Realization of simulations for blinded internal pilot study based on web

AbstractMisspecification of the designing parameters in the planning of a controlled clinical trial may yield an underpowered or an overpowered study. Internal pilot study, a kind of adaptive design, has gained increased attention for its allowing for sample size adjustment, especially blinded sample size adjustment that do not affect the type I error rate. Several methods were proposed to implement internal pilot design in recent years and some software emerges to simulate or implement it. But most of the software is only running on a stand-alone terminal or Client/Server(C/S) mode. We develop a system to simulate it based on Browser/Server(B/S) mode and realized on web. It allows the web users to input corresponding parameters from the web browser such as Internet Explorer to make simulations. The system was constructed with generic database schema design method and coded with Microsoft Visual Basic and Active Server Pages (ASP) programming languages. Web users on internet can use the system to make blinded variance estimate, sample size adjustment and randomization test for internal pilot study. The application of the simulation is demonstrated through an example. Not only blinded sample size adjustment is implemented but also a randomization test is performed. With applications of blinding one-sample variance for sample size recalculation and randomization test, the type I error rate is also controlled successfully

Value of deep learning models based on ultrasonic dynamic videos for distinguishing thyroid nodules

ObjectiveThis study was designed to distinguish benign and malignant thyroid nodules by using deep learning(DL) models based on ultrasound dynamic videos.MethodsUltrasound dynamic videos of 1018 thyroid nodules were retrospectively collected from 657 patients in Zhejiang Cancer Hospital from January 2020 to December 2020 for the tests with 5 DL models.ResultsIn the internal test set, the area under the receiver operating characteristic curve (AUROC) was 0.929(95% CI: 0.888,0.970) for the best-performing model LSTM Two radiologists interpreted the dynamic video with AUROC values of 0.760 (95% CI: 0.653, 0.867) and 0.815 (95% CI: 0.778, 0.853). In the external test set, the best-performing DL model had AUROC values of 0.896(95% CI: 0.847,0.945), and two ultrasound radiologist had AUROC values of 0.754 (95% CI: 0.649,0.850) and 0.833 (95% CI: 0.797,0.869).ConclusionThis study demonstrates that the DL model based on ultrasound dynamic videos performs better than the ultrasound radiologists in distinguishing thyroid nodules

ORP4L Extracts and Presents PIP2 from Plasma Membrane for PLC beta 3 Catalysis : Targeting It Eradicates Leukemia Stem Cells

Leukemia stem cells (LSCs) are a rare subpopulation of abnormal hematopoietic stem cells (HSCs) that propagates leukemia and are responsible for the high frequency of relapse in therapies. Detailed insights into LSCs' survival will facilitate the identification of targets for therapeutic approaches. Here, we develop an inhibitor, LYZ-81, which targets ORP4L with high affinity and specificity and selectively eradicates LCSs in vitro and in vivo. ORP4L is expressed in LSCs but not in normal HSCs and is essential for LSC bioenergetics and survival. It extracts PIP2 from the plasma membrane and presents it to PLC beta 3, enabling IP3 generation and subsequentCa(2+)-dependent bioenergetics. LYZ-81 binds ORP4L competitively with PIP2 and blocks PIP2 hydrolysis, resulting in defective Ca2+ signaling. The results provide evidence that LSCs can be eradicated through the inhibition of ORP4L by LYZ-81, which may serve as a starting point of drug development for the elimination of LSCs to eventually cure leukemia.Peer reviewe

Dominant role of GABAB2 and Gbetagamma for GABAB receptor-mediated-ERK1/2/CREB pathway in cerebellar neurons

gamma-aminobutyric acid type B (GABA(B)) receptor is an allosteric complex made of two subunits, GABA(B1) and GABA(B2). GABA(B2) plays a major role in the coupling to G protein whereas GABA(B1) binds GABA. It has been shown that GABA(B) receptor activates ERK(1/2) in neurons of the central nervous system, but the molecular mechanisms underlying this event are poorly characterized. Here, we demonstrate that activation of GABA(B) receptor by either GABA or the selective agonist baclofen induces ERK(1/2) phosphorylation in cultured cerebellar granule neurons. We also show that CGP7930, a positive allosteric regulator specific of GABA(B2), alone can induce the phosphorylation of ERK(1/2). PTX, a G(i/o) inhibitor, abolishes both baclofen and CGP7930-mediated-ERK(1/2) phosphorylation. Moreover, both baclofen and CGP7930 induce ERK-dependent CREB phosphorylation. Furthermore, by using LY294002, a PI-3 kinase inhibitor, and a C-term of GRK-2 that has been reported to sequester Gbetagamma subunits, we demonstrate the role of Gbetagamma in GABA(B) receptor-mediated-ERK(1/2) phosphorylation. In conclusion, the activation of GABA(B) receptor leads to ERK(1/2) phosphorylation via the coupling of GABA(B2) to G(i/o) and by releasing Gbetagamma subunits which in turn induce the activation of CREB. These findings suggest a role of GABA(B) receptor in long-term change in the central nervous system

GABAB Receptor Subunit GB1 at the Cell Surface Independently Activates ERK1/2 through IGF-1R Transactivation

BACKGROUND: Functional GABA(B) receptor is believed to require hetero-dimerization between GABA(B1) (GB1) and GABA(B2) (GB2) subunits. The GB1 extracellular domain is required for ligand binding, and the GB2 trans-membrane domain is responsible for coupling to G proteins. Atypical GABA(B) receptor responses observed in GB2-deficient mice suggested that GB1 may have activity in the absence of GB2. However the underlying mechanisms remain poorly characterized. METHODOLOGY/PRINCIPAL FINDINGS: Here, by using cells overexpressing a GB1 mutant (GB1asa) with the ability to translocate to the cell surface in the absence of GB2, we show that GABA(B) receptor agonists, such as GABA and Baclofen, can induce ERK1/2 phosphorylation in the absence of GB2. Furthermore, we demonstrate that GB1asa induces ERK1/2 phosphorylation through Gi/o proteins and PLC dependent IGF-1R transactivation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that GB1 may form a functional receptor at the cell surface in the absence of GB2

The endocrine disruptor mono-(2-ethylhexyl)phthalate promotes adipocyte differentiation and induces obesity in mice

The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental ‘window’ contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders

User Willingness toward Knowledge Sharing in Social Networks

Social networks introduce new potential for people to share knowledge with others. However, it is not clear what factors influence user willingness toward knowledge sharing in social networks. Aiming to answer these questions, in this paper we analyze the major factors influencing user willingness toward knowledge sharing in social networks and propose a new research model that is inspired by the technology acceptance model (TAM). In particular, we introduce a new independent variable called perceived value which is described by four aspects: social value, entertainment value, emotion value, and information value. In addition, we introduce a new mediating variable, trust, to reflect the intermediating relationship between perceived value and knowledge-sharing willingness. We conduct an empirical analysis on questionnaire data and present comprehensive results on reliability and validity, factor analysis, correlation analysis, and mediating effects analysis. The results show that perceived value has a significant impact on knowledge-sharing willingness, and trust plays a partial intermediate role between perceived value and knowledge-sharing willingness. Further, we present some research implications for knowledge sharing and learning innovation in social networks, as well as some suggestions for organizations to advance knowledge sharing and learning innovation in the social-network age

Pain Acceptance and Its Associated Factors among Cancer Patients in Mainland China: A Cross-Sectional Study

Background. Pain acceptance is associated with disability, pain interference, depression, and anxiety. Few studies have been conducted on the acceptance of cancer pain and its correlates. Objectives. The aim of this study was to examine the level and correlates of pain acceptance in cancer patients from mainland China. Setting and Participants. The study comprised 156 cancer patients in a tertiary cancer hospital in Hunan Province of China. Design. The study is based on a cross-sectional survey design. Subjects and Methods. The 8-item Chronic Pain Acceptance Questionnaire (CPAQ-8) was completed by 156 cancer patients with chronic pain from a tertiary cancer hospital. Demographics, pain, and negative mood assessed by the Hospital Anxiety and Depression Scale (HADS) were explored in relation to the CPAQ-8 scores using descriptive univariate analysis. Results. For the 156 patients, the mean CPAQ-8 score was 25.99 (SD = 8.56; range: 9 to 44). The scores were associated with age, gender, marital status, pain duration, number of pain sites, and duration of taking analgesics. The total scores on the CPAQ-8 and its two subscales (activity engagement and pain willingness) were negatively correlated with the HADS scores. Conclusions. The findings suggest that the prevalence of pain acceptance is relatively low for Chinese cancer patients. The cancer pain acceptance is affected by age, gender, pain duration, number of pain sites, and duration of taking analgesics. The acceptance of cancer pain is negatively correlated with depression and anxiety. Therefore, patients with risk factors for low pain acceptance should receive more attention in Chinese medical settings

Study on the Control of Saltwater Intrusion Using Subsurface Dams

Subsurface dams are widely used to prevent saltwater intrusion, with good results. This blockage often leads to an accumulation of pollutants and salt on the inland and seaside of the dam, respectively. While the latter is intended, the former effect is not desired and poses a huge problem in groundwater management. In order to quantitatively address this issue and clarify the impact of subsurface dam height, location, and the head difference for the saltwater and freshwater boundary on saltwater wedges and fresh groundwater discharge, a flow tank and numerical model were constructed. The results indicate that there was an optimal effective dam height and location (also the minimum effective dam location) for controlling saltwater intrusion, which corresponded to the maximum groundwater and freshwater discharge. When the various conditions of the numerical model were set according to the flow tank and the dam was 15 cm away from the saltwater boundary, the minimum effective dam height was equal to the aquifer thickness multiplied by 0.36. The dam height reached a height that was slightly higher than the minimum effective height, namely, the ratio of dam height to aquifer thickness was 0.38, which revealed that the freshwater discharge reached its maximum at 22.71 cm3/min, the saline water wedge area was the smallest at 378 cm2, and the prevention effect of saltwater intrusion was the best. Building a dam too high, that was, the ratio of dam height to aquifer thickness exceeded 0.38, resulted in an increased saltwater wedge area and exacerbated aquifer pollution. When the dam was located at the minimum effective distance for preventing saltwater intrusion under a certain dam height and head difference between saltwater and freshwater boundary, that was, the ratio of the distance of the dam to the saltwater boundary to the total length of the aquifer was 0.063, the distance of the dam to the saltwater boundary was the minimum effective distance. Compared to other effective distances, when the dam was at the minimum effective distance, the freshwater discharge reached its maximum at 22.71 cm3/min, and the saltwater wedge area was the smallest at 378 cm2. These conclusions provide a theoretical reference for the impact of subsurface dam construction on the saltwater wedge. This study examines the impact of tides and waves on the water head of the saltwater boundary, and it is also necessary to verify these conclusions through actual field experiments. We will investigate this in future work