Celecoxib concentration predicts decrease in prostaglandin E\u3csub\u3e2\u3c/sub\u3e concentrations in nipple aspirate fluid from high risk women

BACKGROUND: Epidemiologic studies suggest that long term low dose celecoxib use significantly lowers breast cancer risk. We previously demonstrated that 400 mg celecoxib taken twice daily for 2 weeks lowered circulating plasma and breast nipple aspirate fluid (NAF) prostaglandin (PG)E2 concentrations in post- but not premenopausal high risk women. We hypothesized that circulating concentrations of celecoxib influenced PGE2 response, and that plasma levels of the drug are influenced by menopausal status. To address these hypotheses, the aims of the study were to determine: 1) if circulating plasma concentrations of celecoxib correlated with the change in plasma or NAF PGE2 concentrations from baseline to end of treatment, and 2) whether menopausal status influenced circulating levels of celecoxib. METHODS: Matched NAF and plasma were collected from 46 high risk women who were administered celecoxib twice daily for two weeks, 20 subjects receiving 200 mg and 26 subjects 400 mg of the agent. NAF and plasma samples were collected before and 2 weeks after taking celecoxib. RESULTS: In women taking 400 mg bid celecoxib, plasma concentrations of the agent correlated inversely with the change in NAF PGE2 levels from pre- to posttreatment. Nonsignificant trends toward higher celecoxib levels were observed in post- compared to premenopausal women. There was a significant decrease in NAF but not plasma PGE2 concentrations in postmenopausal women who took 400 mg celecoxib (p = 0.03). CONCLUSION: In high risk women taking 400 mg celecoxib twice daily, plasma concentrations of celecoxib correlated with downregulation of PGE2 production by breast tissue. Strategies synergistic with celecoxib to downregulate PGE2 are of interest, in order to minimize the celecoxib dose required to have an effect

Crystallization of Adenylylsulfate Reductase from Desulfovibrio gigas: A Strategy Based on Controlled Protein Oligomerization

Adenylylsulfate reductase (adenosine 5′-phosphosulfate reductase, APS reductase or APSR, E.C.1.8.99.2) catalyzes the conversion of APS to sulfite in dissimilatory sulfate reduction. APSR was isolated and purified directly from massive anaerobically grown Desulfovibrio gigas, a strict anaerobe, for structure and function investigation. Oligomerization of APSR to form dimers–α_2β_2, tetramers–α_4β_4, hexamers–α_6β_6, and larger oligomers was observed during purification of the protein. Dynamic light scattering and ultracentrifugation revealed that the addition of adenosine monophosphate (AMP) or adenosine 5′-phosphosulfate (APS) disrupts the oligomerization, indicating that AMP or APS binding to the APSR dissociates the inactive hexamers into functional dimers. Treatment of APSR with β-mercaptoethanol decreased the enzyme size from a hexamer to a dimer, probably by disrupting the disulfide Cys156—Cys162 toward the C-terminus of the β-subunit. Alignment of the APSR sequences from D. gigas and A. fulgidus revealed the largest differences in this region of the β-subunit, with the D. gigas APSR containing 16 additional amino acids with the Cys156—Cys162 disulfide. Studies in a pH gradient showed that the diameter of the APSR decreased progressively with acidic pH. To crystallize the APSR for structure determination, we optimized conditions to generate a homogeneous and stable form of APSR by combining dynamic light scattering, ultracentrifugation, and electron paramagnetic resonance methods to analyze the various oligomeric states of the enzyme in varied environments

EvIcon: Designing High-Usability Icon with Human-in-the-loop Exploration and IconCLIP

Interface icons are prevalent in various digital applications. Due to limited time and budgets, many designers rely on informal evaluation, which often results in poor usability icons. In this paper, we propose a unique human-in-the-loop framework that allows our target users, i.e., novice and professional UI designers, to improve the usability of interface icons efficiently. We formulate several usability criteria into a perceptual usability function and enable users to iteratively revise an icon set with an interactive design tool, EvIcon. We take a large-scale pre-trained joint image-text embedding (CLIP) and fine-tune it to embed icon visuals with icon tags in the same embedding space (IconCLIP). During the revision process, our design tool provides two types of instant perceptual usability feedback. First, we provide perceptual usability feedback modeled by deep learning models trained on IconCLIP embeddings and crowdsourced perceptual ratings. Second, we use the embedding space of IconCLIP to assist users in improving icons' visual distinguishability among icons within the user-prepared icon set. To provide the perceptual prediction, we compiled IconCEPT10K, the first large-scale dataset of perceptual usability ratings over $10,000$ interface icons, by conducting a crowdsourcing study. We demonstrated that our framework could benefit UI designers' interface icon revision process with a wide range of professional experience. Moreover, the interface icons designed using our framework achieved better semantic distance and familiarity, verified by an additional online user study

Composite type A thymoma and diffuse large B-cell lymphoma

AbstractThe concurrent occurrence of thymoma and diffuse large B-cell lymphoma in the thymus has not been previously reported. We describe a 74-year-old man who presented with general weakness, neck lymphadenopathy, night sweats, and body weight loss. A right anterior mediastinal mass was found on computed tomography of the chest. The immunohistochemical stains AE1/AE3, CD20, CD3, and MUM-1 confirmed the different components of the mediastinal tumor. A heavy-chain gene clonality assay and light-chain gene clonality assay confirmed the B-cell clonality of the mediastinal tumor and neck lymph node. The patient had received a complete course of chemotherapy, and the result of positron emission tomography–computed tomography showed complete remission. The pathologic report of this mass revealed composite type A thymoma and diffuse large B-cell lymphoma. If concurrent or composite thymoma and lymphoma are suspected, a thorough examination of the thymoma with a combination of ancillary studies is recommended to rule out the possibility of concurrent lymphoma

Long-Term Prediction of Emergency Department Revenue and Visitor Volume Using Autoregressive Integrated Moving Average Model

This study analyzed meteorological, clinical and economic factors in terms of their effects on monthly ED revenue and visitor volume. Monthly data from January 1, 2005 to September 30, 2009 were analyzed. Spearman correlation and cross-correlation analyses were performed to identify the correlation between each independent variable, ED revenue, and visitor volume. Autoregressive integrated moving average (ARIMA) model was used to quantify the relationship between each independent variable, ED revenue, and visitor volume. The accuracies were evaluated by comparing model forecasts to actual values with mean absolute percentage of error. Sensitivity of prediction errors to model training time was also evaluated. The ARIMA models indicated that mean maximum temperature, relative humidity, rainfall, non-trauma, and trauma visits may correlate positively with ED revenue, but mean minimum temperature may correlate negatively with ED revenue. Moreover, mean minimum temperature and stock market index fluctuation may correlate positively with trauma visitor volume. Mean maximum temperature, relative humidity and stock market index fluctuation may correlate positively with non-trauma visitor volume. Mean maximum temperature and relative humidity may correlate positively with pediatric visitor volume, but mean minimum temperature may correlate negatively with pediatric visitor volume. The model also performed well in forecasting revenue and visitor volume

Paternal age and 13 psychiatric disorders in the offspring: a population-based cohort study of 7 million children in Taiwan.

Although paternal age has been linked to certain psychiatric disorders, the nature of any causal relationship remains elusive. Here, we aimed to comprehensively assess the magnitude of a wide range of offsprings psychiatric risk conferred by paternal age, leveraging a pedigree inferred from covered-insurance relationship (accuracy >98%) in Taiwans single-payer compulsory insurance program. We also examined whether there is an independent role of paternal age and explored the potential effect of parental age difference. A total cohort of 7,264,788 individuals born between 1980 and 2018 were included; 5,572,232 with sibling(s) were selected for sibling-comparison analyses and 1,368,942 and 1,044,420 children with information of paternal-grandparents and maternal-grandparents, respectively, were selected for multi-generation analyses. Using inpatient/outpatient claims data (1997-2018), we identified schizophrenia, autism, bipolar disorder (BPD), attention deficit-hyperactivity disorder (ADHD), major depressive disorder (MDD), eating disorder (ED), substance use disorder (SUD), mental retardation (MR), tic disorder, obsessive-compulsive disorder (OCD), anxiety, and somatoform disorder. We identified suicides using death certificates. Logistic regression analysis was used to estimate the paternal/maternal/grand-paternal age association with psychiatric risk in the offspring. The total cohort and sibling-comparison cohort resulted in similar estimates. Paternal age had a U-shaped relationship with offsprings MDD, ED, SUD, and anxiety. A very young maternal age (<20 years) was associated with markedly higher risk in offsprings SUD, MR, and suicide. Older paternal age (>25 years) was linearly associated with offsprings schizophrenia, autism, BPD, ADHD, MDD, ED, SUD, MR, OCD, anxiety, and suicide. Older grand-paternal age was linearly associated with offsprings schizophrenia, autism, ADHD, and MR. Dissimilar parental age was positively associated with offsprings ADHD, MDD, SUD, MR, anxiety, and suicide, and negatively associated with offsprings OCD. This comprehensive assessment provides solid evidence for the independent role of paternal age in psychiatric risk in the offspring and clarifies the significance of both early parenthood and delayed paternity