ABSTRACT
The nature of the anomalous metal state has been a major puzzle in condensed matter physics for more than three decades. Here, we report systematic investigation and modulation of the anomalous metal states in high-temperature interface superconductor FeSe films on SrTiO_{3} substrate. Remarkably, under zero magnetic field, the anomalous metal state persists up to 20 K in pristine FeSe films, an exceptionally high temperature standing out from previous observations. In stark contrast, for the FeSe films with nanohole arrays, the characteristic temperature of the anomalous metal state is considerably reduced. We demonstrate that the observed anomalous metal states originate from the quantum tunneling of vortices adjusted by the Ohmic dissipation. Our work offers a perspective for understanding the origin and modulation of the anomalous metal states in two-dimensional bosonic systems.
ABSTRACT
ABSTRACT: Signal peptide (SP) is essential for protein secretion, and pathogenic variants in the SP of factor IX (FIX) have been identified in hemophilia B (HB). However, the underlying mechanism for the genotype-phenotype correlation of these variants has not been well studied. Here, we systematically examined the effects of 13 pathogenic point variants in the SP of FIX using different approaches. Our results showed that these point variants lead to HB by missense variants and/or aberrant premessenger RNA (pre-mRNA) splicing. The missense variants in a hydrophobic core (h-region) mainly affected the cotranslational translocation function of the SP, and those in C-terminal containing cleavage site (c-region) caused FIX deficiency mainly by disturbing the cotranslational translocation and/or cleavage of the SP. Almost absolute aberrant pre-mRNA splicing was only observed in variants of c.82T>G, but a slight change of splicing patterns was found in variants of c.53G>T, c.77C>A, c.82T>C, and c.83G>A, indicating that these variants might have different degrees of impact on pre-mRNA splicing. Although two 6-nt deletion aberrant pre-mRNA splicing products caused FIX deficiency by disturbing the SP cleavage, they could produce some functional mature FIX, and vitamin K could increase the secretion of functional FIX. Taken together, our data indicated that pathogenic variants in the SP of FIX caused HB through diverse molecular mechanisms or even a mixture of several mechanisms, and vitamin K availability could be partially attributed to varying bleeding tendencies in patients carrying the same variant in the SP.
Subject(s)
Factor IX , Hemophilia B , Protein Sorting Signals , RNA Splicing , Hemophilia B/genetics , Factor IX/genetics , Factor IX/metabolism , Humans , Protein Sorting Signals/genetics , Mutation, MissenseABSTRACT
BACKGROUND: The RNA-binding motif single-stranded interacting protein 3 (RBMS3) is a constituent of the RNA-binding motif (RBM) protein family, which assumes a pivotal role in governing cellular biogenesis processes such as the cell cycle and apoptosis. Despite an abundance of studies elucidating RBMS3's divergent roles in the genesis and advancement of various tumors, its involvement in colon cancer remains enigmatic. METHODS: The present investigation employed data analysis from TCGA and GTEx to unveil that RBMS3 expression demonstrated a diminished presence in colon cancer tissues when juxtaposed with normal colon tissues. The effect of RBMS3 and LIM zinc finger domain 1 (LIMS1) on colon cancer was substantiated via animal models and cellular experiments. The connection between RBMS3 and LIM zinc finger domain 1 (LIMS1) was verified by molecular biology methods. RESULTS: The study conclusively ascertained that augmenting RBMS3 expression quells the proliferation, migration, and invasion of colon cancer cells. Furthermore, the inquiry unveiled a plausible mechanism through which RBMS3 impacts the expression of LIMS1 by modulating its mRNA stability. The investigation ascertained that RBMS3 inhibits the progression of colon cancer by regulating LIMS1. The inhibitory function of LIMS1 and RBMS3 is closely intertwined in colon cancer, with knocking down LIMS1 being able to rescue the inhibitory effect of RBMS3 overexpression on the functionality of colon cancer cell CONCLUSIONS: The discernments delineate RBMS3 as a novel suppressor of cancer via LIMS1, thereby bestowing fresh therapeutic possibilities and illuminating the intricacies of colon cancer.
Subject(s)
Colonic Neoplasms , Animals , Apoptosis , Cell Cycle/genetics , Colonic Neoplasms/genetics , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , HumansABSTRACT
Protein degradation is essential for maintaining protein homeostasis. The ubiquitinâproteasome system (UPS) and autophagy-lysosome system are the two primary pathways responsible for protein degradation and directly related to cell survival. In malignant tumors, the UPS plays a critical role in managing the excessive protein load caused by cancer cells hyperproliferation. In this review, we provide a comprehensive overview of the dual roles played by the UPS and autolysosome system in colorectal cancer (CRC), elucidating their impact on the initiation and progression of this disease while also highlighting their compensatory relationship. Simultaneously targeting both protein degradation pathways offers new promise for enhancing treatment efficacy against CRC. Additionally, apoptosis is closely linked to ubiquitination and autophagy, and caspases degrade proteins. A thorough comprehension of the interplay between various protein degradation pathways is highly important for clarifying the mechanism underlying the onset and progression of CRC.
ABSTRACT
Synthetic Aperture Radar (SAR) plays a crucial role in all-weather and all-day Earth observation owing to its distinctive imaging mechanism. However, interpreting SAR images is not as intuitive as optical images. Therefore, to make SAR images consistent with human cognitive habits and assist inexperienced people in interpreting SAR images, a generative model is needed to realize the translation from SAR images to optical ones. In this work, inspired by the processing of the human brain in painting, a novel conditional image-to-image translation framework is proposed for SAR to optical image translation based on the diffusion model. Firstly, considering the limited performance of existing CNN-based feature extraction modules, the model draws insights from the self-attention and long-skip connection mechanisms to enhance feature extraction capabilities, which are aligned more closely with the memory paradigm observed in the functioning of human brain neurons. Secondly, addressing the scarcity of SAR-optical image pairs, data augmentation that does not leak the augmented mode into the generated mode is designed to optimize data efficiency. The proposed SAR-to-optical image translation method is thoroughly evaluated using the SAR2Opt dataset. Experimental results demonstrate its capacity to synthesize high-fidelity optical images without introducing blurriness.
ABSTRACT
OBJECTIVES: This study was to investigate hydroxypropyl methylcellulose (HPMC) film as a carrier for amorphous fluorinated calcium phosphate (AFCP) nanoprecursors to continuously deliver biomimetic remineralization of enamel artificial caries lesions (ACL). MATERIALS AND METHODS: The AFCP/HPMC films were comprised of 25 wt% AFCP nanoparticles and 75 wt% HPMC. They were characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and biocompatibility tests. Forty enamel ACL were prepared and randomly divided into four groups (n = 10): The enamel surfaces were covered with a pure HPMC film, Tooth Mousse Plus (contains 10% CPP-ACP and 0.2% NaF), and AFCP/HPMC film, or without any things (serving as negative control). Subsequently, all samples were alternatively kept in artificial saliva and a modified pH-cycling before they were characterized by Micro-CT, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), attenuated total reflectance (ATR)-FTIR, XRD, and nanoindentation. RESULTS: After the enamel ACL was challenged by pH cycling, Tooth Mousse Plus and AFCP/HPMC film groups exhibited less lesion depth and mineral loss than the negative control and pure HPMC film groups. Additionally, the AFCP/HPMC film group revealed a highest remineralization rate of 55.34 ± 3.10 % among the all groups (p < 0.001). The SEM findings showed that the enamel ACL were densely deposited with minerals in the AFCP/HPMC film group, and the EDX results suggested a higher content of fluorine in the remineralized tissues. In particular, the AFCP/HPMC film group exhibited the best nanomechanical performance after 2 weeks of pH cycling (p < 0.05), with the hardness (H) restored from 0.29 ± 0.19 to 2.69 ± 0.70 GPa, and elastic modulus (Er) restored from 10.77 ± 5.30 to 68.83 ± 12.72 GPa. CONCLUSION: The AFCP/HPMC film might be used as a promising strategy for arresting or reversing incipient enamel caries lesions.
Subject(s)
Dental Caries Susceptibility , Dental Caries , Humans , Hypromellose Derivatives , Tooth Remineralization/methods , Calcium Phosphates , Minerals , Dental Caries/drug therapyABSTRACT
Many studies have provided valuable information about genomic and transcriptomic changes that occur in colorectal cancer. However, protein abundance cannot be reliably predicted by DNA alteration or mRNA expression, which can be partially attributed to posttranscriptional and/or translational regulation of gene expression. In this study, we identified increased translational efficiency (TE) as a hallmark of colorectal cancer by evaluating the transcriptomic and proteomic features of patients with colorectal cancer, along with comparative transcriptomic and ribosome-protected mRNA analysis in colon epithelial cells and colon cancer cells. COP9 signalosome subunit 7B (COPS7B) was among the key genes that consistently showed both significant TE increase and protein elevation without transcriptional alteration in colorectal cancer. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) enhanced the TE of COPS7B mRNA to promote colorectal cancer growth and metastasis. COPS7B was found to be a component of the ribo-interactome that interacted with ribosomes to facilitate ribosome biogenesis and mRNA translation initiation. Collectively, this study revealed the proteomic features of colorectal cancer and highlighted elevated mRNA translation as a hallmark of colorectal cancer. The identification of the IGF2BP3-COPS7B axis underlying the increased protein synthesis rate in colorectal cancer provided a promising therapeutic target to treat this aggressive disease. SIGNIFICANCE: Increased expression of COPS7B mediated by IGF2BP3 elevates the translational efficiency of genes enriched in mRNA translation and ribosome biogenesis pathways, promoting protein synthesis and driving progression in colorectal cancer.
Subject(s)
Colonic Neoplasms , Proteomics , Humans , Colonic Neoplasms/metabolism , Protein Biosynthesis , Ribosomes/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , COP9 Signalosome Complex/metabolism , Transcription Factors/metabolismABSTRACT
Aberrant alternative splicing (AS) events are frequently observed in lung cancer, which can be attributed to aberrant gene AS, alterations in splicing regulatory factors, or changes in splicing regulatory mechanisms. Consequently, the dysregulation of alternative RNA splicing is the fundamental cause of lung cancer. In this review, we have summarized the pivotal role of AS in the development, progression, invasion, metastasis, angiogenesis, and drug resistance of lung cancer. Ultimately, this review emphasizes the potential of AS as biomarkers in lung cancer prognosis and diagnosis, and introduces some applications of AS isoform in the treatment of lung cancer. The comprehension of the AS may provide a glimmer of hope for the eradication of lung cancer.
Subject(s)
Alternative Splicing , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , RNA Splicing Factors/genetics , Prognosis , Biomarkers , Gene Expression Regulation, NeoplasticABSTRACT
Background: The presence of gross extrathyroidal extension (ETE) in thyroid cancer will affect the prognosis of patients, but imaging examination cannot provide a reliable diagnosis for it. This study was conducted to develop a deep learning (DL) model for localization and evaluation of thyroid cancer nodules in ultrasound images before surgery for the presence of gross ETE. Methods: From January 2016 to December 2021 grayscale ultrasound images of 806 thyroid cancer nodules (4451 images) from 4 medical centers were retrospectively analyzed, including 517 no gross ETE nodules and 289 gross ETE nodules. 283 no gross ETE nodules and 158 gross ETE nodules were randomly selected from the internal dataset to form a training set and validation set (2914 images), and a multitask DL model was constructed for diagnosing gross ETE. In addition, the clinical model and the clinical and DL combined model were constructed. In the internal test set [974 images (139 no gross ETE nodules and 83 gross ETE nodules)] and the external test set [563 images (95 no gross ETE nodules and 48 gross ETE nodules)], the diagnostic performance of DL model was verified based on the pathological results. And then, compared the results with the diagnosis by 2 senior and 2 junior radiologists. Findings: In the internal test set, DL model demonstrated the highest AUC (0.91; 95% CI: 0.87, 0.96), which was significantly higher than that of two senior radiologists [(AUC, 0.78; 95% CI: 0.71, 0.85; P < 0.001) and (AUC, 0.76; 95% CI: 0.70, 0.83; P < 0.001)] and two juniors radiologists [(AUC, 0.65; 95% CI: 0.58, 0.73; P < 0.001) and (AUC, 0.69; 95% CI: 0.62, 0.77; P < 0.001)]. DL model was significantly higher than clinical model [(AUC, 0.84; 95% CI: 0.79, 0.89; P = 0.019)], but there was no significant difference between DL model and clinical and DL combined model [(AUC, 0.94; 95% CI: 0.91, 0.97; P = 0.143)]. In the external test set, DL model also demonstrated the highest AUC (0.88, 95% CI: 0.81, 0.94), which was significantly higher than that of one of senior radiologists [(AUC, 0.75; 95% CI: 0.66, 0.84; P = 0.008) and (AUC, 0.81; 95% CI: 0.72, 0.89; P = 0.152)] and two junior radiologists [(AUC, 0.72; 95% CI: 0.62, 0.81; P = 0.002) and (AUC, 0.67; 95 CI: 0.57, 0.77; P < 0.001]. There was no significant difference between DL model and clinical model [(AUC, 0.85; 95% CI: 0.79, 0.91; P = 0.516)] and clinical + DL model [(AUC, 0.92; 95% CI: 0.87, 0.96; P = 0.093)]. Using DL model, the diagnostic ability of two junior radiologists was significantly improved. Interpretation: The DL model based on ultrasound imaging is a simple and helpful tool for preoperative diagnosis of gross ETE thyroid cancer, and its diagnostic performance is equivalent to or even better than that of senior radiologists. Funding: Jiangxi Provincial Natural Science Foundation (20224BAB216079), the Key Research and Development Program of Jiangxi Province (20181BBG70031), and the Interdisciplinary Innovation Fund of Natural Science, Nanchang University (9167-28220007-YB2110).
ABSTRACT
BACKGROUND: DNA-based next-generation sequencing has been widely used in the selection of target therapies for patients with nonsmall cell lung cancer (NSCLC). RNA-based next-generation sequencing has been proven to be valuable in detecting fusion and exon-skipping mutations and is recommended by National Comprehensive Cancer Network guidelines for these mutation types. METHODS: The authors developed an RNA-based hybridization panel targeting actionable driver oncogenes in solid tumors. Experimental and bioinformatics pipelines were optimized for the detection of fusions, single-nucleotide variants (SNVs), and insertion/deletion (indels). In total, 1253 formalin-fixed, paraffin-embedded samples from patients with NSCLC were analyzed by DNA and RNA panel sequencing in parallel to assess the performance of the RNA panel in detecting multiple types of mutations. RESULTS: In analytical validation, the RNA panel achieved a limit of detection of 1.45-3.15 copies per nanogram for SNVs and 0.21-6.48 copies per nanogram for fusions. In 1253 formalin-fixed, paraffin-embedded NSCLC samples, the RNA panel identified a total of 124 fusion events and 26 MET exon 14-skipping events, in which 14 fusions and six MET exon 14-skipping mutations were missed by DNA panel sequencing. By using the DNA panel as the reference, the positive percent agreement and the positive predictive value of the RNA panel were 98.08% and 98.62%, respectively, for detecting targetable SNVs and 98.15% and 99.38%, respectively, for detecting targetable indels. CONCLUSIONS: Parallel DNA and RNA sequencing analyses demonstrated the accuracy and robustness of the RNA sequencing panel in detecting multiple types of clinically actionable mutations. The simplified experimental workflow and low sample consumption will make RNA panel sequencing a potentially effective method in clinical testing.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/diagnosis , Lung Neoplasms/genetics , Mutation , High-Throughput Nucleotide Sequencing/methods , Sequence Analysis, RNA , FormaldehydeABSTRACT
Background: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) has been reported to exhibit an oncogenic effect as an RNA-binding protein (RBP) by promoting tumor cell proliferation, migration and invasion in several tumor types. However, a pan-cancer analysis of IGF2BP3 is not currently available, and the exact roles of IGF2BP3 in prognosis and immunology in cancer patients remain enigmatic. The main aim of this study was to provide visualization of the systemic prognostic landscape of IGF2BP3 in pan-cancer and to uncover the potential relationship between IGF2BP3 expression in the tumor microenvironment and immune infiltration profile. Methods: Raw data on IGF2BP3 expression were obtained from GTEx, CCLE, TCGA, and HPA data portals. We have investigated the expression patterns, diagnostic and prognostic significance, mutation landscapes, functional analysis, and functional states of IGF2BP3 utilizing multiple databases, including HPA, TISIDB, cBioPortal, GeneMANIA, GESA, and CancerSEA. Moreover, the relationship of IGF2BP3 expression with immune infiltrates, TMB, MSI and immune-related genes was evaluated in pan-cancer. IGF2BP3 with drug sensitivity analysis was performed from the CellMiner database. Furthermore, the expression of IGF2BP3 in different grades of glioma was detected by immunohistochemical staining and western blot. Results: We found that IGF2BP3 was ubiquitously highly expressed in pan-cancer and significantly correlated with diagnosis, prognosis, TMB, MSI, and drug sensitivity in various types of cancer. Besides, IGF2BP3 was involved in many cancer pathways and varied in different immune and molecular subtypes of cancers. Additionally, IGF2BP3 is critically associated with genetic markers of immunomodulators in various cancers. Finally, we validated that IGF2BP3 protein expression was significantly higher in glioma than in normal tissue, especially in GBM. Conclusions: IGF2BP3 may be a potential molecular biomarker for diagnosis and prognosis in pan-cancer, especially for glioma. It could become a novel therapeutic target for various cancers.
Subject(s)
Glioma , Multiomics , Neoplasms , Humans , Adenosine , Biomarkers , Glioma/diagnosis , Glioma/genetics , Tumor Microenvironment/genetics , Biomarkers, Tumor/genetics , Neoplasms/diagnosis , Neoplasms/geneticsABSTRACT
Identification of novel molecular signaling targets for non-small cell lung cancer (NSCLC) is important. The present study examined expression, functions and possible underlying mechanisms of the sodium/myo-inositol co-transporter SLC5A3 in NSCLC. The Cancer Genome Atlas (TCGA) database and local NSCLC tissue results demonstrated that SLC5A3 expression in NSCLC tissues (including patient-derived primary NSCLC cells) was significantly higher than that in normal lung tissues and lung epithelial cells. In primary NSCLC cells and immortalized lines, SLC5A3 depletion, using small hairpin RNA (shRNA) and CRSIRP/Cas9 methods, robustly impeded cell proliferation and migration, simultaneously provoking cell cycle arrest and apoptosis. Conversely, ectopic overexpression of SLC5A3 further enhanced proliferation and migration in primary NSCLC cells. The intracellular myo-inositol contents and Akt-mTOR activation were largely inhibited by SLC5A3 silencing or knockout (KO), but were augmented following SLC5A3 overexpression in primary NSCLC cells. Significantly, SLC5A3 KO-induced anti-NSCLC cell activity was largely ameliorated by exogenously adding myo-inositol or by a constitutively-active Akt construct. By employing the patient-derived xenograft (PDX) model, we found that the growth of subcutaneous NSCLC xenografts in nude mice was largely inhibited by intratumoral injection SLC5A3 shRNA adeno-associated virus (AAV). SLC5A3 silencing, myo-inositol depletion, Akt-mTOR inactivation and apoptosis induction were detected in SLC5A3 shRNA virus-injected NSCLC xenograft tissues. Together, elevated SLC5A3 promotes NSCLC cell growth possibly by maintaining myo-inositol contents and promoting Akt-mTOR activation.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Symporters , Animals , Carcinoma, Non-Small-Cell Lung/genetics , Heat-Shock Proteins/metabolism , Humans , Inositol/metabolism , Lung Neoplasms/genetics , Mice , Mice, Nude , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering , Sodium/metabolism , Symporters/genetics , Symporters/metabolism , TOR Serine-Threonine Kinases/metabolismABSTRACT
Lung cancer is the cancer with the highest mortality in the world. So further exploration of the pathogenesis of lung cancer is of great significance. In this study, the specific role and related mechanism of CRIF1 in non-small cell lung cancer (NSCLC) were explored in this research. TheRT-PCR, western blot and IHC assays were used to examine the expression level of CRIF1 in NSCLC tissue, tissue adjacent to carcinoma, NSCLC cell lines and human normal lung epithelial cells. Next, colony formation assay, Alamar blue Kit and EdU assays were employed to examine the proliferation of transfected A549 and NCI-H2009 cells. Measurement of mitochondrial permeability transition pore opening, ATP production and cellular oxygen consumption were used to evaluate the mitochondrial apoptosis of transfected NSCLC cells. Enzymatic activity assays for PYCR1, western blot and flow cytometry assays were used to explore the relationship between PYCR1 and CRIF1. The subcutaneous xenograft tumor mice model was established to explore the role of CRIF1 in vivo. Collectively, results revealed that CRIF1 was upregulated in NSCLC cells and tissues (p < 0.001). CRIF1 promoted proliferation of NSCLC cells (p < 0.001). CRIF1 inhibited mitochondrial apoptosis in NSCLC cells (p < 0.05). Moreover, CRIF1 promoted PYCR1 deacetylation and increased its activity through SIRT3 (p < 0.05). Deacetylation of PYCR1 reversed the antitumor effect of CRIF1 knockdown (p < 0.05). Finally, knockdown of CRIF1 inhibited the tumor growth of NSCLC in vivo (p < 0.05).This research found that CRIF1 promoted the progression of non-small-cell lung cancer by SIRT3- mediated deacetylation of PYCR1.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , MicroRNAs , Sirtuin 3 , Animals , Apoptosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Mice , Pyrroline Carboxylate Reductases , Sirtuin 3/genetics , Sirtuin 3/metabolism , delta-1-Pyrroline-5-Carboxylate ReductaseABSTRACT
Non-small-cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers worldwide with limited effective therapies. Cisplatin (DDP), as the first-line treatment, is always served as a mainstay of chemotherapeutic agents in combination with other drugs for NSCLC treatment. Nevertheless, DDP-based therapy is limited due to the frequent development of chemoresistance and adverse effects. Herein, it is necessary to find a more effective therapeutic approach with less toxicity. Falnidamol (FLD) is a pyrimido-pyrimidine compound and exerts anti-cancer activity. In the present study, we found that FLD could strongly promote the cytotoxicity of DDP and markedly reduce the IC50 values to restrain the proliferation of NSCLC cells. Furthermore, combination of FLD and DDP remarkably induced G2/M cell cycle arrest, DNA damage and mitochondrial apoptosis, which was largely through the induction of reactive oxygen species (ROS). Additionally, FLD/DDP in combination greatly triggered ferroptosis, along with free iron accumulation and enhanced lipid peroxidation. Epithelial to mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR) phosphorylation were also considerably restrained in NSCLC cells co-treated with FLD/DDP. Mechanistically, the combinative treatment significantly reduced DUSP26 expression in NSCLC cells. More studies showed that DUSP26 was strongly up-regulated in human NSCLC samples compared with the paired normal tissues, and high DUSP26 predicted poor overall survival rate among patients. Importantly, we found that DUSP26 suppression intensively reduced the proliferation, EMT process and pEGFR expression in NSCLC cells, whereas facilitated ROS production, DNA damage and cell death; however, opposite phenotype was observed in NSCLC cells over-expressing DUSP26. More importantly, DUSP26 over-expression completely abolished the anti-cancer function of FLD/DDP in NSCLC cells. Animal studies finally confirmed that FLD/DDP in combination efficiently reduced tumor growth and lung metastasis in mice with ameliorated side effects. In conclusion, all these data illustrated that FLD and DDP combinational treatment effectively restrained NSCLC progression, and thus can be served as a promising therapeutic strategy.
Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Dual-Specificity Phosphatases , Lung Neoplasms , Mitogen-Activated Protein Kinase Phosphatases , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Proliferation , Cisplatin/pharmacology , Cisplatin/therapeutic use , Drug Resistance, Neoplasm/genetics , Dual-Specificity Phosphatases/genetics , Dual-Specificity Phosphatases/metabolism , Epithelial-Mesenchymal Transition , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mitogen-Activated Protein Kinase Phosphatases/genetics , Mitogen-Activated Protein Kinase Phosphatases/metabolism , Signal TransductionABSTRACT
BACKGROUND: Cyclin D1 (CCND1) is overexpressed in non-small cell lung cancer (NSCLC) and contributes to its tumorigenesis and progression. Accumulating evidence shows that ubiquitin-specific protease 5 (USP5), an important member of the USP family, acts as a tumor promoter by deubiquitinating and stabilizing oncoproteins. However, neither the mechanism for dysregulated turnover of CCND1 protein nor the association of CCND1 with USP5 in NSCLC is well understood. METHODS: The association of USP5 with CCND1 in human NSCLC cells and clinical tissues was determined by immunoprecipitation/immunoblotting, immunohistochemistry (IHC), and The Cancer Genome Atlas database analyses. The effect of USP5 knockdown or overexpression on NSCLC cell proliferation in vitro was assessed by Cell Counting Kit-8, flow cytometry-based cell cycle, and colony formation assays. The effect of the USP5 inhibitor EOAI3402143 (G9) on NSCLC proliferation in vitro was analyzed by CCK-8 assay. The effect of G9 on NSCLC xenograft tumor growth was also examined in vivo, using athymic BALB/c nude mice. RESULTS: USP5 physically bound to CCND1 and decreased its polyubiquitination level, thereby stabilizing CCND1 protein. This USP5-CCND1 axis promoted NSCLC cell proliferation and colony formation. Further, knockdown of USP5 led to CCND1 degradation and cell cycle arrest in NSCLC cells. Importantly, this tumor-suppressive effect elicited by USP5 knockdown in NSCLC cells was validated in vitro and in vivo through chemical inhibition of USP5 activity using G9. Consistently, G9 downregulated the protein levels of CCND1 in NSCLC cells and xenograft tumor tissues. Also, the expression level of USP5 was positively associated with the protein level of CCND1 in human clinical NSCLC tissues. CONCLUSIONS: This study has provided the first evidence that CCND1 is a novel substrate of USP5. The USP5-CCND1 axis could be a potential target for the treatment of NSCLC.
ABSTRACT
Bayesian networks (BNs) provide a probabilistic, graphical framework for modeling high-dimensional joint distributions with complex correlation structures. BNs have wide applications in many disciplines, including biology, social science, finance and biomedical science. Despite extensive studies in the past, network structure learning from data is still a challenging open question in BN research. In this study, we present a sequential Monte Carlo (SMC)-based three-stage approach, GRowth-based Approach with Staged Pruning (GRASP). A double filtering strategy was first used for discovering the overall skeleton of the target BN. To search for the optimal network structures we designed an adaptive SMC (adSMC) algorithm to increase the quality and diversity of sampled networks which were further improved by a third stage to reclaim edges missed in the skeleton discovery step. GRASP gave very satisfactory results when tested on benchmark networks. Finally, BN structure learning using multiple types of genomics data illustrates GRASP's potential in discovering novel biological relationships in integrative genomic studies.
ABSTRACT
Liver cancer morbidity and mortality rates differ among ethnic groups. In the United States, the burden of liver cancer in Asian Americans (AS) is higher compared to Caucasian Americans (CA). Research on liver cancer health disparities has mainly focused on environmental and socioeconomic factors yet has ignored the genotypic differences among various racial/ethnic groups. This lack of molecular level understanding has hindered the development of personalized medical approaches for liver cancer treatment. To understand the genetic heterogeneity of liver cancer between AS and CA, we performed a systematic analysis of RNA-seq data of AS and CA patients from The Cancer Genome Atlas (TCGA). We used four differential gene expression analysis packages; DESeq2, limma, edgeR, and Superdelta2, to identify the differentially expressed genes. Our analysis identified cytochrome P450-2D6 enzyme (CYP2D6) as the gene with the greatest differential expression with higher levels in AS compared to CA. To scrutinize the underlying mechanism of CYP2D6, Ingenuity Pathway Analysis (IPA) and Cytoscape were conducted and found hepatocyte nuclear factor-4α (HNF4A) and interleukin-6 (IL6) in direct association with CYP2D6. IL6 is downregulated in AS compared to CA, while HNF4A is not significantly different. Herein, we report that CYP2D6 may serve as a putative biomarker in liver cancer health disparities. Its negative association with IL6 proclaims an intricate relationship between CYP2D6 and inflammation in the ethnic differences seen in AS and CA liver cancer patients. The goal of the present study was to understand how genetic factors may contribute to the interethnic variability of liver cancer prevalence and outcomes in AS and CA patients. Identifying ethnic-specific genes may help ameliorate detection, diagnosis, surveillance, and treatments of liver cancer, as well as reduce disease-related incidence and mortality rates in the vulnerable population.
Subject(s)
Carcinoma, Hepatocellular/genetics , Cytochrome P-450 CYP2D6/genetics , Gene Expression Regulation, Neoplastic , Genotype , Liver Neoplasms/genetics , Polymorphism, Genetic , Alleles , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Databases, Genetic , Gene Expression Profiling , Gene Regulatory Networks , Health Status Disparities , Humans , Liver Neoplasms/mortality , Liver Neoplasms/pathologyABSTRACT
MOTIVATION: We developed super-delta2, a differential gene expression analysis pipeline designed for multi-group comparisons for RNA-seq data. It includes a customized one-way ANOVA F-test and a post-hoc test for pairwise group comparisons; both are designed to work with a multivariate normalization procedure to reduce technical noise. It also includes a trimming procedure with bias-correction to obtain robust and approximately unbiased summary statistics used in these tests. We demonstrated the asymptotic applicability of super-delta2 to log-transformed read counts in RNA-seq data by large sample theory based on Negative Binomial Poisson (NBP) distribution. RESULTS: We compared super-delta2 with three commonly used RNA-seq data analysis methods: limma/voom, edgeR and DESeq2 using both simulated and real datasets. In all three simulation settings, super-delta2 not only achieved the best overall statistical power, but also was the only method that controlled type I error at the nominal level. When applied to a breast cancer dataset to identify differential expression pattern associated with multiple pathologic stages, super-delta2 selected more enriched pathways than other methods, which are directly linked to the underlying biological condition (breast cancer). CONCLUSIONS: In conclusion, by incorporating trimming and bias-correction in the normalization step, super-delta2 was able to achieve tight control of type I error. Because the hypothesis tests are based on asymptotic normal approximation of the NBP distribution, super-delta2 does not require computationally expensive iterative optimization procedures used by methods such as edgeR and DESeq2, which occasionally have convergence issues. AVAILABILITY AND IMPLEMENTATION: Our method is implemented in a R-package, 'superdelta2', freely available at: https://github.com/fhlsjs/superdelta2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
ABSTRACT
BACKGROUND: Bronchial reconstruction is one of the most challenging procedures for thoracic surgeons. This study aimed to report the surgical techniques and clinical outcomes of bronchoplastic and sleeve resection for central lung cancer and summarize our center's experience of this challenging procedure over the past 8 years. METHODS: Between January 2013 and April 2021, 54 patients underwent a sleeve resection or a lobectomy with bronchoplasty, including 11 patients who received video-assisted thoracoscopic surgery (VATS) bronchial sleeve resection (4 via the uniportal approach and 7 via the biportal approach). Perioperative parameters and surgical short-term patient outcomes were analyzed to evaluate the safety and feasibility of this surgical procedure. RESULTS: The average operative time and blood loss were 247.8±73.1 (range, 126-455) minutes and 300.4±321.8 (range, 50-1,500) mL, respectively. The mean postoperative length of stay was 10.5±5.8 (range, 4-29) days. Eleven patients underwent additional pulmonary angioplasty or sleeve resection. For patients who underwent biportal VATS sleeve lobectomy, the median operative time was 255 (interquartile range, 179-360) minutes, the median blood loss was 200 (interquartile range, 100-600) mL, and the median postoperative hospital stay was 5 (interquartile range, 5-8) days. For patients who underwent uniportal VATS sleeve lobectomy, the median operative time was 288 (interquartile range, 241.5-343) minutes, the median blood loss was 75 (interquartile range, 50-100) mL, and the median postoperative hospital stay was 5 (interquartile range, 4.5-5.5) days. No anastomosis-related complications or perioperative mortality was observed. CONCLUSIONS: Both bronchoplastic resection and sleeve resection are safe and feasible procedures. Uniportal thoracoscopic sleeve lobectomy can be performed by skilled surgeons with satisfactory short-term outcomes, although it is surgically complicated.
ABSTRACT
Female breast cancer (FBC) incidence rate (IR) varies greatly across counties in the United States (U.S.). Factors contributing to these geographic disparities have not been fully understood at the population level. In this study, we investigated the relationships between the county-level FBC IR and a diverse set of variables in demographics, socioeconomics, life style, health care accessibility, and environment. Our study included 1,277 counties in the U.S. where the female population was 10,000 or above for at least one race/ethnicity. After controlling for the racial/ethnic and other significant factors, percent of husband-wife family households (pHWFH) for a racial/ethnic group in a county is negatively associated with FBC IR (p < 0.001). A 10% increase in married family households may lower a county's IR by 5.2 cases per 100,000 females per year. We also found that PM2.5 (fine inhalable particles with a diameter of 2.5 micrometers or less) is positively associated with FBC IR (p < 0.001). Counties with the highest level of PM2.5 have approximately 4 additional FBC new cases per 100,000 females per year than counties with the lowest level of PM2.5. Furthermore, we found that the county-level factors contributing to FBC IR vary significantly for different racial groups using race-specific models. While confirming most of the previously known patient- and neighborhood-level risk factors (such as race/ethnicity, income, and health care accessibility), our study identified two significant county-level factors contributing to the spatial disparity of FBC IR across the U.S. The newly-identified beneficial factor (marriage) and risk factor (PM2.5), together with the verified known factors, may help provide insights to officials of health departments/organizations for them to make decisions on cancer intervention strategies.