BIBR1532 combined with radiotherapy induces ferroptosis in NSCLC cells and activates cGAS-STING pathway to promote anti-tumor immunity.

BACKGROUND: Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. METHODS: Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. RESULTS: Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. CONCLUSION: This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.

Linear and non-linear relationships between sulfur dioxide and semen quality: A longitudinal study in Anhui, China.

Existing evidence indicates that ambient air pollutants pose a threat to human semen quality; however, these findings are sparse and controversial. Besides, their non-linear dose-response relationship has not yet been well investigated. This study aimed to explore the linear and non-linear associations of gaseous air pollutants exposure with semen quality based on a large longitudinal cohort. A total of 15,112 males (with 28,267 semen tests) from the Anhui prospective assisted reproduction cohort were analyzed. Individual air pollutants exposure before semen tests in four exposure windows (i.e., 0-9, 10-14, 70-90, and 0-90 days) were estimated by inverse distance weighting interpolation. Linear mixed-effects models, cubic spline analysis and piecewise regression were used to test the potential linear and non-linear dose-response relationships. Ambient SO2 exposure was negatively associated with all semen quality parameters (all p values < 0.05), except for the progressive motility in the 0-90 and 70-90 days exposure windows. There were 'J' or 'U' shaped dose-response relationships of ambient SO2 exposure with total sperm count, progressive motility, total motility, progressively motile sperm count, and total motile sperm count (p values for non-linearity < 0.05), but not sperm concentration. Piecewise regression analysis also indicated a negative association of SO2 exposure with semen quality only when SO2 exposure was below the cut-off points identified by cubic spline analyses, which were all smaller than 40 µg/m3, the 2021 updated WHO air quality guideline level for SO2 exposure. Overall, we found that SO2 exposure was negatively associated with semen quality. Ambient SO2 exposure could reach the maximum hazardous dose even below the WHO air quality guideline level for SO2 exposure, suggesting a refinement to the current guideline.

The influence of meteorological factors and total malignant tumor health risk in Wuhu city in the context of climate change.

With the increasing severity of the malignant tumors situation worldwide, the impacts of climate on them are receiving increasing attention. In this study, for the first time, all-malignant tumors were used as the dependent variable and absolute humidity (AH) was innovatively introduced into the independent variable to investigate the relationship between all-malignant tumors and meteorological factors. A total of 42,188 cases of malignant tumor deaths and meteorological factors in Wuhu City were collected over a 7-year (2014-2020) period. The analysis method combines distributed lagged nonlinear modeling (DLNM) as well as generalized additive modeling (GAM), with prior pre-analysis using structural equation modeling (SEM). The results showed that AH, temperature mean (T mean) and diurnal temperature range (DTR) all increased the malignant tumors mortality risk. Exposure to low and exceedingly low AH increases the malignant tumors mortality risk with maximum RR values of 1.008 (95% CI: 1.001, 1.015, lag 3) and 1.016 (95% CI: 1.001, 1.032, lag 1), respectively. In addition, low and exceedingly low T mean exposures also increased the risk of malignant tumors mortality, the maximum RR was 1.020 (95% CI: 1.006, 1.034) for low T mean and 1.035 (95% CI: 1.014, 1.058) for exceedingly low T mean. As for DTR, all four levels (exceedingly low, low, high, exceedingly high, from low to high) of exposure increased the risk of death from malignant tumors, from exceedingly low to exceedingly high maximum RR values of 1.018 (95% CI: 1.004, 1.032), 1.011 (95% CI: 1.005, 1.017), 1.006 (95% CI: 1.001, 1.012) and 1.019 (95% CI: 1.007, 1.031), respectively. The results of the stratified analysis suggested that female appear to be more sensitive to humidity, while male require additional attention to reduce exposure to high level of DTR.

Modulation of IrO6 Chemical Environment for Highly Efficient Oxygen Evolution in Acid.

The sluggish kinetics of the oxygen evolution reaction (OER) limits the commercialization of oxygen electrochemistry, which plays a key role in renewable energy technologies such as fuel cells and electrolyzers. Herein, a facile and practical strategy is developed to successfully incorporate Ir single atoms into the lattice of transition metal oxides (TMOs). The chemical environment of Ir and its neighboring lattice oxygen is modulated, and the lattice oxygen provides lone-pair electrons and charge balance to stabilize Ir single atoms, resulting in the enhancement of both OER activity and durability. In particular, Ir0.08 Co2.92 O4 NWs exhibit an excellent mass activity of 1343.1 A g-1 and turnover frequency (TOF) of 0.04 s-1 at overpotentials of 300 mV. And this catalyst also displays significant stability in acid at 10 mA cm-2 over 100 h. Overall water splitting using Pt/C as the hydrogen evolution reaction catalyst and Ir0.08 Co2.92 O4 NWs as the OER catalyst takes only a cell voltage of 1.494 V to achieve 10 mA cm-2 with a perfect stability. This work demonstrates a simple approach to produce highly active and acid-stable transition metal oxides electrocatalysts with trace Ir.

Sulfur-Induced Vacancies in Ba2Bi1.4Nb0.6O6 Promoting Photocatalytic Tetracycline Hydrochloride Degradation.

Solar-driven photodegradation has attracted great attention, given that it provides a promising solution for eliminating antibiotics in aqueous environments, due to its environmental friendliness and economic feasibility. However, solar conversion efficiencies are restricted by insufficient sunlight absorption and ineffective charge separation/transfer. Herein, the incorporation of sulfur into Ba2Bi1.4Nb0.6O6 nanorods brings about O and S vacancies, leading to significantly enhanced light absorption and charge separation/transport efficiency by almost 4 times. As a result, the obtained material exhibits greatly improved photocatalytic degradation efficiency for tetracycline hydrochloride under visible light irradiation with outstanding stability. The photocatalytic degradation efficiency is highest among the state-of-the-art photocatalysts for tetracycline hydrochloride degradation. This work paves a promising pathway to develop highly efficient photocatalysts with a narrow band gap.

The increased risk of atrial fibrillation in inflammatory arthritis: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia contributing to stroke and sudden cardiac death. Numbers of studies indicated that patients with inflammatory arthritis have an increased risk of AF. The present study aims to assess the risk of AF in inflammatory arthritis patients. METHODS: We systematically searched cohort studies regarding the risk of AF in patients with rheumatoid arthritis, or spondyloarthritis through PubMed, Web of Science, Cochrane Library, Clinical Trials Registry, and China National Knowledge from inception to August 1, 2019. Meta-analysis was performed using fixed effect model, estimating both crude and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Subgroup analysis and meta-regression based on geographic characteristics, comorbidities, and medication use were conducted to explore the source of heterogeneity. RESULTS: Literature search identified 388 potentially relevant studies, and five studies containing seven cohorts of rheumatoid arthritis or spondyloarthritis were included in the meta-analysis. The AF risk of inflammatory arthritis patients was significantly increased compared with health controls (HR = 1.42, 95% CI: 1.36 to 1.49, Z = 14.17, P < .001), and the pooled HR of studies adjusted factor, like demographic characteristics, medications use, and comorbidities, was 1.37 (95% CI: 1.29 to 1.46; Z = 9.82, P < .001). CONCLUSION: Patients with inflammatory arthritis have increased risk of AF, probably due to the underlying chronic inflammation. Although various confounders have been adjusted like medications use and comorbidities, the risk of AF is still significantly increased in inflammatory arthritis patients. ABBREVIATIONS: AF: Atrial fibrillation; AS: Ankylosing spondylitis; CI: Confidence interval; HR: Hazard ratio; NOS: Newcastle-Ottawa scale; NSAIDs: Non-steroid anti-inflammatory drugs; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; SpA: Spondyloarthritis; TNFi: Tumor necrosis factors inhibitor; uSpA: Undifferentiated spondyloarthritis.

MagicChem: a MR system based on needs theory for chemical experiments.

Real chemical experiments may be dangerous or pollute the environment; meanwhile, the preparation of drugs and reagents is time-consuming. Due to the above-mentioned reasons, few experiments can be actually operated by students, which is not conducive to the chemistry learning and the phenomena principle understanding. Recently, due to the impact of Covid-19, many schools adopt online teaching, which is even more detrimental to students' learning of chemistry. Fortunately, MR(mixed reality) technology provides us with the possibility of solving the safety issues and breaking the space-time constraints, while the theory of human needs (Maslow's hierarchical needs) provides us with a way to design a comfortable and stimulant MR system with realistic visual presentation and interaction. The paper combines with the theory of human needs to propose a new needs model for virtual experiment. Based on this needs model, we design and develop a comprehensive MR system called MagicChem, which offers a robust 6-DoF interactive and illumination consistent experimental space with virtual-real occlusion, supporting realistic visual interaction, tangible interaction, gesture interaction with touching, voice interaction, temperature interaction, olfactory interaction and virtual human interaction. User study shows that MagicChem satisfies the needs model better than other MR experimental environments that partially meet the needs model. In addition, we explore the application of the needs model in VR environment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10055-021-00560-z.

Comparative Efficacy and Safety of Common Therapies in Keloids and Hypertrophic Scars: A Systematic Review and Meta-analysis.

OBJECTIVES: At present, there are many therapies for treating keloids and hypertrophic scars, but there is still a lack of treatments that are relatively balanced in efficacy and safety. The study aims to evaluate comprehensively efficacy and safety of common therapies in keloids and hypertrophic scars. METHODS: The literature search was conducted up to May 2019. The traditional meta-analysis was performed on 17 therapies. Bayesian network meta-analysis was conducted on the four most common treatments. The outcome indicators were the numbers of patients with good-to-excellent effect, Vancouver Scar Scale (VSS) and adverse events. RESULTS: There was no significant difference in the efficacy of triamcinolone acetonide (TAC) compared with other monotherapies except for silicone gel sheet and neodymium-yttrium-aluminum-garnet in primary indicator. The combination therapies were superior to TAC, and the results were consistent after the pooled analysis (RR = 0.522, 95% CI 0.332-0.823). The level of VSS in TAC group was higher than that in 5-flurouracil (5-FU) and TAC + 5-FU group, but lower than that in verapamil (VER) group. And the patients treated with TAC were less safe than those treated with verapamil (P = 0.013). Surface under cumulative ranking ranked verapamil and TAC + 5-FU as the favorable efficacy therapies in terms of primary indicator and ranked TAC + 5-FU as the best therapy for VSS, while VER was ranked as the worst. CONCLUSION: This meta-analysis showed that TAC + 5-FU may be the most effective therapy, while verapamil may be a better therapeutic strategy for safety. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Genetic variation of rs7958311 in P2X7R gene is associated with the susceptibility and disease activity of ankylosing spondylitis.

OBJECTIVES: To describe association between the genetic variation of inflammation-associated gene, P2X7R, and ankylosing spondylitis (AS) susceptibility. METHODS: Four single nucleotide polymorphisms (SNPs) of P2 X 7 R gene were genotyped in 673 patients with AS and 687 healthy controls. Allele and genotype frequencies and different genetic models were performed to calculate ORs and 95% CIs, the demographic and clinical characteristics of patients were recorded. The data analyses were also conducted by sex. RESULTS: Compared with controls, genetic variation in rs7958311 but not the other three SNPs was statistically significant in female patients (χ2=6.907, p=0.032). Specifically, the P2 X 7 R gene rs7958311 polymorphism A allele showed a protective effect in AS susceptibility (OR=0.704, p=0.049, pFDR=0.061). In addition, female individuals with GA and/or AA genotypes had a lower risk of having AS compared with those with GG genotype (GA vs GG: OR=0.446, p=0.012, pFDR=0.030; AA vs GG: OR=0.440, p=0.039, pFDR=0.061; GA/AA vs GG: OR=0.445, p=0.009, pFDR=0.030). Furthermore, individuals with A allele (ie, GA/AA vs GG) had a higher disease activity, including Bath Ankylosing Spondylitis Disease Activity Index (overall: Z=- 2.630, p=0.014; male: Z=- 2.243, p=0.025), Schober test (overall: Z=- 3.041, p<0.001; male: Z=- 2.243, p=0.025) and chest expansion (overall: Z=- 3.895, p=0.004; male: Z=- 2.403, p=0.016). CONCLUSION: The allelic variation of rs7958311 SNP in P2X7R gene may have a protective effect on AS susceptibility in females and is associated with disease activity in male patients.

Role of IL-6-mediated expression of NS5ATP9 in autophagy of liver cancer cells.

This study aimed to investigate the relationship between interleukin-6 (IL-6) and NS5ATP9 in autophagy of liver cancer cells. Autophagy is one of the important regulators of the replication of hepatitis C virus and the survival of tumors. IL-6 is a multifunctional cytokine that plays an important role in autophagy and development of many kinds of tumors. However, the role of IL-6 in autophagy has not been fully explored. A previous study had shown that a novel gene, NS5ATP9, could modulate autophagy. The present study demonstrated that human IL-6 recombinant protein induced autophagy of HepG2 cells. Conversely, autophagy decreased after IL-6 was silenced or neutralized with monoclonal antibody against human IL-6. In addition, NS5ATP9 was upregulated by IL-6 via nuclear factor-kappaB activation, as detected by Western blot. Further studies indicated that the induction of autophagy by IL-6 could be attenuated by silencing NS5ATP9. Interestingly, the expression of NS5ATP9, in turn, resulted in the upregulation of IL-6. In conclusion, IL-6 could induce autophagy by expressing NS5ATP9, while NS5ATP9 upregulated IL-6 levels in turn, which further induced autophagy.

Optical microscope for three-dimensional surface displacement and shape measurements at the microscale.

We report a novel optical microscope for full-field, noncontact measurements of three-dimensional (3D) surface deformation and topography at the microscale. The microscope system is based on a seamless integration of the diffraction-assisted image correlation (DAIC) method with fluorescent microscopy. We experimentally demonstrate the microscope's capability for 3D measurements with submicrometer spatial resolution and subpixel measurement accuracy.

Wireless Online Rotation Monitoring System for UAV Motors Based on a Soft-Contact Triboelectric Nanogenerator.

Real-time monitoring of UAV motor speed is crucial for enhancing control performance and ensuring flight safety. However, this task faces challenges such as difficult sensor installation and high costs. This study introduces a wireless rotational speed sensing system based on a UAV-rotary triboelectric nanogenerator (UR-TENG). By employing a carefully designed structure with soft contact and a freestanding-triboelectric-layer mode, UR-TENG exhibits characteristics like low friction, affordability, ease of production, and self-powering capability. This eliminates the need for an external power source and addresses the complexity of installation in the limited space of UAVs. Experimental findings demonstrate that UR-TENG possesses high sensitivity and stability, maintaining the structural integrity of the UAV. The goodness of fit is notably high at 0.99959, with a maximum error rate of only 0.014 within a range of 6270 rpm. Moreover, UR-TENG integrates with a microcontroller unit (MCU) and external circuitry to form a monitoring system. This system transmits electrical signals to a PC via a Wi-Fi module, facilitating real-time rotational speed sensing and anomaly detection. Finally, a practical application demonstration on a UAV validates the adaptability of UR-TENG to complex operational environments. This study presents a promising approach for online rotation monitoring of UAV motors, with potential for commercialization, and introduces new avenues for TENG application in UAV technology.

MiR-10b-5p Regulates Neuronal Autophagy and Apoptosis Induced by Spinal Cord Injury Through UBR7.

This study aimed to explore the effects of miR-10b-5p on autophagy and apoptosis in neuronal cells after spinal cord injury (SCI) and the molecular mechanism. Bioinformatics was used to analyze the differentially expressed miRNAs. The expression of related genes and proteins were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. Cell proliferation was detected by 5-ethynyl-2'-deoxyuridine (EdU), and apoptosis was detected by flow cytometry or terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL). Coimmunoprecipitation confirmed the interaction between UBR7 and Wnt1 or Beclin1. Autophagy was detected by the dansylcadaverine (MDC). The Basso Beattie Bresnahan (BBB) score was used to evaluate motor function, and hematoxylin-eosin (H&E) and Nissl staining were used to detect spinal cord tissue repair and neuronal changes. The result shows that the expression of miR-10b-5p was downregulated in the SCI models, and transfection of a miR-10b-5p mimic inhibited neuronal cell apoptosis. MiR-10b-5p negatively regulated the expression of UBR7, and the inhibitory effect of the miR-10b-5p mimic on neuronal cell apoptosis was reversed by overexpressing UBR7. In addition, UBR7 can regulate apoptosis by affecting the Wnt/ß-catenin pathway by promoting Wnt1 ubiquitination. Treatment with the miR-10b-5p mimic effectively improved motor function, inhibited neuronal cell apoptosis, and promoted spinal cord tissue repair in SCI rats. Overall, miR-10b-5p can alleviate SCI by downregulating UBR7 expression, inhibiting Wnt/ß-catenin signaling pathway ubiquitination to reduce neuronal apoptosis, or inhibiting Beclin 1 ubiquitination to promote autophagy.

Deletion of Mettl3 in mesenchymal stem cells promotes acute myeloid leukemia resistance to chemotherapy.

Acute myeloid leukemia (AML) cell survival and chemoresistance are influenced by the existence of bone marrow mesenchymal stem cells (BMMSCs); however, the pathways by which BMMSCs contribute to these processes remain unclear. We earlier revealed that methyltransferase-like 3 (METTL3) expression is significantly reduced in AML BMMSCs and that METTL3 mediates BMMSC adipogenesis to promote chemoresistance in human AML cell lines in vitro. In this investigation, we evaluated the METTL3 function in vivo. Mice exhibiting a conditional removal of Mettl3 in BMMSCs were developed by mating Prrx1-CreERT2;Mettl3fl/+ mice with Mettl3fl/fl mice using the CRISPR-Cas9 system. The Mettl3 deletion increased bone marrow adiposity, enhanced disease progression in the transplantation-induced MLL-AF9 AML mouse model, and chemoresistance to cytarabine. The removal of Mettl3 in BMMSCs resulted in a significant increase in BMMSC adipogenesis. This effect was attributed to the downregulation of AKT1 expression, an AKT serine/threonine kinase 1, in an m6A-dependent manner. The development of chemoresistance in AML is linked to the promoted adipogenesis of BMMSCs. We conclude that METTL3 expression in BMMSCs has a critical function in limiting AML progression and chemoresistance, providing a basis for the progression of therapeutic approaches for AML.

Role of NAT10-mediated ac4C-modified HSP90AA1 RNA acetylation in ER stress-mediated metastasis and lenvatinib resistance in hepatocellular carcinoma.

Emerging evidence showed that epigenetic regulation plays important role in the pathogenesis of HCC. N4-acetocytidine (ac4C) was an acetylation chemical modification of mRNA, and NAT10 is reported to regulate ac4C modification and enhance endoplasmic reticulum stress (ERS) in tumor metastasis. Here, we report a novel mechanism by which NAT10-mediated mRNA ac4C-modified HSP90AA1 regulates metastasis and tumor resistance in ERS of HCC. Immunohistochemical, bioinformatics analyses, and in vitro and in vivo experiments, e.g., acRIP-Seq, RNA-Seq, and double luciferase reporter experiment, were employed to investigate the effect of NAT10 on metastasis and drug resistance in HCC. The increased expression of NAT10 was associated with HCC risk and poor prognosis. Cell and animal experiments showed that NAT10 enhanced the metastasis ability and apoptosis resistance of HCC cells in ERS and ERS state. NAT10 could upregulate the modification level of HSP90AA1 mRNA ac4C, maintain the stability of HSP90AA1, and upregulate the expression of HSP90AA1, which further promotes the metastasis of ERS hepatoma cells and the resistance to apoptosis of Lenvatinib. This study proposes a novel mechanism by which NAT10-mediated mRNA ac4C modification regulates tumor metastasis. In addition, we demonstrated the regulatory effect of NAT10-HSP90AA1 on metastasis and drug resistance of ERS in HCC cells.

Associations of exposure to blood and urinary heavy metal mixtures with psoriasis risk among U.S. adults: A cross-sectional study.

Accumulating evidence showed that environmental exposure to toxic metals was harmful to human health. However, information about the effects of exposure to metal mixtures on psoriasis was scarce. To investigate the independent and comprehensive associations between heavy metal co-exposure and psoriasis in adults, data of 6534 adults aged 20-80 years from the National Health and Nutrition Examination Survey (NHANES) were used. Among them, 187 (2.86 %) were diagnosed with psoriasis and the rest were participants without psoriasis. We examined the independent and combined associations of 3 blood metals and 11 urinary metals with psoriasis risk. In the single-metal analyses, urinary barium (Ba), cesium (Cs), antimony (Sb), uranium (Ur), and cadmium (Cd) were positively correlated with psoriasis risk, while urinary molybdenum (Mo) was identified as a protective factor for psoriasis. Moreover, weighted quantile sum (WQS) regression and Bayesian kernel machine regression (BKMR) models consistently revealed the positive effect of urinary metal co-exposure on psoriasis risk. The associations were more evident in the young and middle-aged group than the elderly group. In the urinary mixtures, Ba was the highest weighted metal in the whole population and the young and middle-aged people, whereas Sb was the top weighted metal in the elderly group. Additionally, BKMR analysis revealed the potential interaction between certain components of urinary metal mixtures in psoriasis. The results of quantile-based g computation (qgcomp) model further proved the toxic effect of urinary metal mixtures on psoriasis, and the positive linear relationship between urinary Ba and psoriasis risk was identified by restricted cubic splines (RCS) regression. We concluded that co-exposure to multiple heavy metals was associated with psoriasis risk. Given the limitations of the NHANES study, further prospective designed studies are warranted.

Clinicopathological and prognostic significance of the long non-coding RNA HOTAIR high expression in head and neck squamous cell carcinoma: a systematic review and meta-analysis.

Background: Long non-coding RNAs (lncRNAs) have been demonstrated to possess critical biological functions that regulate occurrence and progression of tumors. The HOX transcript antisense intergenic RNA (HOTAIR) is one of the most studied lncRNAs. This study was designed to investigate the association of HOTAIR expressions with clinicopathologic features and prognosis in head and neck squamous cell carcinoma (HNSCC). Methods: The PubMed, Web of Science, Embase, Cochrane Library and SCOPUS databases were searched. The studies published before September 10, 2021 were screened. Two authors independently screened the literature and extracted data based on inclusion and exclusion criteria. Meta-analysis, bias assessment, sensitivity analysis and subgroup analysis were performed to improve accuracy and reliability. Results: Seven studies comprising 546 patients were analysed to clarify the relationship between clinicopathologic features and HOTAIR expression, and six studies with 856 patients were applied to evaluate the effects of HOTAIR expressions on the prognosis. After removing those outliers through Galbraith plots and/or sensitivity analysis, the pooled results showed high HOTAIR expressions were associated with high T stage [odds ratio (OR) =2.32, 95% confidence interval (CI): 1.38-3.89, P=0.001], lymphnode metastasis (OR =2.71, 95% CI: 1.57-4.67, P=0.0003), high TNM stage (OR =3.92, 95% CI: 2.28-6.72, P<0.00001), poor histological grade (OR =2.21, 95% CI: 1.02-4.83, P=0.046), poor overall survival (OS) [hazard ratio (HR) =1.74, 95% CI: 1.19-2.56, P=0.005] and poor disease-free survival (DFS) (HR =1.64, 95% CI: 1.09-2.47, P=0.02). Subgroup analyses of T stage, lymphnode metastasis and histological grade identified possible heterogeneity sources, respectively ethnicity, cut-off, and detection methods. Conclusions: These findings suggest HOTAIR might serve as an excellent prognostic biomarker and predictor of clinicopathologic features in HNSCC.

Label-Free and Homogeneous Electrochemical Biosensor for Flap Endonuclease 1 Based on the Target-Triggered Difference in Electrostatic Interaction between Molecular Indicators and Electrode Surface.

Target-induced differences in the electrostatic interactions between methylene blue (MB) and indium tin oxide (ITO) electrode surface was firstly employed to develop a homogeneous electrochemical biosensor for flap endonuclease 1 (FEN1) detection. In the absence of FEN1, the positively charged methylene blue (MB) is free in the solution and can diffuse onto the negatively charged ITO electrode surface easily, resulting in an obvious electrochemical signal. Conversely, with the presence of FEN1, a 5'-flap is cleaved from the well-designed flapped dumbbell DNA probe (FDP). The remained DNA fragment forms a closed dumbbell DNA probe to trigger hyperbranched rolling circle amplification (HRCA) reaction, generating plentiful dsDNA sequences. A large amount of MB could be inserted into the produced dsDNA sequences to form MB-dsDNA complexes, which contain a large number of negative charges. Due to the strong electrostatic repulsion between MB-dsDNA complexes and the ITO electrode surface, a significant signal drop occurs. The signal change (ΔCurrent) shows a linear relationship with the logarithm of FEN1 concentration from 0.04 to 80.0 U/L with a low detection limit of 0.003 U/L (S/N = 3). This study provides a label-free and homogeneous electrochemical platform for evaluating FEN1 activity.

ARHGEF2/EDN1 pathway participates in ER stress-related drug resistance of hepatocellular carcinoma by promoting angiogenesis and malignant proliferation.

Endoplasmic reticulum (ER) stress is widely involved in the drug resistance of hepatocellular carcinoma (HCC), but the mechanism of ER stress-induced drug resistance involves multiple signaling pathways that cannot be fully explained. Exploring genes associated with ER stress could yield a novel therapeutic target for ER stress-induced drug resistance. By analyzing RNA-sequencing, ATAC-sequencing, and Chip-sequencing data of Tunicamycin (TM)-treated or untreated HCC cells, we found that Rho guanine nucleotide exchange factor 2 (ARHGEF2) is upregulated in HCC cells with ER stress. ARHGEF2 plays an active role in tumor malignant progression. Notwithstanding, no research has been done on the link between ER stress and ARHGEF2. The function of ARHGEF2 as a novel downstream effector of ER stress in the angiogenesis and treatment resistance of HCC was revealed in this work. ARHGEF2 overexpression was linked to malignant development and a poor prognosis in HCC. ER stress stimulates the expression of ARHGEF2 through upregulation of ZNF263. Elevated ARHGEF2 accelerates HCC angiogenesis via the EDN1 pathway, enhances HCC cell proliferation and tumor growth both in vitro and in vivo, and contributes to ER stress-related treatment resistance. HCC cell growth was more inhibited when ARHGEF2 knockdown was paired with targeted medicines. Collectively, we uncovered a previously hidden mechanism where ARHGEF2/EDN1 pathway promotes angiogenesis and participates in ER stress-related drug resistance in HCC.

Bone marrow microenvironment drives AML cell OXPHOS addiction and AMPK inhibition to resist chemotherapy.

The stromal niche plays a pivotal role in AML chemoresistance and energy metabolism reprogramming is a hallmark of a tumor. 5'-Adenosine monophosphate-activated protein kinase (AMPK) is an important energy sensor suppressing mammalian target of rapamycin complex 1 (mTORC1) activity. However, the role of AMPK-mTORC1 pathway on connecting AML cell energy metabolism reprogramming and chemoresistance induced by the bone marrow microenvironment (BMM) is not defined. Here, with a co-culture system that simulates the interaction between BMM and AML cells, it is shown that stromal contact led to a decreased sensitivity to chemotherapy accompanied by an increase of oxidative phosphorylation (OXPHOS) activity and mitochondrial ATP synthesis in AML cells. The increased OXPHOS activity and excessive ATP production promoted chemoresistance of AML cells through inhibiting AMPK activity and in turn activating mTORC1 activity. In an in vivo AML mouse model, depletion of AMPK activity with genetic targeting promoted AML progression and reduced their sensitivity to chemotherapeutic drugs. Collectively, AML cells' acquired increased OXPHOS activity as well as AMPK inhibition could be therapeutically exploited in an effort to overcome BMM-mediated chemoresistance.