Alzheimer's disease (AD) is associated with abnormal functioning of the default mode network (DMN). Functional connectivity (FC) changes to the DMN have been found in patients with amnestic mild cognitive impairment (aMCI), which is the prodromal stage of AD. However, whether or not aMCI also alters the effective connectivity (EC) of the DMN remains unknown. We employed a combined group independent component analysis (ICA) and Bayesian network (BN) learning approach to resting-state functional MRI (fMRI) data from 17 aMCI patients and 17 controls, in order to establish the EC pattern of DMN, and to evaluate changes occurring in aMCI. BN analysis demonstrated heterogeneous regional convergence degree across DMN regions, which were organized into two closely interacting subsystems. Compared to controls, the aMCI group showed altered directed connectivity weights between DMN regions in the fronto-parietal, temporo-frontal, and temporo-parietal pathways. The aMCI group also exhibited altered regional convergence degree in the right inferior parietal lobule. Moreover, we found EC changes in DMN regions in aMCI were correlated with regional FC levels, and the connectivity metrics were associated with patients' cognitive performance. This study provides novel sights into our understanding of the functional architecture of the DMN and adds to a growing body of work demonstrating the importance of the DMN as a mechanism of aMCI.
Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.
HCC; genome-wide; host gene; microRNA; DNA methylation
The role of regional ultrasound in providing clinically relevant information was evaluated in the assessment of regional lymphatics for accurate staging and treatment of breast cancer patients. Regional ultrasound was found to be beneficial in initial staging evaluations.
After completing this course, the reader will be able to:
Describe the ways in which regional ultrasound has contributed to more accurate staging in a population of locally advanced breast cancer patients.Explain how regional nodal information leads to changes in radiation therapy portals and total doses.Discuss the role of regional ultrasound in reflecting a truer level of disease burden in locally advanced breast cancer patients before therapies, including neoadjuvant chemotherapy, may limit knowledge of disease extent and consequently affect radiation treatment planning.
This article is available for continuing medical education credit at CME.TheOncologist.com
Assessment of the regional lymphatics is important for accurate staging and treatment of breast cancer patients. We sought to determine the role of regional ultrasound in providing clinically relevant information. We retrospectively analyzed data from patients who were treated curatively in 1996–2006 at The University of Texas MD Anderson Cancer Center for clinical stage III breast cancer. We compared differences in regional lymph node staging based on ultrasound versus mammography and physical examination in the 865 of 1,200 patients who had external-beam radiation as part of their treatment and regional ultrasound studies as part of their initial evaluation. Ultrasound uniquely identified additional lymph node involvement beyond the level I or II axilla in 37% of the patients (325 of 865), leading to a change in clinical nodal stage. Ninety-one percent of these abnormalities that could be biopsied (266 or 293) were confirmed to contain disease. The sites of additional regional nodal disease were: infraclavicular disease, 32% (275 of 865); supraclavicular disease, 16% (140 of 865); and internal mammary disease, 11% (98 of 865). All patients with involvement in the extra-axillary regional nodal basins received a radiation boost to the involved areas ≥10 Gy. Thus, over one third of patients with advanced breast cancer had their radiation plan altered by the ultrasound findings. Regional ultrasound evaluation in patients with advanced breast cancer commonly revealed abnormalities within and beyond the axilla, which changed the clinical stage of disease and the radiation treatment strategy. Therefore, regional ultrasound is beneficial in the initial staging evaluation for such patients.
Regional ultrasound; Breast cancer; Staging; Locally advanced
Sequential adsorption of poly(styrene sulfonate) (PSS) and proteases in porous nylon yields enzymatic membrane reactors for limited protein digestion. Although a high local enzyme density (~30 mg/cm3) and small pore diameters in the membrane lead to digestion in < 1 s, the low membrane thickness (170 μm) affords control over residence times at the ms level to limit digestion. Apomyoglobin digestion demonstrates that peptide lengths increase as the residence time in the membrane decreases. Moreover, electron transfer dissociation (ETD) tandem mass spectrometry (MS/MS) on a large myoglobin proteolytic peptide (8 kD) provides a resolution of 1–2 amino acids. Under denaturing conditions, limited membrane digestion of bovine serum albumin (BSA) and subsequent ESI-Orbitrap MS analysis reveal large peptides (3 kD–10 kD) that increase the sequence coverage from 53 % (2-s digestion) to 82 % (0.05-s digestion). With this approach we also performed membrane-based limited proteolysis of a large Arabidopsis GTPase, ROOT HAIR DEFECTIVE 3 (RHD3), and showed suitable probing for labile regions near the C-terminus to suggest what protein reconstruction might make RHD3 more suitable for crystallization.
Although numerous prognostic factors have been reported for colorectal cancer liver metastasis (CRLM), few studies have reported intraoperative blood loss (IBL) effects on clinical outcome after CRLM resection.
We retrospectively evaluated the clinical and histopathological characteristics of 139 patients who underwent liver resection for CRLM. The IBL cutoff volume was calculated using receiver operating characteristic curves. Overall survival (OS) and recurrence free survival (RFS) were assessed using the Kaplan–Meier and Cox regression methods.
All patients underwent curative resection. The median follow up period was 25.0 months (range, 2.1–88.8). Body mass index (BMI) and CRLM number and tumor size were associated with increased IBL. BMI (P=0.01; 95% CI = 1.3–8.5) and IBL (P<0.01; 95% CI = 1.6–12.5) were independent OSOs predictors. Five factors, including IBL (P=0.02; 95% CI = 1.1–4.1), were significantly related to RFS via multivariate Cox regression analysis. In addition, OSOs and RFS significantly decreased with increasing IBL volumes. The 5-year OSOs of patients with IBL≤250, 250–500, and >500mL were 71%, 33%, and 0%, respectively (P<0.01). RFS of patients within three IBL volumes at the end of the first year were 67%, 38%, and 18%, respectively (P<0.01).
IBL during CRLM resection is an independent predictor of long term survival and tumor recurrence, and its prognostic value was confirmed by a dose–response relationship.
Plant RNA-dependent RNA Polymerase 1 (RDR1) is an important element of the RNA silencing pathway in the plant defense against viruses. RDR1 expression can be elicited by viral infection and salicylic acid (SA), but the mechanisms of signaling during this process remains undefined. The involvement of hydrogen peroxide (H2O2) and nitric oxide (NO) in RDR1 induction in the compatible interactions between Tobacco mosaic tobamovirus (TMV) and Nicotiana tabacum, Nicotiana benthamiana, and Arabidopsis thaliana was examined. TMV inoculation onto the lower leaves of N. tabacum induced the rapid accumulation of H2O2 and NO followed by the increased accumulation of RDR1 transcripts in the non-inoculated upper leaves. Pretreatment with exogenous H2O2 and NO on upper leaf led to increased RDR1 expression and systemic TMV resistance. Conversely, dimethylthiourea (an H2O2 scavenger) and 2-(4-carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (an NO scavenger) partly blocked TMV- and SA-induced RDR1 expression and increased TMV susceptibility, whereas pretreatment with exogenous H2O2 and NO failed to diminish TMV infection in N. benthamiana plants with naturally occurring RDR1 loss-of-function. Furthermore, in N. tabacum and A. thaliana, TMV-induced H2O2 accumulation was NO-dependent, whereas NO generation was not affected by H2O2. These results suggest that, in response to TMV infection, H2O2 acts downstream of NO to mediate induction of RDR1, which plays a critical role in strengthening RNA silencing to restrict systemic viral infection.
Our aim is to explore the trend of association between the survival rates of colorectal cancer (CRC) and the different clinical characteristics in patients registered from 1960s to 2000s. We hypothesized that the survival rate of CRC increases over time and varies according to anatomic subsites.
Information from a total of 4558 stage T(1-4)N(1-2)M0 CRC patients registered from 1960s to 2008 were analyzed. The association of CRC overall survival with age, gender, tumor locations, time, histopathology types, pathology grades, no. of examined lymph nodes, the T stage, and the N stage was analyzed. The assessment of the influence of prognostic factors on patient survival was performed using Cox’s proportional hazard regression models.
From 1960 to 2008, the studied CRC patients included 2625 (57.6%) and 1933 (42.4%) males and females, respectively. These included 1896 (41.6%) colon cancers, and 2662 (58.4%) rectum cancers. The 5-year survival rate was 49%, 58%, 58%, 70%, and 77% for the time duration of 1960s, 1970s, 1980s, 1990s and 2000s, respectively. An increased 5-year survival rate was observed in the colon cancer and rectum cancer patients. Patients older than 60 years of age were more likely to develop colonic cancer (sigmoid) than rectum cancer (49.2% vs. 39.9%). The Cox regression model showed that only rectum cancer survival was related to time duration.
The overall survival and 5-year survival rates showed an increase from the 1960s to 2000s. There is a trend of rightward shift of tumor location in CRC patients.
The predictive value of thymidylate synthase (TYMS) to sensitivity to pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is controversial. We conducted a meta-analysis of all relevant published data to assess the association of TYMS expression with the clinical outcomes of pemetrexed-based regimen in advanced NSCLC.
Patients and Methods
We conducted an electronic search using using PubMed, Embase, OVID and Cochrane Library databases and manual search. Pooled odds ratio (OR) for the response rate and hazard ratio (HR) for the overall survival and progression free survival were calculated using the software Revman 5.0.
There were 11 studies (n=798) met our criteria for evaluation. Response rate to pemetrexed-based regimen was significantly higher in patients with low/negative TYMS (OR=2.96, 95%CI [1.81, 4.86] P<0.0001). Patients with low/negative TYMS who were treated with pemetrexed-based regimen had longer progression free survival (HR 0.50, 95%CI [0.41, 0.61] P <0.00001) and overall survival (HR 0.41, 95%CI [0.22, 0.78] P=0.007) than those with high/positive TYMS.
Low/negative TYMS expression was significantly associated with higher response rate, longer median survival and longer progression free survival for advanced NSCLC patients receiving pemtrexed-based chemotherapy. Hence, TYMS may be a potential predictor of sensitivity to pemtrexed-based chemotherapy in advanced NSCLC. Large scale prospective clinical trials are still warranted.
hTERTC27 is a newly constructed polypeptide that can induce telomere dysfunction. To study the synergistic antitumor effects of the hTERTC27 polypeptide driven by the early growth response protein-1 (Egr-1) promoter and chemotherapeutic 5-flurorouracil (5-FU) on nasopharyngeal carcinoma, a series of in vitro and in vivo experiments were performed. The results showed that hTERTC27 expression was significantly increased up to 7.21-folds by the 5-FU-activated Egr-1 promoter in C666-1 cells. Overexpressed hTERTC27 made the cells more sensitive to 5-FU, and additionally, inhibited cell proliferation about 20.41%. Combinational therapy of overexpressed hTERTC27 driven by the 5-FU-activated Egr-1 promoter and 5-FU synergistically inhibited cell proliferation and promoted apoptosis of C666-1 cells for about 4.75-fold and 1.76-fold in comparison with a sole therapy of hTERTC27 or 5-FU in vitro. In vivo experiments showed that overexpressed hTERTC27 driven by 5-FU-activated Egr-1 promoter and 5-FU synergistically reduced tumor volume, tumor weight, and local infiltration, which may be relative to tumor cell apoptosis. These results suggest that combinational therapy of overexpressed hTERTC27, which is driven by the 5-FU-activated Egr-1 promoter, and 5-FU may provide a novel approach to treat nasopharyngeal cancer.
5-FU; Egr-1; hTERTC27; nasopharyngeal carcinoma; gene therapy
To assess the clinical significance of WD40 repeat containing 62 (WDR62), a novel centrosome abnormalities-associated gene, in ovarian cancer.
Materials and methods
In this study, WDR62 expression was assessed by western blot (6 ovarian cancer cell lines) and immunohistochemistry (primary epithelial ovarian cancer clinical specimens), and clinical variables were collected by retrospective chart review. Centrosome amplification was assessed by immunofluorescence staining in ovarian cancer cell lines, and by immunohistochemistry staining in ovarian cancer samples.
Six ovarian cancer cell lines exhibited significant WDR62 protein overexpression, and amplification of centrosome. High-grade ovarian cancer specimens exhibited significantly stronger nuclear staining of WDR62 than low-grade ovarian carcinoma specimens (80.4% vs 41.3%; P<0.012). High WDR62 expression was strongly associated with supernumerary centrosome count in tumor cells (P < 0.001).
Our findings suggest that WDR62 overexpression is related to centrosome amplification in ovarian cancer. It may be a novel useful differentiation biomarker and a potential therapy target for OC. Further assessment of WDR62 expression is highly warranted in large, prospective studies.
Ovarian cancer; WDR62; Centrosome
We report a structure-property relationship in gold nanoparticles (NPs), grain-size effects, which not only allow material properties observed on different characteristic length scales to be engineered in a single NP but further enhance those properties due to the coupling among different-size grains. The grain size effects were achieved by creating polycrystalline gold NPs (pAuNPs) with two distinct grain-size populations (5 and 1 nm) comparable to electron mean free path and electron Fermi wavelength (EFW) respectively. Successful integration of molecular and plasmonic properties into a single nanostructure without additional fluorophores enables these highly polycrystalline AuNPs to serve as multimodal probes in a variety of optical microscopic imaging techniques.
Two novel mammalian targets of rapamycin (mTOR) inhibitors everolimus and temsirolimus are now approved by regulatory agencies and have been widely investigated among various types of solid tumors, but the risk of fatal adverse events (FAEs) with these drugs is not well defined.
We searched PubMed, EMBASE, and Cochrane library databases for relevant trials. Eligible studies included prospective phase II and III trials evaluating everolimus and temsirolimus in patients with all malignancies and data on FAEs were available. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
A total of 3322 patients with various advanced solid tumors from 12 trials were included. The overall incidence of mTOR inhibitors associated FAEs was 1.8% (95%CI: 1.3–2.5%), and the incidences of everolimus related FAEs were comparable to that of temsirolimus (1.7% versus 1.8%). Compared with the controls, the use of mTOR inhibitors was associated with an increased risk of FAEs, with a RR of 3.24 (95%CI: 1.21–8.67, p = 0.019). On subgroup analysis, a non-statistically significant increase in the risk of FAEs was found according to different mTOR inhibitors, tumor types or controlled therapy. No evidence of publication bias was observed.
With the present evidence, the use of mTOR inhibitors seems to increase the risk of FAEs in patients with advanced solid tumors. More high quality trials are still needed to investigate this association.
Deltamethrin (DM) insecticides are currently being promoted worldwide for mosquito control, because of the high efficacy, low mammalian toxicity and less environmental impact. Widespread and improper use of insecticides induced resistance, which has become a major obstacle for the insect-borne disease management. Resistance development is a complex and dynamic process involving many genes. To better understand the possible molecular mechanisms involved in DM resistance, a proteomic approach was employed for screening of differentially expressed proteins in DM-susceptible and -resistant mosquito cells. Twenty-seven differentially expressed proteins were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry (MS). Four members of the ubiquitin-proteasome system were significantly elevated in DM-resistant cells, suggesting that the ubiquitin-proteasome pathway may play an important role in DM resistance. Proteasome subunit beta type 6 (PSMB6) is a member of 20S proteasomal subunit family, which forms the proteolytic core of 26S proteasome. We used pharmaceutical inhibitor and molecular approaches to study the contributions of PSMB6 in DM resistance: the proteasome inhibitor MG-132 and bortezomib were used to suppress the proteasomal activity and siRNA was designed to block the function of PSMB6. The results revealed that both MG-132 and bortezomib increased the susceptibility in DM-resistant cells and resistance larvae. Moreover, PSMB6 knockdown decreased cellular viability under DM treatment. Taken together, our study indicated that PSMB6 is associated with DM resistance in mosquitoes and that proteasome inhibitors such as MG-132 or bortezomib are suitable for use as a DM synergist for vector control.
Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). We have previously demonstrated that hypermethylation in candidate genes can be detected in plasma DNA prior to HCC diagnosis. To identify with a genome-wide approach additional genes hypermethylated in HCC that could be used for more accurate analysis of plasma DNA for early diagnosis, we analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor compared to non-tumor tissues. Array data were validated with pyrosequencing in a subset of 5 of these genes; correlation coefficients ranged from 0.92 to 0.97. Analysis of plasma DNA from 38 cases demonstrated that 37% to 63% of cases had detectable hypermethylated DNA (≥5% methylation) for these 5 genes individually. At least one of these genes was hypermethylated in 87% of cases, suggesting that measurement of DNA methylation in plasma samples is feasible. The panel of methylated genes indentified in the current study will be further tested in large cohort of prospectively collected samples to determine their utility as early biomarkers of hepatocellular carcinoma.
Genome-wide; DNA mehtylation; Hepatocellular Carcinoma
Coronary endothelial function (endoFx) is abnormal in patients with established coronary artery disease (CAD) and was recently shown by MRI to relate to the severity of luminal stenosis. Recent advances in MRI now allow the non-invasive assessment of both anatomic and functional (endoFx) changes that previously required invasive studies. We tested the hypothesis that abnormal coronary endoFx is related to measures of early atherosclerosis such as increased coronary wall thickness (CWT).
Methods and Results
Seventeen arteries in fourteen healthy adults and seventeen arteries in fourteen patients with non-obstructive CAD were studied. To measure endoFx, coronary MRI was performed before and during isometric handgrip exercise, an endothelial-dependent stressor and changes in coronary cross-sectional area (CSA) and flow were measured. Black blood imaging was performed to quantify CWT and other indices of arterial remodeling. The mean stress-induced change in CSA was significantly higher in healthy adults (13.5%±12.8%, mean±SD, n=17) than in those with mildly diseased arteries (-2.2±6.8%, p<0.0001, n=17). Mean CWT was lower in healthy subjects (0.9±0.2mm) than in CAD patients (1.4±0.3mm, p<0.0001). In contrast to healthy subjects, stress-induced changes in CSA, a measure of coronary endoFx, correlated inversely with CWT in CAD patients (r= -0.73, p=0.0008).
There is an inverse relationship between coronary endothelial function and local CWT in CAD patients but not in healthy adults. These findings demonstrate that local endothelial-dependent functional changes are related to the extent of early anatomic atherosclerosis in mildly diseased arteries. This combined MRI approach enables the anatomic and functional investigation of early coronary disease.
coronary disease; endothelium; magnetic resonance imaging
Plants have evolved complex processes to ward off attacks by insects. In parallel, insects have evolved mechanisms to thwart these plant defenses. To gain insight into mechanisms that mediate this arms race between plants and herbivorous insects, we investigated the interactions between gramine, a toxin synthesized by plants of the family Gramineae, and glutathione S transferase (GST), an enzyme found in insects that is known to detoxify xenobiotics. Here, we demonstrate that rice (Oryza sativa), a hydrophytic plant, also produces gramine and that rice resistance to brown planthoppers (Nilaparvata lugens, BPHs) is highly associated with in planta gramine content. We also show that gramine is a toxicant that causes BPH mortality in vivo and that knockdown of BPH GST gene nlgst1-1 results in increased sensitivity to diets containing gramine. These results suggest that the knockdown of key detoxification genes in sap-sucking insects may provide an avenue for increasing their sensitivity to natural plant-associated defense mechanisms.
Mitochondrial transcription factor A (TFAM), the first well-characterized transcription factor from vertebrate mitochondria, is closely related to mitochondrial DNA (mtDNA) maintenance and repair. Recent evidence has shown that the ratio of mtDNA to nuclearDNA (nDNA) is increased in both human cells and murine tissues after ionizing radiation (IR). However, the underlying mechanism has not as yet been clearly identified. In the present study, we demonstrated that in human lung adenocarcinoma A549 cells, expression of TFAM was upregulated, together with the increase of the relative mtDNA copy number and cytochrome c oxidase (COX) activity after α-particle irradiation. Furthermore, short hairpin RNA (shRNA)-mediated TFAM knockdown inhibited the enhancement of the relative mtDNA copy number and COX activity caused by α-particles. Taken together, our data suggested that TFAM plays a crucial role in regulating mtDNA amplification and mitochondrial biogenesis under IR conditions.
mitochondrial transcription factor A; ionizing radiation; mitochondrial DNA; mitochondrial biogenesis
Therapeutic interventions in prediabetes are important in the primary prevention of type 2 diabetes (T2D) and its chronic complications. However, little is known about the pharmacogenetic effect of traditional herbs on prediabetes treatment. A total of 194 impaired glucose tolerance (IGT) subjects were treated with traditional hypoglycemic herbs (Tianqi Jiangtang) for 12 months in this study. DNA samples were genotyped for 184 mutations in 34 genes involved in drug metabolism or transportation. Multinomial logistic regression analysis indicated that rs1142345 (A > G) in the thiopurine S-methyltransferase (TPMT) gene was significantly associated with the hypoglycemic effect of the drug (P = 0.001, FDR P = 0.043). The “G” allele frequencies of rs1142345 in the healthy (subjects reverted from IGT to normal glucose tolerance), maintenance (subjects still had IGT), and deterioration (subjects progressed from IGT to T2D) groups were 0.094, 0.214, and 0.542, respectively. Binary logistic regression analysis indicated that rs1142345 was also significantly associated with the hypoglycemic effect of the drug between the healthy and maintenance groups (P = 0.027, OR = 4.828) and between the healthy and deterioration groups (P = 0.001, OR = 7.811). Therefore, rs1142345 was associated with the clinical effect of traditional hypoglycemic herbs. Results also suggested that TPMT was probably involved in the pharmacological mechanisms of T2D.
The etiologic agent of bubonic plague, Yersinia pestis, senses self-produced, secreted chemical signals in a process named quorum sensing. Though the closely related enteric pathogen Y. pseudotuberculosis uses quorum sensing system to regulate motility, the role of quorum sensing in Y. pestis has been unclear. In this study we performed transcriptional profiling experiments to identify Y. pestis quorum sensing regulated functions. Our analysis revealed that acyl-homoserine lactone-based quorum sensing controls the expression of several metabolic functions. Maltose fermentation and the glyoxylate bypass are induced by acyl-homoserine lactone signaling. This effect was observed at 30°C, indicating a potential role for quorum sensing regulation of metabolism at temperatures below the normal mammalian temperature. It is proposed that utilization of alternative carbon sources may enhance growth and/or survival during prolonged periods in natural habitats with limited nutrient sources, contributing to maintenance of plague in nature.
Research suggests that people in Eastern interdependent cultures process information more holistically and attend more to contextual information than do people in Western independent cultures. The current study examined the effects of culture and age on memory for socially meaningful item-context associations in 71 Canadians of Western European descent (35 young and 36 older) and 72 native Chinese citizens (36 young and 36 older). All participants completed two blocks of context memory tasks. During encoding, participants rated pictures of familiar objects. In one block, objects were rated either for their meaningfulness in the independent living context or their typicality in daily life. In the other block, objects were rated for their meaningfulness in the context of fostering relationships with others or for their typicality in daily life. The encoding in each block was followed by a recognition test in which participants identified pictures and their associated contexts. The results showed that Chinese outperformed Canadians in context memory, though both culture groups showed similar age-related deficits in item and context memory. The results suggest that Chinese are at an advantage in memory for socially meaningful item-context associations, an advantage that continues from young adulthood into old age.
The 22q11 deletion syndrome (22q11DS) is characterized by multiple physical and psychiatric abnormalities and is caused by the hemizygous deletion of a 1.5–3Mb region of chromosome 22. 22q11DS constitutes one of the strongest known genetic risks for schizophrenia; schizophrenia arises in as many as 30% of patients with 22q11DS during adolescence or early adulthood. A mouse model of 22q11DS displays an age-dependent increase in hippocampal long-term potentiation (LTP), a form of synaptic plasticity underlying learning and memory. The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA2), which is responsible for loading Ca2+ into the endoplasmic reticulum (ER), is elevated in this mouse model. The resulting increase in ER Ca2+ load leads to enhanced neurotransmitter release and increased LTP. However, the mechanism by which the 22q11 microdeletion leads to SERCA2 overexpression and LTP increase has not been determined. Screening of multiple mutant mouse lines revealed that haploinsufficiency of Dgcr8, a microRNA (miRNA) biogenesis gene in the 22q11DS disease-critical region, causes age-dependent, synaptic SERCA2 overexpression and increased LTP. We found that miR-25 and miR-185, regulators of SERCA2, are depleted in mouse models of 22q11DS. Restoration of these miRNAs to presynaptic neurons rescues LTP in Dgcr8+/− mice. Finally, we show that SERCA2 is elevated in the brains of patients with schizophrenia, providing a link between mouse model findings and the human disease. We conclude that miRNA-dependent SERCA2 dysregulation is a pathogenic event in 22q11DS and schizophrenia.
Previously, we identified the genetic variant −241 (−/G) (rs11453459) in the PP2A-Aα gene (PPP2R1A) promoter and demonstrated that this variant influences the DNA-binding affinity of nuclear factor-kappa B (NF-κB). In this study, we further confirmed that the transcriptional activity of PPP2R1A may be regulated by NF-κB through the functional genetic variant −241 (−/G). Moreover, we also demonstrated that the methylation status of CpG islands in the promoter of PPP2R1A influences the activity of this gene promoter. Few studies have examined the role of this −241 (−/G) variant in genetic or epigenetic regulation in hepatocellular carcinoma (HCC). To investigate whether this functional variant in the PPP2R1A promoter is associated with the risk of HCC and confirm the function of the −241 (−/G) variant in the HCC population, we conducted a case-control study involving 251 HCC cases and 252 cancer-free controls from a Han population in southern China. Compared with the −241 (−−) homozygote, the heterozygous −241 (−G) genotype (adjusted OR = 0.32, 95% confidence interval (CI) = 0.17–0.58, P<0.001) and the −241 (−G)/(GG) genotypes (adjusted OR = 0.38, 95% CI = 0.22–0.67, P = 0.001) were both significantly associated with a reduced risk of HCC. Stratification analysis indicated that the protective role of −241 (−G) was more pronounced in individuals who were ≤ 40 years of age, female and HBV-negative. Our data suggest that the transcriptional activity of PPP2R1A is regulated by NF-κB through the −241 (−/G) variant and by the methylation of the promoter region. Moreover, the functional −241 (−/G) variant in the PPP2R1A promoter contributes to the decreased risk of HCC. These findings contribute novel information regarding the gene transcription of PPP2R1A regulated by the polymorphism and methylation in the promoter region through genetic and epigenetic mechanisms in hepatocarcinogenesis.
Age-related macular degeneration (AMD) is the main cause of blindness and the curative options are limited. The objective of this meta-analysis was to determine the association between aspirin use and risk of AMD.
A comprehensive literature search was performed in PubMed, Embase, Web of Science, and reference lists. A meta-analysis was performed by STATA software.
Ten studies involving 171729 individuals examining the association between aspirin use and risk of AMD were included. Among the included studies, 2 were randomized-controlled trials (RCTs), 4 were case-control studies and 4 were cohort studies. The relative risks (RRs) were pooled using a random-effects model. Relative risks with 95% confidence intervals (CIs) of aspirin use as a risk for AMD. The pooled RR of 10 included studies between the use of aspirin and risk of AMD was 1.09 (95% CI, 0.96–1.24). The same result was detected in early and late stage AMD subgroup analysis. In the subgroup analyses, the pooled RR of RCTs, case-control studies and cohort studies were 0.81 (95% CI, 0.64–1.02), 1.02 (95% CI, 0.92–1.14) and 1.08 (95% CI, 0.91–1.28), respectively.
The use of aspirin was not associated with the risk of AMD.
Our objective is to test the hypothesis that coronary endothelial function (CorEndoFx) does not change with repeated isometric handgrip (IHG) stress in CAD patients or healthy subjects.
Coronary responses to endothelial-dependent stressors are important measures of vascular risk that can change in response to environmental stimuli or pharmacologic interventions. The evaluation of the effect of an acute intervention on endothelial response is only valid if the measurement does not change significantly in the short term under normal conditions. Using 3.0 Tesla (T) MRI, we non-invasively compared two coronary artery endothelial function measurements separated by a ten minute interval in healthy subjects and patients with coronary artery disease (CAD).
Twenty healthy adult subjects and 12 CAD patients were studied on a commercial 3.0 T whole-body MR imaging system. Coronary cross-sectional area (CSA), peak diastolic coronary flow velocity (PDFV) and blood-flow were quantified before and during continuous IHG stress, an endothelial-dependent stressor. The IHG exercise with imaging was repeated after a 10 minute recovery period.
In healthy adults, coronary artery CSA changes and blood-flow increases did not differ between the first and second stresses (mean % change ±SEM, first vs. second stress CSA: 14.8%±3.3% vs. 17.8%±3.6%, p = 0.24; PDFV: 27.5%±4.9% vs. 24.2%±4.5%, p = 0.54; blood-flow: 44.3%±8.3 vs. 44.8%±8.1, p = 0.84). The coronary vasoreactive responses in the CAD patients also did not differ between the first and second stresses (mean % change ±SEM, first stress vs. second stress: CSA: −6.4%±2.0% vs. −5.0%±2.4%, p = 0.22; PDFV: −4.0%±4.6% vs. −4.2%±5.3%, p = 0.83; blood-flow: −9.7%±5.1% vs. −8.7%±6.3%, p = 0.38).
MRI measures of CorEndoFx are unchanged during repeated isometric handgrip exercise tests in CAD patients and healthy adults. These findings demonstrate the repeatability of noninvasive 3T MRI assessment of CorEndoFx and support its use in future studies designed to determine the effects of acute interventions on coronary vasoreactivity.
The association between promoter methylation status and survival was investigated in a large cohort of women with breast cancer, participants in the Long Island Breast Cancer Study Project. Archived tumor tissues (n=839) were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. Vital status was followed through the end of 2005 with a mean follow up time of 8 years. Promoter methylation of 8 breast cancer-related genes was assessed by MethyLight. The frequencies of methylation for HIN1, RASSF1A, DAPK1, GSTP1, CyclinD2, TWIST, CDH1 and RARβ were 62.9%, 85.2%, 14.1%, 27.8%, 19.6%, 15.3%, 5.8% and 27.6%, respectively. Since survival rates of in situ and invasive breast cancers are substantially different, survival analyses were conducted within 670 invasive cases with complete data on all genes. Age-adjusted Cox-proportional hazards models revealed that GSTP1, TWIST and RARβ methylation was significantly associated with higher breast cancer-specific mortality. Methylation of GSTP1 and RARβ were significantly associated with higher all-cause mortality. To investigate the relationship between the number of methylated genes and breast cancer-specific mortality, we included previously published MethyLight data on p16 and APC methylation status. Breast cancer-specific mortality increased in a dose-dependent manner with increasing number of methylated genes (Ptrend = 0.002), although confidence intervals were wide. Our results suggest that promoter methylation, particularly for a panel of genes, has the potential to be used as a biomarker for predicting prognosis in breast cancer.
Promoter methylation; Tumor suppressor gene; Breast cancer; Mortality