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BACKGROUND: Removable partial dentures (RPDs) are widely used as a repair means and have a wide application scope. OBJECTIVE: To explore the effect of using design software in the preclinical teaching of removable partial dentures (RPDs). METHODS: Unreal Engine software was used to build the RPD framework design teaching and training software. All 131 undergraduate students majoring in stomatology in the class of 2018, Kunming Medical University, were randomly divided into three groups and received either traditional experiment teaching, flipped classroom teaching, or software teaching for RPD design. The application effect of the software in the preclinical teaching of RPD design was evaluated by analyzing the examination results and through the use of a questionnaire survey. RESULTS: The differences in the theoretical examination scores among the traditional teaching group, the flipped classroom group, and the software teaching group were not statistically significant (P> 0.05), while the average design scores of upper Kennedy Class I and lower Kennedy Class II subclass II in the software teaching group were significantly higher than those in the traditional teaching group (P< 0.05). Overall, 75% of the students in the software teaching group reported that this teaching method could improve their learning initiative, a higher percentage than in the traditional teaching group (55.8%, P< 0.05). Meanwhile, 90.9% of the students in the software teaching group reported that the software could make RPD-related theoretical knowledge more visual and intuitive, and 93.2% of these students felt it was helpful for understanding the RPD three-dimensional (3D) spatial structure. These percentages were higher than those in the traditional teaching and flipped classroom groups (P< 0.05). CONCLUSION: In the preclinical teaching of RPD design, software training helped the students better understand the 3D structure of RPDs and establish clear design ideas, and it may also be valuable for in-depth research and promotion purposes.

The improvement of 5G network speed has laid the foundation for the generation of short video platforms. With the help of big data, short videos can be more accurate to push the content of interest to customers. As a veteran Chinese Internet giant Tencent, in order to cater to today's fast-rising short video market, Tencent launched "WeChat Channels" to participate in the competition in the short video market. In just two years, the latest data shows that Tencent's WeChat Channel has been able to compete with Tiktok and Kwai. The authors have studied and discussed why the Tencent WeChat Channels can grow so fast in such a short period of time, and what are the implications for those who want to join the industry later. The authors analyze the business model of Wechat Channels through the network effect of short video platforms and positive feedback loops, use SWOT to analyze the competitiveness of WeChat Channels, and analyze the differentiation strategies. Through research, the authors found that the WeChat Channels itself is in the powerful online communication platform "WeChat" ecology, and the natural customer acquisition channel enables the Wechat Channels to quickly complete the original accumulation of basic customers in the early stage, and the unique push mechanism within the circle of friends allows Video account customer stickiness and higher video quality. Therefore, these two important factors have led to the result that the video account has gradually formed its own closed-loop live broadcast business.

The peak at 711 cm−1 is from the V–O stretching vibrational mode. It is selected for ideal photon–phonon resonance absorption frequency.

Knowledge of viral shedding remains limited. Repeated measurement data have been rarely used to explore the influencing factors. In this study, a joint model was developed to explore and validate the factors influencing the duration of viral shedding based on longitudinal data and survival data. We divided 361 patients infected with Delta variant hospitalized in Nanjing Second Hospital into two groups (≤ 21 days group and > 21 days group) according to the duration of viral shedding, and compared their baseline characteristics. Correlation analysis was performed to identify the factors influencing the duration of viral shedding. Further, a joint model was established based on longitudinal data and survival data, and the Markov chain Monte Carlo algorithm was used to explain the influencing factors. In correlation analysis, patients having received vaccination had a higher antibody level at admission than unvaccinated patients, and with the increase of antibody level, the duration of viral shedding shortened. The linear mixed-effects model showed the longitudinal variation of logSARS-COV-2 IgM sample/cutoff (S/CO) values, with a parameter estimate of 0.193 and a standard error of 0.017. Considering gender as an influencing factor, the parameter estimate of the Cox model and their standard error were 0.205 and 0.1093 (P = 0.608), the corresponding OR value was 1.228. The joint model output showed that SARS-COV-2 IgM (S/CO) level was strongly associated with the risk of a composite event at the 95% confidence level, and a doubling of SARS-COV-2 IgM (S/CO) level was associated with a 1.38-fold (95% CI: [1.16, 1.72]) increase in the risk of viral non-shedding. A higher antibody level in vaccinated patients, as well as the presence of IgM antibodies in serum, can accelerate shedding of the mutant virus. This study provides some evidence support for vaccine prevention and control of COVID-19 variants.

PtCu3 intermetallic oxygen reduction electrocatalysts were synthesized via a cuprous sulfide-induced phase transition.

Predicting the penetration depth during electron beam welding (EBW) is important, but the accuracy of current predictive models is highly varied, depending on the type and number of data used. This paper develops and compares several penetration depth prediction models for EBW and uniquely compares the influence of the number and type of data used, as well as the measurement and modelling methods. Although accelerating voltage, beam current and welding speed data are essential modelling inputs, additional data for beam focal position and beam shape, measured using a novel 4-slit beam probing method, greatly improve the accuracy of predictions for models based on an empirical equation, a second-order regression and an artificial neural network (ANN). Optimised models predict weld depths that deviate, on average, by less than 5% from measured depths, are valid for very broad linear electron beam power density ranges (86–324 J/mm) and are close to the estimated 4% inherent variability in the process and its measurement. Within this linear electron beam power density range, the ANN yields accurate and reliable depth predictions, demanding as few as 36 welding trials, decreasing the number required for models that do not consider beam focal position and shape, for the same targeted accuracy, by more than 60%. Adding large volumes of virtual data generated by less reliable analytical or regression models did not improve the predictive capability for the ANN developed in this study.

Creeping fat (CrF), also known as fat wrapping, is a significant disease characteristic of Crohn's disease (CD). The transmural inflammation impairs intestinal integrity and facilitates bacteria translocation, aggravating immune response. CrF is a rich source of pro-inflammatory and pro-fibrotic cytokines with complex immune microenvironment. The inflamed and stricturing intestine is often wrapped by CrF, and CrF is associated with greater severity of CD. The large amount of innate and adaptive immune cells as well as adipocytes in CrF promote fibrosis in the affected intestine by secreting large amount of pro-fibrotic cytokines, adipokines, growth factors and fatty acids. CrF is a potential therapeutic target for CD treatment and a promising bio-marker for predicting response to drug therapy. This review aims to summarize and update the clinical manifestation and application of CrF and the underlying molecular mechanism involved in the pathogenesis of intestinal inflammation and fibrosis in CD.

The high-formwork support is to form and maintain newly poured concrete so that there should be no deformation in the shape. Deflection and shrinkage should be minimum. The intelligent monitoring of high-formwork support based on big data has been dramatically promoted with the advancement of science and technology. The standard of living is constantly improving, and safety is frequently the top priority. The construction industry pays close attention to the safety of high-formwork support during the construction process. Traditional high-formwork support monitoring is based on manual observation and measurement, which is not only time-consuming and labor-intensive but also produces insignificant monitoring data. Because of the strict requirements for pouring quality and construction safety, the traditional high-formwork support has been unable to meet the demand. We must combine information technology to provide the best monitoring means for high-formwork support and effective guarantees for building construction safety. In this paper, we propose an intelligent high-formwork support monitoring system. Every two seconds, the system can obtain equipment monitoring data, which is automatically transmitted. It transmits monitoring data from the collector to the database, thereby avoiding high-formwork support accidents. Decision trees are also used in the analysis of monitoring data. As a result, three decision rules emerge. The main advantages of the intelligent high-formwork support monitoring system are that it is frequently monitored and allows for real-time monitoring. The proposed intelligent high-formwork support monitoring system ensures the safety of the high-formwork support during construction.

Two new species of tetragnathid spiders from Guizhou and Sichuang provinces of China are described: Diphya guiyang J. Zhang & H. Yu, sp. nov. (♂♀) and Diphya weimiani J. Zhang & H. Yu, sp. nov. (♀). Detailed descriptions, diagnoses, and photographs are provided for these two species, as well as a key and a distribution map for Chinese Diphya species. DNA barcodes (a partial fragment of the mitochondrial cytochrome oxidase subunit I gene, COI) of both new species were obtained for species delimitation, matching of different sexes, and future use in molecular studies.

One-Straight-Cut-Heart activities can help teachers support students’ engagement with geometry and can deepen students’ geometric reasoning.

In order to improve the accuracy of bolt positioning for industrial robots, this paper studies the bolt positioning system of industrial robots combined with multieye vision technology. This paper introduces three reconstruction algorithms ART, SIRT, and SART from the perspective of theory and implementation. Moreover, the projection matrix calculated with 0, 1 weighting, length weighting, and linear interpolation weighting is used for three reconstruction algorithms to carry out reconstruction experiments. In addition, this paper combines the actual working conditions of bolt positioning to construct the system of this paper and conducts system simulation research combined with the working conditions of the robot. The research shows that the bolt positioning system based on the multieye vision industrial robot proposed in this paper has a good performance in bolt positioning.

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer with a poor prognosis. Therefore, it is crucial to explore molecular prognostic biomarkers for OSCC. ZEB1 (also known as δEF1) is a member of the zinc finger E-box binding protein family of transcription factors involved in various biological processes, including tumorigenesis, progression, and metastasis. Recent evidence suggests that ZEB1 has a role in the tumorigenicity of oral epithelial cells, although its mode of action needs to be investigated further. To better understand the relationship between ZEB1 and OSCC, we transfected the ZEB1-overexpressing oral squamous cell lines SCC9 and SCC25 with lentivirus and then extracted RNA from the cells for gene expression analysis. Furthermore, the GSE30784 dataset was downloaded from the Gene Expression Omnibus (GEO) database to identify potential biomarkers of OSCC and to assess the potential mechanisms. The criteria for identification of their DEGs were |logFC| > 1 and P

Zuojin Pill (ZJP) has been used to treat gastrointestinal problems in China for hundreds of years.To discover more potential active ingredients and evaluate the gastroprotective mechanisms of ZJP.An approach involving UPLC-Q-Orbitrap HRMS and serum pharmacochemistry was established to screen the multiple chemical constituents of ZJP. Male Sprague-Dawley (SD) rats were divided into six groups: normal control, ulcer control, omeprazole (30 mg/kg), and three ZJP groups (1.0, 2.0 and 4.0 g/kg). After oral treatment with ZJP or omeprazole for 7 days, all groups except the normal control group were orally administered 5 mL/kg ethanol to induce gastric ulceration. Histopathological assessment of gastric tissue was performed by haematoxylin and eosin staining. Antioxidant parameters and inflammatory mediators were determined using ELISA Kit and immunohistochemical analysis.Ninety components were identified in ZJP. Among them, 23 prototypes were found in rat serum after oral administration of ZJP. The ulcer inhibition was over 90.0% for all the ZJP groups. Compared with the ulcer control rats, ZJP (4.0 g/kg) enhanced the antioxidant capacity of gastric tissue: superoxide dismutase (1.33-fold), catalase (2.61-fold), glutathione (2.14-fold), and reduced the malondialdehyde level (0.48-fold). Simultaneously, the ZJP meaningfully lowered the content of tumour necrosis factor-α (0.76-fold), interleukin-6 (0.66-fold), myeloperoxidase (0.21-fold), and nuclear factor kappa B (p65) (0.62-fold).This study showed ZJP could mitigate ethanol-induced rat gastric ulcers, which might benefit from the synergistic actions of multiple ingredients. The findings could support the quality control and clinical trials of ZJP.

Objectives Mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase, T2) is necessary for the catabolism of ketone bodies andisoleucine. T2 deficiency is an autosomal recessive metabolic disorder caused by variant in the ACAT1 gene. In this report, we describe two novel ACAT1 variant identified in a Chinese family. Case presentation The 9-month-old male proband was admitted to the pediatric intensive care unit for altered consciousness. At the time of admission, the patient had acidosis, drowsiness, and respiratory failure. Both urine organic acid analyses and LC–MS/MS suggested T2 deficiency. Novel compound heterozygous variant (c.871G>C and c.1016_1017del) in the ACAT1 gene were detected in the proband by WES and verified through direct sequencing. Family analysis demonstrated that the first variant was transmitted from his father and the second variant was from his mother, indicating autosomal recessive inheritance. This report is the first to describe the association of these variant with T2 deficiency based on genetic testing. Although these variant were identified in the patient’s elder sister and elder brother, they continue to be asymptomatic. Conclusions We identified two novel ACAT1 variants associated with T2 deficiency. The identification expands the spectrum of known variant linked to the disorder.

Genome-wide association studies have suggested a link between primary open-angle glaucoma and the function of ABCA1. ABCA1 is a key regulator of cholesterol efflux and the biogenesis of high-density lipoprotein (HDL) particles. Here, we showed that the POAG risk allele near ABCA1 attenuated ABCA1 expression in cultured cells. Consistently, POAG patients exhibited lower ABCA1 expression, reduced HDL, and higher cholesterol in white blood cells. Ablation of Abca1 in mice failed to form HDL, leading to elevated cholesterol levels in the retina. Counting retinal ganglion cells (RGCs) by using an artificial intelligence (AI) program revealed that Abca1-deficient mice progressively lost RGCs with age. Single-cell RNA sequencing (scRNA-seq) revealed aberrant oxidative phosphorylation in the Abca1

A line of evidence has shown that childhood trauma and patterns of H-shaped sulci in the orbitofrontal cortex (OFC) are associated with cognitive deficits in patients with schizophrenia. Studies have also suggested that childhood trauma is associated with OFC volumetrics. This study investigated the interrelationship between childhood trauma, OFC H-shaped sulci volume and cognitive function in patients with first-episode schizophrenia. We hypothesized that OFC H-shaped sulci volume would mediate the relationship between childhood trauma and cognitive function in patients with first-episode schizophrenia.We recruited patients with first-episode schizophrenia (Patients with first-episode schizophrenia had smaller left OFC H-shaped sulci volumes, more severe childhood trauma experiences and worse cognitive function than healthy controls. CTQ total score and emotional and physical neglect subscores were negatively correlated with left OFC H-shaped sulci volume. CTQ total score and emotional neglect and sexual abuse subscores were negatively correlated with cognitive function in patients with first-episode schizophrenia. Interestingly, the CTQ total score and physical neglect subscore were positively correlated with cognitive function in healthy controls. Left OFC H-shaped sulci volume played a mediating role in CTQ emotional neglect subscore, CTQ total score and MCCB composite score.The small sample size and retrospective design need to be considered.Childhood trauma might contribute to cognitive deficits in patients with first-episode schizophrenia by affecting left OFC H-shaped sulci volume. This finding can help in the design of strategies to improve cognitive function in patients with first-episode schizophrenia.

The age of the Silurian “Lower Red Beds” (LRBs), which occur widely in South China, has long been controversial because of the scarcity of index fossils. Here, we report a fauna with abundant trilobites from the LRBs in Wuhan, Middle Yangtze region, consisting of Aulacopleura (Paraaulacopleura) pijiazhaiensis, ‘Encrinuroides’ yichangensis, Gaotania hubeiensis, Hyrokybe gaotanensis, Japonoscutellum yichangense, Latiproetus latilimbatus, and Ptilillaenus lojopingensis. These trilobites are common in the Leijiatun, upper Xiangshuyuan, Shihniulan, and Lojoping formations in the Upper Yangtze region, and belong to the middle to upper Aeronian Ptilillaenus or ‘Encrinuroides’–Ptilillaenus–Latiproetus assemblages. The discovery of this trilobite assemblage suggests that the LRBs are probably partly of middle–late Aeronian age in the Middle Yangtze region. Thus, the lower boundary of the LRBs is likely diachronous in the Yangtze region, ranging from the middle–late Aeronian to the early Telychian. The discovery of the Ptilillaenus assemblage in the Wuhan LRBs expands the paleogeographic distribution of this assemblage and provides evidence of deeper depositional environment of the LRBs in the study area versus shallow waters in other areas of the Yangtze region.

We investigate the response of the near-equilibrium quark-gluon plasma (QGP) to perturbation at non-hydrodynamic gradients. We propose a conceivable scenario under which sound mode continues to dominate the medium response in this regime. Such a scenario has been observed experimentally for various liquids and liquid metals. We further show this extended hydrodynamic regime (EHR) indeed exists for both the weakly-coupled kinetic equation in the relaxation time approximation (RTA) and the strongly-coupled ${\cal N}=4$ supersymmetric Yang-Mills (SYM) theory. We construct a simple but nontrivial extension of M{\"u}eller-Isareal-Stewart (MIS) theory, namely MIS*, and demonstrate that it describes EHR response for both RTA and SYM theory. This indicates that MIS* equations can potentially be employed to search for QGP EHR via heavy-ion collisions., Comment: 9 pages, 4 figures

Atomically thin narrow-bandgap layered PdSe2 has attracted much attention due to its rich and unique electrical properties. For silicon-compatible device integration, direct wafer-scale preparation of high-quality PdSe2 thin film on a silicon substrate is highly desired. Here, we present the low-temperature synthesis of large-area polycrystalline PdSe2 films grown on SiO2/Si substrates by plasma-assisted metal selenization and investigate their charge carrier transport behaviors. Raman analysis, depth-dependent X-ray photoelectron spectroscopy, and cross-sectional transmission electron microscopy were used to reveal the selenization process. The results indicate a structural evolution from initial Pd to intermediate PdSe2-x phase and eventually to PdSe2. The field-effect transistors fabricated from these ultrathin PdSe2 films exhibit strong thickness-dependent transport behaviors. For thinner films (4.5 nm), a record high on/off ratio of 104 was obtained. While for thick ones (11 nm), the maximum hole mobility is about 0.93 cm2 V-1 S-1, which is the record high value ever reported for polycrystalline films. These findings suggest that our low-temperature-metal-selenized PdSe2 films have high quality and show great potential for applications in electrical devices.

Background: The sedative dexmedetomidine has been shown to reduce mortality in adult patients with severe sepsis, but it is not known whether children benefit. This study explored the effects of dexmedetomidine on the outcomes of children with severe sepsis with mechanical ventilation. Methods: In this retrospective cohort study, children with severe sepsis requiring mechanical ventilation from 2016 to 2020 were categorized as dexmedetomidine and non-dexmedetomidine group. The propensity score matching was performed to match cases in both groups. The primary outcome was 28-day mortality, and the secondary outcomes were acute kidney injury, ventilator-free days, lengths of PICU and hospital stays. The Kaplan-Meier method and was the log-rank test used to estimate the 28-day mortality rate and assess between-group differences. Results: In total, 250 patients were eligible patients: 138 in the dexmedetomidine group and 112 in the non-dexmedetomidinegroup. After 1:1 propensity score matching, 61 children in each group. dexmedetomidine group showed more lower 28-day mortality (9.84% vs 26.23%, P=0.008). During the 7-day observation period after PICU admission, the dexmedetomidine group showed significantly lower neurological and renal sub-scores at day 7 and serum creatinine level at day 3 and day 7. There were no statistical differences in the incidence of acute kidney injury, ventilator-free days, lengths of PICU and hospital stays between the two groups. Conclusions: dexmedetomidine treatment in children with severe sepsis is associated with better outcomes and should therefore be considered for the sedation strategy.

Drought legacy effects refer to the lasting impacts on the carbon cycle from droughts, being a prime uncertainty in predicting future land carbon sink in a changing climate. While previous studies have been focusing on the drought legacy effects on tree growth using tree ring chronologies, the rapid developments of site and satellite observations over the past decades provide us new opportunities to investigate the effects with improved temporal and spatial coverage. For example, retrievals of canopy structure, photosynthesis, evapotranspiration, and vegetation water content would allow for evaluating the differences in recovery processes in magnitude, timing and duration of the legacy effects. Potential asynchrony and divergence among these multiple legacy indicators result in large uncertainties in understanding the full range of vegetation responses to drought. To address this issue, this study aims to leverage the development of a new generation Earth system model (CliMA) in combination with site and satellite observations to understand the various legacy effects on carbon sink responses from site to regional scales. Through investigating the temporal and spatial patterns of legacy effects, our work will gain a comprehensive understanding of drought related carbon cycle feedback and benefit science-based decision making facing changing climate, especially extreme events.

Methane (CH4) levels in the atmosphere increased by 15.1 ± 0.4 ppb in 2020, the highest annual increase from 1984 to 2020, despite a likely decrease in anthropogenic CH4 emissions during COVID-19 confinements. Here, we used bottom-up and top-down methods to quantify the changes in different sources of CH4, and in its atmospheric sink due to the hydroxyl radical (OH) in 2020 compared to 2019. Bottom-up methods showed that, globally, total anthropogenic emissions slightly decreased by ~1.2 Tg CH4 yr-1, fire emissions were lower than in 2019 by ~6.5 Tg CH4 yr-1, and wetland emissions increased by 6.0 ± 2.3 Tg CH4 yr-1. In addition to higher wetland emissions in 2020 than 2019 from bottom-up, we found a decrease of 1.6–1.8% in tropospheric OH concentration relative to 2019, mainly due to lower anthropogenic NOx emissions and associated lower free tropospheric ozone during the confinements. Based on atmospheric CH4 observations from the surface network, and considering the decrease in OH, using top-down inversions, we infer that global net emissions increased by 6.9 ± 2.1 Tg CH4 yr-1 in 2020 relative to 2019, while the global CH4 removal from reaction with OH in the atmosphere decreased in 2020 by 7.5 ± 0.8 Tg CH4 yr-1. Therefore, we attribute the positive growth rate anomaly of atmospheric CH4 in 2020 relative to 2019 to lower OH sink (53 ± 10%) and higher natural emissions (47 ± 16%), mostly from wetlands. Warmer and wetter climate conditions in the Northern Hemisphere promoted wetland emissions, but fires decreased in the Southern Hemisphere, compared to the previous year. Our study highlights that northern microbial emissions of CH4 are highly sensitive to a warmer and wetter climate and could act as a positive feedback in the future. Our study also hints that the global CH4 pledge must be implemented by taking into account NOx emissions trend, whose reduction lengthens the lifetime of atmospheric CH4.

C18H16N4O3S2, monoclinic, C2/c (no. 15), a = 19.694(4) Å, b = 11.450(2) Å, c = 8.3382(16) Å, β = 91.820 ( 2 ) ∘ $91.820{(2)}^{\circ }$ , V = 1879.3(6) Å3, Z = 4, R g t ${R}_{gt}$ (F) = 0.0408, w R r e f $w{R}_{ref}$ (F 2) = 0.1206, T = 296(2) K.

Cities worldwide are experiencing record-breaking summer temperatures. Urban environments exacerbate extreme heat, resulting in not only the urban heat island but also intracity variations in heat exposure. Understanding these disparities is crucial to support equitable climate mitigation and adaptation efforts. We found persistent negative correlations between daytime land surface temperature (LST) and median household income across the Los Angeles metropolitan area based on Ecosystem Spaceborne Thermal Radiometer Experiment on Space Station observations from 2018 to 2021. Lower evapotranspiration resulting from the unequal distribution of vegetation cover is a major factor leading to higher LST in low-income neighborhoods. Disparities worsen with higher regional mean surface temperature, with a $10,000 decrease in income leading to ~0.2°C LST increase at 20°C and up to ~0.7°C at 45°C. With more frequent and intense heat waves projected in the future, equitable mitigation measures, such as increasing surface albedo and tree cover in low-income neighborhoods, are necessary to address these disparities.

Objective To detect the expression of Growth factor binding protein 2 associated binding protein 2 (Gab2) and CT10 regulator of kinase II (CrkII) in ovarian cancer and analyze their clinical significance. To explore the effects of Gab2 and CrkII on the biological behavior of ovarian cancer cells. To analyze the possible molecular mechanism of Gab2 in the development of ovarian cancer. Methods Immunohistochemistry was used to detect the expression of Gab2 and CrkII in ovarian cancer. Chi square test was used to analyze the correlation between Gab2, CrkII and clinical parameters. Using Cox regression model to evaluate the risk factors affecting the prognosis. To analyze the correlation between Gab2, CrkII and survival rate by Kaplan–Meier. Cell experiments were preformed to explore the effects of Gab2 and CrkII on the biological behavior of cells. The interaction between Gab2 and CrkII was explored by immunoprecipitation. Results Immunohistochemistry revealed that high expression of Gab2 and CrkII in ovarian cancer. Patients with high expression of Gab2 or CrkII had higher International Federation of Gynecology and Obstetrics (FIGO) stage, grade and platinum-resistance recurrence. Multivariate analysis showed that Gab2 and CrkII were independent prognostic factors. Kaplan–Meier curve showed that the higher Gab2 and CrkII were, the poor prognosis the patients had. We observed that the overexpression of Gab2 and CrkII promoted the proliferation, metastasis and reduced chemosensitivity of cells. Conversely, the knockdown of Gab2 and CrkII resulted in the opposite results. In CrkII-knockdown cells, we found that Gab2 mediates biological behavior through CrkII. Conclusions The expression of Gab2 and CrkII increase in ovarian cancer. The higher expression of Gab2 and CrkII predict the poor prognosis of patients. Gab2 and CrkII promote the proliferation and migration and reduce the chemosensitivity of cells. Gab2 regulates the biological behaviors of ovarian cancer cells through CrkII.

Background: Natural killer cells play important roles in tumor immune surveillance, and cancer cells must resist this surveillance in order to progress and metastasise. Introduction: The study aimed to explore the mechanism of how breast cancer cells become resistant to the cytotoxicity of NK cells. Methods: We established NK-resistant breast cancer cells by exposing MDA-MB-231 cells and MCF-7 cells to NK92 cells. Profiles of lncRNA were compared between the NK-resistant and parental cell lines. Primary NK cells were isolated by MACS, and the NK attacking effect was tested by non-radioactive cytotoxicity. The change in lncRNAs was analyzed by Gene-chip. The interaction between lncRNA and miRNA was displayed by Luciferase assay. The regulation of the gene was verified by QRT-PCR and WB. The clinical indicators were detected by ISH, IH, and ELISA, respectively. Results: xUCA1 was found to be significantly up-regulated in both NK-resistant cell lines, and we confirmed such up-regulation on its own to be sufficient to render parental cell lines resistant to NK92 cells. We found that UCA1 up-regulated ULBP2 via the transcription factor CREB1, while it up-regulated ADAM17 by “sponging” the miR-26b-5p. ADAM17 facilitated the shedding of soluble ULBP2 from the surface of breast cancer cells, rendering them resistant to killing by NK cells. UCA1, ADAM17, and ULBP2 were found to be expressed at higher levels in bone metastases of breast cancer than in primary tumors. Conclusion: Our data strongly suggest that UCA1 up-regulates ULBP2 expression and shedding, rendering breast cancer cells resistant to killing by NK cells.

Objectives: To evaluate the process and the comprehensiveness of advanced care planning (ACP), we designed a national ACP-OSCE (Objective Structured Clinical Examination) program. Methods: The program was designed as a 40-minute OSCE test. Participants were categorized as different ACP team members to illustrate realistic scenarios. Preceptors were asked to observe ACP professionals’ actions, responses, and communication skills during ACP with standardized patients (SP) through a one-way mirror. Participants’ communication skills, medical expertise, legal knowledge, empathetic response and problem-solving skills of ACP were also self-evaluated before and after OSCE. Thematic analysis was used for qualitative analysis. Results: In Nov 2019, a total of 18 ACP teams with 38 ACP professionals completed the ACP-OSCE program, including 15 physicians, 15 nurses, 5 social workers, and 3 psychologists. After the ACP-OSCE program, the average score of communication skills, medical expertise, legal knowledge, empathetic response, ACP problem-solving all increased. Nurses felt improved in medical expertise, legal knowledge, and problem-solving skills, psychologists and social workers felt improved in legal knowledge, while physicians felt no improved in all domain, statistically. Thematic analysis showed professional skills, doctoral-patient communication, benefit and difficulties of ACP were the topics which participants care about. Meanwhile, most participant agreed that ACP-OSCE program is an appropriate educational tool. Conclusion: This is the first national ACP-OSCE program in Asia. We believe that this ACP-OSCE program could be applied in other countries to improve theACP process and quality.

Background Pulmonary arterial hypertension (PAH) is a complex, fatal disease where disease severity has been associated with the single nucleotide polymorphism (SNP) rs2856830, located near the human leukocyte antigen DPA1 (HLA‐DPA1) gene. We aimed to define the genetic architecture of functional variants associated with PAH disease severity by identifying allele‐specific binding transcription factors and downstream targets that control endothelial pathophenotypes and PAH. Methods and Results Electrophoretic mobility shift assays of oligonucleotides containing SNP rs2856830 and 8 SNPs in linkage disequilibrium revealed functional SNPs via allele‐imbalanced binding to human pulmonary arterial endothelial cell nuclear proteins. DNA pulldown proteomics identified SNP‐binding proteins. SNP genotyping and clinical correlation analysis were performed in 84 patients with PAH at University of Pittsburgh Medical Center and in 679 patients with PAH in the All of Us database. SNP rs9277336 was identified as a functional SNP in linkage disequilibrium ( r 2 >0.8) defined by rs2856830, and the minor allele was associated with decreased hospitalizations and improved cardiac output in patients with PAH, an index of disease severity. SNP pulldown proteomics showed allele‐specific binding of nuclear ACTN4 (alpha actinin 4) protein to rs9277336 minor allele. Both ACTN4 and HLA‐DPA1 were downregulated in pulmonary endothelium in human patients and rodent models of PAH. Via transcriptomic and phenotypic analyses, knockdown of HLA‐DPA1 phenocopied knockdown of ACTN4, both similarly controlling cell structure pathways, immune pathways, and endothelial dysfunction. Conclusions We defined the pathogenic activity of functional SNP rs9277336, entailing the allele‐specific binding of ACTN4 and controlling expression of the neighboring HLA‐DPA1 gene. Through inflammatory or genetic means, downregulation of this ACTN4‐HLA‐DPA1 regulatory axis promotes endothelial pathophenotypes, providing a mechanistic explanation for the association between this SNP and PAH outcomes.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Multiple tumor-derived factors are responsible for the accumulation and expansion of immune-suppressing myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM) in tumors. Here, we show that treatment of tumor-bearing mice with docetaxel in combination with the phosphatidylserine-targeting antibody 2aG4 potently suppressed the growth and progression of prostate tumors, depleted M2-like TAMs, and MDSCs, and increased the presence of M1-like TAMs and mature dendritic cells in the tumors. In addition, the antibody markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. In vitro studies confirmed that 2aG4 repolarized TAMs from an M2- to an M1-like phenotype and drove the differentiation of MDSCs into M1-like TAMs and functional dendritic cells. These data suggest that phosphatidylserine is responsible for the expansion of MDSCs and M2-like TAMs in tumors, and that bavituximab, a phosphatidylserine-targeting antibody currently in clinical trials for cancer, could reverse this process and reactivate antitumor immunity. Cancer Immunol Res; 1(4); 256–68. ©2013 AACR.

1. Measured pKa values of ABBV-167 (Table S1. Ionization constants of ABBV-167) 2. Preparation of ABBV-167 on large scale (Scheme S1: Synopsis of GMP synthesis of ABBV-167) 3. Preparation of clinical ABBV-167 drug supply 4. Animal pharmacokinetics (Table S2. Single dose pharmacokinetics of prodrug 3 and parent venetoclax in mouse and dog after IV dosing of prodrug 3. Table S3. Single dose pharmacokinetics of 3 after oral dosing in mouse and dog. Table S4. Single dose pharmacokinetics of parent venetoclax in mouse and dog after oral dosing of 3.) 5. Clinical study (Study design, Pharmacokinetic and statistical analysis, Safety and tolerability assessments, Clinical pharmacokinetic results, Table S5. Effect of prodrug and food on venetoclax bioavailability, Safety results) 6. Crystallography methods (Protein preparation. BCL-2 ABBV-167 complex crystallization. X-ray structure determination. Table S6. Diffraction data collection and refinement statistics for BCL-2 in complex with ABBV-167 (PDB code 7LHB))

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PDF file - 1565K, Damage to tumor vasculature in LNCaP tumors induced by treatment with 2aG4.

PDF file - 41K, Regression of large subcutaneous LNCaP tumors and prevention of relapse from castration-resistant disease in mice treated with castration combined with 2aG4 plus docetaxel.

PDF file - 1075K, TAMs in LNCaP tumors switch polarity from an M2-like phenotype to an M1-like phenotype after 2aG4 treatment.

PDF file - 2187K, 2aG4 treatment of LNCaP tumor-bearing mice decreases MDSCs, increases TAMs and mature DCs.