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In this paper, new mass features based on inter-view similarity in DBT projection views are proposed for classifying masses, aiming to effectively reducing false-positives (FPs). The proposed features are focused on utilizing inter-view information in projection views. The FPs induced by overlapping tissues of different depth could be observed differently between projection views, while masses could appear similar. To utilize the observation, the inter-view similarity measure is developed by utilizing the normalized cross-correlation between ROIs in projection views. In the analysis of inter-view similarities of masses and FPs, it is showed that inter-view similarities of FPs are lower than those of masses. To that end, new features are proposed to encode aforementioned difference of inter-view similarities between FPs and masses. Experimental results show that the proposed features can improve the mass classification performance in projection views in terms of the area under the ROC curve.

Objective To determine to what extent prostate cancer (PCa) risk prediction is improved by adding prostate-specific antigen (PSA) to a baseline model including genetic risk. Methods Peripheral blood deoxyribonucleic acid was obtained from Caucasian men undergoing prostate biopsy at the University of Toronto (September 1, 2008 to January 31, 2010). Thirty-three PCa risk–associated single nucleotide polymorphisms were genotyped to generate the prostate cancer genetic score 33 (PGS-33). Primary outcome is PCa on study prostate biopsy. Logistic regression, area under the receiver-operating characteristic curves (AUC), and net reclassification improvement were used to compare models. Results Among 670 patients, 323 (48.2%) were diagnosed with PCa. The PGS-33 was highly associated with biopsy-detectable PCa (odds ratio, 1.66; P = 5.86E-05; AUC, 0.59) compared with PSA (odds ratio, 1.33; P = .01; AUC, 0.55). PSA did not improve risk prediction when added to a baseline model (age, family history, digital rectal examination, and PGS-33) for overall risk (AUC, 0.66 vs 0.66; P = .86) or Gleason score ≥7 PCa (AUC, 0.71 vs 0.73; P = .15). Net reclassification improvement analyses demonstrated no appropriate reclassifications with the addition of PSA to the baseline model for overall PCa but did show some benefit for reclassification of men thought to be at higher baseline risk in the high-grade PCa analysis. Conclusion In a baseline model of PCa risk including the PGS-33, PSA does not add to risk prediction for overall PCa for men presenting for “for-cause” biopsy. These findings suggest that PSA screening may be minimized in men at low baseline risk.

Histone H3 methyltransferases are involved in the epigenetic control of transcription and heterochromatin maintenance. In Saccharomyces cerevisiae, deletion of a histone H3 methyltransferase SET1 leads to the induction of a subset of stress responsive genes in a Rad53 dependent manner. This type of induction was observed only in the absence of SET1 and not in the absence of other histone methyltransferases, SET2 or DOT1. We show that the increased expression of the stress responsive genes results from a lack of histone H3 lysine (K) 4 methylation. The loss of mono-methylation on H3 K4 is necessary to increase the expression of the stress responsive genes, while the loss of di- or tri-methylation induced by deletion of either RRM domain of Set1 or the upstream effector molecules hardly affected their expression. These results suggest that mono- and multiple methylation of H3 K4 have different roles. The mono-methylation of H3 K4 might be required for the global integrity of chromatin structure, which is normally monitored by the Rad53 dependent chromatin surveillance system.

An anterior dislocation of the elbow without a fracture of the olecranon is an extremely rare injury. This paper reports a 36-year-old male who stumbled and fell on his outstretched hand during a soccer game. The anteroposterior and lateral radiographs indicated a simple anterior dislocation of the elbow, which was reduced using a closed method. The elbow joint was stable in the range of motion, but the sensation of the two ulnar digits was still reduced. MRI was useful for the identification of the pathoanatomy. At the follow-up examination three months after the initial trauma, the hypesthesia has fully recovered and the patient regained the full range of the elbow and forearm motion without pain and instability. After 18 months, the patient had a normal elbow function, and could play various sports. If an anterior elbow dislocation is detected early, a closed reduction with careful pathoanatomical considerations would be successful.

The purpose of this study was to evaluate the drainage effect of silk suture following aspiration of the bursa as an early treatment of chronic olecranon bursitis. Eleven cases, which have over two weeks of history and over one year of follow-up, were investigated. The average duration of follow-up was 17.5 months. The average symptom duration was 1.8 months. With an aseptic technique, the aspiration of the bursa was done with 18gauge needle and syringe and then the insertion of silk suture through the aspiration needle was performed. The amount of drainage was regularly checked days interval and stitch out was done at the cessation of drainage. At the follow-up, recurrence, infection, pain, and limitation of range of motion were investigated by telephone interview. Redness around the insertion site of silk suture was found in all cases, but there was no active infection or recurrence. The results were satisfactory in all cases and the average time for recovery was 10.5 days. The drainage with silk suture following aspiration of the bursa is less invasive and very effective method in the early treatment of chronic olecranon bursitis.

Homo-oligomerization via a coiled-coil (C-C) domain has been shown to be necessary for the promyelocytic leukemia (PML)-retinoic acid receptor-alpha (RARalpha) fusion protein to acquire oncogenic potential in acute promyelocytic leukemia. We show here that PML(DeltaC-C)-RARalpha, which contains a deletion in its C-C domain, is neither localized as characteristic microspeckles nor modified by small ubiquitin-like modifiers (SUMO). The absence of sumoylation of the DeltaC-C mutant was due to the lack of binding to Ubc9, a SUMO conjugation enzyme. The integrity of RING finger domain was also needed for both sumoylation and microspeckle formation. In GAL4-DNA tethering assays, the DeltaC-C mutant completely lost the inhibitory effect on retinoic acid (RA)-mediated transactivation. Furthermore, the expression of CD14 in U937 cells expressing the DeltaC-C mutant in response to vitamin D3 was markedly higher than in cells expressing PML-RARalpha. However, the RA-mediated induction of C/EBPbeta in cells expressing the DeltaC-C mutant was comparable to that of control cells. Thus, our results suggest that the C-C domain-associated functions of sumoylation, localization as microspeckles, and the inhibition of monocyte differentiation all contribute to the oncogenic activity of PML-RARalpha.

The mouse monoclonal antibody (Mab), SRT10, recognizes a linear epitope of 10 amino acids (ThrPheIleGlyAlaIleAlaThrAspThr). When these epitope-tagged fusion proteins are expressed in mammalian cells, the Mab can detect the tagged proteins by immunoblotting, immunocytochemistry and immunoprecipitation. Here, we describe an efficient method for the purification of SRT-tagged recombinant human creatine kinase (CK) transiently expressed in mammalian cells. This method utilizes the expression of the N-terminal- or C-terminal-tagged CK in transiently transfected HEK293 cells followed by binding to anti-SRT-agarose affinity resin and competitive elution with SRT peptide. Recombinant CK was purified near homogeneity as judged by SDS-PAGE.

The Mre11-Rad50-Nbs1 protein complex has been known to be involved in a variety of DNA metabolic events that involve DNA double-strand breaks (DSBs). The phosphorylation of Mre11 is increased in response to ionizing radiation, which suggests that phosphorylation of Mre11 may be an important regulatory mechanism of this complex. Mre11-phosphorylating kinase activities were observed in Chk2 immunoprecipitates and HeLa nuclear extracts. Through the tandem affinity tagging system and conventional chromatography, this kinase was purified and identified as protein kinase CK2. CK2 phosphorylates Mre11 in vitro. In vitro kinase assay with a series of truncated Mre11 proteins as substrates for CK2 and site-directed mutagenesis showed that serine 649 of Mre11 is mainly phosphorylated by CK2 in vitro. In vivo labeling and phosphopeptide mapping analysis revealed that this phosphorylation occurs in vivo. These data implicate CK2 as a potential upstream regulator of Mre11 function.

Histone acetyltransferase coactivators bind to acetylated histones through their bromodomains and catalyze the acetylation of histone H3 and H4 tails for transcriptional activation. C-terminal binding protein (CtBP) serves as a transcriptional corepressor by recruiting histone deacetylases. However, the precise mechanism by which CtBP represses transcription has not been determined. In this study we found that CtBP1 directly associates with p300 by binding to the PXDLS motif in the bromodomain of p300. Moreover, CtBP1 blocks the accessibility of p300 to histones in an NADH-sensitive manner and thus represses p300-mediated histone acetylation and transcriptional activation. In addition, an NADH-nonresponsive, monomeric mutant, CtBP1 (G183V), was found to strongly repress p300-mediated transcriptional activation. Thus, the dissociation of NADH from CtBP1 leads to the repression of p300-driven general transcriptional activity by CtBP1. These results suggest a novel mechanism whereby CtBP1 serves as an energy-sensing repressor of histone acetyltransferase(s) and thus affects general transcription.

This paper presents the behavior characteristics of steel-concrete interface and analysis method to simulate interface behavior by using push-out results for steel-concrete composite members. In order to analyze the partial-interaction behavior of steel-conc rete interface, the interface is idealized by a number of interface elements. A total of 9 push-out specimens were tested and the test results were utilized to provide the properties of interface element in the analysis. To validate the present study, using a commercial structural analysis program, nonlinear structural analysis were performed for the push-out specimens, and the results of analysis were compared with the test data. The results of this study have shown that the nonlinear, slip-softening, as well as linear-elastic behaviors of steel-concrete interface can be efficiently and accurately simulated by the method of analysis presented in this paper.

A controller is proposed for the robust backstepping control of a class of nonlinear multiple-input multiple-output (MIMO) systems which can be converted to a strict feedback form. The proposed robust backstepping control scheme follows a systematic procedure for the design of control laws and uses time delay estimation (TDE) to estimate the uncertainties such as parameter variations, unknown disturbances, and unmodeled dynamics, etc. The proposed controller can be also applied to nonlinear MIMO systems with unmatched uncertainties. Stability analysis of the closed-loop system which contains the plant and the proposed controller is also studied and hereby a sufficient stability condition for the closed-loop system is proposed. The simulation results show that the control scheme works well with uncertainties and the proposed stability condition is valid. The controller is experimentally verified on a single-link flexible arm to show the effectiveness of the proposed scheme in the complicated systems with uncertainties.

The eukaryotic mRNAs produced by RNA polymerase II (Pol II) are capped with an inverted 7-methyl-guanosine (m7G) linked to the first residue of the mRNA (36). This event occurs by a series of three enzymatic reactions; The 5′ triphosphate end of the nascent RNA Pol II transcript is cleaved by 5′ RNA triphosphatase to produce the diphosphate end. RNA guanylyltransferase forms a covalent enzyme-GMP complex and subsequently caps the RNA substrate by adding a guanosine residue in a 5′-5′ triphosphate linkage. The cap is then methylated by RNA (guanine-7) methyltransferase (23, 39). In higher eukaryotes, a bifunctional monomeric polypeptide carries both the RNA triphosphatase and guanylyltransferase activities, while the capping enzyme from yeast is a complex of RNA triphosphatase and guanylyltransferase subunits (40). The polypeptides are encoded by the CET1 and CEG1 genes, respectively in Saccharomyces cerevisiae, and both are essential for the cell viability. Capping, the first mRNA modification, occurs by the time the transcript is only 25 to 30 nucleotides long in an early transcription phase. Such cotranscriptional capping is mediated by recruitment of capping enzyme machinery to the phosphorylated carboxy-terminal domain (CTD) of the largest subunit of Pol II (7, 15, 22, 51). The CTD of Pol II has an unusual structure with many heptapeptide repeats (YSPTSPS). The capping enzyme binds directly and specifically to the phosphorylated CTD of Pol II via the Ceg1 subunit (yeast) or the guanylyltransferase domain (metazoan). Furthermore, the guanylyltransferase activity of Ceg1 associated with phosphorylated CTD is allosterically regulated by both the Cet1 and phosphorylated CTD to ensure it has a coordinated capping activity (8). The mammalian capping enzyme is also allosterically regulated by an interaction with the phosphorylated CTD (16, 25). The CTD phosphorylated at serine 5 of the heptapeptide repeat appears to be important for the capping reaction because it stimulates the guanylyltransferase activity, although both serine 2 phosphorylation and serine 5 phosphorylation can mediate the protein interaction. An interesting extension to these findings was added by a chromatin immunoprecipitation assay, which provides in vivo evidence that the capping enzyme machinery interacts dynamically with Pol II during a transcription cycle (20, 35). The capping enzyme interacts with Pol II immediately after the serine 5 of CTD is phosphorylated. As serine 5 phosphorylation decreases in an early elongation phase, the capping enzyme dissociates from the transcription complex. Recently, data from several groups have raised the concept of “checkpoints” in transcription, especially in an early phase (summarized in reference 26). As operated during the cell cycle to ensure that each phase of the cycle is complete before the next one begins, checkpoint in early transcription is suggested to play a role in ensuring that only the properly modified RNA at the 5′ end is extended. The Pol II transcription is thus subjected to checkpoint control for the coordinated transcription with mRNA capping (6, 25, 26). Several transcription factors have been reported to play in this window. DSIF, a human homolog of the yeast transcription factor Spt4/Spt5, increases the pausing of Pol II and thus plays a role as a negative factor (42, 46, 49). Within this temporal and spatial interval, while Pol II with the hypophosphorylated CTD is paused at the promoter-proximal region, many factors are intended to target the capping enzymes to increase their recruitment or to enhance their catalytic activities. In addition to TFIIH, which creates a binding epitope for the capping enzyme on CTD by serine 5 phosphorylation, as described above, Spt5 itself interacts with the triphosphatase and guanylyltransferase components of the capping enzyme (21, 27, 44). In the case of human immunodeficiency virus (HIV), DSIF/Spt5-induced transcription arrest allows HIV-encoded Tat to interact with capping enzymes and to stimulate their catalytic activities (5, 6). Phosphorylation of Pol II CTD is critical for the transition to the elongation phase. At this step, the elongation factor P-TEFb, a DRB-sensitive protein kinase, phosphorylates the Pol II CTD and Spt5 (19, 29, 38). HIV Tat also interacts with P-TEFb in this step (29). In S. cerevisae, Ctk1 kinase complex and the Bur1 kinase complex facilitate the transcription elongation (18, 50). The phosphorylation of Pol II CTD is thus meant to lead to the formation of the processive transcription elongation complexes. According to recent reports, the capping enzyme in Schizosaccharomyces pombe interacts with Cdk9/Pch1, a yeast P-TEFb homolog (28). How does the capping enzyme fit into the complicated scheme to delineate it in the order of pausing, capping, and the reversion of pausing in the checkpoint model? If the elongation-competent transition does not occur until the RNA is capped and the capping is the major determinant to shift the Pol II status, it could be indicative that a capping enzyme plays a critical role in regulation of an early transcription in addition to its role in simple cap formation. To study whether the capping enzyme plays a key role in coordinating mRNA processing and transcription elongation, we used a well-characterized yeast system. Because Ceg1, a capping enzyme subunit, contributes to transcription via its typical cap formation activity, this study examined various ceg1 temperature-sensitive alleles to determine if there is any additional role in transcription elongation. Among them ceg1-63 displayed 6-azauracil (6AU) sensitivity and a defect in PUR5 induction by 6AU treatment. This study shows that transcription through the pause sites artificially inserted at the promoter-proximal region was severely inhibited in ceg1-63. We show that such an elongation defect was coupled to the reduced guanylyltransferase activity. However, it happened independently of the turnover of uncapped transcripts. These results indicate that the transcription ternary complexes are held at the promoter as long as their RNAs have not been properly capped. That is, capping enzyme plays a critical role in the promoter-proximal checkpoint window by reinforcing the checkpoint security circuit and probably by reversing the transcription arrest in time. This finding also strongly supports the transcription checkpoint model, in which an early transcription is tightly regulated.

Cell cycle checkpoints are among the multiple mechanisms that eukaryotic cells possess to maintain genomic integrity and minimize tumorigenesis. Ionizing irradiation (IR) induces measurable arrests in the G(1), S, and G(2) phases of the mammalian cell cycle, and the ATM (ataxia telangiectasia mutated) protein plays a role in initiating checkpoint pathways in all three of these cell cycle phases. However, cells lacking ATM function exhibit both a defective G(2) checkpoint and a prolonged G(2) arrest after IR, suggesting the existence of different types of G(2) arrest. Two molecularly distinct G(2)/M checkpoints were identified, and the critical importance of the choice of G(2)/M checkpoint assay was demonstrated. The first of these G(2)/M checkpoints occurs early after IR, is very transient, is ATM dependent and dose independent (between 1 and 10 Gy), and represents the failure of cells which had been in G(2) at the time of irradiation to progress into mitosis. Cell cycle assays that can distinguish mitotic cells from G(2) cells must be used to assess this arrest. In contrast, G(2)/M accumulation, typically assessed by propidium iodide staining, begins to be measurable only several hours after IR, is ATM independent, is dose dependent, and represents the accumulation of cells that had been in earlier phases of the cell cycle at the time of exposure to radiation. G(2)/M accumulation after IR is not affected by the early G(2)/M checkpoint and is enhanced in cells lacking the IR-induced S-phase checkpoint, such as those lacking Nbs1 or Brca1 function, because of a prolonged G(2) arrest of cells that had been in S phase at the time of irradiation. Finally, neither the S-phase checkpoint nor the G(2) checkpoints appear to affect survival following irradiation. Thus, two different G(2) arrest mechanisms are present in mammalian cells, and the type of cell cycle checkpoint assay to be used in experimental investigation must be thoughtfully selected.

ECSIT (evolutionarily conserved signaling intermediate in Toll pathways) is known as a multifunctional regulator in different signals, including Toll-like receptors (TLRs), TGF-β, and BMP. Here, we report a new regulatory role of ECSIT in TLR4-mediated signal. By LPS stimulation, ECSIT formed a high molecular endogenous complex including TAK1 and TRAF6, in which ECSIT interacted with each protein and regulated TAK1 activity, leading to the activation of NF-κB. ECSIT-knockdown THP-1 (ECSIT(KD) THP-1) cells exhibited severe impairments in NF-κB activity, cytokine production, and NF-κB-dependent gene expression, whereas those were dramatically restored by reintroduction of wild type (WT) ECSIT gene. Interestingly, ECSIT mutants, which lack a specific interacting domain for either TAK1 or TRAF6, could not restore these activities. Moreover, no significant changes in both NF-κB activity and cytokine production induced by TLR4 could be seen in TAK1(KD) or TRAF6(KD) THP-1 cells transduced by WT ECSIT, strongly suggesting the essential requirement of TAK1-ECSIT-TRAF6 complex in TLR4 signaling. Taken together, our data demonstrate that the ECSIT complex, including TAK1 and TRAF6, plays a pivotal role in TLR4-mediated signals to activate NF-κB.

In this paper, we propose a novel approach for automated detection of breast masses in three-dimensional (3D) reconstructed slices on digital breast tomosynthesis (DBT). The 3D reconstructed slices provide quasi-3D information with limited resolution along the depth direction due to insufficient sampling in depth direction. This problem could cause an error of general 3D segmentation approaches which have to process information with different resolution at the same time. In order to resolve the problem, this paper proposes an effective mass detection method based on pooled mass probability map. The proposed pooled mass probability map contains slice plane information by fusing mass probabilities of initially detected regions along slices. Extensive and comparative experiments have been conducted using clinical data set to validate the effectiveness of proposed mass detection approach. Experimental results demonstrate the feasibility of proposed pooled mass probability map based approach for detecting masses on 3D reconstructed slices.

Fasting glucose homeostasis is maintained in part through cAMP (adenosine 3′,5′-monophosphate)– dependent transcriptional control of hepatic gluconeogenesis by the transcription factor CREB (cAMP response element–binding protein) and its coactivator CRTC2 (CREB-regulated transcriptional coactivator 2). We showed that PRMT6 (protein arginine methyltransferase 6) promotes fasting-induced transcriptional activation of the gluconeogenic program involving CRTC2. Mass spectrometric analysis indicated that PRMT6 associated with CRTC2. In cells, PRMT6 mediated asymmetric dimethylation of multiple arginine residues of CRTC2, which enhanced the association of CRTC2 with CREB on the promoters of gluconeogenic enzyme–encoding genes. In mice, ectopic expression of PRMT6 promoted higher blood glucose concentrations, which were associated with increased expression of genes encoding gluconeogenic factors, whereas knockdown of hepatic PRMT6 decreased fasting glycemia and improved pyruvate tolerance. The abundance of hepatic PRMT6 was increased in mouse models of obesity and insulin resistance, and adenovirus-mediated depletion of PRMT6 restored euglycemia in these mice. We propose that PRMT6 is involved in the regulation of hepatic glucose metabolism in a CRTC2-dependent manner.

In utero injection of a retroviral vector into the embryonic telencephalon aided by ultrasound backscatter microscopy permits introduction of a gene of interest at an early stage of development. In this study, we compared the tissue distribution of gene expression in adult mice injected with retroviral vectors at different embryonic ages in utero. Following ultrasound image-guided gene delivery (UIGD) into the embryonic telencephalon, adult mice were subjected to whole-body luciferase imaging and immunohistochemical analysis at 6 weeks and 1 year postinjection. Luciferase activity was observed in a wide range of tissues in animals injected at embryonic age 9.5 (E9.5), whereas animals injected at E10.5 showed brain-localized reporter gene expression. These results suggest that mouse embryonic brain creates a closed and impermeable structure around E10. Therefore, by injecting a transgene before or after E10, transgene expression can be manipulated to be local or systemic. Our results also provide information that widens the applicability of UIGD beyond neuroscience studies.

Vocal fold paralysis (VFP) is a frequent complication of surgery of mediastinal structures. This study evaluated the characteristics and short-term treatment outcomes of injection laryngoplasty for unilateral VFP (UVFP) induced by mediastinal lesions.The enrolled patients (n = 60) underwent injection laryngoplasty once because of UVFP and were divided into two groups according to cause (group A, thyroidectomy and group B, mediastinal surgery). Voice analysis was performed preoperatively and at 1 month postoperatively. The glottal gap; the Grade, Roughness, Breathiness, Asthenia, and Strain scale; acoustic analysis; and aerodynamic results were measured.Group A and group B comprised eight and 52 patients, respectively. Group B patients were older than group A patients (P 0.05). The injected volume in group B (0.91 ± 0.23 mL) was larger than that of group A (0.38 ± 0.17 mL; P = 0.022). Group B (13.35 ± 4.69 units) showed a larger glottal gap than group A (6.64 ± 4.05 units; P = 0.017), and the glottal gap decreased after the procedure. In both groups, most preoperative acoustic parameters except roughness improved after injection laryngoplasty. The preoperative maximum phonation time of group B (2.87 ± 1.11 seconds) was shorter than that of group A (7.04 ± 2.58 seconds), and it improved after injection. Mean airflow rate improved significantly after injection in both groups.Mediastinal lesion-induced UVFP is associated with a larger glottal gap than that caused by an injury induced by thyroidectomy. Despite large glottal gap, injection laryngoplasty improves voice outcomes in such types of UVFP.

The relevance of NADH-cytochrome b(5) reductase to the NADH-dependent reduction of D-erythroascorbyl free radical was investigated in Saccharomyces cerevisiae. MCR1, which is known to encode NADH-cytochrome b(5) reductase in S. cerevisiae, was disrupted by the insertion of URA3 gene into the gene of MCR1. In the mcr1 disruptant cells, the activity of NADH-D-erythroascorbyl free radical reductase almost disappeared and the intracellular level of D-erythroascorbic acid was about 11% of that of the congenic wild-type strain. In the transformant cells carrying MCR1 in multicopy plasmid, the intracellular level of D-erythroascorbic acid and the activity of NADH-D-erythroascorbyl free radical reductase increased up to 1.7-fold and 2.1-fold, respectively. Therefore, it indicated that the MCR1 product, mitochondrial NADH-cytochrome b(5) reductase, plays a key role in the NADH-dependent reduction of D-erythroascorbyl free radical in S. cerevisiae. On the other hand, the mcr1 disruptant cells were hypersensitive to hydrogen peroxide and menadione, and overexpression of MCR1 made the cells more resistant against oxidative stress. These results suggested that the mitochondrial NADH-cytochrome b(5) reductase functions as NADH-D-erythroascorbyl free radical reductase and plays an important role in the response to oxidative damage in S. cerevisiae.

In some lower eukaryotes, d -erythroascorbic acid, a five-carbon analog of l -ascorbic acid, is present instead of l -ascorbic acid. We have cloned ALO1 , the gene encoding d -arabinono-1,4-lactone oxidase, which catalyzes the final step of d -erythroascorbic acid biosynthesis in Candida albicans . The ALO1 gene contained a continuous open reading frame of 1,671 bp that encodes a polypeptide consisting of 557 amino acids with a calculated molecular mass of 63,428 Da. To investigate the functional roles of d -erythroascorbic acid in C. albicans , we disrupted or overexpressed the ALO1 gene. In the alo1/alo1 null mutants, the activity of d -arabinono-1,4-lactone oxidase was completely lost and d -erythroascorbic acid could not be detected. When ALO1 on a multicopy plasmid was transformed in C. albicans , the enzyme activity and the intracellular d -erythroascorbic acid level were increased up to 3.4-fold and 4.0-fold, respectively. The alo1/alo1 null mutants of C. albicans showed increased sensitivity towards oxidative stress. Overexpression of ALO1 made the cells more resistant to the same stress. The alo1/alo1 mutants showed defective hyphal growth and attenuated virulence. Taken together, our results suggest that d -erythroascorbic acid functions as an important antioxidant and can be considered one of the virulence factors enhancing the pathogenicity of C. albicans .

Cell cycle arrests in the G(1), S, and G(2) phases occur in mammalian cells after ionizing irradiation and appear to protect cells from permanent genetic damage and transformation. Though Brca1 clearly participates in cellular responses to ionizing radiation (IR), conflicting conclusions have been drawn about whether Brca1 plays a direct role in cell cycle checkpoints. Normal Nbs1 function is required for the IR-induced S-phase checkpoint, but whether Nbs1 has a definitive role in the G(2)/M checkpoint has not been established. Here we show that Atm and Brca1 are required for both the S-phase and G(2) arrests induced by ionizing irradiation while Nbs1 is required only for the S-phase arrest. We also found that mutation of serine 1423 in Brca1, a target for phosphorylation by Atm, abolished the ability of Brca1 to mediate the G(2)/M checkpoint but did not affect its S-phase function. These results clarify the checkpoint roles for each of these three gene products, demonstrate that control of cell cycle arrests must now be included among the important functions of Brca1 in cellular responses to DNA damage, and suggest that Atm phosphorylation of Brca1 is required for the G(2)/M checkpoint.

A small proportion of cancer cells have stem-cell-like properties, are resistant to standard therapy and are associated with a poor prognosis. The metabolism of such drug-resistant cells differs from that of nearby non-resistant cells. In this study, the metabolism of drug-resistant lung adenocarcinoma cells was investigated. The expression of genes associated with oxidative phosphorylation in the mitochondrial membrane was negatively correlated with the prognosis of lung adenocarcinoma. Because the mitochondrial membrane potential (MMP) reflects the functional status of mitochondria and metastasis is the principal cause of death due to cancer, the relationship between MMP and metastasis was evaluated. Cells with a higher MMP exhibited greater migration and invasion than those with a lower MMP. Cells that survived treatment with cisplatin, a standard chemotherapeutic drug for lung adenocarcinoma, exhibited increased MMP and enhanced migration and invasion compared with parental cells. Consistent with these findings, inhibition of mitochondrial activity significantly impeded the migration and invasion of cisplatin-resistant cells. RNA-sequencing analysis indicated that the expression of mitochondrial complex genes was upregulated in cisplatin-resistant cells. These results suggested that drug-resistant cells have a greater MMP and that inhibition of mitochondrial activity could be used to prevent metastasis of drug-resistant lung adenocarcinoma cells.

The rare diseases ataxia-telangiectasia (AT), caused by mutations in the ATM gene, and Nijmegen breakage syndrome (NBS), with mutations in the p95/nbs1 gene, share a variety of phenotypic abnormalities such as chromosomal instability, radiation sensitivity and defects in cell-cycle checkpoints in response to ionizing radiation1,2,3,4. The ATM gene encodes a protein kinase that is activated by ionizing radiation or radiomimetic drugs5,6, whereas p95/nbs1 is part of a protein complex that is involved in responses to DNA double-strand breaks3,7. Here, because of the similarities between AT and NBS, we evaluated the functional interactions between ATM and p95/nbs1. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that p95/nbs1 may not be required for signalling to ATM after ionizing radiation. However, p95/nbs1 was phosphorylated on serine 343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. A p95/nbs1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations link ATM and p95/nbs1 in a common signalling pathway and provide an explanation for phenotypic similarities in these two diseases.

Transforming growth factor β (TGF-β)-activated kinase 1 (TAK1) is a key regulator in the signals transduced by proinflammatory cytokines and Toll-like receptors (TLRs). The regulatory mechanism of TAK1 in response to various tissue types and stimuli remains incompletely understood. Here, we show that ribosomal S6 kinase 1 (S6K1) negatively regulates TLR-mediated signals by inhibiting TAK1 activity. S6K1 overexpression causes a marked reduction in NF-κB and AP-1 activity induced by stimulation of TLR2 or TLR4. In contrast, S6K1(-/-) and S6K1 knockdown cells display enhanced production of inflammatory cytokines. Moreover, S6K1(-/-) mice exhibit decreased survival in response to challenge with lipopolysaccharide (LPS). We found that S6K1 inhibits TAK1 kinase activity by interfering with the interaction between TAK1 and TAB1, which is a key regulator protein for TAK1 catalytic function. Upon stimulation with TLR ligands, S6K1 deficiency causes a marked increase in TAK1 kinase activity that in turn induces a substantial enhancement of NF-κB-dependent gene expression, indicating that S6K1 is negatively involved in the TLR signaling pathway by the inhibition of TAK1 activity. Our findings contribute to understanding the molecular pathogenesis of the impaired immune responses seen in type 2 diabetes, where S6K1 plays a key role both in driving insulin resistance and modulating TLR signaling.

Vacuum interrupters are now widely used for medium voltage switching up to 38kV in such applications as metal-clad switchgears, circuit breakers, etc. Vacuum interrupter minimizes the damage and loss of the contact points at the optimum zero point of current wave after separation of the contact points, due to its quick vacuum insulation recovery characteristics. The fixed and moving electrodes of vacuum interrupter are mated by a driving mechanism within several milliseconds. Therefore, considerable impact forces occur between the electrodes. These impact forces could cause structural damages to vacuum interrupters and shorten fatigue-life of the products. Also, rebound phenomena could occur between the contacts due to the impact forces. It could not only affect mechanical characteristics but also have a strong influence on electrical conditions. Therefore, it is very important for impact analysis to reflect the dynamic characteristics of materials that consists electrodes as well as the static characteristics. As the dynamic behavior of materials is different from the static(or quasi-static) one due to the inertia effect and the stress wave propagation, an adequate experimental technique has to be developed to obtain the dynamic responses for the corresponding level of the strain rate. In this paper, to determine the dynamic characteristics of materials, the Hopkinson bar experiment is carried out, and for decreasing impact forces of a axial type vacuum interrupter, design study is applied in impact analysis with explicit finite element method. The rebound phenomena between the electrodes during impact periods are compared with the one of modified model which is suggested for the improvements in specific parameters.

Salt-inducible kinases (SIKs) are a family of related serine-threonine kinases and are involved in controlling various metabolisms such as liver glucose homeostasis, hepatic lipogenesis, steroidogenesis, and adipogenesis. Here we investigated the regulatory role of SIK proteins in Toll-like receptor 4 (TLR4)-mediated signaling. Overexpression of SIK1 and SIK3, but not SIK2, significantly inhibited nuclear factor-κB activity in response to lipopolysaccharide stimulation and affected the expression of proinflammatory cytokines. In contrast, both SIK1(KD) and SIK3(KD) Raw 264.7 cells exhibit dramatic elevations of nuclear factor-κB activation and activations of downstream signaling molecules, such as TGF-β-activated kinase 1, p38, and c-Jun N-terminal kinase, in response to TLR4 stimulation, indicating that SIK1 and SIK3 are negatively involved in the TLR4-mediated signaling. Through biochemical studies, we found that SIK1 and SIK3 interact with TGF-β-activated kinase 1-binding protein 2 (TAB2), and interrupt the functional complex of TAB2-TNF receptor-associated factor 6 (TRAF6). Interestingly, the molecular interruption is induced to suppress the ubiquitination of TRAF6 in response to TLR4 stimulation. These result suggest that SIK1 and SIK3 negatively regulate TLR4-mediated signaling through the interruption of TAB2-TRAF6 complex and thereby the inhibition of ubiquitination of TRAF6. The present findings can be useful for a better understanding of multilevel interactions between the metabolic and immune systems.

Objective Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. Design We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). Results The analyses showed association peaks on three genetic loci for CA19-9 ( FUT6-FUT3 at 19p13.3, FUT2 - CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10 −13 –3.30×10 −290 ); four for CEA ( ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10 −22 –5.81×10 −209 ); and two for AFP ( AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10 −18 and 1.28×10 −14 ). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p Conclusions This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

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 Men1(-/-) 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 GBX2 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. Cell Death and Disease (2013) 4, e583; doi:10.1038/cddis.2013.98; published online 11 April 2013

The quinoxaline derivatives formed between dehydro-D-erythroascorbic acid (2) and o-phenylenediamine (3) were separated by preparative HPLC and their structures were analyzed by HPLC-MS, UV-vis spectrophotometry and 1H NMR spectroscopy. The reaction of 2 with an excess amount of 3 in 5% aq m-phosphoric acid gave three different products, depending on the concentration of 2: below 0.1 mM of 2, only 3-(D-glycero-1,2-dihydroxyethyl)quinoxaline-2-carboxylic γ-lactone (4) was produced, between 0.1 to 5 mM of 2, another product, 2,2′-anhydro-[2-hydroxy-3-(D-glycero-2,3-dihydroxypropanal-1-yl)quinoxaline] (5) was formed as well as 4, and over 10 mM of 2, the third product, 2,1′-anhydro-[2-hydroxy-4-(D-glycero-1,2-dihydroxyethyl)-1,5-benzodiazepin-3-one] (6) was formed as well as 4 and 5, with an overall production yield over 95%. Quinoxaline 6 was slowly converted to 4 via 5. Based on these results, it was concluded that all three products retain the lactone ring moiety of 2, and the most stable product...

Two interconvertible enediol group-containing reductones were produced nonenzymatically from L-xylosone in citrate-phosphate buffer (pH 6.0). These compounds were oxidized by ascorbate oxidase (E.C. 1.10.3.3.) and had ability to reduce 2.6-dichloroindophenol. GLC-MS analysis of trimethylsilylated L-xylosone indicates that it exists in several tautomeric forms including the enediol group-containing reductones which are L-glycero-2-pentenopyranose and L-glycero-2-pentenofuranose. The production rates of both reductones from L-xylosone were proportional to pH within a pH range 4 to 7, and above that pH range further degradation of the reductones occurred.

We report on the case of double-layered medial meniscus, which was overlying anterior to mid portion of the medial meniscus. The upper accessory meniscus was connected to the anterior portion of the normal medial meniscus. And its periphery was connected to the joint capsule. The posterior portion of the upper accessory meniscus was connected to the joint capsule. This case demonstrates an interesting and rare anatomical abnormality of the medial meniscus. We report on the case with a review of the literature.

Checkpoint kinase 2 (CHK2) kinase is a key mediator in many cellular responses to genotoxic stresses, including ionizing radiation (IR) and topoisomerase inhibitors. Upon IR, CHK2 is activated by ataxia telangiectasia mutated kinase and regulates the S-phase and G1-S checkpoints, apoptosis and DNA repair by phosphorylating downstream target proteins, such as p53 and Brca1. In addition, CHK2 is thought to be a multi-organ cancer susceptibility gene. In this study, we used a tandem affinity purification strategy to identify proteins that interact with CHK2 kinase. Cyclin-dependent kinase 11 (CDK11)(p110) kinase, implicated in pre-mRNA splicing and transcription, was identified as a CHK2-interacting protein. CHK2 kinase phosphorylated CDK11(p110) on serine 737 in vitro. Unexpectedly, CHK2 kinase constitutively phosphorylated CDK11(p110) in a DNA damage-independent manner. At a molecular level, CDK11(p110) phosphorylation was required for homodimerization without affecting its kinase activity. Overexpression of CHK2 promoted pre-mRNA splicing. Conversely, CHK2 depletion decreased endogenous splicing activity. Mutation of the phosphorylation site in CDK11(p110) to alanine abrogated its splicing-activating activity. These results provide the first evidence that CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110).

WIP1 (wild-type p53-induced phosphatase 1) functions as a homeostatic regulator of the ataxia telangiectasia mutated (ATM)-mediated signaling pathway in response to ionizing radiation (IR). Here we identify homeodomain-interacting protein kinase 2 (HIPK2) as a protein kinase that targets WIP1 for phosphorylation and proteasomal degradation. In unstressed cells, WIP1 is constitutively phosphorylated by HIPK2 and maintained at a low level by proteasomal degradation. In response to IR, ATM-dependent AMPKα2-mediated HIPK2 phosphorylation promotes inhibition of WIP1 phosphorylation through dissociation of WIP1 from HIPK2, followed by stabilization of WIP1 for termination of the ATM-mediated double-strand break (DSB) signaling cascade. Notably, HIPK2 depletion impairs IR-induced γ-H2AX foci formation, cell-cycle checkpoint activation, and DNA repair signaling, and the survival rate of hipk2+/- mice upon γ-irradiation is markedly reduced compared to wild-type mice. Taken together, HIPK2 plays a critical role in the initiation of DSB repair signaling by controlling WIP1 levels in response to IR.

BACKGROUND: Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. MATERIALS/METHODS: To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. RESULTS: We identified two loci that were associated with %fPSA at a genome-wide significance level (P

Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33×10−11 and P = 1.83×10−9, respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5′ and 3′ of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19×10−22 to 5.62×10−97. HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P, Author Summary The complement system plays important roles in the innate and adaptive immune functions. C3 and C4 participate in almost all physiological activities and activated pathways as key complement members and host defense proteins. Identifying the genes that influence serum levels of C3 and C4 may help to elucidate the factors and mechanisms underlying the complement system. The genome-wide association studies (GWAS) have shown great success in revealing robust associations in both quantitative and qualitative traits. In this study, we performed a two-stage GWAS in a large cohort from the Chinese male population to examine the roles of common genetic variants on serum C3 and C4 levels. Our research identified genetic determinants associated with the quantitative levels of C3 and C4. Overall, our study highlights an intricate regulation of complement levels and potentially reveals novel mechanisms that may be followed up with additional functional studies.

Time Series Analysis is a statistical methodology for analyzing time series data, which are data points measured over time, in order to extract data characteristics and meaningful information. Time Series Analysis is an important subject because time series data are generated in many disciplines, e.g., economics, engineering, health science, meteorology, etc. The objective of this paper is to provide a selected, annotated bibliography of core scholarly resources on time series analysis for librarians, graduate students, faculty, and researchers. Each resource in the bibliography is classified into the following subfield categories: (1) applied or theoretical approach, (2) univariate or multivariate approach, (3) frequency or time domain, (4) frequentist or Bayesian, (5) linear or nonlinear, (6) parametric or nonparametric, (7) software applications and (8) applications to various disciplines. Librarians will be able to use this selected, annotated bibliography for collection development to support teaching and research.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates – one via a weighted PCa ‘risk’ score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

Many differentially methylated genes have been identified in prostate cancer (PCa), primarily using candidate gene-based assays. Recently, several global DNA methylation profiles have been reported in PCa, however, each of these has weaknesses in terms of ability to observe global DNA methylation alterations in PCa. We hypothesize that there remains unidentified aberrant DNA methylation in PCa, which may be identified using higher resolution assay methods. We used the newly developed Illumina HumanMethylation450 BeadChip in PCa (n = 19) and adjacent normal tissues (n = 4) and combined these with gene expression data for identifying new DNA methylation that may have functional consequences in PCa development and progression. We also confirmed our methylation results in an independent data set. Two aberrant DNA methylation genes were validated among an additional 56 PCa samples and 55 adjacent normal tissues. A total 28,735 CpG sites showed significant differences in DNA methylation (FDR adjusted P

Background: Intertrochanteric fractures of the femur are the most common type of fracture, and are an increasing occurrence due to the aging of the population. The objectives of our study are to predict the fate of intertrochanteric fractures treated with intramedullary hip nails by assessing the postoperative fracture stability utilizing the newly developed scoring system, and to help rehabilitate these patients. Methods: Eighty-two patients with intertrochanteric fractures that were treated with intramedullary hip nails between December, 2004 and January, 2011 were subjected to this study. The patients who could be followed for a minimum of one year postoperatively were enrolled. The immediate postoperative conditions were determined by radiograms: reduction status (3 parameters/4 points: contact accuracy of posteromedial cortex, severity of angulation, and distraction), fixation status (3 parameters/3 points: tip-apex distance, location of tip of the lag screw, entry point of the intramedullary nail), and fracture type (1 parameter/1 point: stable or unstable type by the Kyle’s classification). Postoperative reduction loss and fixation failure were checked by radiograms taken at a minimum 3 months postoperative. Results: Reduction loss and fixation failure were observed in 14 consecutive patients (17%). The fixation failure rate was 100% (2 patients) in score 1, 60% (3 out of the 5 patients) in score 2, 39% (3 out of the 8 patients) in score 3, and 50% (4 out of the 8 patients) in score 4 groups. There were fixation failures only in 1 out of 13 patients with score 5, and in 1 out of 18 patients with score 6. There was no fixation failure in 17 patients with score 7 and 11 patients with score 8. Conclusions: Maintenance of the fracture reduction by the stable fixation in the patient scores over 5 could be predicted by the postoperative radiograms.

Prostate-specific antigen (PSA) is a commonly used cancer biomarker for prostate cancer, and is often included as part of routine physical examinations in China. Serum levels of PSA may be influenced by genetic factors as well as other factors. A genome-wide association study (GWAS) conducted in a European population successfully identified six genetic loci that were significantly associated with PSA level. In this study, we aimed to identify common genetic variants that are associated with serum level of PSA in a Chinese population. We also evaluated the effects of those variants by creating personalized PSA cutoff values. A two-stage GWAS of PSA level was performed among men age 20-69 years and self-reported cancer-free participants that underwent routine physical examinations at several hospitals in Guangxi Province, China. Single nucleotide polymorphisms (SNPs) significantly associated with PSA levels in the first stage of sample (N = 1,999) were confirmed in the second stage of sample (N = 1,496). Multivariate linear regression was used to assess the independent contribution of confirmed SNPs and known covariates, such as age, to the level of PSA. SNPs in three regions were significantly associated with levels of PSA in this two-stage GWAS, and had combined P values between 4.62 × 10(-17) and 6.45 × 10(-37). The three regions are located on 1q32.1 at SLC45A3, 10q11.23 at MSMB, and 19q13.33 at KLK3. The region 1q32.1 at SLC45A3 was identified as a novel locus. Genetic variants contributed significantly more to the variance of PSA level than known covariates such as age. Personalized cutoff values of serum PSA, calculated based on the inheritance of these associated SNPs, differ considerably among individuals. Identification of these genetic markers provides new insight into the molecular mechanisms of PSA. Taking individual variation into account, these genetic variants may improve the performance of PSA to predict prostate cancer.

Recently, genome-wide association studies (GWAS) have identified over 12 single-nucleotide polymorphisms (SNPs) associated with bladder cancer risk in populations of European descent. However, effects of these SNPs in bladder cancer have not been systemically evaluated in the Chinese population. We conducted association studies of 12 SNPs in a Chinese population of 184 cases and 962 controls. These SNPs were previously identified in European GWAS and a fine mapping study. The reported risk alleles of rs798766 on TACC3 at 4p16 and rs9624880 on MYC at 8q24 were significantly associated with increased bladder cancer risk with P-values of 0.003 and 0.03, respectively. Next, we performed a meta-analysis, by combining our study with previous association studies performed in Chinese. In the meta-analysis, the reported risk allele for four SNPs were significantly associated with increased bladder cancer risk, including rs798766 on TACC3 at 4p16, rs9624880 on MYC at 8q24, rs2294008 on PSCA at 8q24, and rs2736100 on TERT at 5p15. The meta-analysis P-values for the four SNPs ranged from 0.017 to 5.52E-05. The results from our study suggest that a sub-set of bladder cancer risk-associated SNPs identified from the European population are also associated with bladder cancer risk in the Chinese population. Additional studies with larger sample sizes are needed to further confirm our results.

Genome-wide association studies (GWAS) have identified ∼30 single-nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. To test the hypothesis that other sequence variants in the genome may interact with those 32 known PCa risk-associated SNPs identified from GWAS to affect PCa risk, we performed a systematic evaluation among three existing PCa GWAS populations: CAncer of the Prostate in Sweden population, a Johns Hopkins Hospital population, and the Cancer Genetic Markers of Susceptibility population, with a total sample size of 4723 PCa cases and 4792 control subjects. Meta-analysis of the interaction term between each of those 32 SNPs and SNPs in the genome was performed in three PCa GWAS populations. The most significant interaction detected was between rs12418451 in MYEOV and rs784411 in CEP152, with a P(interaction) of 1.15 × 10(-7) in the meta-analysis. In addition, we emphasized two pairs of interactions with potential biological implication, including an interaction between rs7127900 near insulin-like growth factor-2 (IGF2)/IGF2AS and rs12628051 in TNRC6B, with a P(interaction) of 3.39 × 10(-6) and an interaction between rs7679763 near TET2 and rs290258 in SYK, with a P(interaction) of 1.49 × 10(-6). Those results show statistical evidence for novel loci interacting with known risk-associated SNPs to modify PCa risk. The interacting loci identified provide hints on the underlying molecular mechanism of the associations with PCa risk for the known risk-associated SNPs. Additional studies are warranted to further confirm the interaction effects detected in this study.