Resveratrol is known to be an effective chemo-preventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this ...study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.
DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive.
Here we show that hypoxia induces nuclear 6mA modification through a DNA ...methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α.
We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.
The detection of audio tampering plays a crucial role in ensuring the authenticity and integrity of multimedia files. This paper presents a novel approach to identifying tampered audio files by ...leveraging the unique Electric Network Frequency (ENF) signal, which is inherent to the power grid and serves as a reliable indicator of authenticity. The study begins by establishing a comprehensive Chinese ENF database containing diverse ENF signals extracted from audio files. The proposed methodology involves extracting the ENF signal, applying wavelet decomposition, and utilizing the autoregressive model to train effective classification models. Subsequently, the framework is employed to detect audio tampering and assess the influence of various environmental conditions and recording devices on the ENF signal. Experimental evaluations conducted on our Chinese ENF database demonstrate the efficacy of the proposed method, achieving impressive accuracy rates ranging from 91% to 93%. The results emphasize the significance of ENF-based approaches in enhancing audio file forensics and reaffirm the necessity of adopting reliable tamper detection techniques in multimedia authentication.
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The combination of EGF, CHIR99021, A83-01, SB431542, VPA, and Y27632 (EGF/CASVY) facilitates the derivation of trophoblast stem (TS) cells from human blastocysts and first-trimester, but not term, ...cytotrophoblasts. The mechanism underlying this chemical induction of TS cells remains elusive. Here we demonstrate that the induction efficiency of cytotrophoblast is determined by functional antagonism of the placental transcription factor GCM1 and the stemness regulator ΔNp63α. ΔNp63α reduces GCM1 transcriptional activity, whereas GCM1 inhibits ΔNp63α oligomerization and autoregulation. EGF/CASVY cocktail activates ΔNp63α, thereby partially inhibiting GCM1 activity and reverting term cytotrophoblasts into stem cells. By applying hypoxia condition, we can further reduce GCM1 activity and successfully induce term cytotrophoblasts into TS cells. Consequently, we identify mitochondrial creatine kinase 1 (CKMT1) as a key GCM1 target crucial for syncytiotrophoblast differentiation and reveal decreased CKMT1 expression in preeclampsia. Our study delineates the molecular underpinnings of trophoblast stemness and differentiation and an efficient method to establish TS cells from term placentas.
Two‐dimensional (2D) tin (Sn)‐based perovskites have recently received increasing research attention for perovskite transistor application. Although some progress is made, Sn‐based perovskites have ...long suffered from easy oxidation from Sn2+ to Sn4+, leading to undesirable p‐doping and instability. In this study, it is demonstrated that surface passivation by phenethylammonium iodide (PEAI) and 4‐fluorophenethylammonium iodide (FPEAI) effectively passivates surface defects in 2D phenethylammonium tin iodide (PEA2SnI4) films, increases the grain size by surface recrystallization, and p‐dopes the PEA2SnI4 film to form a better energy‐level alignment with the electrodes and promote charge transport properties. As a result, the passivated devices exhibit better ambient and gate bias stability, improved photo‐response, and higher mobility, for example, 2.96 cm2 V−1 s−1 for the FPEAI‐passivated films—four times higher than the control film (0.76 cm2 V−1 s−1). In addition, these perovskite transistors display non‐volatile photomemory characteristics and are used as perovskite‐transistor‐based memories. Although the reduction of surface defects in perovskite films results in reduced charge retention time due to lower trap density, these passivated devices with better photoresponse and air stability show promise for future photomemory applications.
Surface passivation of two‐dimensional PEA2SnI4 films with organic ligands proves to be effective in protecting the films from oxygen and moisture, and in improving the performance of the transistors. On the one hand, the degradation rate after passivation is retarded. On the other hand, passivation leads to fewer defect states and better energy‐level alignment, yielding higher mobility and light‐induced photocurrents.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
MALDI-TOF spectrometry has not been used for urinary exosome analysis. We used it for determining UC biomarkers. From 2012 to 2015, we enrolled 129 consecutive patients with UC and 62 participants ...without UC. Exosomes from their urine were isolated, and analyzed through MALDI-TOF spectrometry. Immunohistochemical (IHC) analysis of another 122 UC and 26 non-UC tissues was conducted to verify the discovered biomarkers. Two peaks at m/z 5593 (fragmented peptide of alpha-1-antitrypsin; sensitivity, 50.4%; specificity, 96.9%) and m/z 5947 (fragmented peptide of histone H2B1K sensitivity, 62.0%; specificity, 92.3%) were identified as UC diagnosis exosome biomarkers. UC patients with detectable histone H2B1K showed 2.29- and 3.11-fold increased risks of recurrence and progression, respectively, compared with those with nondetectable histone H2B1K. Verification results of IHC staining revealed significantly higher expression of alpha 1-antitrypsin (p = 0.038) and H2B1K (p = 0.005) in UC tissues than in normal tissues. The expression of alpha 1-antitrypsin and H2B1K in UC tissues was significantly correlated with UC grades (p < 0.05). Urinary exosome proteins alpha 1-antitrypsin and histone H2B1K, which are identified through MALDI-TOF analysis, could facilitate rapid diagnosis and prognosis of UC.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
To evaluate the practicability of combining prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) for the detection of clinically significant prostate cancer ...(csPC) in an Asian population.
Patients and methods
We prospectively enrolled patients who underwent prostate biopsy due to elevated serum prostate-specific antigen (PSA > 4 ng/mL) and/or abnormal digital rectal examination in a tertiary referral center. Before prostate biopsy, the serum samples were tested for PSA, free PSA, and p2PSA to calculate PHI. Besides, mpMRI was performed using a 3-T scanner and reported in the Prostate Imaging Reporting and Data System version 2 (PI-RADS v2). The diagnostic performance of PHI, mpMRI, and combination of both was assessed.
Result
Among 102 subjects, 39 (38.2%) were diagnosed with PC, including 24 (23.5%) with csPC (Gleason ≥ 7). By the threshold of PI-RADS ≥ 3, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to predict csPC were 100%, 44.9%, 35.8%, and 100%, respectively. By the threshold of PHI ≥ 30, the sensitivity, specificity, PPV, and NPV to predict csPC were 91.7%, 43.6%, 33.3%, and 94.4%, respectively. The area under the receiver operator characteristic curve of combining PHI and mpMRI was greater than that of PHI alone (0.873 vs. 0.735,
p
= 0.002) and mpMRI alone (0.873 vs. 0.830,
p
= 0.035). If biopsy was restricted to patients with PI-RADS 5 as well as PI-RADS 3 or 4 and PHI ≥ 30, 50% of biopsy could be avoided with one csPC patient being missed.
Conclusion
The combination of PHI and mpMRI had higher accuracy for detection of csPC compared with PHI or mpMRI alone in an Asian population.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Purpose
Currently, there are no accurate markers for predicting potentially lethal prostate cancer (PC) before biopsy. This study aimed to develop urine tests to predict clinically ...significant PC (sPC) in men at risk.
Methods
Urine samples from 928 men, namely, 660 PC patients and 268 benign subjects, were analyzed by gas chromatography/quadrupole time-of-flight mass spectrophotometry (GC/Q-TOF MS) metabolomic profiling to construct four predictive models. Model I discriminated between PC and benign cases. Models II, III, and GS, respectively, predicted sPC in those classified as having favorable intermediate risk or higher, unfavorable intermediate risk or higher (according to the National Comprehensive Cancer Network risk groupings), and a Gleason sum (GS) of ≥ 7. Multivariable logistic regression was used to evaluate the area under the receiver operating characteristic curves (AUC).
Results
In Models I, II, III, and GS, the best AUCs (0.94, 0.85, 0.82, and 0.80, respectively; training cohort, N = 603) involved 26, 24, 26, and 22 metabolites, respectively. The addition of five clinical risk factors (serum prostate-specific antigen, patient age, previous negative biopsy, digital rectal examination, and family history) significantly improved the AUCs of the models (0.95, 0.92, 0.92, and 0.87, respectively). At 90% sensitivity, 48%, 47%, 50%, and 36% of unnecessary biopsies could be avoided. These models were successfully validated against an independent validation cohort (N = 325). Decision curve analysis showed a significant clinical net benefit with each combined model at low threshold probabilities. Models II and III were more robust and clinically relevant than Model GS.
Conclusion
This urine test, which combines urine metabolic markers and clinical factors, may be used to predict sPC and thereby inform the necessity of biopsy in men with an elevated PC risk.
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Digital game-based learning is a popular strategy for engaging students by making learning fun. Actively involving students as designers and producers of digital games may have even greater potential ...for student empowerment through enhancing concentration and engagement, fostering higher order thinking, and improving learning outcomes. Thus, this study empirically investigated the impact of digital game authoring on students' concentration, critical thinking skills, and academic achievement. A total of 67 students in two seventh-grade classes participated in this 19-week-long experiment, and were divided into an experimental group (32 students designing digital games) and a comparison group (35 students designing Flash animations). The interdisciplinary approach involved integrating biology and computer programming classes. Students in the experimental group designed digital games based upon biology course content, while the comparison group collaboratively produced Flash animations based upon the same course content. The experimental results, using MANCOVA for pretest, posttest, and delayed posttest scores, demonstrate significant improvements in critical thinking skills, and academic achievement, with increased retention of both course content and critical thinking skills observed for the delayed posttest. For concentration, a relative advantage for the experimental group as compared with the comparison group was noted, but did not reach statistical significance. Based on the results of this study, implications for practitioners and researchers are provided, including the integration of programming or computer science with other courses for digital game authoring and the evaluation of other learning outcomes such as creative thinking, problem-solving, and flow.
•Student design of digital games empowers learners to construct knowledge.•Student-designed digital games improve critical thinking and academic achievement.•Student-designed games can effectively integrate course content with ICT skills.•Challenge, complexity, creativity, and collaboration enhance digital game design.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Chamaecyparis formosensis is an endemic species of Taiwan, threatened from intensive use and illegal felling. An individual identification system for C. formosensis is required to provide scientific ...evidence for court use and deter illegal felling. In this study, 36 polymorphic simple sequence repeat markers were developed. By applying up to 28 non-linked of the developed markers, it is calculated that the cumulative random probability of identity (CP
) is as low as 1.652 × 10
, and the identifiable population size is up to 60 million, which is greater than the known C. formosensis population size in Taiwan. Biogeographical analysis data show that C. formosensis from four geographic areas belong to the same genetic population, which can be further divided into three clusters: SY (Eastern Taiwan), HV and GW (Northwestern Taiwan), and MM (Southwestern Taiwan). The developed system was applied to assess the provenance of samples with 88.44% accuracy rate and therefore can serve as a prescreening tool to reduce the range required for comparison. The system developed in this study is a potential crime-fighting tool against illegal felling.
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