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Kelembagaan masyarakat adat Waropen secara legal berdasarkan peraturan perundang-undangan belum terbentuk di Provinsi Papua Barat. Untuk itu, kegiatan ini menjadi urgensi yang harus dilakukan dalam rangka penguatan dan penataan kelembagaan adat. Tujuan kegiatan ini adalah untuk (1) membangun kesadaran dan solidaritas sosial; (2) mendorong kohesivitas sosial yang harmoni; (3) membentuk organisasi modern berbasis adat; (4) membangun organisasi sebagai benteng penerus nilai dan tradisi luhur; dan (5) ikut berpartisipasi dalam pembangunan. Luarannya adalah diharapkan berkontribusi dalam (1) memahami wilayah dan karateristik budaya Waropen yang sama dan berbeda pada setiap kampung, keret dan rumah; dan (2) menyusun kelengkapan organisasi lembaga adat dan kemasyarakatan dalam mendukung pelestarian adat dan budaya Waropen. Mitra dalam kegiatan ini adalah (1) Pemerintah Provinsi Papua Barat, (2) Pemerintah Kabupaten Waropen, (3) Pemerintah Kabupaten Manokwari, dan (4) Dewan Adat Daerah Suku Waropen Provinsi Papua. Metode kegiatan ini adalah participatory learning and action (PLA) dengan paradigma sosio-etnografis agar dapat belajar pada komunitas, menempatkan nilai yang sama antara pengetahuan dan pengalaman masyarakat adat, dan kapasitasnya dalam memberikan solusi atas masalah yang mempengaruhinya. Bentuk kegiatannya terdiri atas: (1) Musyawarah Besar, dan Pengukuhan. Hasil kegiatannya adalah terbentuknya kelembagaan: (1) Struktur Organisasi dan Tata Kerja Adat, (2) Peradilan Adat, dan (3) Kerukunan Keluarga Waropen

Globalisation is an area where supporters and non-supporters of left- and right-wing parties disagree, both for domestic and international policies. Populists see metropolitan elites as ‘corrupt’ and oppose policies that encourage globalisation in trade, immigration, and multi-culturalism. Media play important roles in providing pro- and anti-globalisation content, both in traditional and digital media. We use a unique combination of large-scale web-tracking and cross-country survey data to study the interactions between populism, media trust, consumption, and globalisation attitudes in the US and Germany. We find country variances for different aspects of globalisation, particularly among the supporters of right-wing populist parties or leaders. Populist anti-elitism and a feeling of powerlessness in relation to influencing the country's politics are two important factors behind the backlash against globalisation. We also find that a higher level of trust in public service media is associated with more supportive attitudes toward globalisation.

Supplementary Table 2 from Glutathione Peroxidase 3, Deleted or Methylated in Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis

Supplementary Figures 1-2 from Interaction of Integrin-Linked Kinase and Miniature Chromosome Maintenance 7–Mediating Integrin α7 Induced Cell Growth Suppression

Mutation of integrin α7 (ITGA7) was previously identified in multiple human malignancies. Restoration of ITGA7 expression in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and cell motility both in vitro and in vivo. In this study, we showed that integrin-linked kinase (ILK) binds with miniature chromosome maintenance 7 (MCM7), a DNA replication licensing protein. A 58–amino acid ILK binding motif was identified in the NH2-terminus of MCM7. The expression of ITGA7 induced the phosphorylation of MCM7. Knocking down of ILK abrogated ITGA7-induced MCM7 phosphorylation. ANK, the dominant-negative mutant of ILK, also blocked the phosphorylation of MCM7 induced by ITGA7. The phosphorylation of MCM7 reduced MCM7 chromatin association and inhibited cell growth. A MCM7 mutant that does not bind with ILK did not respond to ITGA7 stimulation, and behaved similarly to a dominant MCM7-negative mutant and neutralized the effect of ITGA7. We conclude that ILK interaction with MCM7 and MCM7 phosphorylation may be a critical event in ITGA7 signaling pathway, leading to tumor suppression. Cancer Res; 70(11); 4375–84. ©2010 AACR.

Glutathione peroxidase 3 is a selenium-dependent enzyme playing a critical role in detoxifying reactive oxidative species and maintaining the genetic integrity of mammalian cells. In this report, we found that the expression of glutathione peroxidase 3 (GPx3) was widely inactivated in prostate cancers. Complete inactivation of GPx3 correlates with a poor clinical outcome. Deletions (hemizygous and homozygous) of GPx3 gene are frequent in prostate cancer samples, occurring in 39% of the samples studied. The rate of methylation of the GPx3 exon 1 region in prostate cancer samples reaches 90%. Overexpression of GPx3 in prostate cancer cell lines induced the suppression of colony formation and anchorage-independent growth of PC3, LNCaP, and Du145 cells. PC3 cells overexpressing GPx3 reduced invasiveness in Matrigel transmigration analysis by an average of 2.7-fold. Xenografted PC3 cells expressing GPx3 showed reduction in tumor volume by 4.8-fold, elimination of metastasis (0/16 versus 7/16), and reduction of animal death (3/16 versus 16/16). The tumor suppressor activity of GPx3 seems to relate to its ability to suppress the expression of c-met. The present findings suggest that GPx3 is a novel tumor suppressor gene. [Cancer Res 2007;67(17):8043–50]

Supplementary Table 1 from Glutathione Peroxidase 3, Deleted or Methylated in Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis

Supplementary Figure 1 from Glutathione Peroxidase 3, Deleted or Methylated in Prostate Cancer, Suppresses Prostate Cancer Growth and Metastasis

Anemia is an important public health problem, and accurate estimates may inform policy and programs. Although hemoglobin assessment of venous blood via automated hematology analyzers (AHA) is recommended, most population-based surveys are based on analysis of capillary blood via portable hemoglobinometers to estimate anemia prevalence.To evaluate screening methods for hemoglobin and anemia assessment using paired venous samples.Participants were women of reproductive age (15-40y) who were not pregnant or lactating. Paired venous whole blood samples (n = 896) were analyzed for hemoglobin (Hb) via portable hemoglobinometer (HemoCue 301) and Coulter Counter AHA. Anemia and severe anemia were defined as Hb12.0 and8.0 g/dL, respectively. Bland-Altman methods were used to assess level of agreement for Hb results (mean difference, standard deviation of differences, limits of agreement). Diagnostic accuracy parameters (sensitivity, specificity, positive predictive value, negative predictive value, accuracy) were calculated to evaluate HemoCue performance compared to the AHA reference, overall and by sociodemographic, nutritional, and metabolic characteristics.The estimated anemia prevalence was significantly lower via HemoCue vs. AHA (36.3% vs. 41.6%; p-value0.0001). The HemoCue had 84.4% accuracy for anemia screening and 98.8% for severe anemia, compared to the AHA reference. The HemoCue had 74.8% sensitivity and 91.2% specificity, compared to AHA. HemoCue sensitivity was higher in WRA with iron deficiency (SF15.0 μg/L 81.6% vs. SF ≥15.0 μg/L: 41.3%), and lower in WRA with metabolic risk factors, including overweight (BMI≥25.0 kg/m2; 63.9% vs. 78.8%), or elevated CRP (CRP1.0 mg/L: 67.2% vs. ≤1.0 mg/L: 82.9%), trunk fat (TF35%: 62.7% vs. ≤35%: 80.1), or whole-body fat (WBF35%: 63.9% vs. ≤35%: 80.3%).Findings suggest that women with anemia may be incorrectly identified as not anemic via portable hemoglobinometer, and the anemia prevalence may be underestimated at the population level. Registration number: NCT04048330.

Background Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. Methods Intranasal dexmedetomidine 2 µg · kg−1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. Results A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors’ study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h−1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h−1. The simulation indicated that at the dose of 2 µg · kg−1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml−1 within 20 min, and the average peak concentration of 0.563 ng · ml−1 could be attained at 61 min. Conclusions The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg−1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background COVID-19 pandemic presented an unexpected challenge for the surgical community in general and Minimally Invasive Surgery (MIS) specialists in particular. This document aims to summarize recent evidence and experts’ opinion and formulate recommendations to guide the surgical community on how to best organize the recovery plan for surgical activity across different sub-specialities after the COVID-19 pandemic. Methods Recommendations were developed through a Delphi process for establishment of expert consensus. Domain topics were formulated and subsequently subdivided into questions pertinent to different surgical specialities following the COVID-19 crisis. Sixty-five experts from 24 countries, representing the entire EAES board, were invited. Fifty clinicians and six engineers accepted the invitation and drafted statements based on specific key questions. Anonymous voting on the statements was performed until consensus was achieved, defined by at least 70% agreement. Results A total of 92 consensus statements were formulated with regard to safe resumption of surgery across eight domains, addressing general surgery, upper GI, lower GI, bariatrics, endocrine, HPB, abdominal wall and technology/research. The statements addressed elective and emergency services across all subspecialties with specific attention to the role of MIS during the recovery plan. Eighty-four of the statements were approved during the first round of Delphi voting (91.3%) and another 8 during the following round after substantial modification, resulting in a 100% consensus. Conclusion The recommendations formulated by the EAES board establish a framework for resumption of surgery following COVID-19 pandemic with particular focus on the role of MIS across surgical specialities. The statements have the potential for wide application in the clinical setting, education activities and research work across different healthcare systems.

Most covalent organic frameworks (COFs) are synthesized using solvothermal conditions (>120 °C, >72 h) in harmful organic solvents. We report a strategy for rapidly synthesizing imine-linked COFs (< 60 min) in aqueous acetic acid using sonochemistry, avoiding most of the downsides of solvothermal methods. We first synthesized seven known COFs using this method and obtained crystallinity and porosity comparable to or better than materials from previously reported solvothermal routes. This sonochemical method even works in highly sustainable solvents, such as food-grade vinegar. The generality of the method was demonstrated by preparing two unreported COFs. Finally, we showed that one sonochemical COF is an excellent photocatalyst for sacrificial hydrogen evolution from water with a more sustained catalytic performance than its solvothermal analog. The speed, ease and generality of this sonochemical method with no sacrifice in material quality makes it an enabling methodology for rapid discovery of new functional COF materials.

Micro eccentric shaft has important application in many high-tech fields because of its small specific gravity, material and energy saving. The surface texture generated during processing has an indispensable influence on the surface integrity and the final functional capability. However, due to the micro scale and weak rigidity, it is difficult to characterize the surface texture and evaluate the functionality by traditional quantitative parameters. In order to comprehensively realize the surface texture characterization and functional analysis, a mathematical model is established to analyze the surface texture machined with different cutting tools. AnchorThe machining deformation of the micro eccentric shaft machined during turn-milling with different cutting tools is compensated. Then the surface microscopic profile and functional performance of the surface texture are analyzed by amplitude distribution function (ADF) and bearing area curve (BAC), and the surface texture is also evaluated by fractal dimension, which can avoid the effect of scale and resolution. Furthermore, power spectrum density (PSD) is utilized to analyze the relationship between the process dynamic state and geometrical specification of the surface texture. It is shown that the microscopic height distribution of surface machined by flat end milling cutter tends to be more random and there are more microscopic geometric features than that of the ball end milling cutter. The machined surface obtained by the flat end milling cutter has better load bearing, wear resistance and liquid retention capability.

Partial discharge insulators diagnostic as a tool of personnel protection is studied in this paper. The electrical field of normal and defective insulators was simulated. Experiments of PD measurement were performed. Electrical field simulation results showed the high intensity of electrical field (EFI) in porcelain insulator with a cut and in epoxy compound insulator with a crack. Experimental research showed the highest partial discharges intensity in cases of high EFI obtained in the simulation. The experimental data analysis showed that partial discharges diagnostics might be effective for insulators only when using the voltage above the operating one. Only 16 kV and higher allowed reliably detect the defect presence in the experiments. Therefore, this method cannot be recommended for supporting insulators diagnostic before the disconnector use to decrease electrical traumatism personnel. Besides, partial discharges monitoring is also not effective enough for the researched defect types detection.

Chinese Internet users have in recent years experienced increasingly diversified choices of information formats (text, short videos, and stream videos), information content (news, fictions, and lifestyle), as well as information platforms(news apps, search engines, and mobile social media). Chinese booming digital cultural industry has created a dynamic information ecology for grassroots Internet users. Meanwhile, Chinese Internet users have employed different approaches to collecting, distinguishing, and handling information available online, with some more sophisticated than the others in managing the massive amount of information and identify misinformation or disinformation. While previous empirical research on Chinese Internet has focused on the how the Internet has influenced economic activities, political participation, and social networks, yet little is known about how Chinese Internet users seek information on the Internet: What information sources do they trust? What information categories are considered essential for different user groups? What are the main concerns users have during the information-seeking process? Whether or not differentiated information-seeking practices could result in a new form of the digital divide? Answering these questions will help to build a deeper understanding of how Chinese users domesticate the Internet into users’ daily lives as not only a tool of communication but also a gateway to informationseeking. In this paper, I will combine survey data collected from two randomly selected samples in a village (N1 = 128) and a factory (N2 = 229), 55 individual interviews, and four focus group studies, to study information-seeking practices in digital era among rural and urban Internet users in Central China. The paper will start with a quantitative analysis of information sources, information categories, and 3 information-seeking process and their relationship with demographic and Internet use variables. To understand different contexts in information-seeking practices, I will use qualitative data to focus on three approaches to information seeking, namely, pulling from search engines, information seeking through encountering, and information seeking through information proxies. I aim to explore how the Internet has embedded into individuals’ everyday lives as an information channel, what different information-seeking approaches and strategies employed. Findings from this research will enrich the understanding of the complexities and nuances of using the Internet for everyday information-seeking practices in China and will also reveal how Chinese grassroots users perceive the Internet in a marketplace of digital information.

Additional file 1: Figure S1. Combined Bisulfite Restriction Analysis (COBRA) and MeDIP-qPCR Validation of Six Differentially Methylated Identified Probes Two different methods were used to validate probes identified by MeDIP-chip analysis in biological replicates after 5 day shRNA induction. Detailed information of array probes (Table S2), COBRA characteristics (Table S3), and MeDIP-chip vs. MeDIP-qPCR comparisons (Table S4) are provided. We show that methylation levels in the original DNA sample are represented by the relative amounts of digested and undigested PCR product in a linearly quantitative fashion. MeDIP-qPCR results are presented as mean+SD of technical triplicates (**P

Additional file 2: Table S1. Significantly altered genes that contain a CTCF binding site in the TSS and significant hyper- or hypomethylation on methylation array. Table S2: Common hypermethylation CGs containing CTCF binding sites in both prostate and breast tumors. Table S3. Differentially methylated CGs in both prostate and breast tumors. Table S4: Cytoscan Probes’ Characteristics Used in Array Validation. Table S5: Combined Bisulfite Restriction Analysis (COBRA) Assay Characteristics (Related to Additional file 1: Fig. S1). Table S6: Primer sequences of COBRA and MeDIP-qPCR used for Validation of Cytoscan Array (Related to Additional file 1: Fig. S1). Table S7: MeDIP-qPCR Performed region and methylation values after CTCF knockdown. Table S8: Primers Used for ChIP-qPCR and MeDIP-qPCR in Extended Knockdown Studies (Related to Fig.3 and Additional file 1: Fig. S3)

Study on virulence test of Beauveria bassiana strain Wamena spore concentration toward ( Hypothenemus hampei Ferr.) has conducted at Laboratorium of Hayati BPTP Dinas Perkebunan Provinsi Papua during February to April 2010. This study aimed to identify the effectiveness of B . bassiana strain Wamena which has potency as agent to control pest on fruit of Coffea sp caused by H. hampei . by dipping fruit of Coffea sp into spore suspension. Complete random design was used in this study. Four concentrations ( 0; 0.01%; 0.02%; 0.03% ; 0.04% and 0.05% of B. bassiana spore and four replicates for each concentration were used. Mortality of H. hampei was observed. Results of this study showed that all concentrations of spore killed imago of Hypothenemus hampei Ferr. The highest mortality reached 85.625% at 0.05% of spore within 10 days. Therefore, it could be concluded that 0.05% of spore as effective concentration to control H. hampei . Key words: Beauveria bassiana strain Wamena, Hypothenemus hampei Ferr., Coffea sp., and spore as effective concentration.

Background & Aims DNA mismatch repair deficiency drives microsatellite instability (MSI). Cells with MSI accumulate numerous frameshift mutations. Frameshift mutations affecting cancer-related genes may promote tumorigenesis and, therefore, are shared among independently arising MSI tumors. Consequently, such recurrent frameshift mutations can give rise to shared immunogenic frameshift peptides (FSPs) that represent ideal candidates for a vaccine against MSI cancer. Pathogenic germline variants of mismatch repair genes cause Lynch syndrome (LS), a hereditary cancer syndrome affecting approximately 20–25 million individuals worldwide. Individuals with LS are at high risk of developing MSI cancer. Previously, we demonstrated safety and immunogenicity of an FSP-based vaccine in a phase I/IIa clinical trial in patients with a history of MSI colorectal cancer. However, the cancer-preventive effect of FSP vaccination in the scenario of LS has not yet been demonstrated. Methods A genome-wide database of 488,235 mouse coding mononucleotide repeats was established, from which a set of candidates was selected based on repeat length, gene expression, and mutation frequency. In silico prediction, in vivo immunogenicity testing, and epitope mapping was used to identify candidates for FSP vaccination. Results We identified 4 shared FSP neoantigens (Nacad [FSP-1], Maz [FSP-1], Senp6 [FSP-1], Xirp1 [FSP-1]) that induced CD4/CD8 T cell responses in naive C57BL/6 mice. Using VCMsh2 mice, which have a conditional knockout of Msh2 in the intestinal tract and develop intestinal cancer, we showed vaccination with a combination of only 4 FSPs significantly increased FSP-specific adaptive immunity, reduced intestinal tumor burden, and prolonged overall survival. Combination of FSP vaccination with daily naproxen treatment potentiated immune response, delayed tumor growth, and prolonged survival even more effectively than FSP vaccination alone. Conclusions Our preclinical findings support a clinical strategy of recurrent FSP neoantigen vaccination for LS cancer immunoprevention.

Specifically targeting genomic rearrangements and mutations in tumor cells has remained an elusive goal in cancer therapy. Here, we use Cas9-based genome editing to introduce the gene for the pro-drug converting enzyme ‘herpes simplex virus type 1 thymidine kinase’ (HSV1-tk) into the genome of cancer cells that carry unique sequences resulting from genome rearrangements. Specifically, we targeted the breakpoints of TMEM135-CCDC67 and MAN2A1-FER fusions in human prostate cancer or hepatocellular carcinoma cells in vitro and in mouse xenografts. We designed one adenovirus to deliver the nickase Cas9D10A and gRNAs targeting the breakpoint sequences and another to deliver an EGFP-HSV1-tk construct flanked by sequences homologous to those surrounding the breakpoint. Infection with both viruses resulted in breakpoint-dependent expression of EGFP-tk and ganciclovir-mediated apoptosis. When mouse xenografts were treated with adenoviruses and ganciclovir, all animals showed reduction of tumor burden with no mortality over the observation period. Our results suggest that Cas9-mediated suicide gene insertion might be a viable genotype-specific therapy for cancer.

Cellular stress response 1 (CSR1) is a tumor suppressor gene that plays an important role in regulating cell death. In this report, we show that the N-terminus of CSR1 interacts with splicing factor 3A, subunit 3 (SF3A3). The SF3A3 binding motif was identified in the region of amino acids 62-91 of CSR1 through cell-free binding analyses. The interaction between CSR1 and SF3A3 led to migration of SF3A3 from nucleus to cytoplasm. The cytoplasmic redistribution of SF3A3 significantly reduced the splicing efficiency of epidermal growth factor receptor and platelet-derived growth factor receptor. Induction of CSR1 or down-regulation of SF3A3 also significantly reduced the splicing activity of oxytocin reporter gene both in vivo and in vitro. Mutant CSR1 that lacks the SF3A3 binding motif contained no RNA splicing regulatory activity, while the peptide corresponding to the SF3A3 binding motif in CSR1 interfered with the wild-type CSR1 mediated inhibition of RNA splicing. Interaction of CSR1 and SF3A3 is essential for CSR1 mediated cell death. To our knowledge, this is the first report demonstrating that RNA splicing is negatively regulated by redistribution of a splicing factor. © 2016 Wiley Periodicals, Inc.

The gut microbiota plays an essential role in the health of bees. Scientific evidence suggests that diet and infection can affect the gut microbiota and modulate the health of the gut; however, the interplay between those two factors and the bee gut microbiota is not well known. In this study, we used a high-throughput sequencing method to monitor the changes of gut microbiota associated with both feeding types and Nosema ceranae infection. Our results showed that the gut microbiota composition and diversity of Asian honey bee were significantly associated with both feeding types and the N. ceranae infection. More interestingly, bees fed with beebread showed higher microbiota stability and lower mortality rates than those fed with sugar water when infected by N. ceranae. Those data suggest that beebread has the potential not only to provide better nutrition but also help to establish a more stable gut microbiota to protect bees against N. ceranae infection., The gut microbiota plays an essential role in the health of bees. To elucidate the effect of feed and Nosema ceranae infection on the gut microbiota of honey bee (Apis cerana), we used 16S rRNA sequencing to survey the gut microbiota of honey bee workers fed with sugar water or beebread and inoculated with or without N. ceranae. The gut microbiota of A. cerana is dominated by Serratia, Snodgrassella, and Lactobacillus genera. The overall gut microbiota diversity was show to be significantly differential by feeding type. N. ceranae infection significantly affects the gut microbiota only in bees fed with sugar water. Higher abundances of Lactobacillus, Gluconacetobacter, and Snodgrassella and lower abundances of Serratia were found in bees fed with beebread than in those fed with sugar water. N. ceranae infection led to a higher abundance of Snodgrassella and a lower abundance of Serratia in sugar-fed bees. Imputed bacterial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways showed the significant metagenomics functional differences by feeding and N. ceranae infections. Furthermore, A. cerana workers fed with sugar water showed lower N. ceranae spore loads but higher mortality than those fed with beebread. The cumulative mortality was strongly positive correlated (rho = 0.61) with the changes of overall microbiota dissimilarities by N. ceranae infection. Both feeding types and N. ceranae infection significantly affect the gut microbiota in A. cerana workers. Beebread not only provides better nutrition but also helps establish a more stable gut microbiota and therefore protects bees in response to N. ceranae infection. IMPORTANCE The gut microbiota plays an essential role in the health of bees. Scientific evidence suggests that diet and infection can affect the gut microbiota and modulate the health of the gut; however, the interplay between those two factors and the bee gut microbiota is not well known. In this study, we used a high-throughput sequencing method to monitor the changes of gut microbiota associated with both feeding types and Nosema ceranae infection. Our results showed that the gut microbiota composition and diversity of Asian honey bee were significantly associated with both feeding types and the N. ceranae infection. More interestingly, bees fed with beebread showed higher microbiota stability and lower mortality rates than those fed with sugar water when infected by N. ceranae. Those data suggest that beebread has the potential not only to provide better nutrition but also help to establish a more stable gut microbiota to protect bees against N. ceranae infection.

Fusion transcript formation is one of the fundamental mechanisms that drives the development of prostate cancer. Because of the advance of high-throughput parallel sequencing, many fusion transcripts have been discovered. However, the discovery rate of fusion transcripts specific for prostate cancer is lagging behind the discoveries made on chromosome abnormalities of prostate cancer. Recent analyses suggest that many fusion transcripts are present in both benign and cancerous tissues. Some of these fusion transcripts likely represent important components of normal gene expression in cells. It is necessary to identify the criteria and features of fusion transcripts that are specific for cancer. In this review, we discuss optimization of RNA sequencing depth for fusion transcript discovery and the characteristics of fusion transcripts in normal prostate tissues and prostate cancer. We also propose a new classification of cancer-specific fusion transcripts on the basis of their tail gene fusion protein product and the roles that these fusions may play in cancer development.

Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and overexpressed in a variety of human malignancies. In this report, we show that MCM7 binds SF3B3. The binding motif is located in the N terminus (amino acids 221–248) of MCM7. Knockdown of MCM7 or SF3B3 significantly increased unspliced RNA of epidermal growth factor receptor, platelet-derived growth factor receptor, and c-Met. A dramatic drop of reporter gene expression of the oxytocin exon 1-intron-exon 2-EGFP construct was also identified in SF3B3 and MCM7 knockdown PC3 and DU145 cells. The MCM7 or SF3B3 depleted cell extract failed to splice reporter RNA in in vitro RNA splicing analyses. Knockdown of SF3B3 and MCM7 leads to an increase of cell death of both PC3 and DU145 cells. Such cell death induction is partially rescued by expressing spliced c-Met. To our knowledge, this is the first report suggesting that MCM7 is a critical RNA splicing factor, thus giving significant new insight into the oncogenic activity of this protein.

We demonstrate a compact, all-fiber-integrated laser system that delivers Raman solitons with a duration of ~100 fs and pulse energy of up to 13.3 nJ, continuously wavelength tunable from 1.98 to 2.29 µm via Raman-induced soliton self-frequency shift (SSFS) in a thulium-doped fiber amplifier. We realize a >90% efficiency of Raman conversion, the highest reported value from SSFS-based sources. This enables us to achieve >10 nJ soliton energy from 2.16 to 2.29 µm range, the highest energy demonstrated above 2.22 µm from an SSFS-assisted all-fiber tunable single-soliton-pulse source. Our simple and compact all-fiber tunable laser could serve as an efficient ~2 µm femtosecond source for a wide range of mid-IR applications.

We demonstrate a compact, all-fiber-integrated laser system that delivers Raman solitons with a duration of ~100 fs and pulse energy of up to 13.3 nJ, continuously wavelength tunable from 1.98 to 2.29 µm via Raman-induced soliton self-frequency shift (SSFS) in a thulium-doped fiber amplifier. We realize a >90% efficiency of Raman conversion, the highest reported value from SSFS-based sources. This enables us to achieve >10 nJ soliton energy from 2.16 to 2.29 µm range, the highest energy demonstrated above 2.22 µm from an SSFS-assisted all-fiber tunable single-soliton-pulse source. Our simple and compact all-fiber tunable laser could serve as an efficient ~2 µm femtosecond source for a wide range of mid-IR applications.

Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1(-/-) , Msh2(-/-) , Msh2(LoxP/LoxP) ) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.

Using 532 nm parallel nanosecond pulsed laser, the decolorization of methylene blue (MB) in aqueous suspensions of gold nanoparticles (GNPs) was studied. The effects of various experimental parameters, such as irradiation time, laser energy, and initial MB concentration on the decolorization rate were investigated. Experiments using real samples of textile dyeing wastewater were also carried out to examine the effectiveness of the method in more complex samples. From the results, the following conclusions may be drawn: (i) Under the optimum conditions (pH 7.19, 135 mJ laser energy, 4 mg/L MB concentration, and 11.6 mg/L GNP concentration), the rate of MB decolorization could reach 94% in 15 min. The decolorization follows pseudo-first-order kinetics; (ii) The amount of MB decreased rapidly during the decolorization. No intermediates of the decolorization could be detected by high-performance liquid chromatography. These observations indicate that MB was decolorized through a very rapid degradation mechanism; (iii) The rate of MB decolorization increased with the increase in laser energy (at laser energies of 0 to 135 mJ); and, (iv) The efficient decolorization of MB in real samples of textile dyeing wastewater was achieved at a decolorization rate of about 85% in 15 min.

Metallothioneins (MTs) are a group of metal binding proteins thought to play a role in the detoxification of heavy metals. Here we showed by microarray and validation analyses that MT1h, a member of MT, is down-regulated in many human malignancies. Low expression of MT1h was associated with poor clinical outcomes in both prostate and liver cancer. We found that the promoter region of MT1h was hypermethylated in cancer and that demethylation of the MT1h promoter reversed the suppression of MT1h expression. Forced expression of MT1h induced cell growth arrest, suppressed colony formation, retarded migration, and reduced invasion. SCID mice with tumour xenografts with inducible MT1h expression had lower tumour volumes as well as fewer metastases and deaths than uninduced controls. MT1h was found to interact with euchromatin histone methyltransferase 1 (EHMT1) and enhanced its methyltransferase activity on histone 3. Knocking down of EHMT1 or a mutation in MT1h that abrogates its interaction with EHMT1 abrogated MT1h tumour suppressor activity. This demonstrates tumour suppressor activity in a heavy metal binding protein that is dependent on activation of histone methylation.

Background & Aims Human tumors and liver cancer cell lines express the product of a fusion between the first 13 exons in the mannosidase α class 2A member 1 gene ( MAN2A1 ) and the last 6 exons in the FER tyrosine kinase gene ( FER ), called MAN2A1−FER . We investigated whether MAN2A1−FER is expressed by human liver tumors and its role in liver carcinogenesis. Methods We performed reverse transcription polymerase chain reaction analyses of 102 non−small cell lung tumors, 61 ovarian tumors, 70 liver tumors, 156 glioblastoma multiform samples, 27 esophageal adenocarcinomas, and 269 prostate cancer samples, as well as 10 nontumor liver tissues and 20 nontumor prostate tissues, collected at the University of Pittsburgh. We also measured expression by 15 human cancer cell lines. We expressed a tagged form of MAN2A1−FER in NIH3T3 and HEP3B (liver cancer) cells; Golgi were isolated for analysis. MAN2A1−FER was also overexpressed in PC3 or DU145 (prostate cancer), NIH3T3 (fibroblast), H23 (lung cancer), and A-172 (glioblastoma multiforme) cell lines and knocked out in HUH7 (liver cancer) cells. Cells were analyzed for proliferation and in invasion assays, and/or injected into flanks of severe combined immunodeficient mice; xenograft tumor growth and metastasis were assessed. Mice with hepatic deletion of PTEN were given tail-vein injections of MAN2A1−FER . Results We detected MAN2A1−FER messenger RNA and fusion protein (114 kD) in the hepatocellular carcinoma cell line HUH7, as well as in liver tumors, esophageal adenocarcinoma, glioblastoma multiforme, prostate tumors, non−small cell lung tumors, and ovarian tumors, but not nontumor prostate or liver tissues. MAN2A1−FER protein retained the signal peptide for Golgi localization from MAN2A1 and translocated from the cytoplasm to Golgi in cancer cell lines. MAN2A1−FER had tyrosine kinase activity almost 4-fold higher than that of wild-type FER, and phosphorylated the epidermal growth factor receptor at tyrosine 88 in its N-terminus. Expression of MAN2A1 − FER in 4 cell lines led to epidermal growth factor receptor activation of BRAF, MEK, and AKT; HUH7 cells with MAN2A1 − FER knockout had significant decreases in phosphorylation of these proteins. Cell lines that expressed MAN2A1 − FER had increased proliferation, colony formation, and invasiveness and formed larger (>2-fold) xenograft tumors in mice, with more metastases, than cells not expressing the fusion protein. HUH7 cells with MAN2A1 − FER knockout formed smaller xenograft tumors, with fewer metastases, than control HUH7 cells. HUH7, A-172, and PC3 cells that expressed MAN2A1−FER were about 2-fold more sensitive to the FER kinase inhibitor crizotinib and the epidermal growth factor receptor kinase inhibitor canertinib; these drugs slowed growth of xenograft tumors from MAN2A1−FER cells and prevented their metastasis in mice. Hydrodynamic tail-vein injection of MAN2A1 − FER resulted in rapid development of liver cancer in mice with hepatic disruption of Pten . Conclusions Many human tumor types and cancer cell lines express the MAN2A1 − FER fusion, which increases proliferation and invasiveness of cancer cell lines and has liver oncogenic activity in mice.

New technologies in gene transfer combined with experimental embryology make the chicken embryo an excellent model system for gene function studies. The techniques of in ovo electroporation, in vitro culture for ex ovo electroporation and retrovirus-mediated gene transfer have already been fully developed in chicken. Yet to our knowledge, there are no definite descriptions on the features and application scopes of these techniques. The survival rates of different in vitro culture methods were compared and the EGFP expression areas of different gene transfer techniques were explored. It was that the optimal timings of removing embryo for EC culture and Petri dish system was at E1.5 and E2.5, respectively; and optimal timing of injecting retrovirus is at E0. Results indicated that the EC culture, in ovo electroporation, the Petri dish system and retrovirus-mediated method are, respectively, suitable for the very early, early, late and whole embryonic stages in chicken. Comparison of different gene transfer methods and establishment of optimal timings are expected to provide a better choice of the efficient method for a particular experiment.

The prediction of prostate cancer clinical outcome remains a major challenge after the diagnosis, even with improved early detection by prostate-specific antigen (PSA) monitoring. To evaluate whether copy number variation (CNV) of the genomes in prostate cancer tumor, in benign prostate tissues adjacent to the tumor (AT), and in the blood of patients with prostate cancer predicts biochemical (PSA) relapse and the kinetics of relapse, 241 samples (104 tumor, 49 matched AT, 85 matched blood, and 3 cell lines) were analyzed using Affymetrix SNP 6.0 chips. By using gene-specific CNV from tumor, the genome model correctly predicted 73% (receiver operating characteristic P = 0.003) cases for relapse and 75% (P < 0.001) cases for short PSA doubling time (PSADT

Expression of glutathione peroxidase 3 (GPx3) is down-regulated in a variety of human malignancies. Both methylation and deletion of GPx3 gene underlie the alterations of GPx3 expression in prostate cancer. A strong correlation between the down-regulation of GPx3 expression and progression of prostate cancer and the suppression of prostate cancer xenografts in SCID mice by forced expression of GPx3 suggests a tumor suppression role of GPx3 in prostate cancer. However, the mechanism of GPx3-mediated tumor suppression remains unclear. In this report, GPx3 was found to interact directly with p53-induced gene 3 (PIG3). Forced overexpression of GPx3 in prostate cancer cell lines DU145 and PC3 as well as immortalized prostate epithelial cells RWPE-1 increased apoptotic cell death. Expression of GPx3(x73c), a peroxidase-negative OPAL codon mutant, in DU145 and PC3 cells also increased cell death. The induced expression of GPx3 in DU145 and PC3 cells resulted in an increase in reactive oxygen species and caspase-3 activity. These activities were abrogated by either knocking down PIG3 or mutating the PIG3 binding motif in GPx3 or binding interference from a peptide corresponding to PIG3 binding motif in GPx3. In addition, UV-treated RWPE-1 cells underwent apoptotic death, which was partially prevented by knocking down GPx3 or PIG3, suggesting that GPx3-PIG3 signaling is critical for UV-induced apoptosis. Taken together, these results reveal a novel signaling pathway of GPx3-PIG3 in the regulation of cell death in prostate cancer.

P450c17, a key steroidogenic enzyme, plays important roles in the production of sex steroid and cortisol. In teleost, there are two types of P450c17, P450c17-I possessing 17α-hydroxylase and 17, 20-lyase activities, and P450c17-II only possessing 17α-hydroxylase activity. This work describes the molecular cloning of the cDNA encoding the barfin flounder (Verasper moseri) P450c17-I and P450c17-II by means of RT-PCR and 5' and 3' rapid amplification of cDNA ends (RACE) analyses and mRNA expression profiles analyzing by semiquantitative RT-PCR. Respectively, P450c17-I and P450c17-II mRNA levels in the testes correlated with serum testosterone (T) level, as well as gonadosomatic index (GSI) of males during specific stages of spermatogenesis. P450c17-I and P450c17-II mRNA were expressed in the testis and ovary, suggesting that both of them participate in the production of sex steroid in barfin flounder gonads. P450c17-I mRNA was undetectable; in contrast, P450c17-II mRNA was detected at the highest level in the head kidney, meaning that only P450c17-II is involved in the production of cortisol in barfin flounder. The results demonstrated that both of P450c17-I and P450c17-II participate in the production of sex steroid in male barfin flounder gonads.

The effects of 16 sugars (arabinose, cellobiose, fructose, galactose, gentiobiose, glucose, inositol, lactose, maltose, mannitol (a sugar alcohol), mannose, melibiose, ribose, sorbitol, trehalose, and xylose) on sweet potato whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) survival were determined using in vitro bioassays. Of these sugars, arabinose, mannose, ribose, and xylose were strongly inhibitory to both nymphal and adult survival. When 10% mannose was added to the nymphal diet, 10.5%, 1.0%, and 0% developed to the 2nd, 3rd, and 4th instars, respectively. When 10% arabinose was added, 10.8% and 0% of the nymphs molted to the 2nd and 3rd instars, respectively. Addition of 10% xylose or ribose completely terminated B. tabaci development, preventing the molt to the 2(nd) instar. With decreasing sugar concentrations the inhibitory effect was significantly reduced. In tests using adults, arabinose, galactose, inositol, lactose, maltose, mannitol, mannose, melibiose, ribose, sorbitol, trehalose, and xylose significantly reduced mean day survival. Mortality rates were highest when arabinose, mannitol, mannose, ribose, or xylose was added to the diet. Mean day survival was less than 2 days when adults were fed on diet containing 10% of any one of these five sugars. When lower concentrations of sugars were used there was a decrease in mortality. Mode of action studies revealed that toxicity was not due to the inhibition of alpha glucosidase (converts sucrose to glucose and fructose) and/or trehalulose synthase (converts sucrose to trehalulose) activity. The result of agarose gel electrophoresis of RT-PCR products of bacterial endosymbionts amplified from RNA isolated from whiteflies fed with 10% arabinose, mannose, or xylose indicated that the concentration of endosymbionts in mycetomes was not affected by the toxic sugars. Experiments in which B. tabaci were fed on diets that contained radio-labeled sucrose, methionine or inulin and one or none (control) of the highly toxic sugars showed that radioactivity (expressed in DPM) in the body, in excreted honeydew and/or carbon dioxide, was significantly reduced as compared to controls. Thus, it appears that the ability of insecticidal sugars to act as antifeedants is responsible for their toxicity to B. tabaci.

Objective.To examine whether plasma adiponectin level is correlated with osteonecrosis of the femoral head (ONFH).Methods.Blood adiponectin level in patients with nontraumatic ONFH (n = 120) was compared with a group of healthy subjects (n = 120). Patients with hip osteoarthritis (OA; n = 30) and traumatic ONFH (n = 45) were included as controls. Potential compounding factors, such as plasma low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1 (apo A1), apolipoprotein B (apo B), total cholesterol (TC), triglycerides (TG), and C-reactive protein (CRP) were also examined.Results.Patients with nontraumatic ONFH had significantly lower plasma levels of adiponectin than the healthy controls (7.14 ± 3.53 vs 10.93 ± 3.41 μg/ml, respectively; p < 0.001). Adiponectin level was positively correlated with HDL (r = 0.282, p < 0.001) and age (r = 0.145, p = 0.01), yet negatively correlated with body mass index (r = −0.70, p < 0.001), TG (r = −0.55, pConclusion.Low adiponectin level is significantly associated with the presence of nontraumatic ONFH. This biomarker may be useful in assessing the potential presence of nontraumatic ONFH.

Mutation of integrin α7 (ITGA7) was previously identified in multiple human malignancies. Restoration of ITGA7 expression in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and cell motility both in vitro and in vivo. In this study, we showed that integrin-linked kinase (ILK) binds with miniature chromosome maintenance 7 (MCM7), a DNA replication licensing protein. A 58–amino acid ILK binding motif was identified in the NH2-terminus of MCM7. The expression of ITGA7 induced the phosphorylation of MCM7. Knocking down of ILK abrogated ITGA7-induced MCM7 phosphorylation. ANK, the dominant-negative mutant of ILK, also blocked the phosphorylation of MCM7 induced by ITGA7. The phosphorylation of MCM7 reduced MCM7 chromatin association and inhibited cell growth. A MCM7 mutant that does not bind with ILK did not respond to ITGA7 stimulation, and behaved similarly to a dominant MCM7-negative mutant and neutralized the effect of ITGA7. We conclude that ILK interaction with MCM7 and MCM7 phosphorylation may be a critical event in ITGA7 signaling pathway, leading to tumor suppression. Cancer Res; 70(11); 4375–84. ©2010 AACR.

Liver supports multiple homeostatic functions of the body and maintains an appropriate size for the needs of the organism by combining (as needed) cell proliferation (to restore or increase weight) and apoptosis (to decrease weight, or in response to injury). Liver consists of hepatocytes, the main functional cells of the liver, as well as endothelial cells, stellate cells, Kupffer cells, and biliary cells. For all the hepatic cells to function properly, the interaction with extracellular matrix (ECM) is of utmost importance.1 Previous studies have shown that liver undergoes matrix breakdown and remodeling at the early stages of regeneration after partial hepatectomy.1-5 Hepatocytes depend on ECM for their differentiation in culture and they rapidly lose hepatocyte specific gene expression when maintained in the absence of matrix. Differentiation and normal hepatocyte cyto-architecture is quickly restored, however, on addition of complex matrix environments (e.g., Matrigel or collagen gels).1,6-8 Restoration of differentiation is accompanied with decrease in hepatocyte proliferation and loss of responsiveness to hepatocyte growth factor (HGF) and epidermal growth factor (EGF).9 Communication between cells and the ECM is achieved through integrins and the associated integrinproximal adhesion molecules.10 Through multiple protein–protein interactions and signaling events, these molecules transmit signals from the ECM to the interior of the cell and regulate many fundamental cellular processes. Integrin-linked kinase (ILK) is a β1- and β3-integrin-interacting cell matrix adhesion protein that has been shown to be crucial for a number of cellular processes such as survival, differentiation, proliferation, migration, and angiogenesis.11-15 Recent studies have shown that ILK plays a key role in the activation of hepatic stellate cells and thus in the development of liver fibrosis16 as well as during liver wound healing.17,18 We showed recently that removal of ILK from hepatocytes in culture results in loss of differentiation,19 whereas acute elimination of ILK by injection of adenovirus expressing Cre recombinase in the tail vein of ILKflox/flox mice led to massive hepatocyte apoptosis.20 In our current study, we used the mouse model of targeted ablation of a gene in a specific organ by the LoxP-Cre system and eliminated ILK from mouse liver by expression of Cre recombinase in ILKflox/flox mouse livers through promoters whose expression is specific to hepatocytes.21

BACKGROUND Integrins are the major adhesive molecules in mammalian cells. Each integrin subtype plays a unique role in cell differentiation and embryo development. However, integrin involvement in carcinogenesis has not been well defined. METHODS We identified mutations in integrin alpha7 by sequencing genomic DNAs and cDNAs from 122 specimens, including 62 primary human tumor samples, four cell lines, and 56 matched normal tissues. We evaluated the tumor suppressor activity of integrin alpha7 with colony formation, soft agar colony growth, and cell migration assays by forcing its expression in PC-3 and Du145 prostate cancer cells and SK-UT-1 leiomyosarcoma cells. PC-3 and Du145 xenograft tumors with increased levels of integrin alpha7 in severe combined immune deficient mice were used to assess the effect of integrin alpha7 on tumor growth and metastasis. Immunostaining was used to localize and to measure the level of integrin alpha7 in 701 and 141 specimens of prostate and smooth muscle, respectively. A meta-analysis of integrin alpha7 mRNA microarray data from four studies was performed. Kaplan-Meier analyses were used to assess survival. All statistical tests were two-sided. RESULTS Integrin alpha7 mutations that generate truncations were found in specimens of 16 of 28 prostate cancers (57%, 95% confidence interval [CI] = 37% to 76%), five of 24 hepatocellular carcinomas (21%, 95% CI = 7% to 42%), five of six glioblastomas multiforme (83%, 95% CI = 36% to 99%), and one of four leiomyosarcomas (25%, 95% CI = 0.6% to 81%). Integrin alpha7 mutations were associated with increased recurrence of human prostate cancer (nine recurrences among 13 patients with integrin alpha7 mutations versus one among eight without such mutations; odds ratio [OR] = 14, 95% CI = 1.15 to 782, P = .024) and hepatocellular carcinoma (five recurrences among eight patients with integrin alpha7 mutations versus one among 16 without such mutations, OR = 21, 95% CI = 1.6 to 1245; P = .007). Forced expression of normal integrin alpha7 in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and metastasis both in vitro and in vivo. Focal or no integrin alpha7 expression in human prostate cancer and soft tissue leiomyosarcoma was associated with a reduction of metastasis-free survival (for example, for prostate cancer with focal or no expression, 5-year metastasis-free survival was 32%, 95% CI = 24.4% to 40.3%, and for prostate cancer with at least weak expression, it was 85%, 95% CI = 79% to 91%; P

Cellular stress response 1 (CSR1) is a tumor suppressor gene that plays an important role in regulating cell death. In this report, we show that the N-terminus of CSR1 interacts with splicing factor 3A, subunit 3 (SF3A3). The SF3A3 binding motif was identified in the region of amino acids 62-91 of CSR1 through cell-free binding analyses. The interaction between CSR1 and SF3A3 led to migration of SF3A3 from nucleus to cytoplasm. The cytoplasmic redistribution of SF3A3 significantly reduced the splicing efficiency of epidermal growth factor receptor and platelet-derived growth factor receptor. Induction of CSR1 or down-regulation of SF3A3 also significantly reduced the splicing activity of oxytocin reporter gene both in vivo and in vitro. Mutant CSR1 that lacks the SF3A3 binding motif contained no RNA splicing regulatory activity, while the peptide corresponding to the SF3A3 binding motif in CSR1 interfered with the wild-type CSR1 mediated inhibition of RNA splicing. Interaction of CSR1 and SF3A3 is essential for CSR1 mediated cell death. To our knowledge, this is the first report demonstrating that RNA splicing is negatively regulated by redistribution of a splicing factor. © 2016 Wiley Periodicals, Inc.

Accurate prediction of prostate cancer clinical courses remains elusive. In this study, we performed whole genome copy number analysis on leukocytes of 273 prostate cancer patients using Affymetrix SNP6.0 chip. Copy number variations (CNV) were found across all chromosomes of the human genome. An average of 152 CNV fragments per genome was identified in the leukocytes from prostate cancer patients. The size distributions of CNV in the genome of leukocytes were highly correlative with prostate cancer aggressiveness. A prostate cancer outcome prediction model was developed based on large size ratio of CNV from the leukocyte genomes. This prediction model generated an average prediction rate of 75.2%, with sensitivity of 77.3% and specificity of 69.0% for prostate cancer recurrence. When combined with Nomogram and the status of fusion transcripts, the average prediction rate was improved to 82.5% with sensitivity of 84.8% and specificity of 78.2%. In addition, the leukocyte prediction model was 62.6% accurate in predicting short prostate specific antigen doubling time. When combined with Gleason’s grade, Nomogram and the status of fusion transcripts, the prediction model generated a correct prediction rate of 77.5% with 73.7% sensitivity and 80.1% specificity. To our knowledge, this is the first study showing that CNVs in leukocyte genomes are predictive of clinical outcomes of a human malignancy.

Miniature chromosome maintenance 7 (MCM7) is an essential component of DNA replication licensing complex. Recent studies indicate that MCM7 is amplified and over-expressed in a variety of human mal...

In this paper, a penalty equilibrating 3-D mixed element based on a modified Hu–Washizu variational functional has been proposed to improve the accuracy of the elasto-plastic analysis for irregular meshes. In order to construct this element, a penalty term, which can enforce the stress components to satisfy the equilibrium equations in a weak form, is introduced into the Hu–Washizu three-field functional to “penalize” the false stress caused by the distorted meshes. The selection of the penalty factor has also been discussed in detail. Unlike traditional hybrid or mixed elements, the performance of this element is not so sensitive to mesh distortion. Furthermore, compared with hybrid stress elements, the proposed element based on the three-field variational principle is more suitable for material non-linear analysis. Numerical examples including elastic and elasto-plastic analyses have demonstrated the improved performance of the proposed element.

Miniature chromosome maintenance (MCM) proteins play critical roles in DNA replication licensing, initiation and elongation. MCM8, one of the MCM proteins playing critical role in DNA repairing and recombination, was found to have over-expression and increased DNA copy number in a variety of human malignancies. The gain of MCM8 is associated with aggressive clinical features of several human cancers. Increased expression of MCM8 in prostate cancer is associated with cancer recurrence. Forced expression of MCM8 in RWPE1 cells, the immortalized but non-transformed prostate epithelial cell line, exhibited fast cell growth and transformation, while knocked down of MCM8 in PC3, DU145 and LNCaP cells induced cell growth arrest, and decreased tumor volumes and mortality of severe combined immunodeficiency mice xenografted with PC3 and DU145 cells. MCM8 bound cyclin D1 and activated Rb protein phosphorylation by cyclin-dependent kinase 4 in vitro and in vivo. The cyclin D1/MCM8 interaction is required for Rb phosphorylation and for S phase entry in cancer cells. As a result, our study showed that copy number increase and overexpression of MCM8 may play critical roles in human cancer development. Note: This abstract was not presented at the meeting. Citation Format: Jian-Hua Luo, Dong-Mei He, Baoguo Ren, Yan Yu. Oncogenic activity of amplified miniature chromosome maintenance 8 in human malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 303. doi:10.1158/1538-7445.AM2017-303

Influence of spin manufacturing process on properties of the spun single mode fiber is investigated, a unidirectional spinning preform during the drawing process. The drawing speed constant is 1 m/min. The results show that pitch of the spun fiber exists; that mode field diameter (MFD) is obviously smaller; that cutoff wavelength and polarization mode dispersion (PMD) are decreased significantly, and then the loss is increased significantly when the spun fiber pitch is lower than 1.5 mm. It is very important for the fiber-optic gyroscope and fiber-optic current sensors to optimize spinning design to obtain relatively good spun fibers.

Different DNA mismatch repair (MMR)-deficient mouse strains have been developed as models for the inherited cancer predisposing Lynch syndrome. It is completely unresolved, whether coding mononucleotide repeat (cMNR) gene mutations in these mice can contribute to intestinal tumorigenesis and whether MMR-deficient mice are a suitable molecular model of human microsatellite instability (MSI)-associated intestinal tumorigenesis. A proof-of-principle study was performed to identify mouse cMNR-harboring genes affected by insertion/deletion mutations in MSI murine intestinal tumors. Bioinformatic algorithms were developed to establish a database of mouse cMNR-harboring genes. A panel of five mouse noncoding mononucleotide markers was used for MSI classification of intestinal matched normal/tumor tissues from MMR-deficient (Mlh1(-/-) , Msh2(-/-) , Msh2(LoxP/LoxP) ) mice. cMNR frameshift mutations of candidate genes were determined by DNA fragment analysis. Murine MSI intestinal tumors but not normal tissues from MMR-deficient mice showed cMNR frameshift mutations in six candidate genes (Elavl3, Tmem107, Glis2, Sdccag1, Senp6, Rfc3). cMNRs of mouse Rfc3 and Elavl3 are conserved in type and length in their human orthologs that are known to be mutated in human MSI colorectal, endometrial and gastric cancer. We provide evidence for the utility of a mononucleotide marker panel for detection of MSI in murine tumors, the existence of cMNR instability in MSI murine tumors, the utility of mouse subspecies DNA for identification of polymorphic repeats, and repeat conservation among some orthologous human/mouse genes, two of them showing instability in human and mouse MSI intestinal tumors. MMR-deficient mice hence are a useful molecular model system for analyzing MSI intestinal carcinogenesis.

DNA methylation is one of the most important epigenetic mechanisms in regulating gene expression. Genome hypermethylation has been speculated as a critical mechanism in human malignancies. However, whole genome quantification of DNA methylation of human malignancies has rarely been investigated, and the significance of the genome distribution of CpG methylation is unclear. In this report, we performed whole genome methylation sequencing to investigate the methylation profiles of 13 prostate samples, including 5 prostate cancers, 4 matched benign prostate tissues adjacent to cancer and 4 age-matched organ donor prostate tissues. Our results showed that alterations of methylation patterns occurred in prostate cancer and benign prostate tissues adjacent to cancer in comparison with age matched organ donor prostates. Over 95% alterations of genome methylation occurred in sequences outside CpG islands. Only a small fraction of the methylated CpG islands exerts an impact on RNA expression. Both intragene and pr...