Menin, encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, is a tumor suppressor that leads to multiple endocrine tumors upon loss of its function. Menin functions as a transcriptional activator by tethering MLL complex to mediate histone H3 K4 methylation. It also functions as a repressor. However, the molecular mechanism of how menin contributes to the opposite outcome in gene expression is largely unknown. Here, we investigated the role of menin in the epigenetic regulation of transcription mediated by histone covalent modification. We show that the global methylation level of histone H3 K9, as well as H3 K4, was decreased in
MEF cells. Consistently, menin was able to interact with the suppressor of variegation 3–9 homolog family protein, SUV39H1, to mediate H3 K9 methylation.
This interaction decreased when patient-derived MEN1 mutation was introduced into the SUV39H1-interaction domain. We show that menin mediated different chromatin changes depending on target genes. Chromatin immunoprecipitation studies showed that menin directly associated with the
promoter and menin-dependent recruitment of SUV39H1 was essential for chromatin remodeling and transcriptional regulation. These results provide a molecular basis of how menin functions as a transcriptional repressor and suggest that menin-dependent integration of H3 K9 methylation might play an important role in preventing tumors.
menin; tumor suppressor; histone methylation; SUV39H1
Salivary duct carcinoma (SDC) is a rare malignancy of high-grade pathological type. We evaluated clinical outcomes and prognostic factors in 35 patients with SDC treated post-operatively with adjuvant radiation.
We retrospectively assessed overall survival, locoregional control and disease-free survival in 35 patients with SDC of the major salivary glands who underwent surgery and were subsequently treated with radiotherapy. The evaluated prognostic factors included gender, age, symptom duration, tumour site, tumour size, TNM classification, and the following pathological features: perineural invasion, lymphovascular invasion, extraparenchymal invasion and resection-margin status.
Of the 35 patients, 30 (85.7%) were male. Median age at initial diagnosis was 62 years (range 38–75 years). The parotid gland was the main site affected in 22 patients (62.9%). 18 patients (51.5%) had pathological T3/T4 tumours, and 26 (74.3%) showed pathological nodal involvement. Actuarial 5-year locoregional control, disease-free survival and overall survival rates were 63.3%, 47.4% and 55.1%, respectively. The cause-specific death rate was 31.4% (n=11). Pathological nodal involvement was correlated with distant metastasis (p=0.011). Lymphovascular invasion was significantly prognostic for distant metastasis-free survival (p=0.049), locoregional control (p=0.012) and overall survival (p=0.003) in a Cox proportional hazard model, whereas perineural invasion was only significantly prognostic for overall survival (p=0.005).
Surgery and post-operative radiotherapy were effective for locoregional control. Lymphovascular invasion and perineural invasion were significant prognostic factors in patients with SDC.
The purpose of this study was to identify genes that are differentially expressed in chemosensitive serous papillary ovarian carcinomas relative to those expressed in chemoresistant tumours.
To identify novel candidate biomarkers, differences in gene expression were analysed in 26 stage IIIC/IV serous ovarian adenocarcinomas (12 chemosensitive tumours and 14 chemoresistant tumours). We subsequently investigated the immunohistochemical expression of GRIA2 in 48 independent sets of advanced ovarian serous carcinomas.
Microarray analysis revealed a total of 57 genes that were differentially expressed in chemoresistant and chemosensitive tumours. Of the 57 genes, 39 genes were upregulated and 18 genes were downregulated in chemosensitive tumours. Five differentially expressed genes (CD36, LIFR, CHL1, GRIA2, and FCGBP) were validated by quantitative real-time PCR. The expression of GRIA2 was validated at the protein level by immunohistochemistry, and patients with GRIA2 expression showed a longer progression-free and overall survival (P=0.051 and P=0.031 respectively).
We found 57 differentially expressed genes to distinguish between chemosensitive and chemoresistant tumours. We also demonstrated that the expression of GRIA2 among the differentially expressed genes provides better prognosis of patients with advanced serous papillary ovarian adenocarcinoma.
gene expression profiling; microarray; ovarian serous adenocarcinoma; GRIA2; survival
The title compound, C17H13ClO6, is an asymmetric alicyclic dianhydride containing a chloromethyl-substituted tetrahydronaphthalene moiety. The cyclohexene ring in the tetrahydronaphthalene moiety exhibits an envelope conformation with the tertiary C atom as the flap The dihedral angle between the two anhydride rings is 79.96 (6)°, while those between the benzene ring and the non-fused and fused anhydride rings are 71.03 (5) and 42.57 (7)°, respectively. In the crystal, molecules are connected by weak C—H⋯O interactions, forming a three-dimensional supramolecular structure.
The construction and performance of a Ka-band pulsed electron paramagnetic resonance (EPR) cryogenic probehead that incorporates dielectric resonator (DR) is presented. We demonstrate that the use of DR allows one to optimize pulsed double electron–electron resonance (DEER) measurements utilizing large resonator bandwidth and large amplitude of the microwave field B1. In DEER measurements of Gd-based spin labels, use of this probe finally allows one to implement the potentials of Gd-based labels in distance measurements. Evidently, this DR is well suited to any applications requiring large B1-fields and resonator bandwidths, such as electron spin echo envelope modulation spectroscopy of nuclei having low magnetic moments and strong hyperfine interactions and double quantum coherence dipolar spectroscopy as was recently demonstrated in the application of a similar probe based on an loop-gap resonator and reported by Forrer et al. (J Magn Reson 190:280, 2008).
An inverse association between alcoholic beverage intake and risk of renal cell cancer has been suggested in recent studies.
We examined the association between alcoholic beverages and renal cell cancer risk in a meta-analysis. We identified relevant studies by searching the database of PubMed, EMBASE, and MEDLINE published through August 2011. We combined the study-specific relative risks (RRs) using a random-effects model.
A total of 20 case–control studies, 3 cohort studies, and 1 pooled analysis of cohort studies were included in the meta-analysis. We observed that alcoholic beverage intake was associated with a lower risk of renal cell cancer in combined analysis of case–control and cohort studies; for total alcoholic beverage intake, combined RRs (95% confidence intervals) comparing top with bottom categories were 0.76 (0.68–0.85) in case–control studies, and 0.71 (0.63–0.78) in cohort studies (P for difference by study design=0.02). The inverse associations were observed for both men and women and for each specific type alcoholic beverage (beer, wine, and liquor). Also, we found that one drink per day of alcoholic beverage conferred the reduction in renal cell cancer risk, but further drinking above that level did not add benefit.
The findings from our meta-analysis support the hypothesis that alcoholic beverage intake is inversely associated with a lower risk of renal cell cancer, with moderate consumption conferring the protection and higher consumption conferring no additional benefits.
alcohol; renal cell cancer; meta-analysis
Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR-18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC.
CTGF; NPC; miR-18b; PI3K/AKT
Estimates of the coalescent effective population size Ne can be poorly correlated with the true population size. The relationship between Ne and the population size is sensitive to the way in which birth and death rates vary over time. The problem of inference is exacerbated when the mechanisms underlying population dynamics are complex and depend on many parameters. In instances where nonparametric estimators of Ne such as the skyline struggle to reproduce the correct demographic history, model-based estimators that can draw on prior information about population size and growth rates may be more efficient. A coalescent model is developed for a large class of populations such that the demographic history is described by a deterministic nonlinear dynamical system of arbitrary dimension. This class of demographic model differs from those typically used in population genetics. Birth and death rates are not fixed, and no assumptions are made regarding the fraction of the population sampled. Furthermore, the population may be structured in such a way that gene copies reproduce both within and across demes. For this large class of models, it is shown how to derive the rate of coalescence, as well as the likelihood of a gene genealogy with heterochronous sampling and labeled taxa, and how to simulate a coalescent tree conditional on a complex demographic history. This theoretical framework encapsulates many of the models used by ecologists and epidemiologists and should facilitate the integration of population genetics with the study of mathematical population dynamics.
Pulse Dipolar Spectroscopy (PDS); Gd(III) tags; oligonucleotides; DEER; distance measurements
We report an in-plane optical spectroscopy study on the iron-selenide superconductor K0.75Fe1.75Se2. The measurement revealed the development of a sharp reflectance edge below Tc at frequency much smaller than the superconducting energy gap on a relatively incoherent electronic background, a phenomenon which was not seen in any other Fe-based superconductors so far investigated. Furthermore, the feature could be noticeably suppressed and shifted to lower frequency by a moderate magnetic field. Our analysis indicates that this edge structure arises from the development of a Josephson-coupling plasmon in the superconducting condensate. Together with the transmission electron microscopy analysis, our study yields compelling evidence for the presence of nanoscale phase separation between superconductivity and magnetism. The results also enable us to understand various seemingly controversial experimental data probed from different techniques.
Admixed populations have been used for inferring migrations, detecting natural selection, and finding disease genes. These applications often use a simple statistical model of admixture rather than a modeling perspective that incorporates a more realistic history of the admixture process. Here, we develop a general model of admixture that mechanistically accounts for complex historical admixture processes. We consider two source populations contributing to the ancestry of a hybrid population, potentially with variable contributions across generations. For a random individual in the hybrid population at a given point in time, we study the fraction of genetic admixture originating from a specific one of the source populations by computing its moments as functions of time and of introgression parameters. We show that very different admixture processes can produce identical mean admixture proportions, but that such processes produce different values for the variance of the admixture proportion. When introgression parameters from each source population are constant over time, the long-term limit of the expectation of the admixture proportion depends only on the ratio of the introgression parameters. The variance of admixture decreases quickly over time after the source populations stop contributing to the hybrid population, but remains substantial when the contributions are ongoing. Our approach will facilitate the understanding of admixture mechanisms, illustrating how the moments of the distribution of admixture proportions can be informative about the historical admixture processes contributing to the genetic diversity of hybrid populations.
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
Meiotic recombination is a fundamental cellular mechanism in sexually reproducing organisms and its different forms, crossing over and gene conversion both play an important role in shaping genetic variation in populations. Here, we describe a coalescent-based full-likelihood Markov chain Monte Carlo (MCMC) method for jointly estimating the crossing-over, gene-conversion, and mean tract length parameters from population genomic data under a Bayesian framework. Although computationally more expensive than methods that use approximate likelihoods, the relative efficiency of our method is expected to be optimal in theory. Furthermore, it is also possible to obtain a posterior sample of genealogies for the data using this method. We first check the performance of the new method on simulated data and verify its correctness. We also extend the method for inference under models with variable gene-conversion and crossing-over rates and demonstrate its ability to identify recombination hotspots. Then, we apply the method to two empirical data sets that were sequenced in the telomeric regions of the X chromosome of Drosophila melanogaster. Our results indicate that gene conversion occurs more frequently than crossing over in the su-w and su-s gene sequences while the local rates of crossing over as inferred by our program are not low. The mean tract lengths for gene-conversion events are estimated to be ∼70 bp and 430 bp, respectively, for these data sets. Finally, we discuss ideas and optimizations for reducing the execution time of our algorithm.
In this work, we continue to explore Gd(III) as a possible spin label for high field Double Electron Electron Resonance (DEER) based distance measurements in biological molecules with flexible geometry. For this purpose, a bis-Gd(III) complex with a flexible “bridge” was used as a model. The distances in the model were expected to be distributed in the range of 5-26 Å, allowing us to probe the shortest limits of accessible distances which were found to be as small as 13 Å. The upper distance limit for these labels was also evaluated and was found to be about 60 Å. Various pulse duration setups can result in apparent differences in the distribution function derived from DEER kinetics due to short distance limit variations. The advantages, such as the ability to perform measurements at cryogenic temperatures and high repetition rates simultaneously, the use of very short pumping and observation pulses without mutual interference, the lack of orientational selectivity, as well as the shortcomings, such as the limited mw operational frequency range and intrinsically smaller amplitude of oscillation related to dipolar interaction as compared with nitroxide spin labels are discussed. Most probably the use of nitroxide and Gd based labels for distance measurements will be complementary depending on the particulars of the problem and the availability of instrumentation.
Gd(III) spin labels; high-field DEER; Ka and W-bands
A rapid real-time PCR (RT-PCR) approach was developed to detect the bft gene subtypes in Bacteroides fragilis isolated from fecal samples. DNA obtained from diarrhea (110) and nondiarrhea (150) samples was evaluated. Subtype 1 was observed in 9 (8.2%) diarrhea and 7 (4.7%) nondiarrhea samples. Subtype 2 was not detected in any DNA samples, and subtype 3 was observed in only 1 diarrhea sample. The presence of the bft-1 gene did not show any statistically significant differences between the groups of children. This technique could be used to evaluate a possible correlation between disease and the presence of B. fragilis enterotoxin.
The aim of this study was to investigate the movement, and the factors that influence such movement, of pancreatic lesions and to provide a reference for determination of planning target volume (PTV) during stereotactic radiotherapy. We implanted 19 gold markers into the inner pancreatic tumours of 16 pancreatic carcinoma patients percutaneously under B-ultrasonographic guidance. The marked motion of pancreatic lesions in the x (right–left), y (superoinferior) and z (anteroposterior) directions was measured using an X-ray simulator system. Based on the statistical analysis of the detected movements, we investigated the relevant influencing factors of pancreatic lesions with multinomial linear regression. Data showed that the mean motion amplitudes of pancreatic lesions were 0.16 cm ± 0.06 (range 0.1–0.3 cm) in the x direction, 0.25 cm ± 0.12 (range 0.1–0.4 cm) in the y direction and 0.88 cm ± 0.24 (0.5–1.6 cm) in the z direction. Motion amplitude was not correlated with the height, weight or age of the patients nor with the location or size of the tumour. The motion of pancreatic lesions was mainly influenced by the respiratory motion and has maximal amplitude in the z direction. Therefore, motion in the z direction should be given a priority consideration while determining the PTV.
The anomalous photovoltaic effect (APE) in ferroelectric thin films has been utilized for the development of an optical micro-detector active in the visible range (from 350 to 800 nm). La-doped Pb(Zr,Ti)O3 (PLZT) ferroelectric films epitaxially grown on Pt(001)/Mg(001) substrate were fabricated into micro-detector arrays and characterized as to their optical response. The Au/PLZT/Pt/MgO device was self-polarized in the as-deposited form with the polarization vector perpendicular to film surface. The heterostructure photovoltage response ranged from 100 to 200 mV, and the photocurrent was ~30 nA/cm2 for devices of ~250 μm diameter under illumination of 100 mW/cm2 at wavelengths from 400 to 580 nm. Such micro-detectors can be used for optical sensors in MEMS devices as well as for electrical stimulators of biological cells.
photo-detector; optical; ferroelectric; photo-voltage; thin-film
The imaging characteristics of two popular kV cone-beam CT (CBCT) and two MVCT systems utilised in image-guided radiation therapy (IGRT) were evaluated.
Materials and methods:
The study was performed on Varian Clinac iX, Elekta Synergy S, Siemens Oncor, and Tomotherapy. A CT phantom (Catphan-504, Phantom Laboratory, Salem, NY) was scanned for measurements of image quality including image noise, uniformity, density accuracy, spatial resolution, contrast linearity, and contrast resolution. The measurement results were analysed using in-house image analysis software. Reproducibility, position correction, and geometric accuracy were also evaluated with markers in a smaller alignment phantom. The performance evaluation compared volumetric image properties from these four systems with those from a conventional diagnostic CT (CCT).
It was shown that the linearity of the two kV CBCT was fairly consistent with CCT. The Elekta CBCT with half-circle 27-cm FOV had higher CT numbers than the other three systems. The image noises of the Elekta kV CBCT, Siemens MV CBCT, and Tomotherapy fan-beam CT (FBCT) are about 2–4 times higher than that of the Varian CBCT. The spatial resolutions of two kV CBCTs and two MV CBCTs were 8-11 lp/cm and 3-5 lp/cm, respectively.
Elekta CBCT provided a faster image reconstruction and low dose per scan for half-circle scanning. Varian CBCT had relatively lower image noise. Tomotherapy FBCT had the best uniformity.
Cone beam CT; MVCT; tomotherapy; image quality; IGRT
Defects in lipid metabolism have been found to be linked to several diseases, among which atherosclerosis, hypertension, obesity, and diabetes are the most important. Although cancer is chiefly a genetic disease, dietary lipid intake and metabolism are related to some cancer risks, including the risk for ovarian cancer. Higher intake of dietary lipids, systemic lipid metabolism malfunction, and abnormal serum lipid levels are somehow related to ovarian cancer. Overexpression of some lipid metabolic enzymes are also found in ovarian cancer. In this review article, we summarize the relationships between lipid intake, lipid metabolism, and ovarian cancer.
Ovarian cancer; lipids; metabolism; cholesterol; fatty acid synthase; phospholipids
We have built a wireless implantable microelectronic device for transmitting cortical signals transcutaneously. The device is aimed at interfacing a microelectrode array cortical to an external computer for neural control applications. Our implantable microsystem enables presently 16-channel broadband neural recording in a non-human primate brain by converting these signals to a digital stream of infrared light pulses for transmission through the skin. The implantable unit employs a flexible polymer substrate onto which we have integrated ultra-low power amplification with analog multiplexing, an analog-to-digital converter, a low power digital controller chip, and infrared telemetry. The scalable 16-channel microsystem can employ any of several modalities of power supply, including via radio frequency by induction, or infrared light via a photovoltaic converter. As of today, the implant has been tested as a sub-chronic unit in non-human primates (~ 1 month), yielding robust spike and broadband neural data on all available channels.
Neural Interface; Brain Computer Interface; Neural Prosthesis
Lumbar disc disease (LDD) is one of the leading causes of disability in the working‐age population. A functional single‐nucleotide polymorphism (SNP), +1184T→C, in exon 8 of the cartilage intermediate layer protein gene (CILP) was recently identified as a risk factor for LDD in the Japanese population (odds ratio (OR) 1.61, 95% CI 1.31 to 1.98), with implications for impaired transforming growth factorβ1 signalling.
To validate this finding in two different ethnic cohorts with LDD.
This SNP and flanking SNPs were analysed in 243 Finnish patients with symptoms of LDD and 259 controls, and in 348 Chinese subjects with MRI‐defined LDD and 343 controls.
Results and conclusion
The results showed no evidence of association in the Finnish (OR = 1.35, 95% CI 0.97 to 1.87; p = 0.14) or the Chinese (OR = 1.05, 95% CI 0.77 to 1.43; p = 0.71) samples, suggesting that cartilage intermediate layer protein gene is not a major risk factor for symptoms of LDD in Caucasians or in the general population that included individuals with or without symptoms.
Mesenchymal stem cells (MSCs) derived from adult tissues are an important candidate cell type for cell-based tissue engineering and regenerative medicine. Currently, clinical applications for MSCs require additional surgical procedures to harvest the autologous MSCs (i.e., from bone marrow) or commercial allogeneic alternatives. We have recently identified a population of mesenchymal progenitor cells (MPCs) in traumatized muscle tissue that has been surgically debrided from traumatic orthopaedic extremity wounds. The purpose of this study was to evaluate whether MPCs derived from traumatized muscle may provide a clinical alternative to bone-marrow MSCs by comparing their morphology, proliferation capacity, cell surface epitope profile and differentiation capacity. After digesting the muscle tissue with collagenase, the MPCs cells were enriched by a direct plating technique. The morphology and proliferation rate of the muscle-derived MPCs was similar to bone-marrow derived MSCs. Both populations expressed cell surface markers characteristic for MSCs (CD 73, CD 90 and CD105), and did not express markers typically absent on MSCs (CD14, CD34 and CD45). After 21 days in specific differentiation media, the histological staining and gene expression of the MPCs and MSCs was characteristic for differentiation into osteoblasts, chondrocytes and adipocytes but not into myoblasts. Our findings demonstrate that traumatized muscle-derived MPCs exhibit similar phenotype and resemble MSCs derived from the bone marrow. MPCs harvested from traumatized muscle tissue may be considered for applications in tissue engineering and regenerative medicine following orthopaedic trauma requiring circumferential debridement.
Mesenchymal Stem Cells; Multipotent Progenitor Cells; Muscle Stem Cells; Heterotopic Ossification; Regenerative Medicine; Orthopaedic Trauma
In this report, we describe a patient presenting with the superficial spreading type of early gastric cancer (egc) accompanied by cancerous ulcers. Disease progression and treatment outcome are discussed. After symptoms persisted for more than 1 year, the patient underwent total gastrectomy with D2 lymph node dissection. The patient was diagnosed with superficial spreading cancer (ssc), accompanied by an extensive iic lesions. The progression of this patient suggests that the co-occurrence of cancerous ulcers may contribute to egc development to some extent. As is known, egc often develops into advanced gastric cancer with time. However, in our case, we observed a process during which partial cancerous changes developed into ssc over 18 months. Superficial spreading cancer should be considered an egc variant, which may have the ability to spread superficially along the stomach wall without invading the muscularis propria. But we speculate that, if gene expression changes for some reason, the malignant ssc cells may acquire the ability to grow deeply into the stomach wall. Eventually, Borrmann type iv gastric cancer may develop.
Superficial gastric cancer; cancerous ulcer; Borrmann type iv
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease, characterized by chronic, erosive polyarthritis and by the presence of various autoantibodies in serum and synovial fluid. Since rheumatoid factor (RF) was first described, a number of other autoantibodies have been discovered in RA patients. The autoantigens recognized by these autoantibodies include cartilage components, chaperones, enzymes, nuclear proteins and citrullinated proteins. However, the clinical significances and pathogenic roles of these antibodies are largely unknown except for RF and anticitrullinated protein antibodies (ACPAs), whose clinical usefulness has been acknowledged due to their acceptable sensitivities and specificities, and prognostic values. This review presents and discusses the current state of the art regarding RF and ACPA in RA.