibition; Emotion; fMRI; Go/No-go task; Prefrontal cortex
20.  Body Mass Index and Breast Cancer Defined by Biological Receptor Status in Pre-Menopausal and Post-Menopausal Women: A Multicenter Study in China 
PLoS ONE  2014;9(1):e87224.
Background
Few studies have investigated the association between body mass index (BMI) and breast cancer with consideration to estrogen/progesterone/human epidermal growth factor type 2 receptor status (ER/PR/HER2) in the breast tissue among Chinese pre- and post-menopausal women.
Methods
Four thousand two hundred and eleven breast cancer patients were selected randomly from seven geographic regions of China from 1999 to 2008. Demographic data, risk factors, pathologic features, and biological receptor status of cases were collected from the medical charts. Chi-square test, fisher exact test, rank-correlation analysis, and multivariate logistic regression model were adopted to explore whether BMI differed according to biological receptor status in pre- and post-menopausal women.
Results
Three thousand two hundred and eighty one eligible cases with BMI data were included. No statistically significant differences in demographic characteristics were found between the cases with BMI data and those without. In the rank-correlation analysis, the rates of PR+ and HER2+ were positively correlated with increasing BMI among post-menopausal women (rs BMI, PR+ = 0.867, P = 0.001; rs BMI, HER2+ = 0.636, P = 0.048), but the ER+ rates did not vary by increasing BMI. Controlling for confounding factors, multivariate logistic regression models with BMI<24 kg/m2 as the reference group were performed and found that BMI≥24 kg/m2 was only positively correlated with PR+ status among post-menopausal breast cancer cases (adjusted OR = 1.420, 95% CI: 1.116–1.808, Wald = 8.116, P = 0.004).
Conclusions
Post-menopausal women with high BMI (≥24 kg/m2) have a higher proportion of PR+ breast cancer. In addition to effects mediated via the estrogen metabolism pathway, high BMI might increase the risk of breast cancer by other routes, which should be examined further in future etiological mechanism studies.
doi:10.1371/journal.pone.0087224
PMCID: PMC3906138  PMID: 24489874
21.  RNA Interference Depletion of the Halloween Gene Disembodied Implies its Potential Application for Management of Planthopper Sogatella furcifera and Laodelphax striatellus 
PLoS ONE  2014;9(1):e86675.
Sogatella furcifera and Laodelphax striatellus are economically important rice pests in China by acting as vectors of several rice viruses, sucking the phloem sap and blocking the phloem vessels. Ecdysteroid hormone 20-hydroxyecdysone regulates insect development and reproduction. A cytochrome P450 monooxygenase CYP302A1 (22-hydroxylase), encoded by the Halloween gene disembodied (dib), plays a critical role in ecdysteroidogenesis. The objective of this study is to test whether dib genes are potential targets for RNA interference-based management of S. furcifera and L. striatellus. We cloned and characterized Sfdib and Lsdib. The open reading frame regions of dib genes were generated and used for designing and constructing dsRNA fragments. Experiments were conducted using oral delivery of dsdib to investigate the effectiveness of RNAi in S. furcifera and L. striatellus nymphs. Real-time quantitative reverse transcriptase-PCR analysis demonstrated that continuous ingestion of dsdib at the concentration of 0.01, 0.05 and 0.50 mg/ml diminished Sfdib expression levels by 35.9%, 45.1% and 66.2%, and ecdysone receptor (SfEcR) gene mRNA levels by 34.0%, 36.2% and 58.5% respectively in S. furcifera, and decreased Lsdib expression level by 18.8%, 35.8% and 56.7%, and LsEcR mRNA levels by 25.2%, 46.8% and 68.8% respectively in L. striatellus. The reduction in dib and EcR transcript abundance resulted in observable phenotypes. The development of nymphs was impaired and the survival was negatively affected. Our data will enable the development of new insect control strategies and functional analysis of vital genes in S. furcifera and L. striatellus nymphs.
doi:10.1371/journal.pone.0086675
PMCID: PMC3904942  PMID: 24489765
22.  Metabolic mapping of deep brain structures and associations with symptomatology in autism spectrum disorders 
Structural neuroimaging studies in autism report atypical volume in deep brain structures which are related to symptomatology. Little is known about metabolic changes in these regions, and how they vary with age and sex, and/or relate to clinical behaviors. Using magnetic resonance spectroscopy we measured N-acetylaspartate, choline, creatine, myoinositol and glutamate in the caudate, putamen, and thalamus of 20 children with autism and 16 typically developing controls (7–18 years). Relative to controls, individuals with autism had elevated glutamate/creatine in the putamen. In addition, both groups showed age-related increases in glutamate in this region. Boys, relative to girls had increased choline/creatine in the thalamus. Lastly, there were correlations between glutamate, choline, and myoinositol in all three regions, and behavioral scores in the ASD group. These findings suggest changes in deep gray matter neurochemistry, which are sensitive to diagnosis, age and sex, and are associated with behavioral differences.
doi:10.1016/j.rasd.2013.10.003
PMCID: PMC3897261  PMID: 24459534
Magnetic resonance spectroscopy; Autism spectrum disorders; Deep gray matter; Caudate nucleus; Putamen; Thalamus and social cognition
23.  Risk Factors for Breast Cancer Among Chinese Women: A 10-Year Nationwide Multicenter Cross-Sectional Study 
Journal of Epidemiology  2014;24(1):67-76.
Background
The characteristics of established risk factors for breast cancer may vary among countries. A better understanding of local characteristics of risk factors may help in devising effective prevention strategies for breast cancer.
Methods
Information on exposures to risk factors was collected from the medical charts of 4211 women with breast cancer diagnosed during 1999–2008. The distributions of these exposures among regions, and by menopausal status and birth period, were compared with the χ2 test. Crude associations between the selected factors and breast cancer were estimated using the cases in the present study and a representative control population, which was selected from qualified published studies.
Results
As compared with cases from less developed regions, those from more developed regions were significantly more likely to be nulliparous, had fewer childbirths (P < 0.05), and were less likely to have breastfed (P = 0.08). As compared with premenopausal cases, postmenopausal cases were more likely to be overweight and to have breastfed and had more childbirths (P < 0.05). The number of live births and rate of breastfeeding decreased in relation to birth period (P for trends <0.001). Overweight, late menopause, and family history of breast cancer were significantly associated with breast cancer among Chinese women.
Conclusions
Breast cancer incidence was associated with nulliparity and history of breastfeeding. Population attributable risks should be assessed, especially for more developed areas and young women. The effects of body mass index, age at menopause, and family history of breast cancer should be given priority during assessment of breast cancer risk among Chinese women.
doi:10.2188/jea.JE20120217
PMCID: PMC3872527  PMID: 24270059
breast cancer; risk factors; nationwide; multicenter
24.  Cognition–Emotion Integration in the Anterior Insular Cortex 
Cerebral Cortex (New York, NY)  2012;23(1):20-27.
Both cognitive and affective processes require mental resources. However, it remains unclear whether these 2 processes work in parallel or in an integrated fashion. In this functional magnetic resonance imaging study, we investigated their interaction using an empathy-for-pain paradigm, with simultaneous manipulation of cognitive demand of the tasks and emotional valence of the stimuli. Eighteen healthy adult participants viewed photographs showing other people's hands and feet in painful or nonpainful situations while performing tasks of low (body part judgment) and high (laterality judgment) cognitive demand. Behavioral data showed increased reaction times and error rates for painful compared with nonpainful stimuli under laterality judgment relative to body part judgment, indicating an interaction between cognitive demand and stimulus valence. Imaging analyses showed activity in bilateral anterior insula (AI) and primary somatosensory cortex (SI), but not posterior insula, for main effects of cognitive demand and stimulus valence. Importantly, cognitive demand and stimulus valence showed a significant interaction in AI, SI, and regions of the frontoparietal network. These results suggest that cognitive and emotional processes at least partially share common brain networks and that AI might serve as a key node in a brain network subserving cognition–emotion integration.
doi:10.1093/cercor/bhr367
PMCID: PMC3513949  PMID: 22275476
cognition; emotion; empathy; fMRI; insula
25.  An information theory account of cognitive control 
Our ability to efficiently process information and generate appropriate responses depends on the processes collectively called cognitive control. Despite a considerable focus in the literature on the cognitive control of information processing, neural mechanisms underlying control are still unclear, and have not been characterized by considering the quantity of information to be processed. A novel and comprehensive account of cognitive control is proposed using concepts from information theory, which is concerned with communication system analysis and the quantification of information. This account treats the brain as an information-processing entity where cognitive control and its underlying brain networks play a pivotal role in dealing with conditions of uncertainty. This hypothesis and theory article justifies the validity and properties of such an account and relates experimental findings to the frontoparietal network under the framework of information theory.
doi:10.3389/fnhum.2014.00680
PMCID: PMC4151034  PMID: 25228875
cognitive control; information theory; uncertainty; entropy; frontoparietal network

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