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A graphene-base hot electron transistor integrated with a 2D material heterojunction is demonstrated as a frequency modulator. Our device can operate as a doubler or tripler with AC signals from 100 kHz to 10 MHz in single tunneling transistor.

肺腺癌的早期精準診斷以及其抗藥性的生成一直是臨床上的挑戰。近年來發現 到微核酸 29C 以及類二型賴氨酸氧化酶分別扮演的抑癌以及促癌角色。然而,微核 酸 29C/ 類二型賴氨酸氧化酶軸線的臨床意義以及生物功能尚未釐清。本研究應用 多體學策略探討微核酸 29C/ 類二型賴氨酸氧化酶軸線是否可作為肺腺癌預測模組以 及作為治療標的的潛力。自 cBioPortal 伺服器擷取 7,561 件肺腺癌檢體中,微核酸 29C 的突變光譜展現隨機分布,擴增率僅 3%,且基因套數變化不影響病人存活時 間。相比之下,低表達微核酸 29C 與短存活時間顯著相關,且與類二型賴氨酸氧化 酶呈現負相關。高表達類二型賴氨酸氧化酶與短存活時間顯著相關,並且與 CD8 陽 性 T 細胞呈現負相關,而與癌相關纖維母細胞呈現正相關,顯示出抑制免疫的腫瘤 微環境特徵。此外,微核酸 29C 與臨床分期呈現負向關聯性。TargetScan 生資工具 預測出微核酸 29C 的 3’ 端可標靶類二型賴氨酸氧化酶的兩處 3’ 端未轉譯區,核苷 酸位序 555-561 以及 757-763,表明微核酸 29C 有抑制類二型賴氨酸氧化酶的潛力。 總結本研究發現低表達微核酸 29C 連同高表達類二型賴氨酸氧化酶可預測肺腺癌不 良預後。微核酸 29C/ 類二型賴氨酸氧化酶軸線指出一肺腺癌新生物路徑以及治療 標的。 The early, precise diagnosis and drug resistance of lung adenocarcinoma (LUAD) remains a challenging issue. The tumor suppression role of microRNA- 29C (MIR29C) and the tumor promotion role of lysyl oxidase-like 2 (LOXL2) have recently been observed. However, the clinical implication and biological function of MIR29C/lysyl oxidase-like 2 (LOXL2) axis remains unclear. In this study, we utilized the multi-omic approach to investigate whether the MIR29C/LOXL2 axis can serve as a prediction panel and determine its potential as therapeutic targets. Using the cBioPortal server, the mutation landscape of MIR29C in LUAD samples showed that the mutation spectrum presented a random distribution and the amplification rate was as low as 3%, while LOXL2 presented as 6%. The copy number alteration of MIR29C had no effect on the overall survival (OS) rate, whereas that of LOXL2 was associated with poor OS. In contrast, the low expression of MIR29C was significantly associated with shorter OS. MIR29C negatively correlated with LOXL2 mRNA level. High expression of LOXL2 was significantly associated with shorter OS, and connected with lower infiltration levels of CD8+T cells and higher infiltrate levels of cancer associated fibroblast, representing hallmarks of an immunosuppressive tumor microenvironment. In addition, MIR29C showed a negative association with advanced stages. Using TargetScan Release 7.2, MIR29C-3p was predicted to target LOXL2 3’UTR at position 555-561 and position 757-763, suggesting its inhibitory potential on LOXL2 expression. In summary, this study revealed that low expression of MIR29C and high expression of LOXL2 predict poor outcomes for LUAD patients. The MIR29C/LOXL2 axis may point out a new biological pathway that could be a potential therapeutic target for LUAD. &nbsp

Hepatocellular carcinoma (HCC) is a highly invasive malignancy. Recently, GATOR1 (Gap Activity TOward Rags 1) complexes have been shown to play an important role in regulating tumor growth. NPRL2 is a critical component of the GATOR1 complex. Therefore, this study used NPRL2 knockdown to investigate how GATORC1 regulates the prognosis and development of HCC via the mammalian target of rapamycin (mTOR) and autophagy signaling pathways. We established HepG2 cells with NPRL2 knockdown using small interfering RNA (siRNA) and short hairpin RNA (shRNA) systems. The siRNA-mediated and shRNA-mediated NPRL2 down-regulation significantly reduced the expression of NPRL2 and two other GATPOR1 complex components, NPRL3 and DEPDC5, in HepG2 cells; furthermore, the efficient down-regulation of NPRL2 protein expression by both the shRNA and siRNA systems enhanced the proliferation, migration, and colony formation in vitro. Additionally, the NPRL2 down-regulation significantly increased HCC growth in the subcutaneous and orthotopic xenograft mouse models. The NPRL2 down-regulation increased the Rag GTPases and mTOR activation and inhibited autophagy in vitro and in vivo. Moreover, the NPRL2 level in the tumors was significantly associated with mortality, recurrence, the serum alpha fetoprotein level, the tumor size, the American Joint Committee on Cancer stage, and the Barcelona Clinic Liver Cancer stage. Low NPRL2, NPRL3, DEPDC5, and LC3, and high p62 and mTOR protein expression in the tumors was significantly associated with disease-free survival and overall survival in 300 patients with HCC after surgical resection. Conclusion: The efficient down-regulation of NPRL2 significantly increased HCC proliferation, migration, and colony formation in vitro, and increased HCC growth in vivo. Low NPRL2 protein expression in the tumors was closely correlated with poorer clinical outcomes in patients with HCC. These results provide a mechanistic understanding of HCC and aid the development of treatments for HCC.

Background The inner membrane mitochondrial protein (IMMT) is a central unit of the mitochondrial contact site and cristae organizing system (MICOS). While researchers continue to demonstrate the physiological function of IMMT in regulating mitochondrial dynamics and preserving mitochondrial structural integrity, the roles of IMMT in clinicopathology, the tumor immune microenvironment (TIME), and precision oncology in breast cancer (BC) remain unclear. Methods Multi-omics analysis was used here to evaluate the diagnostic and prognostic value of IMMT. Web applications aimed at analyzing the whole tumor tissue, single cells, and spatial transcriptomics were used to examine the relationship of IMMT with TIME. Gene set enrichment analysis (GSEA) was employed to determine the primary biological impact of IMMT. Experimental verification using siRNA knockdown and clinical specimens of BC patients confirmed the mechanisms behind IMMT on BC cells and the clinical significance, respectively. Potent drugs were identified by accessing the data repositories of CRISPR-based drug screenings. Results High IMMT expression served as an independent diagnostic biomarker, correlated with advanced clinical status, and indicated a poor relapse-free survival (RFS) rate for patients with BC. Although, the contents of Th1, Th2, MSC, macrophages, basophil, CD4 + T cell and B cell, and TMB levels counteracted the prognostic significance. Single-cell level and whole-tissue level analyses revealed that high IMMT was associated with an immunosuppressive TIME. GSEA identified IMMT perturbation as involved in cell cycle progression and mitochondrial antioxidant defenses. Experimental knockdown of IMMT impeded the migration and viability of BC cells, arrested the cell cycle, disturbed mitochondrial function, and increased the ROS level and lipid peroxidation. The clinical values of IMMT were amenable to ethnic Chinese BC patients, and can be extrapolated to some other cancer types. Furthermore, we discovered that pyridostatin acted as a potent drug candidate in BC cells harboring an elevated IMMT expression. Conclusion This study combined a multi-omics survey with experimental verification to reveal the novel clinical significance of IMMT in BC, demonstrating its role in TIME, cancer cell growth and mitochondrial fitness, and identified pyridostatin as a promising drug candidate for the development of precision medicine.

ObjectiveDespite the relatively high prevalence of attention deficit hyperactivity disorder (ADHD), the impairment of ADHD in women is underestimated due to the different ways the phenomenon manifests compared to traditional male symptoms. In order to close the gender gap in diagnosis and treatment, this study aims to explore the impact of gender on auditory and visual attention in children with and without ADHD.MethodA total of 220 children with and without ADHD participated in this study. Their auditory and visual attention performances were analyzed by comparative computerized auditory and visual subtests.ResultsAuditory and visual attention performance in children with and without ADHD did affect by gender, including typically developing (TD) boys are better than TD girls at distinguishing visual targets from non-target stimuli. When performing attention tasks, TD girls generally maintained a cautious response, which was different from TD boys, who generally adopted positive response methods. ADHD girls suffered from more serious auditory inattention problems than ADHD boys; however, ADHD boys suffered from more auditory and visual impulsive problems than ADHD girls. The internal attention problems of female ADHD children were broader than that of their male ADHD peers and were also more severe, especially in problems of auditory omission and auditory response acuity.ConclusionsADHD children had a significant gap in auditory and visual attention performance compared to TD children. The research results support the impact of gender on the performance of auditory and visual attention in children with and without ADHD.

Objective Numerous studies support that simple visual search tests may not be sufficient to differentiate children with and without attention-deficit/hyperactivity disorder (ADHD), especially for older school-aged children. This study aimed to explore whether the high spatial uncertainty visual search tasks can effectively discriminate older school-aged children with ADHD from their typically developing (TD) peers. Method In a randomized, two-period crossover design, 122 school-aged children (61 ADHD and 61 TD subjects), aged 10–12 years old, were measured using comparable visual search tasks with structured and unstructured layouts. Results First, the discriminant effectiveness of unstructured visual search tasks, which are associated with high-level spatial uncertainty, is superior to structured ones. Second, combining accuracy and speed into a Q score is a more sensitive measure than accuracy or time calculated alone in visual search tasks. A more in-depth ROC analysis showed that all variables could accurately identify ADHD from their TD peers under unstructured visual search tasks, with the index of the Q score performing best (AUR = 0.956). Third, the development of detectability, which represents the ability to distinguish between target and non-target, is approaching maturity in 10–12-year-old children with ADHD. However, these children showed severe deficits in dealing with disorganized distractors when performing visual search tasks with high-level spatial uncertainty. Conclusions The findings of this study support that older school-aged children with ADHD demonstrate less efficient search performance than their TD peers in complex/difficult visual search tasks, especially under higher spatial uncertainty.

The study aimed to determine the oil content and identify fatty acid methyl esters such as stearate, palmitate, linolenate, linoleate, and oleate in seeds and nuts like candlenut, peanut, sesame, sunflower, and sacha inchi. Oil extraction was carried out using Soxtec 8000TM and n-hexane solvent. The samples were dried at 50℃. The extraction conditions optimized were temperature 135℃, n-hexane 50 mL, boiling time 40 min, and total extraction time 115 min. Identification of fatty acids was carried out using Attenuated Total Reflection (ATR), Nuclear Magnetic Resonance (NMR), and Gas Chromatography-Flames Ionization Detector (GC-FID). The oil percentage detected in each sample was candlenut (59.95%), peanut (40.08%), sesame (57.06%), sunflower (43.97%), and sacha inchi (51.71). The ATR results show that the flour of nuts and seeds has a strong vibrational frequency of the O−H molecule. Linolenate was detected at a chemical shift of 0.975 ppm in NMR spectra and was found in sacha inchi and candlenut. The ATR, NMR, and GC-FID results showed that all samples contained unsaturated fatty acids. Candlenut, peanut, sesame, and sacha inchi were rich in linoleate (ω-6) as much as 25.68%, 20.15%, 26.38%, and 20.73%, respectively. Oleate was abundant in sesame (21.87%) and sunflower (16.78%). Linolenate was found only in sacha inchi (22.88%). The maximum percentage of stearate was found in sunflower (4.02%) followed by sesame (2.96%), candlenut (1.81%), sacha inchi (1.52%), and peanut (0.71%). This research provides useful information on fatty acid profiles beneficial for health, especially stearic acid, which can substitute trans fatty acids harmful to health.

The two objectives of this systematic review were to examine the following: (1) the difference in sensory processing areas (auditory, visual, vestibular, touch, proprioceptive, and multi-sensory) between children with and without developmental coordination disorder (DCD), and (2) the relationship between sensory processing and motor coordination in DCD. The following databases were comprehensively searched for relevant articles: PubMed, Science Direct, Web of Science, and Cochrane library. There were 1107 articles (published year = 2010 to 2021) found in the initial search. Full-text articles of all possibly relevant citations were obtained and inspected for suitability by two authors. The outcome measures were sensory processing impairments and their relationship with motor coordination. A total of 10 articles met the inclusion criteria. Children with DCD showed significant impairments in visual integration, tactile integration, proprioceptive integration, auditory integration, vestibular integration, and oral integration processes when compared with typically developing children. Evidence also supported that sensory processing impairments were associated with poor motor coordination in DCD. Preliminary support indicated that DCD have sensory processing impairments in visual, tactile, proprioceptive, auditory, and vestibular areas, which might contribute to participation restriction in motor activities. It is important to apply sensory integration therapy in rehabilitation programs for DCD in order to facilitate participation in daily activities.

Background: Interleukin-6 (IL-6) was found to induce aberrant methylation in critical genes involved in insulin signaling and angiogenesis in humans, presumably due to protein stabilization of DNA methyltransferases. Whether IL-6 and DNMT1 impact breast cancer (BC) prognosis remains unknown. Methods TIMER2.0 web server was used for comprehensive analysis from TCGA. Associations between DNMT1 and IL-6 in tumor immune microenvironment was explored via single cell sequencing (SCS) from TISCH. IL-6 and DNMT1 expressions were investigated in tissue microarray of our own cohort (n = 285) as well as in BC cell-lines. Invasion activity was compared between high and low IL-6/DNMT expressing BC cell-lines treated with/without IL-6 antibody. Results DNMT1 mRNA was significantly higher in the BC tissues (p

Background: Human endothelial progenitor cells (hEPCs), originating from hemangioblasts in bone marrow (BM), migrate into the blood circulation, differentiate into endothelial cells, and could act as an alternative tool for tissue regeneration. In addition, trimethylamine-N-oxide (TMAO), one of the gut microbiota metabolites, has been identified as an atherosclerosis risk factor. However, the deleterious effects of TMAO on the neovascularization of hEPCs have not been studied yet. Results: Our results demonstrated that TMAO dose-dependently impaired human stem cell factor (SCF)-mediated neovascularization in hEPCs. The action of TMAO was through the inactivation of Akt/endothelial nitric oxide synthase (eNOS), MAPK/ERK signaling pathways, and an upregulation of microRNA (miR)-221. Docosahexaenoic acid (DHA) could effectively inhibit the cellular miR-221 level and induce the phosphorylation level of Akt/eNOS, MAPK/ERK signaling molecules, and neovascularization in hEPCs. DHA enhanced cellular amounts of reduced form glutathione (GSH) through an increased expression of the gamma-glutamylcysteine synthetase (γ-GCS) protein. Conclusions: TMAO could significantly inhibit SCF-mediated neovascularization, in part in association with an upregulation of miR-221 level, inactivation of Akt/eNOS and MAPK/ERK cascades, suppression of γ-GCS protein, and decreased levels of GSH and GSH/GSSG ratio. Furthermore, the DHA could alleviate the detrimental effects of TMAO and induce neovasculogenesis through suppression of miR-221 level, activation of Akt/eNOS and MAPK/ERK signaling cascades, increased expression of γ-GCS protein, and increment of cellular GSH level and GSH/GSSG ratio in hEPCs.

This study assessed the benefits and efficacy of bariatric surgery (BS) in reducing the risk of cancer in Asians with morbid obesity. Records for patients aged between 18 and 55 years whose diagnoses corresponded with the ICD-9 codes for obesity and BS were extracted from the National Health Insurance Research Database (NHIRD) in Taiwan between 2000 and 2015. The patients who underwent BS (BS group), those who did not undergo BS (NS group), and the general population (GP group) were propensity score matched. The outcome was newly diagnosed malignancy. Data were extracted from the Registry for Catastrophic Illness Patient Database (RCIPD) of the NHIRD. The BS group developed significantly less malignancy (1.18%) than the GP group (1.46%, p = 0.0364). There was no statistically significant difference in malignancy risk between the BS and GP groups (aHR =1.00, p = 0.9997). The NS group developed significantly higher malignancy (2.48%) than the GP group (1.97%, p < 0.0001). There was a significantly higher malignancy risk in the NS group (aHR =1.22, p < 0.0001) than in the GP group. In the subgroup analysis, the malignancy risks of the NS group were significantly higher in the subgroup of men aged between 18 and 35 years (aHR =1.37, p = 0.003) and women aged between 18 and 35 years (aHR = 1.62, p < 0.0001), and 35–55 years (aHR = 1.27, p < 0.0001). All the subgroup analyses between the BS and GP groups demonstrated no significant differences. Our study demonstrated that BS reduced the risk of malignancy in patients with morbid obesity, particularly in women and young men.

(1) Background: Interleukin-6 (IL-6) is a multifunctional cytokine that was found to cause epigenetic changes by regulating DNA methyltransferase 1 (DNMT1). IL-6 has al-so been found to promote tumor progression and chemoresistance in numerous types of cancers. However, it remains unknown how IL-6 and DNMT1 may impact prognosis in different breast cancer types. (2) Methods: Patient survival rate in breast cancer patients and DNMT1 expression pattern was examined in TCGA datasets. Protein expression pattern of IL-6 and DNMT1 were investigated in the tissue microarray in our cohort (n=285, Show Chwan Memorial Hospital, Changhua) by immunohistochemistry (IHC). IL-6 and DNMT1 expressions were examined in breast cancer cell-lines. Cell invasion activity was compared between high and low IL-6/DNMT expressing breast cancer cell lines, and between cells treated with/without IL-6 antibody. (3) Results: DNMT1 mRNA level was significantly higher in the breast tumor tissues (p (4) Conclusions: IL-6-DNMT1 axis could be responsible for HER2-positive breast cancer progression in tumor immune microenvironment. Our study suggests that IL-6 inhibition in combination with anti-HER2 therapy might be an effective approach in particular for HER2-positive patients with a potential to become a standard therapeutic strategy.

As the source of several anticancer drugs, the marine environment is a treasure trove for the discovery of new drugs. In this study, a sesterterpenoid-type natural product heteronemin was investigated as a potential ferroptotic agent in the pancreatic cancer cell line (Panc-1). The effect of heteronemin on lipid peroxidation and autophagy- and ferritin-related protein expressions was examined using spectrophotometric and immunoblotting techniques, respectively. As well, several preclinical cell-based tests were used for the anticancer assessment. Results: Heteronemin at 55 nM concentration reduced cell viability by 50%. Heteronemin-induced cell death was reversed by a ferroptosis inhibitor, Ferrostatin-1. The levels of ferroptosis markers and malondialdehyde (MDA) were upregulated by heteronemin treatment while glutathione peroxidase-4 (GPX4) protein expression was downregulated. Also, significant alterations in ferritinophagy- and iron-related proteins (Atg5, Atg7, FTL, STEAP3, and DMT-1) were observed in Panc-1 cells (p < 0.05). Conclusions: The obtained results indicated that heteronemin exerted its pharmacological effect via triggering ferroptosis in pancreatic cancer. The potent cytotoxic effect of heteronemin suggested its potential development as a drug lead in the war against cancer.

Background To present a case with a history of laser in situ keratomileusis (LASIK) developing diffuse lamellar keratitis (DLK) after diamond burr superficial keratectomy (DBSK) for recurrent corneal erosion (RCE). Case presentation A 25-year-old man presented with multiple episodes of RCE one year after femtosecond-assisted LASIK for myopia correction. Because conservative treatments failed to halt the repetitive attack of RCE, he underwent epithelial debridement and DBSK. However, severe foreign body sensation and blurred vision developed on postoperative day one. The next day, slit lamp biomicroscopy revealed DLK manifested as diffuse granular infiltrates at the flap interface. After topical corticosteroid treatment, the inflammation resolved gradually, and his vision recovered to 20/20. Conclusions Diffuse lamellar keratitis is a rare post-LASIK complication that can be triggered by DBSK, which causes impairment of the corneal epithelial integrity and subsequent inflammation at the flap interface. For post-LASIK patients with RCE, alternative treatments, such as anterior stromal puncture, may be considered to avoid extensive disruption of corneal epithelium and DLK development depending on the size and the location of the lesions.

Triple-negative breast cancer (TNBC) is characterized by poor outcome and the most challenging breast cancer type to treat worldwide. TNBC manifests distinct profile of mitochondrial functions, which dictates reprogrammed metabolism, fosters tumor progression, and notably serves as therapeutic targets. Mitochondrial microRNAs (mitomiRs) are a group of microRNAs that critically modulate mitochondrial homeostasis. By a pathway-centric manner, mitomiRs tightly orchestrate metabolic reprogramming, redox status, cell apoptosis, mitochondrial dynamics, mitophagy, mitochondrial DNA (mtDNA) maintenance, and calcium balance, leading to an emerging field of study in various cancer types, including TNBC. We herein review the recent insights into the roles and mechanism of mitomiRs in TNBC and highlight its clinical value in diagnosis and prognosis as well as vital advances on therapeutics of preclinical and clinical studies.

Objectives. Our study investigated the effects of 830 nm light-emitting diode therapy (LEDT) for postexercise delayed-onset muscle soreness (DOMS). Methods. In this randomized control study, healthy participants were randomized into LEDT and placebo groups. LEDT (output frequency = 10 Hz; wavelength = 830 nm; total output power = 210 mW; and dose = 315 J/cm2) was applied to six sites in the damaged quadriceps for 10 min. The placebo group received sham LEDT with no energy output. The nondominant leg was chosen for DOMS induction, using an eccentric exercise. Visual analog scale (VAS) scores for muscle soreness, pressure pain threshold (PPT), thigh circumference, joint range of motion, and muscle strength were assessed before and immediately after exercise and at 24, 48, 72, and 96 h postexercise. Results. Forty participants were divided into the LEDT group (n = 20) and the placebo group (n = 20). Compared with the placebo group, the LEDT group exhibited significant increases in PPT values at 48, 72, and 96 h postexercise ( p < 0.05 ). The joint range of motion was significantly different between the LEDT and placebo groups at 72 and 96 h postexercise ( p < 0.05 ). No significant intergroup differences were noted in thigh circumference and muscle strength ( p < 0.05 ). Conclusion. The application of 830 nm LEDT on postexercise DOMS pain exerted an analgesic effect but did not affect the muscle repair process. Future studies should elucidate the beneficial effects of 830 nm LEDT on muscle recovery or performance.

Mycotoxins are naturally occurring toxins produced by certain molds and can be found in nuts, cereals, fruits, and oils. Furthermore, current food processing systems cannot wholly remove mycotoxins. The adverse health effects of chewing betel nut containing mycotoxins range from long-term consequences such as immune deficiency. In this study, a rapid solid-phase extraction (SPE) method to LC-MS/MS system was developed to determine nine mycotoxins in commonly used five types of betel nut products. The SPE eluate was injected into a Phenomenex UHPLC Kinetex Polar C18 Column (2.1 × 100 mm, 2.6 mm) and detected by an Agilent 6470 triple-quadrupole mass spectrometer. All mycotoxins were separated under 6.8 min with electrospray ionization in multiple reaction monitoring modes. The calibration curves ranged from 0.5 to 600 ng/mL (r2>0.99), LOQ values were between 0.25 to10 ng/mL, and LOD values were between 5 to 20 ng/mL. All the QCs have shown precision, and the accuracy range for intra-day and inter-day did not exceed 14.3% (RSD) and 91.2 to 117.6% (relative error). The matrix effect and extraction recovery for five types of betel nuts were in the range of 81.5 to 99.2% and 70.1 to 113.9%, respectively (except deoxynivalenol).

This study presents the design, implementation, and characterization of 1D resonant type micro-electro-mechanical-systems (MEMS) piezoelectric scanning mirrors with different actuator designs to investigate their influences on the figure of merits (FoMs) for automotive light detection and ranging application. The MEMS scanning mirrors are driven by lead zirconate titanate (PZT) thin film in this study owing to its outstanding piezoelectric properties. Three different beam-type piezoelectric actuators are designed, including the reference meander straight-beam actuator design, and the proposed meander curved-beam and straight-curved tapered beam actuator designs. Simulations show the scan angle enhancement for two proposed designs, yet the resonant scanning frequency of meander curved-beam design dropped to below the 2 kHz requirement. To evaluate the designs, scanning mirrors with two proposed actuators are fabricated and tested. Measurements show that the resonant frequencies for the two proposed MEMS scanning mirrors are 1735 Hz and 2578 Hz, respectively. Two proposed designs respectively have the maximum optical angles of 48.1° and 50.6° at the 20 Vpp driving voltage. Due to the much higher stress on the beam structure induced by the misalignment of PZT film, the actuator could not reach the predicted scanning angle of near 80°. In comparison of the two proposed designs, the straight-curved tapered beam actuator design could enhance the FoM for about 56%. In summary, the performances of piezoelectric MEMS scanning mirror can be improved by varying the designs of length and shape of actuator, and the distribution of PZT film on the suspended actuator is also a critical design concern.

Background Targeting the HGF/MET signaling pathway has been a viable therapeutic strategy for various cancer types due to hyperactivation of HGF/MET axis occurs frequently that leads to detrimental cancer progression and recurrence. Deciphering novel molecule mechanisms underlying complex HGF/MET signaling network is therefore critical to development of effective therapeutics for treating MET-dependent malignancies. Results Using isobaric mass tag-based quantitative proteomics approach, we identified IFITM3, an interferon-induced transmembrane protein that was highly expressed in micro-dissected gastric cancer (GC) tumor regions relative to adjacent non-tumor epithelia. Analyses of GC clinical specimens revealed that expression IFITM3 was closely correlated to advanced pathological stages. IFITM3 has been reported as a PIP3 scaffold protein that promotes PI3K signaling. In present study, we unprecedentedly unraveled that IFITM3 associated with MET and AKT to facilitate HGF/MET mediated AKT signaling crosstalk in suppressing FOXO3, consequently leading to c-MYC mediated GC progression. In addition, gene ontology analyses of the clinical GC cohort revealed significant correlation between IFITM3-associated genes and targets of c-MYC, which is a crucial downstream effector of HGF/MET pathway in cancer progression. Moreover, we demonstrated ectopic expression of IFITM3 suppressed FOXO3 expression, consequently led to c-MYC induction to promote tumor growth, cell metastasis, cancer stemness as well as chemoresistance. Conversely, depletion of IFITM3 resulted in suppression of HGF triggered cellular growth and migration via inhibition of AKT/c-MYC signaling in GC. Conclusions In summary, our present study unveiled a novel regulatory mechanism for c-MYC-driven oncogenesis underlined by IFITM3-mediated signaling crosstalk between MET associated AKT signaling cascade.

The early diagnosis, prognostic prediction, and personalized therapy of lung adenocarcinoma (LUAD) remains a challenging issue.

We aim to investigate the association of mood disorders with age-related macular degeneration (AMD). This retrospective cohort study used data from 2000 and 2016 from National Health Insurance Research Database (NHIRD) in Taiwan. Patients with AMD diagnosis formed the exposed group, and an age- and sex-matched group without AMD served as the nonexposed group. Main outcomes were the incidence of mood disorders including psychological counseling, behavior therapy, sleep or anxiety-related disorders, and major depressive disorders (MDDs) in the exposed and non-exposed groups. The Cox proportional hazard regression analysis was used to evaluate the incidence and adjusted hazard ratio (aHR) of mood disorders. A total of 5916 and 11,832 individuals with and without AMD were enrolled into the exposed and nonexposed groups. There were 1017 (17.19%) and 1366 (11.54%) episodes of mood disorders occurred in the exposed and nonexposed groups, respectively. The aHRs of any psychological counseling, behavioral therapy, sleep or anxiety-related disorders, and MDD were significantly higher in patients with AMD than in those without AMD (all P P 70 years, and women without AMD. In conclusion, AMD occurrence leads to an increased rate of mood disorders, particularly among those with dry-AMD, middle aged participants (aged 50–70), and women.

Background and Objectives: Flail chest typically results from major trauma to the thoracic cage and is accompanied by multiple rib fractures. It has been well documented that surgical fixation of rib fractures can decrease both morbidity and mortality rates. This study aimed to evaluate the effectiveness of a dedicated APS Rib Fixation System, which features a pre-contoured design based on anatomical rib data of the Asian population. Materials and Methods: We reviewed 43 consecutive patients, who underwent surgical stabilization for flail chest with the traditional Mini bone plate (n = 20), APS plate (n = 13), or Mini + APS (n = 10). Demographic and injury variables were documented. We used X-ray radiography to determine plate fractures and screw dislocations after surgical fixation. Results: No statistical differences were noted in the demographic or injury variables. APS plates demonstrated fewer cases of plate fractures and screw dislocations than Mini plates (OR = 0.091, p = 0.008). Conclusions: The pre-contoured design of the APS plate demonstrated a superior rib implant failure rate as compared to the traditional Mini bone plate. Our study indicates that the APS plate may serve as an effective surgical tool for the treatment of flail chest.

Objectives. Evidence for the effects of acupuncture on delayed-onset muscle soreness (DOMS) is inconsistent. The aim of this study was to explore the effects of acupuncture on DOMS. Methods. Studies investigating the effect of acupuncture on DOMS in humans that were published before March 2020 were obtained from eight electronic databases. The affected muscles, groups, acupuncture points, treatment sessions, assessments, assessment times, and outcomes of the included articles were reviewed. The data were extracted and analyzed via a meta-analysis. Results. A total of 15 articles were included, and relief of DOMS-related pain was the primary outcome. The statistical meta-analysis showed that there were no significant differences between acupuncture and sham/control groups, except for acupuncture for DOMS on day 1 (total SMD = −0.62; 95% CI = −1.12∼0.11, P<0.05) by comparing with control groups. Conclusion. Acupuncture for DOMS exhibited very-small-to-small and small-to-moderate effects on pain relief for the sham and no acupuncture conditions, respectively. Evidence indicating the effects of acupuncture on DOMS was little because the outcome data during the follow-up were insufficient to perform an effective meta-analysis.

Graphene oxide (GO) has the ability to absorb certain compounds, and it can be modified with functional groups for different purposes; for instance, iron oxide (IO) nanoparticles can be used to concentrate analyte by a magnet. Recently, many kinds of GO have been developed, such as single-layer GO (SLGO), two-to-four layers of GO (i.e., few-layer GO, FLGO2–4), and four-to-eight layers of GO (i.e., multi-layer GO, MLGO4–8). However, the abilities of these layered GO coated with IO nanoparticles have not been investigated. In this study, we conducted a novel analysis of glimepiride by using layered GO-coated magnetic clusters of IO nanoparticles that were synthesized through a simple and facile emulsion-solvent evaporation method. The methodology is based on (i) enrichment of glimepiride using the layered GO-coated magnetic clusters of IO nanoparticles (IO@SLGO, IO@FLGO2–4, and IO@MLGO4–8), and (ii) rapid determination using magnetic cluster–based surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-TOFMS). We found that IO@MLGO4–8, the magnetic cluster with the greatest number of GO layers, had the best limit of detection (28.6 pmol/μL for glimepiride). The number of GO layers played a significant role in increasing the sensitivity of the SALDI-MS, indicating that the size of GO in the magnetic clusters contributed to the desorption/ionization efficiency. To the best of our knowledge, this is the first study to enrich glimepiride using magnetic clusters of different GO types and to show that the glimepiride in HLB purified urine adsorbed by magnetic clusters can be analyzed by SALDI-TOFMS.

High-risk neuroblastoma is associated with low long-term survival rates due to recurrence or metastasis. Retinoids, including 13-cis-retinoic acid (13cRA), are commonly used for the treatment of high-risk neuroblastoma after myeloablative therapy; however, there are significant side effects and resistance rates. In this study, we demonstrated that 13cRA has a better antiproliferative effect in MYCN-amplified neuroblastoma cells than in MYCN-nonamplified neuroblastoma cells. In MYCN-amplified SK-N-DZ cells, 13cRA induced significant upregulation of toll-like receptor 3 (TLR3) and mitochondrial antiviral-signaling protein (MAVS) expression in a time-dependent manner. Furthermore, poly (I:C), a synthetic agonist of TLR3, effectively synergized with 13cRA to enhance antiproliferative effects through upregulation of the innate immune signaling and the mitochondrial stress response, leading to augmentation of the apoptotic response in 13cRA-responsive cancer cells. In addition, the 13cRA/poly (I:C) combination induced neural differentiation through activation of retinoic acid receptors beta (RAR-β), restoring expression of α-thalassemia/mental retardation syndrome X-linked (ATRX) protein, and inhibiting vessel formation, leading to retarded tumor growth in a mouse xenograft model. These results suggest that the combination of poly (I:C) and RA may provide synergistic therapeutic benefits for treatment of patients with high-risk neuroblastoma.

Residual stress builds up during the fabrication of components via laser powder bed fusion (L-PBF) process which causes parts to fail due to the crack initiation and growth, low fatigue life, and fall outside of the specified dimensions. During the thermal loading, the grain size affected by strain hardening and flow softening is altered at the subsurface through dynamic recrystallization (DRx) and subsequent recovery. The yield strength of the alloys is largely determined by the size of nucleated grains, and it has a substantial influence on flow stress and residual stress build-up. In this work, a physics-based analytical model is proposed to predict the residual stress affected by the strain hardening, flow softening, and microstructural evolution during L-PBF process with IN718 as a material system for exploration. The temperature field is predicted using a transient moving point heat source approach. Due to the non-uniform heating, materials experience high thermal stress which may exceed the yield strength of the material. The thermal stress is obtained from Green’s functions of stresses due to the point body load. A material constitutive flow stress model known as Johnson-Cook is used to determine the yield surface. This flow stress model is modified to incorporate the effects of flow softening and grain size. The dynamic recrystallization and grain refinement models are used to calculate the grain size using recrystallized volume fraction from nucleation and growth rates. As a result of the cyclic heating and cooling and the fact that the material is yielded, the residual stress build-up is precited using incremental plasticity and kinematic hardening behavior of the metal according to the property of volume invariance in plastic deformation in coupling with the equilibrium and compatibility conditions. Results from the analytical residual stress model showed good agreement with X-ray diffraction measurements used to determine the residual stresses in the IN718 specimens built via L-PBF.

Isoflavones are the major bioactive components in soybeans. Sequential window acquisition of all theoretical fragment ions (SWATH) is a kind of data-independent acquisition (DIA), such that all fragments of each precursor will be preserved in a SWATH-Mass Spectrometry (SWATH-MS) run. In this study, a high-throughput SWATH-MS method for the determination of 12 isoflavones in soybeans was established. Furthermore, amino acids, saponins can be semi-quantitated from the same SWATH-MS data. Combination of targeted quantification and untargeted profiling with SWATH, all bioactive compounds were analyzed within 5 min in 10 min run time, and the method had good linear regression with r2 > 0.99. The precisions (RSD %) of the intra-day and inter-day analyses ranged from 2.11% to 18.7%, and the accuracies (RE%) ranged from −14.39% to 17.48%. The matrix effect ranged from 88.66% to 114.82%. Moreover, 7 varieties of soybeans were analyzed and compared with this robust screening method.

A high-fat diet is responsible for hepatic fat accumulation that sustains chronic liver damage and increases the risks of steatosis and hepatocellular carcinoma (HCC). MicroRNA-29a (miR-29a), a key regulator of cellular behaviors, is present in anti-fibrosis and modulator tumorigenesis. However, the increased transparency of the correlation between miR-29a and the progression of human HCC is still further investigated. In this study, we predicted HIF-1α and ANGPT2 as regulators of HCC by the OncoMir cancer database and showed a strong positive correlation with HIF-1α and ANGPT2 gene expression in HCC patients. Mice fed the western diet (WD) while administered CCl4 for 25 weeks induced chronic liver damage and higher HCC incidence than without fed WD mice. HCC section staining revealed signaling upregulation in ki67, severe fibrosis, and steatosis in WD and CCl4 mice and detected Col3a1 gene expressions. HCC tissues significantly attenuated miR-29a but increased in HIF-1α, ANGPT2, Lox, Loxl2, and VEGFA expression. Luciferase activity analysis confirms that miR-29a specific binding 3'UTR of HIF-1α and ANGPT2 to repress expression. In summary, miR-29a control HIF-1α and ANGPT2 signaling in HCC formation. This study insight into a novel molecular pathway by which miR-29a targeting HIF-1α and ANGPT2 counteracts the incidence of HCC development.

Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the marine actinomycetes Streptomyces sp., with potent anti-proliferative activity against prostate cancers. Lu01-M blocked cell proliferation with IC50 values of 1.03 ± 0.31, 2.12 ± 0.38, 1.27 ± 0.25 μg/mL in human prostate cancer PC3, DU145, and LNCaP cells, respectively. Lu01-M induced cytotoxic activity through multiple mechanisms including cell apoptosis, necroptosis, autophagy, ER stress, and inhibiting colony formation and cell migration. Lu01-M induced cell cycle arrest at the G2/M phase and DNA damage. However, the activity of autophagy induced survival response in cancer cells. Our findings suggested that Lu01-M holds the potential to be developed as an anti-cancer agent against prostate cancers.

Background The detection rate of Barcelona Clinic Liver Cancer (BCLC) very-early-stage hepatocellular carcinoma (HCC) is increasing because of advances in surveillance and improved imaging technologies for high-risk populations. Surgical resection (SR) and radiofrequency ablation (RFA) are both first‐line treatments for very-early-stage HCC, but the differences in clinical outcomes between patients treated with SR and RFA remain unclear. This study investigated the prognosis of SR and RFA for very-early‐stage HCC patients with long‐term follow‐up. Methods This study was retrospectively collected data on the clinicopathological characteristics, overall survival (OS), and disease-free survival (DFS) of 188 very-early-stage HCC patients (≤ 2 cm single HCC). OS and DFS were analyzed using the Kaplan–Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. Results Of the 188 HCC patients, 103 received SR and 85 received RFA. The median follow‐up time was 56 months. The SR group had significantly higher OS than the RFA group (10-year cumulative OS: 55.2% and 31.3% in the SR and RFA groups, respectively). No statistically significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 45.9% and 32.6% in the SR and RFA groups, respectively). After PSM, the OS in the SR group remained significantly higher than that in the RFA group (10-year cumulative OS: 54.7% and 42.2% in the SR and RFA groups, respectively). No significant difference was observed in DFS between the SR and RFA groups (10-year cumulative DFS: 43.0% and 35.4% in the SR and RFA groups, respectively). Furthermore, in the multivariate Cox regression analysis, treatment type (hazard ratio (HR): 0.54, 95% confidence interval (CI): 0.31–0.95; P = 0.032) and total bilirubin (HR: 1.92; 95% CI: 1.09–3.41; P = 0.025) were highly associated with OS. In addition, age (HR: 2.14, 95% CI: 1.36–3.36; P = 0.001) and cirrhosis (HR: 1.79; 95% CI: 1.11–2.89; P = 0.018) were strongly associated with DFS. Conclusion For patients with very-early-stage HCC, SR was associated with significantly higher OS rates than RFA. However, no significant difference was observed in DFS between the SR and RFA groups.

As the highest yield crop worldwide, citrus peels that possess bioactive compounds were discarded as a futile by-product. Ultrasonication with environmentally friendly solvent (50% ethanol and ddH

Background Identifying prognostic factors and therapeutic strategies for single large hepatocellular carcinoma (HCC) is crucial. This retrospective study investigated prognostic factors in patients with single large HCC (≥5 cm) and Child–Pugh (CP) class A liver disease and recommended therapeutic strategies. Methods In total, 305 patients with single large HCC and CP class A liver disease but without distant metastasis or macrovascular invasion were included. Their clinicopathological data, overall survival (OS), and progression-free survival (PFS) were recorded. OS and PFS rates were analyzed using the Kaplan–Meier method and Cox regression analysis. Results In this study, 77.8% of the patients were men; the median age was 63 years. Approximately 34.1% of the patients had cirrhosis and 89.6% had CP class A5 disease. The most common initial treatment was resection (49.5%), followed by transarterial chemoembolization (TACE; 48.2%). OS and PFS rates 1, 5, and 10 years after initial treatment were 88.6%, 58.0%, and 46.8% and 73.6%, 48.2%, and 31.3%, respectively. OS and PRS rates were significantly higher in patients receiving surgical resection than in those receiving TACE. The 1-, 5-, and 10-year OS rates were 94.6%, 76.7%, and 66.7% after resection and 83.1%, 39.0%, and 26.6% after TACE. The 1-, 5-, and 10-year PRS rates were 82.5%, 55.7%, and 51.0% after resection and 64.3%, 40.5%, and 22.7% after TACE. In multivariate analysis, CP class A5/6 (A5 vs. A6; hazard ratio [HR]: 0.23; 95% confidence interval [CI]: 0.15–0.38, P < 0.001) and initial treatment (resection vs. TACE; HR: 0.22; 95% CI: 0.15–0.36, P < 0.001; resection vs. other treatments; HR: 0.37; 95% CI: 0.17–0.65, P = 0.016) were significantly associated with OS. In addition, CP class A5/6 (A5 vs. A6; HR: 0.32; 95% CI: 0.18–0.56, P < 0.001) and initial treatment (resection vs. TACE; HR: 0.30; 95% CI: 0.16–0.51, P < 0.001; resection vs. other treatments; HR: 0.51; 95% CI: 0.26–0.81, P = 0.042) were significantly associated with PFS. Conclusion Surgical resection achieved significantly higher OS and PRS rates than TACE. Surgical resection is an effective and safe therapy for single large HCC.

The aim of the current study was to investigate the relationship between nasopharyngeal carcinoma (NPC) and dry eye disease (DED) using the National Health Insurance Research Database (NHIRD) of Taiwan. A retrospective cohort study was conducted, and patients with an NPC diagnosis were included. Next, one NPC patient was matched to four non-NPC participants via demographic data and systemic comorbidities. In total, 4184 and 16,736 participants were enrolled in the NPC and non-NPC groups, respectively. The primary outcome was the development of DED one year after the diagnosis of NPC. Cox proportional hazard regression was applied to estimate the adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) of DED. In this study, 717 and 2225 DED cases were found in the NPC and non-NPC groups, respectively, and the NPC group showed a significantly higher incidence of DED development compared to the non-NPC group (aHR: 1.45, 95% CI: 1.33–1.58, p < 0.0001) in the multivariable analysis. The other covariates that were positively correlated with DED development included age over 40 years, an education level higher than senior high school, hypertension, DM, allergic pulmonary diseases, allergic otolaryngologic diseases, and allergic dermatological diseases (all p < 0.05). In conclusion, the presence of NPC is an independent risk factor for subsequent DED.

Parkinson disease (PD) is the second-most common neurodegenerative disease. The characteristic pathology of progressive dopaminergic neuronal loss in people with PD is associated with iron accumulation and is suggested to be driven in part by the novel cell death pathway, ferroptosis. A unique modality of cell death, ferroptosis is mediated by iron-dependent phospholipid peroxidation. The mechanisms of ferroptosis inhibitors enhance antioxidative capacity to counter the oxidative stress from lipid peroxidation, such as through the system xc−/glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis and the coenzyme Q10 (CoQ10)/FSP1 pathway. Another means to reduce ferroptosis is with iron chelators. To date, there is no disease-modifying therapy to cure or slow PD progression, and a recent topic of research seeks to intervene with the development of PD via regulation of ferroptosis. In this review, we provide a discussion of different cell death pathways, the molecular mechanisms of ferroptosis, the role of ferroptosis in blood–brain barrier damage, updates on PD studies in ferroptosis, and the latest progress of pharmacological agents targeting ferroptosis for the intervention of PD in clinical trials.

Prostate adenocarcinoma (PRAD) is the most common histological subtype of prostate cancer. Post-treatment biochemical recurrence is a challenging issue. ATAD1 (ATPase Family AAA Domain Containing 1) plays a vital role in mitochondrial proteostasis and apoptosis activity, while its clinical value in PRAD and its impact on the tumor microenvironment (TME) remain unanswered. In this study, we aimed to investigate the clinical value and possible mechanisms of ATAD1 in PRAD via multi-omics analysis. Using cBioPortal, we confirmed that ATAD1 alteration was associated with gene expression and unfavorable DFS. Deep deletion predominantly occurred in PRAD. By integrating DriverDBv3 and GEPIA2, we noted ATAD1 downregulation in PRAD tissues compared to normal tissues, associated with unfavorable DFS in PRAD patients. DNA repair genes ATM, PARP1and BRCA2 had positive associations with ATAD1 expression. We found that the generalization value of ATAD1 could be applied to other cancers such as KIRC and UCEC. In addition, LinkedOmics identified that the functional involvement of ATAD1 participates in mitochondrial structure and cell cycle progression. Using TIMER analysis, we demonstrated that ATAD1 downregulation correlated with an immunosuppressive TME. Furthermore, we accessed a GSE55062 dataset on UALCAN and discovered the involvement of ERG-mediated transcriptional repression on ATAD1 downregulation. Cross-association screening of shATAD1 efficacy vs. altered mRNAs identified 190 perturbed mRNAs. Then, functional enrichment analysis using the Metascape omics tool recognized that shATAD1-perturbed mRNAs are primarily in charge of the activation of Wnt/β-catenin pathway and lipid metabolic processes. In conclusion, multi-omics results reveal that ATAD1 downregulation is a clinical biomarker for pathological diagnosis and prognosis for patients with PRAD. Reduced ATAD1 may be involved in the enhanced activity of mitochondria and cell cycle, as well as possibly shaping an immunosuppressive TME. ERG serves as an upstream transcriptional repressor of ATAD1. Downstream mechanisms of ATAD1 are involved in Wnt/β-catenin pathway and lipid metabolic processes.