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Objective The UPrEPU mobile app is a self-monitoring system to enable men who have sex with men to optimize their pre-exposure prophylaxis adherence for HIV prevention. The app was designed to accommodate a rather complicated event-driven dosing schedule. We aim to evaluate the usability of the UPrEPU app and its effectiveness in improving adherence monitoring. Methods From May to October 2020, 35 participants were enrolled for the usability study and followed up for 4 months. Blood samples for the drug concentration in the dried blood spots were obtained once during the second to fourth follow-up visits. The effectiveness of adherence monitoring was analyzed using Cohen's kappa statistic to calculate the concordance between the average number of pills taken and drug concentration in the dried blood spots. Results Overall retention was 91.4% (32 participants) at the end of the study. Participants used the app for a mean of 29 days and made 2565 data entries in total, with an average of 76 data entries. The average systematic usability scale score for the app was 71.5, indicating acceptable usability. Slight agreement was reached between the dried blood spots measurement and the number of pills taken and recorded in the app (weighted kappa: 0.21). Conclusions Our user-centered UPrEPU app demonstrated that it could accommodate both daily and event-driven dosing schedules for men who have sex with men clients with acceptable usability scores. We confirmed that complex behaviors such as different drug-dosing regimens that are contingent on sexual behaviors could be incorporated into the design of a mobile app.

BACKGROUND New innovative technologies, such as mobile apps, have been developed to increase pre-exposure prophylaxis (PrEP) adherence and the use of log sex diaries. The contiguity of mobile apps reduces the recall bias that generally affects reported condom and PrEP use. However, none of the currently used mobile apps were designed for event-driven PrEP users, and few studies have demonstrated the potential usage of sex diary data to facilitate the understanding of the different HIV risks among heterogeneous profiles of sex diaries and PrEP use. OBJECTIVE We aim to discriminate the heterogeneous profiles of sex events and PrEP use and examine the risk of condomless anal sex among different types of sex events. METHODS We recruited 35 adult men who have sex with men from two medical centers in Taiwan since May 2020 and followed up for four months. Participants were on PrEP or willing to take PrEP. They were asked to log their sex events, PrEP use, and dosing regimens on a mobile app to improve their PrEP adherence. Latent class analysis was used to distinguish profiles of sex events and PrEP use. Indicators included correct intake of PrEP for each sex event, participants’ sexual positioning, partner’s HIV status, and age. RESULTS A total of 551 sex events were classified into three classes by latent class analysis: PrEP nonadherent flip-flopping (234/551, 42%), PrEP imperfect-adherent power bottoming (284/551, 52%), and PrEP adherent serodiscordant topping (33/551, 6%). “PrEP nonadherent flip-flopping” sex events were more likely to involve condomless anal sex than “PrEP imperfect-adherent power bottoming” (OR 1.83, 95% CI 1.03-3.25) after considering random intercepts for individuals, and this class needed to increase their PrEP adherence and use of condoms. “PrEP imperfect-adherent power bottoming” realized their own risk and packaged PrEP with condoms to protect themselves. Up to 99% (32/33) of sex events in “PrEP adherent serodiscordant topping” were protected by PrEP, but all of the sex events in this group were condomless. CONCLUSIONS Using the sex diary data could advance the capacity to identify high-risk groups. HIV prevention strategy should be more flexible and combine PrEP with condom use for future HIV prevention.

Our study's main purpose is to emphasise the significance of medical knowledge of pathophysiology before machine learning. We investigated whether combining domain knowledge with machine learning results might increase accuracy and minimise the number of bio-features used to detect obstructive sleep apnea (OSA). The present study analysed data on 36 self-reported symptoms and 24 clinical features obtained from 3,495 patients receiving polysomnography at a regional hospital and a medical centre. The area under the receiver operating characteristic (AUC) curve was used to evaluate patients with and without moderate or severe OSA using three prediction models on the basis of various estimation methods: the multiple logistic regression (MLR), support vector machine (SVM), and neural network (NN) methods. Odds ratios stratified by gender and age were also measured to account for clinicians' common sense. We discovered that adding the self-reported snoring item improved the AUC by 0.01-0.10 and helped us to rapidly achieve the optimum level. The performance of four items (gender, age, body mass index [BMI], and snoring) was comparable with that of adding two or more items (neck and waist circumference) for predicting moderate to severe OSA (Apnea-Hypopnea Index ≥15 events/hr) in all three prediction models, demonstrating the medical knowledge value of pathophysiology. The four-item test sample AUCs were 0.83, 0.84, and 0.83 for MLR, SVM, and NN, respectively. Participants with regular snoring and a BMI of ≥25 kg/m2 had a greater chance of moderate to severe OSA according to the stratified adjusted odds ratios. Combining domain knowledge into machine learning could increase efficiency and enable primary care physicians to refer for an OSA diagnosis earlier.

Posttranscriptional modifications in RNA have been considered to contribute to disease pathogenesis and tumor progression. NOL1/NOP2/Sun domain family member 2 (NSUN2) is an RNA methyltransferase that promotes tumor progression in several cancers. Pancreatic cancer relapse inevitably occurs even in cases where primary tumors have been successfully treated. Associations of cancer progression due to reprogramming of the cancer methyl-metabolome and the cancer genome have been noted, but the effect of base modifications, namely 5-methylcytosine (m

Background: The dense fibrotic stroma enveloping pancreatic tumors is a major cause of drug resistance. Pancreatic stellate cells (PSCs) in the stroma can be activated to induce intra-tumor fibrosis and worsen patient survival; however, the molecular basics for the regulation of PSC activation remains unclear. Methods: The in vitro coculture system was used to study cancer cell-PSC interactions. Atomic force microscopy was used to measure the stiffness of tumor tissues and coculture gels. Cytokine arrays, qPCR, and Western blotting were performed to identify the potential factors involved in PSC activation and to elucidate underlying pathways. Results: PSC activation characterized by α-SMA expression was associated with increased pancreatic tumor stiffness and poor prognosis. Coculture with cancer cells induced PSC activation, which increased organotypic coculture gel stiffness and cancer cell invasion. Cancer cells-derived PAI-1 identified from coculture medium could activate PSCs, consistent with pancreatic cancer tissue microarray analysis showing a strong positive correlation between PAI-1 and α-SMA expression. Suppression by knocking down PAI-1 in cancer cells demonstrated the requirement of PAI-1 for coculture-induced PSC activation and gel stiffness. PAI-1 could be upregulated by KRAS in pancreatic cancer cells through ERK. In PSCs, inhibition of LRP-1, ERK, and c-JUN neutralized the effect of PAI-1, suggesting the contribution of LRP-1/ERK/c-JUN signaling. Furthermore, activated PSCs might exacerbate malignant behavior of cancer cells via IL-8 because suppression of IL-8 signaling reduced pancreatic tumor growth and fibrosis in vivo. Conclusions: KRAS-mutant pancreatic cancer cells can activate PSCs through PAI-1/LRP-1 signaling to promote fibrosis and cancer progression.

Background Daily and on-demand pre-exposure prophylaxis (PrEP) has been well demonstrated to effectively prevent HIV acquisition for men who have sex with men (MSM). More than half of the MSM PrEP users in Taiwan prefer on-demand PrEP; however, on-demand PrEP involves a complicated dosing regimen because it requires precoital and postcoital dosing and sex events are hard to anticipate. Although there are a growing number of mobile apps designed to improve access to HIV prevention services and HIV medication adherence, few mobile apps focus on adherence to PrEP or are designed to accommodate a complicated, on-demand PrEP dosing schedule. Objective The aim of this project is to evaluate the usability of a newly developed mobile app (UPrEPU) to assist MSM PrEP users to self-monitor their adherence to either daily or on-demand PrEP using a user-centered scheme. Methods This research will be conducted in 2 phases: app development and usability study. In the app development phase, we will first conduct formative research with end users and stakeholders through in-depth interviews; the results will provide PrEP users’ and PrEP navigators’ personas as material used in the app conceptualization stage. PrEP navigators are individuals in the health care system that help HIV-negative individuals who need assistance in accessing PrEP care. A low-fidelity prototype of the app feature will be formatted by applying a participatory design approach to engage PrEP users, designers, and app developers in the design process of the app. Then, a high-fidelity prototype of the app will be developed for the usability study and refined iteratively by the multidisciplinary team and new internal testers. Internal testers include the research team consisting of experts in public health, infectious disease, and industrial design and a close network of the research team that is taking PrEP. In the usability study phase, we will enroll 70 MSM PrEP users and follow them up for 4 months. Usability, feasibility, and effectiveness of adherence monitoring will be evaluated. Results Refinement of the UPrEPU app is currently ongoing. The usability study commenced in May 2020. Conclusions The UPrEPU app is one of the first apps designed to help MSM PrEP users to self-manage their PrEP schedule better regardless of dosing modes. With a design-thinking approach and adapting to the cultural context in Taiwan’s MSM population, this novel app will have substantial potential to be acceptable and feasible and contribute to the reduction of new HIV infections. Trial Registration ClinicalTrials.gov NCT04248790; https://clinicaltrials.gov/ct2/show/NCT04248790 International Registered Report Identifier (IRRID) PRR1-10.2196/20360

Statistical modeling with sparsity has become an active research topic in the fields of statistics and machine learning. Because the true sparsity pattern of a model is generally unknown aforehand, it is often explored by a sparse estimation procedure, like least absolute shrinkage and selection operator (lasso). In this study, a penalized least squares (PLS) method for structural equation modeling (SEM) with ordinal data is developed. PLS describes data generation by an underlying response approach, and uses a least squares (LS) fitting function to construct a penalized estimation criterion. A numerical simulation was used to compare PLS with existing penalized likelihood (PL) in terms of averaged mean square error, absolute bias, and the correctness of the model. Based on these empirical findings, a hybrid PLS was also proposed to improve both PL and PLS. The hybrid PLS first chooses an optimal sparsity pattern by PL, then estimates model parameters by an unpenalized LS under the model selected by PL. We also extended PLS to cases of mixed type data and multi-group analysis. All proposed methods could be realized in the R package lslx.

Background Cancer subtype switching, which involves unclear cancer cell origin, cell fate decision, and transdifferentiation of cells within a confined tumor microenvironment, remains a major problem in pancreatic cancer (PDA). Results By analyzing PDA subtypes in The Cancer Genome Atlas, we identified that epigenetic silencing of apoptosis-associated tyrosine kinase (AATK) inversely was correlated with mRNA expression and was enriched in the quasi-mesenchymal cancer subtype. By comparing early mouse pancreatic lesions, the non-invasive regions showed AATK co-expression in cells with acinar-to-ductal metaplasia, nuclear VAV1 localization, and cell cycle suppression; but the invasive lesions conversely revealed diminished AATK expression in those with poorly differentiated histology, cytosolic VAV1 localization, and co-expression of p63 and HNF1α. Transiently activated AATK initiates acinar differentiation into a ductal cell fate to establish apical-basal polarization in acinar-to-ductal metaplasia. Silenced AATK and ectopically expressed p63 and HNF1α allow the proliferation of ductal PanINs in mice. Conclusion Epigenetic silencing of AATK regulates the cellular transdifferentiation, proliferation, and cell cycle progression in converting PDA-subtypes.

BACKGROUND Daily and on-demand pre-exposure prophylaxis (PrEP) has been well demonstrated to effectively prevent HIV acquisition for men who have sex with men (MSM). More than half of the MSM PrEP users in Taiwan prefer on-demand PrEP; however, on-demand PrEP involves a complicated dosing regimen because it requires precoital and postcoital dosing and sex events are hard to anticipate. Although there are a growing number of mobile apps designed to improve access to HIV prevention services and HIV medication adherence, few mobile apps focus on adherence to PrEP or are designed to accommodate a complicated, on-demand PrEP dosing schedule. OBJECTIVE The aim of this project is to evaluate the usability of a newly developed mobile app (UPrEPU) to assist MSM PrEP users to self-monitor their adherence to either daily or on-demand PrEP using a user-centered scheme. METHODS This research will be conducted in 2 phases: app development and usability study. In the app development phase, we will first conduct formative research with end users and stakeholders through in-depth interviews; the results will provide PrEP users’ and PrEP navigators’ personas as material used in the app conceptualization stage. PrEP navigators are individuals in the health care system that help HIV-negative individuals who need assistance in accessing PrEP care. A low-fidelity prototype of the app feature will be formatted by applying a participatory design approach to engage PrEP users, designers, and app developers in the design process of the app. Then, a high-fidelity prototype of the app will be developed for the usability study and refined iteratively by the multidisciplinary team and new internal testers. Internal testers include the research team consisting of experts in public health, infectious disease, and industrial design and a close network of the research team that is taking PrEP. In the usability study phase, we will enroll 70 MSM PrEP users and follow them up for 4 months. Usability, feasibility, and effectiveness of adherence monitoring will be evaluated. RESULTS Refinement of the UPrEPU app is currently ongoing. The usability study commenced in May 2020. CONCLUSIONS The UPrEPU app is one of the first apps designed to help MSM PrEP users to self-manage their PrEP schedule better regardless of dosing modes. With a design-thinking approach and adapting to the cultural context in Taiwan’s MSM population, this novel app will have substantial potential to be acceptable and feasible and contribute to the reduction of new HIV infections. CLINICALTRIAL ClinicalTrials.gov NCT04248790; https://clinicaltrials.gov/ct2/show/NCT04248790 INTERNATIONAL REGISTERED REPORT PRR1-10.2196/20360

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In the past two decades, statistical modelling with sparsity has become an active research topic in the fields of statistics and machine learning. Recently, Huang, Chen and Weng (2017, Psychometrika, 82, 329) and Jacobucci, Grimm, and McArdle (2016, Structural Equation Modeling: A Multidisciplinary Journal, 23, 555) both proposed sparse estimation methods for structural equation modelling (SEM). These methods, however, are restricted to performing single-group analysis. The aim of the present work is to establish a penalized likelihood (PL) method for multi-group SEM. Our proposed method decomposes each group model parameter into a common reference component and a group-specific increment component. By penalizing the increment components, the heterogeneity of parameter values across the population can be explored since the null group-specific effects are expected to diminish. We developed an expectation-conditional maximization algorithm to optimize the PL criteria. A numerical experiment and a real data example are presented to demonstrate the potential utility of the proposed method.

The clear importance of mutated KRAS as a therapeutic target has driven the investigation of multiple approaches to inhibit oncogenic KRAS signaling at different molecular levels. However, no KRAS-targeted therapy has reached the clinic to date, which underlies the intrinsic difficulty in developing effective, direct inhibitors of KRAS. Thus, this article provides an overview of the history and recent progress in the development of pharmacological strategies to target oncogenic KRAS with small molecule agents. Mechanistically, these KRAS-targeted agents can be classified into the following four categories. (1) Small-molecule RAS-binding ligands that prevent RAS activation by binding within or outside the nucleotide-binding motif. (2) Inhibitors of KRAS membrane anchorage. (3) Inhibitors that bind to RAS-binding domains of RAS-effector proteins. (4) Inhibitors of KRAS expression. The advantage and limitation of each type of these anti-KRAS agents are discussed.

Most statistical inference methods were established under the assumption that the fitted model is known in advance. In practice, however, researchers often obtain their final model by some data-driven selection process. The selection process makes the finally fitted model random, and it also influences the sampling distribution of the estimator. Therefore, implementing naive inference methods may result in wrong conclusions-which is probably a prime source of the reproducibility crisis in psychological science. The present study accommodates three valid state-of-the-art postselection inference methods for structural equation modeling (SEM) from the statistical literature: data splitting (DS), postselection inference (PoSI), and the polyhedral (PH) method. A simulation is conducted to compare the three methods with the commonly used naive procedure under selection events made by L1-penalized SEM. The results show that the naive method often yields incorrect inference, and that the valid methods control the coverage rate in most cases with their own pros and cons. Real world data examples show the practical use of the valid inference methods.

The highly homeostasis-resistant nature of cancer cells leads to their escape from treatment and to liver metastasis, which in turn makes pancreatic ductal adenocarcinoma (PDAC) difficult to treat, especially the squamous/epithelial-to-mesenchymal transition (EMT)-like subtype. As the molecular mechanisms underlying tumour heterogeneity remain elusive, we investigated whether epigenetic regulation might explain inter-individual differences in the progression of specific subtypes. DNA methylation profiling performed on cancer tissues prior to chemo/radiotherapy identified one hypermethylated CpG site (CpG6882469) in the VAV1 gene body that was correlated with demethylation of two promoter CpGs (CpG6772370/CpG6772811) in both PDAC and peripheral blood. Transforming growth factor β treatment induced gene-body hypermethylation, dissociation of DNMT1 from the promoter, and VAV1 expression via SMAD4 and mutant KrasG12D. Pharmacological inhibition of TGFβ-VAV1 signalling decreased the squamous/EMT-like cancer cells, promoted nuclear VAV1 localization, and enhanced the efficacy of gemcitabine in prolonging the survival of KPfl/flC mice. Together, the three VAV1 CpGs serve as biomarkers for prognosis and early detection, and the TGFβ-VAV1 axis represents a therapeutic target.

A novel centralized microwave jet burner system is proposed here that can be used as a test platform to enable studies of plasma-assisted combustion (PAC) under various operation conditions and combustible mixtures. Spectroscopic characterizations of this burner are conducted using optical emission spectrum with methane/O2/N2 and methane/O2/Ar mixtures for comparison to distinguish the effects of the bath gas on flame enhancement and to delineate the flame enhancement mechanism of microwave induced plasma. The results show that the flame enhancement, by applying a nonequilibrium plasma, is more efficient when the dilution inert N2 in the air is replaced by Ar. The bath gas in the oxidizer stream plays an important role in the flame enhancement mechanism for the PAC system through more efficient direct impact of excited electrons on oxygen in the plasma and resulting in earlier initiation of the chain reactions through branched OH formation reactions in the flame.

The concept of green building integrates a variety of strategies during the design, construction and operation of building projects. The use of green building materials represents one very crucial strategy during the design and construction of a building. Recycling green building materials refer to those building materials reproduced from other materials, namely, reclaim the waste or discarded materials to produce the building materials. In Taiwan, gypsum boards are widely used in the building industry as facing materials for walls and ceilings due to their very good mechanical and thermal properties, as well as fire endurance. The goal of this study is to develop a new recycling green building material which could reuse the daily waste materials, color changeable and give inspiration to improve the characters of green building materials . In this study, six waste materials in our daily lives were mixed with the allochroic powder and gypsum powder to create thermochromic face bricks. The experiment modules were Groups A, B, C, and D, and mixed with allochroic powders of different specifications. The findings showed that Group C had the most significant RGB variation. In terms of the G value of Group C, the variations of the six materials were wood chips 81.9%>, newspaper 78%>, concrete 75.6%>, fallen leaves 66.6%>, iron powder 59.2%>, and silt 50.9%. In conclusion, allochroic faced bricks can be applied to both interior and exterior walls of different types of buildings in the future, thus, the buildings have different colors at different temperatures and times, cater to the changeful effects of future architectural appearances. Regarding the landscape, building and interior designers can construct artistic creations of shell collages.

Background In this computer simulation study, the authors investigated the frequency distribution of labial bone perforation (LBP) between various sagittal root position (SRP) classes with respect to the anterior maxillary osseous housing and evaluated the associated factors correlated with a higher risk of LBP when performing a virtual immediate implant surgery in the esthetic zone. Methods The authors analyzed cone-beam computed tomography (CBCT) images from 285 qualified study participants (1,449 teeth) to determine the probability of LBP when associated with selected variables, such as tooth type, SRP class, and morphologic parameters. The authors examined associated factors and analyzed the adjusted odds ratios by means of multiple logistic regression analysis. Results The overall probability of LBP was 81.7%, which presented statistically significant differences between each specific tooth type and SRP class (all P Conclusions When a clinician performs an immediate implant in the anterior esthetic zone, he or she should be aware that the specific tooth type, SRP class, and morphologic features of fossa concavities are associated with a risk of experiencing LBP. Practical Implications Presurgical cross-sectional images can be analyzed to identify anatomic features relative to LBP in the maxillary esthetic region, and this can avoid unpleasant complications, specifically when performing immediate implant procedures.

Background This study sought to determine which factors are correlated to a higher risk of lingual plate perforation (LPP) when placing a virtual implant in the area of the anticipated extraction site of the posterior mandible. Methods Computed tomographic images of 300 patients (1,279 teeth) were analyzed in regard to the shape of the mandible (convergent, parallel, or undercut type), dimensional parameters of lingual concavity (angle, height, depth) and its relation to the inferior alveolar canal (zones A, B, C), distance from root apex to inferior alveolar canal, and probability of LPP. The odds ratio of variables was determined by multiple logistic regression modeling. Results The overall probability of LPPs on virtual implant placement was 3.1%. This perforation was most commonly observed at the second molar and with a U-type ridge. After adjusting cofounders, a concave point located in zone A is 17.34 times more likely to have a LPP than one in zone C. The probability of LPPs was reduced by 34% for every 1-millimeter increase in distance from root apex to inferior alveolar canal on virtual implant placement of posterior mandible region. Conclusions Three-dimensional cone-beam computed tomographic imaging is essential for planning immediate implant placement in the anticipated extraction sites of the posterior mandible region as proved by anatomic findings that can only be understood from preoperative imaging analysis. Practical Implications Presurgical cross-sectional images can be analyzed to identify anatomic features relative to the lingual concavities in the posterior mandible region, which can help to avoid unpleasant complications, specifically when performing immediate implant procedures.

Environmental issues have become a topical subject in recent years. Numerous recycling resources can be found in our living environment, such as fallen leaves, wood chips, recovered iron powder, waste newspaper, waste concrete, reservoir silt, etc., which are utilizable waste materials. Related regulations stipulate that the waste blending ratio of recycling green building materials should be higher than 50%. In this study, three waste materials, including wood chips, concrete, and waste newspaper, were mixed with gypsum and dissolved in thermochromic material, which is made into bricks. The thermal radiation of sunlight can be absorbed by the bricks to change the hue. The experimental modules were divided into ABCD groups, which were mixed with allochroic powder of different specifications. The RGB values of bricks at different temperatures and hours were measured by a color analyzer. The results showed that the rate of change in the RGB values of the ABCD groups is higher than 10.9% when the day–night temperature difference exceeds 5 °C. These allochroic bricks can be applied to the external walls of buildings, providing landscape, building, and interior designers with another media for artistic creation.

The proposed resistance-locked loop (RLL) can achieve high PSRR of $-$ 16 dB digital low dropout (DLDO) regulator without consuming much power which is the drawback in prior arts. Even at light loads, the RLL can be shut down for power saving. Furthermore, the duty compensator ensures DLDO stability under different duty ratio of supply voltage. The operation voltage of proposed DLDO can be down to 0.6 V and the peak current efficiency is 99.99%. The test chip was fabricated in 40 nm CMOS process with all the transistors implemented by core device for small silicon area.

Model comparison is one useful approach in applications of structural equation modeling. Akaike’s information criterion (AIC) and the Bayesian information criterion (BIC) are commonly used for selecting an optimal model from the alternatives. We conducted a comprehensive evaluation of various model selection criteria, including AIC, BIC, and their extensions, in selecting an optimal path model under a wide range of conditions over different compositions of candidate set, distinct values of misspecified parameters, and diverse sample sizes. The chance of selecting an optimal model rose as the values of misspecified parameters and sample sizes increased. The relative performance of AIC and BIC type criteria depended on the magnitudes of the parameter misspecified. The BIC family in general outperformed AIC counterparts unless under small values of omitted parameters and sample sizes, where AIC performed better. Scaled unit information prior BIC (SPBIC) and Haughton's BIC (HBIC) demonstrated the highest accuracy ratios across most of the conditions investigated in this simulation.

To investigate the prevalence and morphological parameters of lingual concavity, and whether these factors are related to a higher risk of inferior alveolar nerve (IAN) injury when performing an immediate implant surgery in posterior mandible region.The CBCT images from 237 subjects (1008 teeth) were analysed the shape of the mandibles (C, P, U type), dimensional parameters of lingual concavity (angle, height, depth), and its relation to inferior alveolar canal (IAC) (A, B, C zone), RAC (distance from root apex to IAC) and probability of IAN injury. Multiple logistic regression modelling to determine the odds ratio of variables that made an important contribution to the probability of IAN injury and to adjust for confounding variables.The U type ridge (46.7%) and the most concave point located at C zone (48.8%) are most prevalent in this region. The mandibular second molar presents highest risk for IAN injury than other tooth type (p0.001), which were 3.82 times to occur IAN injury than the mandibular second premolar. The concave point located at A zone and B zone were 7.82 and 3.52 times than C zone to have IAN damage, respectively. The probability of IAN injury will reduce 26% for every 1mm increase in RAC (p0.001).The tooth type, morphological features of lingual concavities, and RAC are associated with risks of IAN injury during immediate implant placement.Pre-surgical mapping of the IAC and identification of its proximity relative to the lingual concavity in the posterior mandible regions may avoid unpleasant complications, specifically when performing immediate implant procedures.

the charge recycling match (CRM) technique is proposed to reduce dynamic power dissipation in display column drivers. The CRM technique can save much power in some polarity operation, which is hard to have charge recycling in conventional techniques. Theoretical analysis and experimental result show maximum dynamic power reduction of 12% and 30% in column inversion panel with R/G/B stripe pixel arrangement and Zigzag panel, respectively. The proposed method is suitable for voltage mode driving scheme and capacitive loading display column driver special in thin-film-transistor (TFT) liquid crystal displays (LCDs) and active mode organic light-emission-diode (AMOLED) display. A complete method application including circuit structure, algorithm and hardware implement are demonstrated in TFT-LCD application.

SummaryEarly-onset prostate cancer (EO-PCA) represents the earliest clinical manifestation of prostate cancer. To compare the genomic alteration landscapes of EO-PCA with “classical” (elderly-onset) PCA, we performed deep sequencing-based genomics analyses in 11 tumors diagnosed at young age, and pursued comparative assessments with seven elderly-onset PCA genomes. Remarkable age-related differences in structural rearrangement (SR) formation became evident, suggesting distinct disease pathomechanisms. Whereas EO-PCAs harbored a prevalence of balanced SRs, with a specific abundance of androgen-regulated ETS gene fusions including TMPRSS2:ERG, elderly-onset PCAs displayed primarily non-androgen-associated SRs. Data from a validation cohort of > 10,000 patients showed age-dependent androgen receptor levels and a prevalence of SRs affecting androgen-regulated genes, further substantiating the activity of a characteristic “androgen-type” pathomechanism in EO-PCA.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. This study was aimed at evaluating the efficacy of AR-42 (formerly OSU-HDAC42), a novel histone deacetylase (HDAC) inhibitor currently in clinical trials, in suppressing tumor growth and/or cancer-induced muscle wasting in murine models of PDAC. EXPERIMENTAL DESIGN: The in vitro antiproliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines (AsPC-1, COLO-357, PANC-1, MiaPaCa-2, BxPC-3, SW1990). AsPC-1 subcutaneous xenograft and transgenic KP fl/fl C (LSL-Kras G12D ;Trp53 flox/flox ;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting. RESULTS: Growth suppression in AR-42–treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers, which was associated with the hallmark features of HDAC inhibition, including p21 upregulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in the AsPC-1 xenograft and KP fl/fl C models by 78% and 55%, respectively, at the end of treatment. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. Additionally, AR-42 as a single agent preserved muscle size and increased grip strength in KP fl/fl C mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone. CONCLUSIONS: These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer.

A procedure for estimating the reliability of test scores in the context of ecological momentary assessment (EMA) was proposed to take into account the characteristics of EMA measures. Two commonly used test scores in EMA were considered: the aggregated score (AGGS) and the within-person centered score (WPCS). Conceptually, AGGS and WPCS represent the interindividual differences and the intraindividual differences, respectively. The reliability coefficients for AGGS and WPCS were derived using a multilevel factor model with a serial correlation structure framework. Point estimates and confidence intervals of these coefficients were obtained using Mx ( Neale, Boker, Xie, & Maes, 2004 ). A simulation study showed that the proposed procedure performed well empirically. Diary data from Huang (2009) , which recorded daily joy level of 110 undergraduate students for 8 days, was used to illustrate the applicability of the proposed method.

LCD panel with the LED backlight can be controlled by the proposed linear regulation control (LRC) technique for high efficiency and low cost. The LRC technique removes most of the external passive components, which include inductor, E-cap, freewheel diode, and blocking diode. Due to single-stage operation without two-stage power consumption, small volume and high efficiency can be simultaneously ensured. Furthermore, the PLL function can guarantee the line voltage and current to be in phase so as to realize the high power factor (PF) for green power. High efficiency of 85% at 110Vrms and 87% at 220Vrms, high PF of 0.98 at 110Vrms and 0.96 at 220Vrms, and low THD of 18% at 110Vrms and 19% at 220Vrms are achieved.

A series of 1-arylsulfonyl-5-(N-hydroxyacrylamide)indoles has been identified as a new class of histone deacetylase inhibitors. Compounds 8, 11, 12, 13, and 14 demonstrated stronger antiproliferative activities than 1 (SAHA) with GI(50) values ranging from 0.36 to 1.21 μM against Hep3B, MDA-MB-231, PC-3, and A549 human cancer cell lines. Lead compound 8 showed remarkable HDAC 1, 2, and 6 isoenzymes inhibitory activities with IC(50) values of 12.3, 4.0, 1.0 nM, respectively, which are comparable to 1. In in vivo efficacy evaluation against lung A549 xenograft model, 8 displayed better antitumor activity than compound 1.

Details of the evolution of strategies toward convergent assembly of the histone deacetylase inhibiting natural product largazole exploiting γ,δ-unsaturated-α,β-epoxy-aldehydes and a thiazole-thiazoline containing ω-amino-acid are described. The initial N-heterocyclic carbene mediated redox amidation exploying these two types of building blocks representing largazole's structural domains of distinct biosynthetic origin directly afforded the seco-acid of largazole. This was accomplished without any protecting groups resident upon either thioester bearing epoxy-aldehyde or the tetrapeptide. However, the ineffective production of largazole via the final macrolactonization led to an alternative intramolecular esterification/macrolactamization strategy employing the established two building blocks. This provided largazole along with its C2-epimer via an unexpected inversion of the α-stereocenter at the valine residue. The biological evaluation demonstrated that both largazole and 2-epi-largazole led to dose-dependent increases of acetylation of histone H3, indicating their potencies as class I histone deacetylase selective inhibitiors. Enhanced p21 expression was also induced by largazole and its C2 epimer. In addition, 2-epi-largazole displayed more potent activity than largazole in cell viability assays against PC-3 and LNCaP prostate cancer cell lines.

This study investigates the mechanism by which histone deacetylase (HDAC) inhibitors up-regulate histone H3 lysine 4 (H3K4) methylation. Exposure of LNCaP prostate cancer cells and the prostate tissue of transgenic adenocarcinoma of the mouse prostate mice to the pan- and class I HDAC inhibitors (S)-(+)-N-hydroxy-4-(3-methyl-2-phenyl-butyrylamino)-benzamide (AR42), N-(2-aminophenyl)-4-[N-(pyridine-3-yl-methoxycarbonyl)-aminomethyl]-benzamide (MS-275), and vorinostat led to differential increases in H3K4 methylation. Chromatin immunoprecipitation shows that this accumulation of methylated H3K4 occurred in conjunction with decreases in the amount of the H3K4 demethylase RBP2 at the promoter of genes associated with tumor suppression and differentiation, including KLF4 and E-cadherin. This finding, together with the HDAC inhibitor-induced up-regulation of KLF4 and E-cadherin, suggests that HDAC inhibitors could activate the expression of these genes through changes in histone methylation status. Evidence indicates that this up-regulation of H3K4 methylation was attributable to the suppressive effect of these HDAC inhibitors on the expression of RBP2 and other JARID1 family histone demethylases, including PLU-1, SMCX, and LSD1, via the down-regulation of Sp1 expression. Moreover, shRNA-mediated silencing of the class I HDAC isozymes 1, 2, 3, and 8, but not that of the class II isozyme HDAC6, mimicked the drug effects on H3K4 methylation and H3K4 demethylases, which could be reversed by ectopic Sp1 expression. These data suggest a cross-talk mechanism between HDACs and H3K4 demethylases via Sp1-mediated transcriptional regulation, which underlies the complexity of the functional role of HDACs in the regulation of histone modifications.

This study is aimed at the pharmacological exploitation of alpha-tocopheryl succinate (1) to develop potent antiadhesion agents. Considering the structural cooperativity between the phytyl chain and the carboxylic terminus in determining the antiadhesion activity, our structural optimization led to compound 5 ([2-(4,8-dimethyl-non-1-enyl)-2,5,7,8-tetramethyl-chroman-6-yloxy]-acetic acid), which exhibited an-order-of-magnitude higher potency than 1 in blocking the adhesion of 4T1 metastatic breast cancer cells to extracellular matrix proteins (IC(50), 0.6 microM versus 10 microM). Evidence indicates that the ability of compound 5 to block cell adhesion and migration was attributable to its effect on disrupting focal adhesion and actin cytoskeletal integrity by facilitating the degradation of focal adhesion kinase. Interactions between tumor cells and the ECM in the tumor microenvironment have been increasingly recognized as critical modulators of the metastatic potential of tumor cells. Consequently, the ability of compound 5 to block such interactions provides a unique pharmacological tool to shed light onto mechanisms that govern cell adhesion and tumor metastasis.

As part of our effort to understand the mechanism underlying alpha-tocopheryl succinate [vitamin E succinate (VES)]-mediated antitumor effects, we investigated the signaling pathway by which VES suppresses androgen receptor (AR) expression in prostate cancer cells. VES and, to a greater extent, its truncated derivative TS-1 mediated transcriptional repression of AR in prostate cancer cells but not in normal prostate epithelial cells; a finding that underscores the differential susceptibility of normal versus malignant cells to the antiproliferative effect of these agents. This AR repression was attributable to the ability of VES and TS-1 to facilitate the proteasomal degradation of the transcription factor Sp1. This mechanistic link was corroborated by the finding that proteasome inhibitors or ectopic expression of Sp1 protected cells against drug-induced AR ablation. Furthermore, evidence suggests that the destabilization of Sp1 by VES and TS-1 resulted from the inactivation of Jun N-terminal kinases (JNKs) as a consequence of increased phosphatase activity of protein phosphatase 2A (PP2A). Stable transfection of LNCaP cells with the dominant-negative JNK1 plasmid mimicked drug-induced Sp1 repression, whereas constitutive activation of JNK kinase activity or inhibition of PP2A activity by okadaic acid protected Sp1 from VES- and TS-1-induced degradation. From a mechanistic perspective, the ability of VES and TS-1 to activate PP2A activity underscores their broad spectrum of effects on multiple signaling mechanisms, including those mediated by Akt, mitogen-activated protein kinases, nuclear factor kappaB, Sp1 and AR. This pleiotropic effect in conjunction with low toxicity suggests the translational potential for developing TS-1 into potent PP2A-activating agents for cancer therapy.

This study sought to determine which factors are correlated to a higher risk of lingual plate perforation (LPP) when placing a virtual implant in the area of the anticipated extraction site of the posterior mandible.Computed tomographic images of 300 patients (1,279 teeth) were analyzed in regard to the shape of the mandible (convergent, parallel, or undercut type), dimensional parameters of lingual concavity (angle, height, depth) and its relation to the inferior alveolar canal (zones A, B, C), distance from root apex to inferior alveolar canal, and probability of LPP. The odds ratio of variables was determined by multiple logistic regression modeling.The overall probability of LPPs on virtual implant placement was 3.1%. This perforation was most commonly observed at the second molar and with a U-type ridge. After adjusting cofounders, a concave point located in zone A is 17.34 times more likely to have a LPP than one in zone C. The probability of LPPs was reduced by 34% for every 1-millimeter increase in distance from root apex to inferior alveolar canal on virtual implant placement of posterior mandible region.Three-dimensional cone-beam computed tomographic imaging is essential for planning immediate implant placement in the anticipated extraction sites of the posterior mandible region as proved by anatomic findings that can only be understood from preoperative imaging analysis.Presurgical cross-sectional images can be analyzed to identify anatomic features relative to the lingual concavities in the posterior mandible region, which can help to avoid unpleasant complications, specifically when performing immediate implant procedures.

In this computer simulation study, the authors investigated the frequency distribution of labial bone perforation (LBP) between various sagittal root position (SRP) classes with respect to the anterior maxillary osseous housing and evaluated the associated factors correlated with a higher risk of LBP when performing a virtual immediate implant surgery in the esthetic zone.The authors analyzed cone-beam computed tomography (CBCT) images from 285 qualified study participants (1,449 teeth) to determine the probability of LBP when associated with selected variables, such as tooth type, SRP class, and morphologic parameters. The authors examined associated factors and analyzed the adjusted odds ratios by means of multiple logistic regression analysis.The overall probability of LBP was 81.7%, which presented statistically significant differences between each specific tooth type and SRP class (all P.001). After adjusting for other factors, the authors found that the maxillary central incisor was 2.37 times more likely to have LBP than the canine. SRP class I was 4.9 times more likely to be associated with LBP when compared with SRP class IV.When a clinician performs an immediate implant in the anterior esthetic zone, he or she should be aware that the specific tooth type, SRP class, and morphologic features of fossa concavities are associated with a risk of experiencing LBP.Presurgical cross-sectional images can be analyzed to identify anatomic features relative to LBP in the maxillary esthetic region, and this can avoid unpleasant complications, specifically when performing immediate implant procedures.

MUC1-C overexpression has been associated with the progression of pancreatic tumors by promoting the aggressive and metastatic phenotypes. As MUC1 is a STAT3 target gene, STAT3 plays a major role in regulating MUC1-C expression. In this study, we report an alternative mechanism by which integrin-linked kinase (ILK) post-transcriptionally modulates the expression of MUC1-C by maintaining its protein stability in pancreatic cancer cells. We found that ILK acts in concert with STAT3 to facilitate IL-6-mediated upregulation of MUC1-C; ILK depletion was equally effective as STAT3 depletion in abolishing IL-6-induced MUC1-C overexpression without disturbing the phosphorylation or cellular distribution of STAT3. Conversely, ectopic expression of constitutively active ILK increased MUC1-C expression, though this increase was not noted with kinase-dead ILK. This finding suggests the requirement of the kinase activity of ILK in regulating MUC1-C stability, which was confirmed by using the ILK kinase inhibitor T315. Furthermore, our data suggest the involvement of protein kinase C (PKC)δ in mediating the suppressive effect of ILK inhibition on MUC1-C repression. For example, co-immunoprecipitation analysis indicated that ILK depletion-mediated MUC1-C phosphorylation was accompanied by increased phosphorylation of PKCδ at the activation loop Thr-507 and increased binding of PKCδ to MUC1-C. Conversely, ILK overexpression resulted in decreased PKCδ phosphorylation. From a mechanistic perspective, the present finding, together with our recent report that ILK controls the expression of oncogenic KRAS through a regulatory loop, underscores the pivotal role of ILK in promoting pancreatic cancer progression.

Model selection is a popular strategy in structural equation modeling (SEM). To select an "optimal" model, many selection criteria have been proposed. In this study, we derive the asymptotics of several popular selection procedures in SEM, including AIC, BIC, the RMSEA, and a two-stage rule for the RMSEA (RMSEA-2S). All of the results are derived under weak distributional assumptions and can be applied to a wide class of discrepancy functions. The results show that both AIC and BIC asymptotically select a model with the smallest population minimum discrepancy function (MDF) value regardless of nested or non-nested selection, but only BIC could consistently choose the most parsimonious one under nested model selection. When there are many non-nested models attaining the smallest MDF value, the consistency of BIC for the most parsimonious one fails. On the other hand, the RMSEA asymptotically selects a model that attains the smallest population RMSEA value, and the RESEA-2S chooses the most parsimonious model from all models with the population RMSEA smaller than the pre-specified cutoff. The empirical behavior of the considered criteria is also illustrated via four numerical examples.

A penalized likelihood (PL) method for structural equation modeling (SEM) was proposed as a methodology for exploring the underlying relations among both observed and latent variables. Compared to the usual likelihood method, PL includes a penalty term to control the complexity of the hypothesized model. When the penalty level is appropriately chosen, the PL can yield an SEM model that balances the model goodness-of-fit and model complexity. In addition, the PL results in a sparse estimate that enhances the interpretability of the final model. The proposed method is especially useful when limited substantive knowledge is available for model specifications. The PL method can be also understood as a methodology that links the traditional SEM to the exploratory SEM (Asparouhov & Muthen in Struct Equ Model Multidiscipl J 16:397-438, 2009). An expectation-conditional maximization algorithm was developed to maximize the PL criterion. The asymptotic properties of the proposed PL were also derived. The performance of PL was evaluated through a numerical experiment, and two real data illustrations were presented to demonstrate its utility in psychological research.

The embedded fully self-biased switched-capacitor (FSBSC) with single-inductor high voltage bipolar-output (SIHBO) converter is proposed to achieve the energy and area-efficient driving scheme for the paper-like cholesteric liquid crystal display (Ch-LCD), which becomes the next generation of electronic readers in the consumer markets. As the compact power management module, SIHBO converter can provide +/-35V bipolar outputs for row driving. Besides, the embedded FSBSC is utilized to generate the different voltage levels for modulating the gray-color in column driving scheme. This combination carries out the effective driving operation for Ch-LCD through the demand of timing control unit. Experimental results show the achievement of +/-35V output voltage in the SIHBO converter and the variety voltage levels generated from FSBSC. The peak efficiency is up to 84% with the silicon area of 6.53 mm2.

Vitamin E is a fat-soluble vitamin that includes isomers of tocopherols and tocotrienols which are known for their antioxidant properties. Tocopherols are the predominant form encountered in the diet and through supplementation, and have garnered interest for their potential cancer therapeutic and chemopreventive effects, which include the dephosphorylation of Akt, a serine/threonine kinase that plays a pivotal role in important cellular processes, such as cell growth, survival, metabolism and motility. Full catalytic activation of Akt requires phosphorylation at both Thr308 and Ser473. Dephosphorylation of Ser473 drastically reduces Akt catalytic activity and the number of downstream substrates it can regulate. The mechanism by which α- and γ-tocopherol facilitate the selective dephosphorylation of the kinase Akt at Ser473 was investigated. We showed that this site-specific Akt dephosphorylation was mediated through the pleckstrin homology (PH) domain-dependent recruitment to the plasma membrane of Akt and PHLPP1 (PH domain leucine-rich repeat protein phosphatase, isoform 1), a phosphatase that dephosphorylates Akt at Ser473. The ability of α- and γ-tocopherol to induce PHLPP-mediated Akt inhibition established PHLPP as a “druggable” target. We structurally optimized these tocopherols to obtain derivatives with greater in vitro potency and in vivo tumor-suppressive activity in two prostate xenograft tumor models. Binding affinities for the PH domains of Akt and PHLPP1 were greater than for other PH domain-containing proteins, which may underlie the preferential membrane recruitment of these proteins. Molecular modeling revealed the structural determinants of the interaction with the PH domain of Akt that may inform strategies for continued structural optimization. These findings describe a mechanism by which tocopherols facilitate the dephosphorylation of Akt at Ser473, thereby providing insights into the mode of antitumor action of tocopherols and a rationale for the translational development of tocopherols into novel PH domain-targeted Akt inhibitors.

Epigenetic regulation via abnormal activation of histone deacetylases (HDACs) is a mechanism that leads to cancer initiation and promotion. Activation of HDACs results in transcriptional upregulation of human telomerase reverse transcriptase (hTERT) and increases telomerase activity during cellular immortalization and tumorigenesis. However, the effects of HDAC inhibitors on the transcription of hTERT vary in different cancer cells. Here, we studied the effects of a novel HDAC inhibitor, AR42, on telomerase activity in a PTEN-null U87MG glioma cell line. AR42 increased hTERT mRNA in U87MG glioma cells, but suppressed total telomerase activity in a dose-dependent manner. Further analyses suggested that AR42 decreases the phosphorylation of hTERT via an Akt-dependent mechanism. Suppression of Akt phosphorylation and telomerase activity was also observed with PI3K inhibitor LY294002 further supporting the hypothesis that Akt signaling is involved in suppression of AR42-induced inhibition of telomerase activity. Finally, ectopic expression of a constitutive active form of Akt restored telomerase activity in AR42-treated cells. Taken together, our results demonstrate that the novel HDAC inhibitor AR42 can suppress telomerase activity by inhibiting Akt-mediated hTERT phosphorylation, indicating that the PI3K/Akt pathway plays an important role in the regulation of telomerase activity in response to this HDAC inhibitor.