Integrated genomic characterization of endometrial carcinoma

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ∼25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours.

Nuclear instruments and methods in physics research section B : beam interactions with materials and atoms

The impact-induced deposition of Al13 clusters with icosahedral structure on Ni(0 0 1) surface was studied by molecular dynamics (MD) simulation using Finnis–Sinclair potentials. The incident kinetic energy (Ein) ranged from 0.01 to 30 eV per atom. The structural and dynamical properties of Al clusters on Ni surfaces were found to be strongly dependent on the impact energy. At much lower energy, the Al cluster deposited on the surface as a bulk molecule. However, the original icosahedral structure was transformed to the fcc-like one due to the interaction and the structure mismatch between the Al cluster and Ni surface. With increasing the impinging energy, the cluster was deformed severely when it contacted the substrate, and then broken up due to dense collision cascade. The cluster atoms spread on the surface at last. When the impact energy was higher than 11 eV, the defects, such as Al substitutions and Ni ejections, were observed. The simulation indicated that there exists an optimum energy range, which is suitable for Al epitaxial growth in layer by layer. In addition, at higher impinging energy, the atomic exchange between Al and Ni atoms will be favourable to surface alloying.

In vitro models for investigating keratinocyte responses to ultraviolet B radiation

This thesis describes the use of 2- and 3-dimensional cell-based models for studying how skin cells respond to ultraviolet radiation. These methods were used to investigate skin damage and repair after exposure to radiation in the context of skin cancer development. Interactions between different skin cell types were demonstrated as being significant in protecting against ultraviolet radiation-induced skin damage. This has important implications in understanding how skin cancers occur, as well as in the development of new strategies to prevent and treat them.

Vibrational spectroscopy of the borate mineral olshanskyite Ca3[B(OH)4]4(OH)2

The mineral olshanskyite is one of many calcium borate minerals which has never been studied using vibrational spectroscopy. The mineral is unstable and decomposes upon exposure to an electron beam. This makes the elemental analysis using EDX techniques difficult. Both the Raman and infrared spectra show complexity due to the complexity of the structure. Intense Raman bands are found at 989, 1,003, 1,025 and 1,069 cm-1 with a shoulder at 961 cm-1 and are assigned to trigonal borate units. The Raman bands at 1,141, 1,206 and 1,365 cm-1 are assigned to OH in-plane bending of BOH units. A series of Raman bands are observed in the 2,900–3,621cm-1 spectral range and are assigned to the stretching vibrations of OH and water. This complexity is also reflected in the infrared spectra. Vibrational spectroscopy enables aspects of the structure of olshanskyite to be elucidated.

Genetic diversity of cultured and wild populations of the giant freshwater prawn Macrobrachium rosenbergii (de Man, 1879) based on microsatellite analysis

Freshwater prawn (Macrobrachium rosenbergii) culture in the Western Hemisphere is primarily, if not entirely, derived from 36 individual prawns originally introduced to Hawaii from Malaysia in 1965 and 1966. Little information is available regarding genetic variation within and among cultured prawn stocks worldwide. The goal of the current study was to characterize genetic diversity in various prawn populations with emphasis on those cultured in North America. Five microsatellite loci were screened to estimate genetic diversity in two wild (Myanmar and India-wild) and seven cultured (Hawaii-1, Hawaii-2, India-cultured, Israel, Kentucky, Mississippi and Texas) populations. Average allelic richness ranged from 3.96 (Israel) to 20.45 (Myanmar). Average expected heterozygosity ranged from 0.580 (Israel) to 0.935 (Myanmar). Many of the cultured populations exhibited reduced genetic diversity when compared with the Myanmar and the India-cultured populations. Significant deficiency in heterozygotes was detected in the India-cultured, Mississippi and Kentucky populations (overall Fis estimated of 0.053, 0.067 and 0.108 respectively) reflecting moderate levels of inbreeding. Overall estimate of fixation index (Fst = 0.1569) revealed moderately high levels of differentiation among the populations. Outcome of this study provide a baseline assessment of genetic diversity in some available strains that will be useful for the development of breeding programmes.

A class B switch-mode assisted linear amplifier

A switch-mode assisted linear amplifier (SMALA) combining a linear (Class B) and a switch-mode (Class D) amplifier is presented. The usual single hysteretic controlled half-bridge current dumping stage is replaced by two parallel buck converter stages, in a parallel voltage controlled topology. These operate independently: one buck converter sources current to assist the upper Class B output device, and a complementary converter sinks current to assist the lower device. This topology lends itself to a novel control approach of a dead-band at low power levels where neither class D amplifier assists, allowing the class B amplifier to supply the load without interference, ensuring high fidelity. A 20 W implementation demonstrates 85% efficiency, with distortion below 0.08% measured across the full audio bandwidth at 15 W. The class D amplifier begins assisting at 2 W, and below this value, the distortion was below 0.03%. Complete circuitry is given, showing the simplicity of the additional class D amplifier and its corresponding control circuitry.

Relative abundance of full-length and truncated FOXP1 isoforms is associated with differential NFκB activity in Follicular Lymphoma

FOXP1 is a transcriptional repressor that has been proposed to repress the expression of some NFκB-responsive genes. Furthermore, truncated forms of FOXP1 have been associated with a subtype of Diffuse Large B-cell Lymphoma characterised by constitutive NFκB activity, indicating that they may inhibit this repression. We have shown that FL tumors have increased relative abundance of truncated FOXP1 isoforms and this is associated with increased expression of NFκB-associated genes. Our results provide strong evidence that relative FOXP1 isoform abundance is associated with NFκB activity in FL, and could potentially be used as a marker for this gene signature.

The B subunit of coagulation factor XIII is linked to renin and the Duffy blood group to α-spectrin on human chromosome 1

Family linkage studies were used to detect two linkage relationships on human chromosome 1. The B subunit of coagulation factor XIII showed significant linkage to renin with a maximum lod score of 5.071 at a distance of 10 cM. Significant linkage was also shown between the Duffy blood group and α-spectrin with linkage results giving a combined lod score of 3.194 at 5 cM.

GEF-H1-RhoA signaling pathway mediates LPS-induced NF-κB transactivation and IL-8 synthesis in endothelial cells

Secretion of proinflammatory cytokines by LPS activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in this process is not well understood. In the present study, we determined the roles of GEF-H1 (Guanine-nucleotide exchange factor-H1)-RhoA signalling in LPS-induced interleukin-8 (IL-8, CXCL8) production in endothelial cells. First, we observed that GEF-H1 expression was upregulated in a dose- and time-dependent manner as consistent with TLR4 (Toll-like receptor 4) expression after LPS stimulation. Afterwards, Clostridium difficile toxin B-10463 (TcdB-10463), an inhibitor of Rho activities, reduced LPS-induced NF-κB phosphorylation. Inhibition of GEF-H1 and RhoA expression reduced LPS-induced NF-κB and p38 phosphorylation. TLR4 knockout blocked LPS-induced activity of RhoA, however, MyD88 knockout did not impair the LPS-induced activity of RhoA. Nevertheless, TLR4 and MyD88 knockout both significantly inhibited transactivation of NF-κB. GEF-H1-RhoA and MyD88 both induced significant changes in NF-κB transactivation and IL-8 synthesis. Co-inhibition of GEF-H1-RhoA and p38 expression produced similar inhibitory effects on LPS-induced NF-κB transactivation and IL-8 synthesis as inhibition of p38 expression alone, thus confirming that activation of p38 was essential for the GEF-H1-RhoA signalling pathway to induce NF-κB transactivation and IL-8 synthesis. Taken together, these results demonstrate that LPS-induced NF-κB activation and IL-8 synthesis in endothelial cells are regulated by the MyD88 pathway and GEF-H1-RhoA pathway.

Epstein-Barr virus-positive diffuse large B-cell lymphoma of the elderly expresses EBNA3A with conserved CD8+ T-cell epitopes

Post-transplantation lymphoproliferative disorders (PTLD) arise in the immunosuppressed and are frequently Epstein-Barr virus (EBV) associated. The most common PTLD histological sub-type is diffuse large B-cell lymphoma (EBV+DLBCL-PTLD). Restoration of EBV-specific T-cell immunity can induce EBV+DLBCL-PTLD regression. The most frequent B-cell lymphoma in the immunocompetent is also DLBCL. ‘EBV-positive DLBCL of the elderly’ (EBV+DLBCL) is a rare but well-recognized DLBCL entity that occurs in the overtly immunocompetent, that has an adverse outcome relative to EBV-negative DLBCL. Unlike PTLD (which is classified as viral latency III), literature suggests EBV+DLBCL is typically latency II, i.e. expression is limited to the immuno-subdominant EBNA1, LMP1 and LMP2 EBV-proteins. If correct, this would be a major impediment for T-cell immunotherapeutic strategies. Unexpectedly we observed EBV+DLBCL-PTLD and EBV+DLBCL both shared features consistent with type III EBV-latency, including expression of the immuno-dominant EBNA3A protein. Extensive analysis showed frequent polymorphisms in EBNA1 and LMP1 functionally defined CD8+ T-cell epitope encoding regions, whereas EBNA3A polymorphisms were very rare making this an attractive immunotherapy target. As with EBV+DLBCL-PTLD, the antigen presenting machinery within lymphomatous nodes was intact. EBV+DLBCL express EBNA3A suggesting it is amenable to immunotherapeutic strategies.

The role of EBV-encoded microRNAs in B cell differentiation

Epstein Barr virus (EBV) is a common γ-herpes virus, infecting approximately 90% of the world‟s population. It is also one of the first known viruses known to be oncogenic, and is associated with a number of tumour types, primarily lymphomas. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and many human miRNAs have been associated with the development of malignancies including cancer. EBV was the first human virus identified to express miRNAs and encodes more than 40 miRNAs within its genome. Yet, an understanding of the targets of EBV-miRNAs, and thereby the function of them in pathogenesis remains sadly limited. This study identifies a potential novel target of EBV-miRNAs, MECP2 and characterises the miRNA:mRNA interactions between two previously identified novel targets; Bim and EBF1. In particular, this study focuses upon the interaction between EBF1 and the EBV-miRNA BART11-5p, demonstrating a 151bp region of the EBF1 3‟UTR that is capable of mediating the silencing of luciferase expression by BART11-5p but is not capable of silencing a full length EBF1-3‟UTR luciferase construct. This study provides evidence that EBF1 may be a target of one or more EBV-miRNAs.

Epidemiological trend of hepatitis B, liver cirrhosis and liver cancer during 1990 - 2007 in Shandong province, China [山东省乙型肝炎、肝硬化及肝癌流行趋势分析]

Objective To analyze the epidemiological trend of hepatitis B, liver cirrhosis and liver cancer during 1990 to 2007 in Shandong province, and to evaluate the effectiveness of hepatitis B prevention and control measures, so as to provide evidence for policy-making. Methods Based on the routine incidence data of hepatitis B, mortality data of hepatitis B, liver cirrhosis, liver cancer and demographic data, the incidence rate, mortality rate and age-specific mortality rate were calculated and analyzed with simple linear regression model. Results A total of 437094 cases of hepatitis B were reported during 1990 - 2007 with an average yearly morbidity of 27.32 per 100 000 persons and a decreased trend for the 0-9 years old children. At the same time, the adjusted mortality rate for hepatitis B and liver cirrhosis showed a decreased trend and the combined mortality rate decreased from 17.55 /100 000 in 1990 to 4.01 /100 000 in 2007. The mortality of liver cancer was stable during this time (P = 0. 9998). Conclusion Immunization of hepatitis B vaccine may have lowered the incidence of hepatitis B in the target population and the overall mortality rates of liver cirrhosis and liver cancer. Abstract in Chinese 目的 了解山东省1990～2007年乙肝、肝硬化和肝癌的流行状况及变化趋势,初步评价乙肝预防控制措施的效果,为今后防治决策制定提供参考. 方法 根据报告的乙肝发病资料和乙肝、肝硬化、肝癌死亡资料以及历年人口资料,利用发病率、死亡率、年龄别死亡率等指标对上述3种疾病进行流行趋势的分析,并建立简单线性回归模型进行统计分析. 结果 1990～2007年山东省共报告乙肝病例437 094例,年均总发病率为27.32/10万,并呈上升趋势,而0～9岁年龄组的发病率呈显著下降趋势.乙肝和肝硬化调整死亡率下降趋势明显,两者合并死亡率由1990年的17.55/10万下降到2007年的4.01/10万.肝癌调整死亡率基本稳定(P=0.999 8). 结论 做好乙肝疫苗的免疫接种不仅可降低目标人群乙肝的发病,并将最终降低与此相关的肝硬化和肝癌的死亡率.

Epidemiological Trend of Hepatitis B in Shandong Province of China, 1990 - 2007 []

Objective To analyze the epidemiological trend of hepatitis B from 1990 to 2007 in Shandong province, and to find the high risk population so as to explore the further control strategy. Methods Based on the routine reporting incidence data of hepatitis B and demographic data of Shandong province, the incidence rates and sex - specific, age - specific incidence rates of hepatitis B were calculated and statistically analyzed in the simple linear regression model. Results The total number of hepatitis B was 437 094, the annual average morbidity was 27132 per 100 000 population during 1990 to 2007. The incidence of men (38142 per 100 000) was higher than that for women (15183 per 100 000) 1The annual incidence rate of hepatitis B indicated an increasing trend for the whole population, while a decreased trend for the 0～9 year - old children p resented in the past 18 years. It showed that the average age of onset moved to the older. Conclusion Young adult men are the high-risk groups for the onset of hepatitis B. For the prevention of hepatitis B, the immunization of hepatitis B vaccine should be enhanced for other groups, especially for the high - risk population on the basis of imp roving the immunization coverage rate for newborns.

Use of serum and blood samples on filter paper to improve the surveillance of dengue in Pacific Island Countries

Background In Pacific Island Countries (PICs) the epidemiology of dengue is characterized by long-term transmission of a single dengue virus (DENV) serotype. The emergence of a new serotype in one island country often indicates major outbreaks with this serotype will follow in other PICs. Objectives Filter paper (FP) cards on which whole blood or serum from dengue suspected patients had been dried was evaluated as a method for transportation of this material by standard mail delivery throughout the Pacific. Study design Twenty-two FP-dried whole blood samples collected from patients in New Caledonia and Wallis & Futuna Islands, during DENV-1 and DENV-4 transmission, and 76 FP-dried sera collected from patients in Yap State, Majuro (Republic of Marshall Islands), Tonga and Fiji, before and during outbreaks of DENV-2 in Yap State and DENV-4 in Majuro, were tested for the presence of DENV RNA, by serotype specific RT-PCR, at the Institut Louis Malardé in French Polynesia. Results The serotype of DENV could be determined, by a variety of RT-PCR procedures, in the FP-dried samples after more than three weeks of transport at ambient temperatures. In most cases, the sequencing of the envelope gene to genotype the viruses also was possible. Conclusions The serotype and genotype of DENV can be determined from FP-dried serum or whole blood samples transported over thousands of kilometers at ambient, tropical, temperatures. This simple and low-cost approach to virus identification should be evaluated in isolated and resource poor settings for surveillance for a range of significant viral diseases.