Mice lacking NF-κB1 exhibit marked DNA damage responses and more severe gastric pathology in response to intraperitoneal tamoxifen administration

Tamoxifen (TAM) has recently been shown to cause acute gastric atrophy and metaplasia in mice. We have previously demonstrated that the outcome of Helicobacter felis infection, which induces similar gastric lesions in mice, is altered by deletion of specific NF-κB subunits. Nfkb1-/- mice developed more severe gastric atrophy than wild-type (WT) mice 6 weeks after H. felis infection. In contrast, Nfkb2-/- mice were protected from this pathology. We therefore hypothesized that gastric lesions induced by TAM may be similarly regulated by signaling via NF-κB subunits. Groups of five female C57BL/6 (WT), Nfkb1-/-, Nfkb2-/- and c-Rel-/- mice were administered 150 mg/kg TAM by IP injection. Seventy-two hours later, gastric corpus tissues were taken for quantitative histological assessment. In addition, groups of six female WT and Nfkb1-/- mice were exposed to 12 Gy γ-irradiation. Gastric epithelial apoptosis was quantified 6 and 48 h after irradiation. TAM induced gastric epithelial lesions in all strains of mice, but this was more severe in Nfkb1-/- mice than in WT mice. Nfkb1-/- mice exhibited more severe parietal cell loss than WT mice, had increased gastric epithelial expression of Ki67 and had an exaggerated gastric epithelial DNA damage response as quantified by γH2AX. To investigate whether the difference in gastric epithelial DNA damage response of Nfkb1-/- mice was unique to TAM-induced DNA damage or a generic consequence of DNA damage, we also assessed gastric epithelial apoptosis following γ-irradiation. Six hours after γ-irradiation, gastric epithelial apoptosis was increased in the gastric corpus and antrum of Nfkb1-/- mice. NF-κB1-mediated signaling regulates the development of gastric mucosal pathology following TAM administration. This is associated with an exaggerated gastric epithelial DNA damage response. This aberrant response appears to reflect a more generic sensitization of the gastric mucosa of Nfkb1-/- mice to DNA damage

Diagnosis of oesophageal cancer by detection of minichromosome maintenance 5 protein in gastric aspirates

Symptomatic oesophageal cancer is usually advanced and the prognosis poor. Lethality of symptomatic oesophageal cancer has motivated screening for these diseases earlier in their evolution, but reliable methods for early diagnosis remain elusive. We have demonstrated that dysregulated expression of minichromosome maintenance (MCM) proteins 2–7 is characteristic of early epithelial carcinogenesis, and that these key DNA replication initiation factors can be used as diagnostic markers for cervical and genito-urinary tract cancer. In this study, we investigated whether minichromosome maintenance protein 5 (Mcm5) can be used to detect oesophageal cancer cells in gastric aspirates. Two monoclonal antibodies raised against His-tagged human Mcm5 were used in a time-resolved immunofluorometric assay to measure Mcm5 levels in cells isolated from gastric aspirates of 40 patients undergoing gastroscopy for suspected or known oesophageal carcinoma or symptoms of dyspepsia. The test discriminated with high specificity and sensitivity between patients with and without oesophageal cancer (85% sensitivity (95% confidence interval (CI)=62–97%), 85% specificity (CI=66–96%)), as demonstrated by the large area under the receiver operating characteristics curve (0.93 (95% CI=0.85–0.99)). Elevated levels of Mcm5 in gastric aspirates are highly predictive of oesophageal cancer. This simple test for oesophageal cancer is readily automated with potential applications in primary diagnosis, surveillance and screening

Diagnosis of prostate cancer by detection of minichromosome maintenance 5 protein in urine sediments

Background: The accuracy of prostate-specific antigen (PSA) testing in prostate cancer detection is constrained by low sensitivity and specificity. Dysregulated expression of minichromosome maintenance (Mcm) 2–7 proteins is an early event in epithelial multistep carcinogenesis and thus MCM proteins represent powerful cancer diagnostic markers. In this study we investigate Mcm5 as a urinary biomarker for prostate cancer detection. Methods: Urine was obtained from 88 men with prostate cancer and from two control groups negative for malignancy. A strictly normal cohort included 28 men with complete, normal investigations, no urinary calculi and serum PSA <2 ng ml–1. An expanded control cohort comprised 331 men with a benign final diagnosis, regardless of PSA level. Urine was collected before and after prostate massage in the cancer patient cohort. An immunofluorometric assay was used to measure Mcm5 levels in urine sediments. Results: The Mcm5 test detected prostate cancer with 82% sensitivity (confidence interval (CI)= 72–89%) and with a specificity ranging from 73 (CI=68–78%) to 93% (CI=76–99%). Prostate massage led to increased Mcm5 signals compared with pre-massage samples (median 3440 (interquartile range (IQR) 2280 to 5220) vs 2360 (IQR <1800 to 4360); P=0.009), and was associated with significantly increased diagnostic sensitivity (82 vs 60%; P=0.012). Conclusions: Urinary Mcm5 detection seems to be a simple, accurate and noninvasive method for identifying patients with prostate cancer. Large-scale prospective trials are now required to evaluate this test in diagnosis and screening

How Local is the Local Diversity? Reinforcing Sequential Determinantal Point Processes with Dynamic Ground Sets for Supervised Video Summarization

The large volume of video content and high viewing frequency demand automatic video summarization algorithms, of which a key property is the capability of modeling diversity. If videos are lengthy like hours-long egocentric videos, it is necessary to track the temporal structures of the videos and enforce local diversity. The local diversity refers to that the shots selected from a short time duration are diverse but visually similar shots are allowed to co-exist in the summary if they appear far apart in the video. In this paper, we propose a novel probabilistic model, built upon SeqDPP, to dynamically control the time span of a video segment upon which the local diversity is imposed. In particular, we enable SeqDPP to learn to automatically infer how local the local diversity is supposed to be from the input video. The resulting model is extremely involved to train by the hallmark maximum likelihood estimation (MLE), which further suffers from the exposure bias and non-differentiable evaluation metrics. To tackle these problems, we instead devise a reinforcement learning algorithm for training the proposed model. Extensive experiments verify the advantages of our model and the new learning algorithm over MLE-based methods

Effects of the trawling ban on demersal fish communities in the marine environment of Hong Kong, South China

Oral PresentationFisheries & Marine Resources ManagementFishery resources in Hong Kong have been over-exploited since the 1970s. In 2010, there were still around 400 trawlers operating in local waters. These trawlers nonselectively catch marine organisms of all sizes, while exerting severe physical damage to the benthic ecosystem. To mitigate the associated impacts of overfishing and trawling, the Government of the Hong Kong Special Administrative Region has imposed a territory-wide trawling ban across local marine waters since 31 December 2012. This study aims to investigate if the trawl-ban policy is effective to facilitate recovery of demersal fish resources, in terms of species diversity, abundance and biomass, in Hong Kong. Under an approved scientific permit, trawl surveys were conducted using a commercial shrimp trawler in eastern (EW), western (WW) and southern waters (SW) of Hong Kong from ...postprin

Optimality of mutation and selection in germinal centers

The population dynamics theory of B cells in a typical germinal center could play an important role in revealing how affinity maturation is achieved. However, the existing models encountered some conflicts with experiments. To resolve these conflicts, we present a coarse-grained model to calculate the B cell population development in affinity maturation, which allows a comprehensive analysis of its parameter space to look for optimal values of mutation rate, selection strength, and initial antibody-antigen binding level that maximize the affinity improvement. With these optimized parameters, the model is compatible with the experimental observations such as the ~100-fold affinity improvements, the number of mutations, the hypermutation rate, and the "all or none" phenomenon. Moreover, we study the reasons behind the optimal parameters. The optimal mutation rate, in agreement with the hypermutation rate in vivo, results from a tradeoff between accumulating enough beneficial mutations and avoiding too many deleterious or lethal mutations. The optimal selection strength evolves as a balance between the need for affinity improvement and the requirement to pass the population bottleneck. These findings point to the conclusion that germinal centers have been optimized by evolution to generate strong affinity antibodies effectively and rapidly. In addition, we study the enhancement of affinity improvement due to B cell migration between germinal centers. These results could enhance our understandings to the functions of germinal centers.Comment: 5 figures in main text, and 4 figures in Supplementary Informatio

Spatial variation in trophic structure of Demersal Fish Communities in the marine environment of Hong Kong, South China

Poster presentation: P-55Fisheries & Marine Resources ManagementHong Kong’s western coastal waters (WW) situated at the Pearl River Estuary are heavily influenced by freshwater and sediment discharges from the Pearl River, while its eastern waters (EW) are mainly affected by oceanic and tidal currents. The southern waters (SW) are positioned along this estuarine-oceanic salinity gradient. Such variations in hydrography and salinity drive differences in trophic structure in local marine ecosystems. This study aimed to investigate the spatial variation in trophic structure of six demersal fish communities in WW (inner and outer estuary), EW (inner and outer Tolo Channel) and SW (waters in southeast and around Lamma). Stable isotopic ratios of δ13C and δ15N of all benthic fishes caught in trawl surveys during July-September and ...postprin

Acquisition of pneumococci specific effector and regulatory Cd4+ T cells localising within human upper respiratory-tract mucosal lymphoid tissue

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4(+) T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4(+) T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25(hi) T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4(+) T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines

Menopausal symptoms assessment among middle age women in Kushtia, Bangladesh

<p>Abstract</p> <p>Background</p> <p>There are few menopausal study data available in South East Asia especially in Bangladesh. This study was conducted in a well populated town named Kushtia, which is located in the western part of Bangladesh.</p> <p>Objectives</p> <p>This study was aimed to document the menopausal-related symptoms among middle age women of Kushtia region of Bangladesh.</p> <p>Methods</p> <p>By using modified MRS (Menopause Rating Scale) questionnaire, 509 women aged 40-70 years were interviewed to document symptoms commonly associated with menopause.</p> <p>Findings</p> <p>The mean age of menopause was 51.14 years. The most prevalent symptoms reported include, feeling tired (92.90%); headache (88.80%); joint and muscular discomfort (76.20%); physical and mental exhaustion (60.90%) and sleeplessness (54.40%) which are followed by depressive mood (37.30%); irritability (36%); dryness of vagina (36%); hot flushes and sweating (35.80%); anxiety (34.20%). However, noted less frequent symptoms were sexual problem (31.20%); cardiac discomfort (19.10%) and bladder problem (12.80%).</p> <p>Conclusions</p> <p>The prevalence of menopausal symptoms found in this study correspond to other studies on Asian women however the prevalence of classical menopausal symptoms of hot flushes and sweating were lower compared to studies on Caucasian women.</p

Sequence and Phylogenetic Analysis of SSU rRNA Gene of Five Microsporidia

The complete small subunit rRNA (SSU rRNA) gene sequences of five microsporidia including Nosemaheliothidis, and four novel microsporidia isolated from Pieris rapae, Phyllobrotica armta, Hemerophila atrilineata, and Bombyx mori, respectively, were obtained by PCR amplification, cloning, and sequencing. Two phylogenetic trees based on SSU rRNA sequences had been constructed by using Neighbor-Joining of Phylip software and UPGMA of MEGA4.0 software. The taxonomic status of four novel microsporidia was determined by analysis of phylogenetic relationship, length, G+C content, identity, and divergence of the SSU rRNA sequences. The results showed that the microsporidia isolated from Pieris rapae, Phyllobrotica armta, and Hemerophila atrilineata have close phylogenetic relationship with the Nosema, while another microsporidium isolated from Bombyx mori is closely related to the Endoreticulatus. So, we temporarily classify three novel species of microsporidia to genus Nosema, as Nosema sp. PR, Nosema sp. PA, Nosema sp. HA. Another is temporarily classified into genus Endoreticulatus, as Endoreticulatus sp. Zhenjiang. The result indicated as well that it is feasible and valuable to elucidate phylogenetic relationships and taxonomic status of microsporidian species by analyzing information from SSU rRNA sequences of microsporidia