Corrigendum: CMTM6 as a candidate risk gene for cervical cancer: comprehensive bioinformatics study.

[This corrects the article DOI: 10.3389/fmolb.2022.983410.].

ARID1A regulates DNA repair through chromatin organization and its deficiency triggers DNA damage-mediated anti-tumor immune response.

AT-rich interaction domain protein 1A (ARID1A), a SWI/SNF chromatin remodeling complex subunit, is frequently mutated across various cancer entities. Loss of ARID1A leads to DNA repair defects. Here, we show that ARID1A plays epigenetic roles to promote both DNA double-strand breaks (DSBs) repair pathways, non-homologous end-joining (NHEJ) and homologous recombination (HR). ARID1A is accumulated at DSBs after DNA damage and regulates chromatin loops formation by recruiting RAD21 and CTCF to DSBs. Simultaneously, ARID1A facilitates transcription silencing at DSBs in transcriptionally active chromatin by recruiting HDAC1 and RSF1 to control the distribution of activating histone marks, chromatin accessibility, and eviction of RNAPII. ARID1A depletion resulted in enhanced accumulation of micronuclei, activation of cGAS-STING pathway, and an increased expression of immunomodulatory cytokines upon ionizing radiation. Furthermore, low ARID1A expression in cancer patients receiving radiotherapy was associated with higher infiltration of several immune cells. The high mutation rate of ARID1A in various cancer types highlights its clinical relevance as a promising biomarker that correlates with the level of immune regulatory cytokines and estimates the levels of tumor-infiltrating immune cells, which can predict the response to the combination of radio- and immunotherapy.

Intra-Beam Interference Mitigation for the Downlink Transmission of the RIS-Assisted Hybrid Millimeter Wave System.

Millimeter-wave (mmWave) communication systems leverage the directional beamforming capabilities of antenna arrays equipped at the base stations (BS) to counteract the inherent high propagation path loss characteristic of mmWave channels. In downlink mmWave transmissions, i.e., from the BS to users, distinguishing users within the same beam direction poses a significant challenge. Additionally, digital baseband precoding techniques are limited in their ability to mitigate inter-user interference within identical beam directions, representing a fundamental constraint in mmWave downlink transmissions. This study introduces an innovative analog beamforming-based interference mitigation strategy for downlink transmissions in reconfigurable intelligent surface (RIS)-assisted hybrid analog-digital (HAD) mmWave systems. This is achieved through the joint design of analog beamformers and the corresponding coefficients at both the RIS and the BS. We first present derived closed-form approximation expressions for the achievable rate performance in the proposed scenario and establish a stringent upper bound on this performance in a large number of RIS elements regimes. The exclusive use of analog beamforming in the downlink phase allows our proposed transmission algorithm to function efficiently when equipped with low-resolution analog-to-digital/digital-to-analog converters (A/Ds) at the BS. The energy efficiency of the downlink transmission is evaluated through the deployment of six-bit A/Ds and six-bit pulse-amplitude modulation (PAM) signals across varying numbers of activated RIS elements. Numerical simulation results validate the effectiveness of our proposed algorithms in comparison to various benchmark schemes.

A Low-Complexity Hand Gesture Recognition Framework via Dual mmWave FMCW Radar System.

In this paper, we propose a novel low-complexity hand gesture recognition framework via a multiple Frequency Modulation Continuous Wave (FMCW) radar-based sensing system. In this considered system, two radars are deployed distributively to acquire motion vectors from different observation perspectives. We first independently extract reflection points of the interested target from different radars by applying the proposed neighboring reflection points detection method after processing the traditional 2-dimensional Fast Fourier Transform (2D-FFT). The obtained sufficient corresponding information of detected reflection points, e.g., distances, velocities, and angle information, can be exploited to synthesize motion velocity vectors to achieve a high signal-to-noise ratio (SNR) performance, which does not require knowledge of the relative position of the two radars. Furthermore, we utilize a long short-term memory (LSTM) network as well as the synthesized motion velocity vectors to classify different gestures, which can achieve a significantly high accuracy of gesture recognition with a 1600-sample data set, e.g., 98.0%. The experimental results also illustrate the robustness of the proposed gesture recognition systems, e.g., changing the environment background and adding new gesture performers.

Pinellia ternata (Thunb.) Breit. attenuates the allergic airway inflammation of cold asthma via inhibiting the activation of TLR4-medicated NF-kB and NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Pinellia ternata (Thunb.) Breit. (PT) has been demonstrated to be effective against the allergic airway inflammation (AAI) in clinical practices, especially in cold asthma (CA). Until now, the active ingredients, protective effect, and possible mechanism of PT against CA remain unknown. AIM OF THE STUDY: The aim of this investigation was to examine the therapeutic impact and elucidate the underlying mechanism of PT on the AAI of CA. METHODS: The compositions of PT water extract were determined via the UPLC-Q-TOF-MS/MS. The ovalbumin (OVA) and cold-water baths were used to induce CA in female mice. Morphological characteristic observations, expectorant effect, bronchial hyperreactivity (BHR), excessive mucus secretion, and inflammatory factors were used to uncover the treatment effect of PT water extract. In addition, the mucin 5AC (MUC5AC) mRNA and protein levels and the aquaporin 5 (AQP5) mRNA and protein levels were detected via qRT-PCR, immunohistochemistry (IHC), and western blotting. Moreover, the protein expressions associated with the TLR4, NF-κB, and NLRP3 signaling pathway were monitored by western blot analysis. RESULTS: Thirty-eight compounds were identified from PT water extract. PT showed significant therapeutic effects on mice with cold asthma in terms of expectorant activity, histopathological changes, airway inflammation, mucus secretion, and hyperreactivity. PT exhibited good anti-inflammatory effects in vitro and in vivo. The expression levels of MUC5AC mRNA and protein decreased significantly, while AQP5 expression levels increased significantly in the lung tissues of mice after administration with PT as compared to mice induced by CA. Furthermore, the protein expressions of TLR4, p-iκB, p-p65, IL-1ß, IL-18, NLRP3, cleaved caspase-1, and ASC were markedly reduced following PT treatment. CONCLUSIONS: PT attenuated the AAI of CA by modulating Th1- and Th2-type cytokines. PT could inhibit the TLR4-medicated NF-kB signaling pathway and activate the NLRP3 inflammasome to reduce CA. This study provides an alternative therapeutic agent of the AAI of CA after administration with PT.

Upregulated Long Non-coding RNA Lnc-MRPL39-2:1 Induces the Growth and Invasion of Nasopharyngeal Carcinoma by Binding to HuR and Stabilizing ß-Catenin mRNA.

Long non-coding RNAs (lncRNAs) have been to regulate tumor progression and therapy resistance through various molecular mechanisms. In this study, we investigated the role of lncRNAs in nasopharyngeal carcinoma (NPC) and the underlying mechanism. Using lncRNA arrays to analyze the lncRNA profiles of the NPC and para-tumor tissues, we detected the novel lnc-MRPL39-2:1, which was validated by in situ hybridization and by the 5' and 3' rapid amplification of the cDNA ends. Further, its role in NPC cell growth and metastasis was verified in vitro and in vivo. The researchers conducted the RNA pull-down assays, mass spectrometry (MS), dual-luciferase reporter assays, RNA immunoprecipitation (RIP) assays, and the MS2-RIP assays were then used to identify the lnc-MRPL39-2:1-interacting proteins and miRNAs. We found that lnc-MRPL39-2:1, which was highly expressed in in NPC tissues, was related to a poor prognosis in NPC patients. Furthermore, lnc-MRPL39-2:1 was shown to induce the growth and invasion of NPC by interacting directly with the Hu-antigen R (HuR) to upregulate ß-catenin expression both in vivo and in vitro. Lnc-MRPL39-2:1 expression was also suppressed by microRNA (miR)-329. Thus, these findings indicate that lnc-MRPL39-2:1 is essential in NPC tumorigenesis and metastasis and highlight its potential as a prognostic marker and therapeutic target for NPC.

Cancer-Associated Fibroblasts Promote Radioresistance of Breast Cancer Cells via the HGF/c-Met Signaling Pathway.

PURPOSE: Cancer-associated fibroblasts (CAFs) are an integral part of the tumor microenvironment (TME), which is involved in therapy resistance. This study aimed to investigate the role of CAFs in radiosensitivity of breast cancer cells. METHODS AND MATERIALS: The CAFs were isolated from the breast cancer tissues, and the conditioned medium was collected to culture breast cancer cells. Radiation-induced DNA damage was evaluated by immunofluorescence and western blotting. Cytokine array and enzyme-linked immunosorbent assay were performed to analyze the secretion of cytokines and growth factors. An in vitro clonogenic survival assay and in vivo xenograft mouse model were performed to determine the radiosensitivity of breast cancer cells. Finally, the expression of hepatocyte growth factor (HGF) and c-Met in the breast cancer tissues were detected by immunohistochemistry. RESULTS: The CAFs were found to secrete HGF to activate the c-Met signaling pathway, which induced epithelial-to-mesenchymal transition, growth, and radioresistance of breast cancer cells. Furthermore, radiation was observed to enhance HGF secretion by CAFs and increase c-Met expression in breast cancer cells, which led to HGF/c-Met signaling pathway activation. Moreover, radiation-induced tumor necrosis factor α (TNFα) secretion by breast cancer cells promoted CAF proliferation and HGF secretion. Additionally, HGF and c-Met high expression were associated with worse recurrence-free survival in patients with breast cancer who had received radiation therapy. CONCLUSIONS: The findings revealed that HGF and TNFα are critical for the crosstalk between breast cancer cells and CAFs in the TME and that the HGF/c-Met signaling pathway is a promising therapeutic target for radiosensitizing breast cancer.

Exosomal B7-H4 from irradiated glioblastoma cells contributes to increase FoxP3 expression of differentiating Th1 cells and promotes tumor growth.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor. Although numerous postoperative therapeutic strategies have already been developed, including radiotherapy, tumors inevitably recur after several years of treatment. The coinhibitory molecule B7-H4 negatively regulates T cell immune responses and promotes immune escape. Exosomes mediate intercellular communication and initiate immune evasion in the tumor microenvironment (TME). OBJECTIVE: This study aimed to determine whether B7-H4 is upregulated by radiation and loaded into exosomes, thus contributing to immunosuppression and enhancing tumor growth. METHODS: Iodixanol density-gradient centrifugation and flow cytometry were used to verify exosomal B7-H4. Naïve T cells were differentiated into Th1 cells, with or without exosomes. T cell-secreted cytokines and markers of T cell subsets were measured. Mechanistically, the roles of B7-H4, and ALIX in GBM were analyzed using databases and tissue samples. Co-immunoprecipitation, and pull-down assays were used to tested the direct interactions between ATM and ALIX or STAT3. In vitro ATM kinase assays, western blotting, and site-directed mutation were used to assess ATM-mediated STAT3 phosphorylation. Finally, the contribution of exosomal B7-H4 to immunosuppression and tumor growth was investigated in vivo. RESULTS: Exosomes from irradiated GBM cells decreased the anti-tumor immune response of T cell in vitro and in vivo via delivered B7-H4. Mechanistically, irradiation promoted exosome biogenesis by increasing the ATM-ALIX interaction. Furthermore, the ATM-phosphorylated STAT3 was found to directly binds to the B7-H4 promoter to increase its expression. Finally, the radiation-induced increase in exosomal B7-H4 induced FoxP3 expression during Th1 cell differentiation via the activated STAT1 pathway. In vivo, exosomal B7-H4 decreased the radiation sensitivity of GBM cells, and reduced the survival of GBM mice model. CONCLUSION: This study showed that radiation-enhanced exosomal B7-H4 promoted immunosuppression and tumor growth, hence defining a direct link between irradiation and anti-tumor immune responses. Our results suggest that co-administration of radiotherapy with anti-B7-H4 therapy could improve local tumor control and identify exosomal B7-H4 as a potential tumor biomarker.

A Metabolism-Related Gene Prognostic Index Bridging Metabolic Signatures and Antitumor Immune Cycling in Head and Neck Squamous Cell Carcinoma.

Background: In the era of immunotherapy, predictive or prognostic biomarkers for head and neck squamous cell carcinoma (HNSCC) are urgently needed. Metabolic reprogramming in the tumor microenvironment (TME) is a non-negligible reason for the low therapeutic response to immune checkpoint inhibitor (ICI) therapy. We aimed to construct a metabolism-related gene prognostic index (MRGPI) for HNSCC bridging metabolic characteristics and antitumor immune cycling and identified the immunophenotype, genetic alternations, potential targeted inhibitors, and the benefit of immunotherapy in MRGPI-defined subgroups of HNSCC. Methods: Based on The Cancer Genome Atlas (TCGA) HNSCC dataset (n = 502), metabolism-related hub genes were identified by the weighted gene co-expression network analysis (WGCNA). Seven genes were identified to construct the MRGPI by using the Cox regression method and validated with an HNSCC dataset (n = 270) from the Gene Expression Omnibus (GEO) database. Afterward, the prognostic value, metabolic activities, genetic alternations, gene set enrichment analysis (GSEA), immunophenotype, Connectivity map (cMAP), and benefit of immunotherapy in MRGPI-defined subgroups were analyzed. Results: The MRGPI was constructed based on HPRT1, AGPAT4, AMY2B, ACADL, CKM, PLA2G2D, and ADA. Patients in the low-MRGPI group had better overall survival than those in the high-MRGPI group, consistent with the results in the GEO cohort (cutoff value = 1.01). Patients with a low MRGPI score display lower metabolic activities and an active antitumor immunity status and more benefit from immunotherapy. In contrast, a higher MRGPI score was correlated with higher metabolic activities, more TP53 mutation rate, lower antitumor immunity ability, an immunosuppressive TME, and less benefit from immunotherapy. Conclusion: The MRGPI is a promising indicator to distinguish the prognosis, the metabolic, molecular, and immune phenotype, and the benefit from immunotherapy in HNSCC.

LHX2 facilitates the progression of nasopharyngeal carcinoma via activation of the FGF1/FGFR axis.

BACKGROUND: Distant metastasis and recurrence remain the main obstacle to nasopharyngeal carcinoma (NPC) treatment. However, the molecular mechanisms underlying NPC growth and metastasis are poorly understood. METHODS: LHX2 expression was examined in NPC cell lines and NPC tissues using quantitative reverse transcription-polymerase chain reaction, western blotting and Immunohistochemistry assay. NPC cells overexpressing or silencing LHX2 were used to perform CCK-8 assay, colony-formation assay, EdU assay, wound-healing and invasion assays in vitro. Xenograft tumour models and lung metastasis models were involved for the in vivo assays. The Gene Set Enrichment Analysis (GSEA), ELISA assay, western blot, chromatin immunoprecipitation (ChIP) assay and Luciferase reporter assay were applied for the downstream target mechanism investigation. RESULTS: LIM-homeodomain transcription factor 2 (LHX2) was upregulated in NPC tissues and cell lines. Elevated LHX2 was closely associated with poor survival in NPC patients. Ectopic LHX2 overexpression dramatically promoted the growth, migration and invasion of NPC cells both in vitro and in vivo. Mechanistically, LHX2 transcriptionally increased the fibroblast growth factor 1 (FGF1) expression, which in turn activated the phosphorylation of STAT3 (signal transducer and activator of transcription 3), ERK1/2 (extracellular regulated protein kinases 1/2) and AKT signalling pathways in an autocrine and paracrine manner, thereby promoting the growth and metastasis of NPC. Inhibition of FGF1 with siRNA or FGFR inhibitor blocked LHX2-induced nasopharyngeal carcinoma cell growth, migration and invasion. CONCLUSIONS: Our study identifies the LHX2-FGF1-FGFR axis plays a key role in NPC progression and provides a potential target for NPC therapy.

Strongest Angle-of-Arrival Estimation for Hybrid Millimeter Wave Architecture with 1-Bit A/D Equipped at Transceivers.

This paper proposes an effective strongest angles of arrival (AoAs) estimation algorithm for a hybrid millimeter wave (mmWave) communication system with 1-bit analog-to-digital/digital-to-analog converters (A/Ds) equipped at transceivers. The proposed algorithm aims to reduce the required number of estimation overheads, while maintaining the root mean square error (RMSE) of strongest AoA estimates at the base station. We obtain the quantization thresholds of A/Ds for different signal-to-noise ratios (SNRs) and numbers of antennas via numerical simulations, based on which, the strongest AoAs can be estimated with a small amount of overheads. The proposed algorithm is compared with conventional schemes including 1-bit FFT and 1-bit exhaustive search, as well as 1-bit Cramér-Rao lower bound. Simulation results verify the effectiveness of our proposed algorithm in terms of reducing estimation overheads while maintaining reasonable estimation performance in low SNRs.

Construction and Verification of a Glycolysis-Associated Gene Signature for the Prediction of Overall Survival in Low Grade Glioma.

The overall survival of patients with lower grade glioma (LGG) that might develop into high-grade malignant glioma shows marked heterogeneity. The currently used clinical evaluation index is not sufficient to predict precise prognostic outcomes accurately. To optimize survival risk stratification and the personalized management of patients with LGG, there is an urgent need to develop an accurate risk prediction model. The TCGA-LGG dataset, downloaded from The Cancer Genome Atlas (TCGA) portal, was used as a training cohort, and the Chinese Glioma Genome Atlas (CGGA) dataset and Rembrandt dataset were used as validation cohorts. The levels of various cancer hallmarks were quantified, which identified glycolysis as the primary overall survival-related risk factor in LGGs. Furthermore, using various bioinformatic and statistical methods, we developed a strong glycolysis-related gene signature to predict prognosis. Gene set enrichment analysis showed that in our model, high-risk glioma correlated with the chemoradiotherapy resistance and poor survival. Moreover, based on established risk model and other clinical features, a decision tree and a nomogram were built, which could serve as useful tools in the diagnosis and treatment of LGGs. This study indicates that the glycolysis-related gene signature could distinguish high-risk and low-risk patients precisely, and thus can be used as an independent clinical feature.

A Multi-Omics Pan-Cancer Analysis of 4EBP1 in Cancer Prognosis and Cancer-Associated Fibroblasts Infiltration.

Background: Eukaryotic Translation Initiation Factor 4E Binding Protein 1 (4EBP1) involved in inhibition of protein translation and synthesis. However, the phosphoprotein of 4EBP1 (p-4EBP1) promotes the translation and synthesis of several proteins, including multiple classic oncogenic proteins. The prognostic significance of 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 in Pan-cancer are still unclear. Methods: In this study, we provided a multi-Omics investigation for the prognostic value of 4EBP1 mRNA, 4EBP1 protein, and different 4EBP1 phosphoproteins in a Pan-cancer manner based on the TCGA projects. We explored the correlation between 4EBP1 expression and the cancer-associated fibroblast (CAFs) infiltration, respectively using the EPIC, MCPCOUNTER, and TIDE algorithms. The functional states of 4EBP1 were explored using single-cell sequencing analysis in Pan-Cancer. Immunohistochemistry staining was used to detect and verify the expression of 4EBP1 in several cancers. Results: 4EBP1 mRNA was aberrantly overexpressed in most cancers, and was associated with the poor prognosis in ten cancers. Notably, increased 4EBP1 mRNA expression significantly correlated with tumor staging and worse prognosis in BRCA, KIRC, and KIRP, while having the opposite effect in STAD. 4EBP1 expression was associated with the CAFs infiltration level in ten cancer types. Interestingly, the correlation between 4EBP1 and CAFs infiltration had pronounced heterogeneity in digestive system tumors and urinary system tumors. In BLCA, KIRC, and ACC as well as BRCA, 4EBP1 was significantly positively correlated with CAFs infiltration and was associated with a poor prognosis. In STAD and COAD, 4EBP1 is negatively correlated with CAFs infiltration and was associated with a better prognosis. Lastly, the expression and prognostic significance of 4EBP1 protein and different p-4EBP1 varied enormously among cancers. Conclusion: Our multi-omics study indicates that 4EBP1-driven CAFs infiltration is associated with cancer prognosis and 4EBP1 mRNA, 4EBP1 protein, and p-4EBP1 proteins may serve as potential prognostic biomarkers and therapeutic targets in diverse cancer.

Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced profibrotic fibroblast responses.

Radiotherapy can induce various adverse effects including fibrosis in cancer patients. Radiation-induced aberrant expression of profibrotic genes has been associated with dysregulated epigenetic mechanisms. Pan-BET (bromodomain and extraterminal domain) inhibitors, such as JQ1 and I-BET151, have been reported to attenuate the profibrotic response after irradiation. Despite their profound preclinical efficacy, the clinical utility of pan-inhibitors is limited due to observed cytotoxicicities. Recently, inhibitors were developed that selectively target the first (BD1) and second (BD2) bromodomain of the BET proteins (iBET-BD1 [GSK778] and iBET-BD2 [GSK046]). Here, their potential to attenuate radiation-induced fibroblast activation with low-toxicity was investigated. Our results indicated that cell proliferation and cell cycle progression in fibroblasts from BJ cells and six donors were reduced when treated with I-BET151 and iBET-BD1, but not with iBET-BD2. After irradiation, induction of DGKA and profibrotic markers, especially COL1A1 and ACTA2, was attenuated with all BET inhibitors. H3K27ac enrichment was similar at the DGKA enhancer region after I-BET151 treatment and irradiation, but was reduced at the COL1A1 transcription start site and the ACTA2 enhancer site. iBET-BD2 did not change H3K27ac levels in these regions. BRD4 occupancy at these regions was not altered by any of the compounds. Cell migration activity was measured as a characteristic independent of extracellular matrix production and was unchanged in fibroblasts after irradiation and BET inhibitor-treatment. In conclusion, iBET-BD2 efficiently suppressed radiation-induced expression of DGKA and profibrotic markers without showing cytotoxicity. Thus BD2-selective targeting is a promising new therapeutic avenue for further investigations to prevent or attenuate radiotherapy-induced fibrosis.

Application of smog chambers in atmospheric process studies.

Smog chamber experimental systems, which have been widely used in laboratory simulation for studying atmospheric processes, are comprehensively reviewed in this paper. The components, development history, main research topics and main achievements of smog chambers are introduced. Typical smog chambers in the world, including their volumes, wall materials, light sources and features, are summarized and compared. Key factors of smog chambers and their influences on the simulation of the atmospheric environment are discussed, including wall loss, wall emission and background pollutants. The features of next-generation smog chambers and their application prospect in future studies of the atmospheric environment are also outlined in this paper.

Increased MCL-1 synthesis promotes irradiation-induced nasopharyngeal carcinoma radioresistance via regulation of the ROS/AKT loop.

Worldwide, nasopharyngeal carcinoma (NPC) is a rare head and neck cancer; however, it is a common malignancy in southern China. Radiotherapy is the most important treatment strategy for NPC. However, although radiotherapy is a strong tool to kill cancer cells, paradoxically it also promotes aggressive phenotypes. Therefore, we mimicked the treatment process in NPC cells in vitro. Upon exposure to radiation, a subpopulation of NPC cells gradually developed resistance to radiation and displayed cancer stem-cell characteristics. Radiation-induced stemness largely depends on the accumulation of the antiapoptotic myeloid cell leukemia 1 (MCL-1) protein. Upregulated MCL-1 levels were caused by increased stability and more importantly, enhanced protein synthesis. We showed that repeated ionizing radiation resulted in persistently enhanced reactive oxygen species (ROS) production at a higher basal level, further promoting protein kinase B (AKT) signaling activation. Intracellular ROS and AKT activation form a positive feedback loop in the process of MCL-1 protein synthesis, which in turn induces stemness and radioresistance. AKT/MCL-1 axis inhibition attenuated radiation-induced resistance, providing a potential target to reverse radiation therapy-induced radioresistance.

A New Type of Quartz Smog Chamber: Design and Characterization.

Since the 1960s, many indoor and outdoor smog chambers have been developed worldwide. However, most of them are made of Teflon films, which have relatively high background contaminations due to the wall effect. We developed the world's first medium-size quartz chamber (10 m3), which is jointed with 32 pieces of 5 mm thick polished quartz glasses and a stainless-steel frame. Characterizations show that this chamber exhibits excellent performance in terms of relative humidity (RH) (2-80%) and temperature (15-30 ± 1 °C) control, mixing efficiency of the reactants (6-8 min), light transmittance (>90% above 290 nm), and wall loss of pollutants. The wall loss rates of the gas-phase pollutants are on the order of 10-4 min-1 at 298 K under dry conditions. It is 0.08 h-1 for 100-500 nm particles, significantly lower than those of Teflon chambers. The photolysis rate of NO2 (JNO2) is automatically adjustable to simulate the diurnal variation of solar irradiation from 0 to 0.40 min-1. The inner surface of the chamber can be repeatedly washed with deionized water, resulting in low background contaminations. Both experiments (toluene-NOx and α-pinene-ozone systems) and box model demonstrate that this new quartz chamber can provide high-quality data for investigating SOA and O3 formation in the atmosphere.

CMTM6 as a candidate risk gene for cervical cancer: Comprehensive bioinformatics study.

Background: CKLF like MARVEL transmembrane domain containing 6 (CMTM6) is an important programmed cell death 1 ligand 1 regulator (PD-L1). CMTM6 was reported as an important regulator of PD-L1 by promoting PD-L1 expression in tumor cells against T cells. However, the function of CMTM6 in cervical cancer is not well characterized. In addition, the role of CMTM6 in the induction of epithelial-mesenchymal transition (EMT) in the context of cervical cancer is unknown. Methods: In this study, we evaluated the role of CMTM6, including gene expression analysis, miRNA target regulation, and methylation characteristic, using multiple bioinformatics tools based on The Cancer Genome Atlas (TCGA) database. The expression of CMTM6 in cervical cancer tissues and non-cancerous adjacent tissues was assessed using immunohistochemistry. In vitro and in vivo function experiments were performed to explore the effects of CMTM6 on growth and metastasis of cervical cancer. Results: Human cervical cancer tissues showed higher expression of CMTM6 than the adjacent non-cancerous tissues. In vitro assays showed that CMTM6 promoted cervical cancer cell invasion, migration, proliferation, and epithelial-mesenchymal transition via activation of mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK)/p38 signaling pathway. We identified transcription factors (TFs), miRNAs, and immune cells that may interact with CMTM6. Conclusion: These results indicate that CMTM6 is a potential therapeutic target in the context of cervical cancer.

ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition.

The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.

Epigenetic Modulation of Radiation-Induced Diacylglycerol Kinase Alpha Expression Prevents Pro-Fibrotic Fibroblast Response.

Radiotherapy, a common component in cancer treatment, can induce adverse effects including fibrosis in co-irradiated tissues. We previously showed that differential DNA methylation at an enhancer of diacylglycerol kinase alpha (DGKA) in normal dermal fibroblasts is associated with radiation-induced fibrosis. After irradiation, the transcription factor EGR1 is induced and binds to the hypomethylated enhancer, leading to increased DGKA and pro-fibrotic marker expression. We now modulated this DGKA induction by targeted epigenomic and genomic editing of the DGKA enhancer and administering epigenetic drugs. Targeted DNA demethylation of the DGKA enhancer in HEK293T cells resulted in enrichment of enhancer-related histone activation marks and radiation-induced DGKA expression. Mutations of the EGR1-binding motifs decreased radiation-induced DGKA expression in BJ fibroblasts and caused dysregulation of multiple fibrosis-related pathways. EZH2 inhibitors (GSK126, EPZ6438) did not change radiation-induced DGKA increase. Bromodomain inhibitors (CBP30, JQ1) suppressed radiation-induced DGKA and pro-fibrotic marker expression. Similar drug effects were observed in donor-derived fibroblasts with low DNA methylation. Overall, epigenomic manipulation of DGKA expression may offer novel options for a personalized treatment to prevent or attenuate radiotherapy-induced fibrosis.