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Intravascular large B-cell lymphoma (IVLBCL) is a highly aggressive type of non-Hodgkin’s lymphoma. The clinical manifestations and imaging of this disease are nonspecific, making diagnosis challenging. We report a case of a patient with recurrent stroke-like symptoms, primarily characterized by hemiplegia, vertigo, ataxia, and proteinuria. Brain MRI revealed multiple cerebral infarctions, microbleeds, and meningeal enhancement. Ultimately, the patient was diagnosed with IVLBCL through a brain tissue biopsy, and involvement of the kidneys was suspected. We suggest considering IVLBCL in patients who present with recurrent stroke-like symptoms, fluctuating neurological deficits, the aforementioned MRI findings, and involvement of other organs. Additionally, central nervous system vasculitis(CNSV) may represent a transitional manifestation of the disease. Pathological biopsy is the gold standard for diagnosis. We hope that through this case, doctors can gain a deeper understanding of IVLBCL, enabling early diagnosis and timely treatment to improve prognosis.

Chimeric antigen receptor (CAR) T cells have demonstrated outstanding therapeutic success in hematological malignancies. Yet, their efficacy against solid tumors remains constrained due to inadequate infiltration of cytotoxic T and CAR-T cells in the tumor microenvironment (TME), a factor correlated with poor prognosis in patients with solid tumors. To overcome this limitation, we engineered CAR-T cells to secrete CXCL10 and IL15 (10 × 15 CAR-T), which sustain T cell viability and enhance their recruitment, thereby amplifying the long-term cytotoxic capacity of CAR-T cells in vitro. In a xenograft model employing NUGC4-T21 cells, mice receiving 10 × 15 CAR-T cells showed superior tumor reduction and extended survival rates compared to those treated with second-generation CAR-T cells. Histopathological evaluations indicated a pronounced increase in cytotoxic T cell accumulation in the TME post 10 × 15 CAR-T cell treatment. Therefore, the synergistic secretion of CXCL10 and IL15 in these CAR-T cells enhances T cell recruitment and adaptability within tumor tissues, improving tumor control. This approach may offer a promising strategy for advancing CAR-T therapies in the treatment of solid tumors.

Abstract Nuclear factor-kappaB (NF-ĸB) plays a crucial role in both innate and adaptive immune systems, significantly influencing various physiological processes such as cell proliferation, migration, differentiation, survival, and stemness. The function of NF-ĸB in cancer progression and response to chemotherapy has gained increasing attention. This review highlights the role of NF-ĸB in inflammation control, biological mechanisms, and therapeutic implications in cancer treatment. NF-ĸB is instrumental in altering the release of inflammatory factors such as TNF-α, IL-6, and IL-1β, which are key in the regulation of carcinogenesis. Specifically, in conditions including colitis, NF-ĸB upregulation can intensify inflammation, potentially leading to the development of colorectal cancer. Its pivotal role extends to regulating the tumor microenvironment, impacting components such as macrophages, fibroblasts, T cells, and natural killer cells. This regulation influences tumorigenesis and can dampen anti-tumor immune responses. Additionally, NF-ĸB modulates cell death mechanisms, notably by inhibiting apoptosis and ferroptosis. It also has a dual role in stimulating or suppressing autophagy in various cancers. Beyond these functions, NF-ĸB plays a role in controlling cancer stem cells, fostering angiogenesis, increasing metastatic potential through EMT induction, and reducing tumor cell sensitivity to chemotherapy and radiotherapy. Given its oncogenic capabilities, research has focused on natural products and small molecule compounds that can suppress NF-ĸB, offering promising avenues for cancer therapy.

ABSTRACT Purpose Upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) share histomorphological and therapeutic features but distinct epidemiologic and clinicopathologic characteristics. We examined alterations of chromatin regulatory genes in molecular subtypes, clonal relatedness, and T‐cell receptor (TCR) diversity in UTUC and UCB. Materials and Methods Targeted next‐generation sequencing or whole‐exome DNA sequencing and TCR sequencing were conducted with 34 UTUC and 49 UCB specimens from 63 patients. Tumors were subtyped based on the expression of CK5 and GATA3. Results of tissue microarray of 78 muscle‐invasive bladder cancer (MIBC) samples were used as prognostic factors of different subtypes of MIBC. Results Chromatin regulatory genes were frequently mutated in both UTUC and UCB. Rapid relapse and progression of non‐MIBC are correlated with alterations of KMT2C and EP300. Frequency of alterations in chromatin regulatory genes is higher in UTUC patients with SBS22 and SBS2 signatures and lower in UCB patients with SBS2 and SBS6 signatures. GATA3 and CK5 double‐positive patients with higher frequencies of SMARCA4, ARID1A, and EP300 mutations have better prognoses than patients with basal subtypes. Although UTUC and UCB in the same patient can be either clonally related or developed independently, mutated genes in chromatin pathway were enriched in the related clones. Compared to UTUC, UCB had more deleterious mutations in DNA damage repair (DDR) genes, higher levels of tumor mutation burden (TMB) and copy number variations (CNVs), as well as higher TCR clonality and lower TCR diversity. Conclusions Since genetic alterations of the chromatin pathway genes are important in both UTUC and UCB, they could serve as potential biomarkers for predicting disease progression and therapeutic targets. Differences in mutation frequencies of DDR pathway, TMB, CNV, and TCR might be the contributing factors for the distinct responses to immune checkpoint inhibitor (ICI) between UTUC and UCB.

Abstract Background The aim is to establish and verify reference intervals (RIs) for serum tumor markers for an apparently healthy elderly population in Southwestern China using an indirect method. Methods Data from 35,635 apparently healthy elderly individuals aged 60 years and above were obtained in West China Hospital from April 2020 to December 2021. We utilized the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate outliers. Subgroups are divided according to gender and age to examine the division of RIs. The Z-test was used to compare differences between groups, and 95% distribution RIs were calculated using a nonparametric method. Results In the study, we observed that the RIs for serum ferritin and Des-γ-carboxy prothrombin (DCP) were wider for men, ranging from 64.18 to 865.80 ng/ml and 14.00 to 33.00 mAU/ml, respectively, compared to women, whose ranges were 52.58 to 585.88 ng/ml and 13.00 to 29.00 mAU/ml. For other biomarkers, the overall RIs were established as follows: alpha-fetoprotein (AFP) 0–6.75 ng/ml, carcinoembryonic antigen (CEA) 0–4.85 ng/ml, carbohydrate antigen15-3 (CA15-3) for females 0–22.00 U/ml, carbohydrate antigen19-9 (CA19-9) 0–28.10 U/ml, carbohydrate antigen125 (CA125) 0–20.96 U/ml, cytokeratin 19 fragment (CYFRA21-1) 0–4.66 U/ml, neuron-specific enolase (NSE) 0–19.41 ng/ml, total and free prostate-specific antigens (tPSA and fPSA) for males 0–5.26 ng/ml and 0–1.09 ng/ml. The RIs for all these biomarkers have been validated through our rigorous processes. Conclusion This study preliminarily established 95% RIs for an apparently healthy elderly population in Southwestern China. Using real-world data and an indirect method, simple and reliable RIs for an elderly population can be both established and verified, which are suitable for application in various clinical laboratories.

ObjectivesTo construct deep learning-assisted diagnosis models based on automatic segmentation of ultrasound images to facilitate radiologists in differentiating benign and malignant parotid tumors.MethodsA total of 582 patients histopathologically diagnosed with PGTs were retrospectively recruited from 4 centers, and their data were collected for analysis. The radiomics features of six deep learning models (ResNet18, Inception_v3 etc) were analyzed based on the ultrasound images that were obtained under the best automatic segmentation model (Deeplabv3, UNet++, and UNet). The performance of three physicians was compared when the optimal model was used and not. The Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) were utilized to evaluate the clinical benefit of the optimal model.ResultsThe Deeplabv3 model performed optimally in terms of automatic segmentation. The ResNet18 deep learning model had the best prediction performance, with an area under the receiver-operating characteristic curve of 0.808 (0.694−0.923), 0.809 (0.712−0.906), and 0.812 (0.680−0.944) in the internal test set and external test sets 1 and 2, respectively. Meanwhile, the optimal model-assisted clinical and overall benefits were markedly enhanced for two out of three radiologists (in internal validation set, NRI: 0.259 and 0.213 [p = 0.002 and 0.017], IDI: 0.284 and 0.201 [p = 0.005 and 0.043], respectively; in external test set 1, NRI: 0.183 and 0.161 [p = 0.019 and 0.008], IDI: 0.205 and 0.184 [p = 0.031 and 0.045], respectively; in external test set 2, NRI: 0.297 and 0.297 [p = 0.038 and 0.047], IDI: 0.332 and 0.294 [p = 0.031 and 0.041], respectively).ConclusionsThe deep learning model constructed for automatic segmentation of ultrasound images can improve the diagnostic performance of radiologists for PGTs.

Bladder cancer is one of the most common malignancies of the urinary tract and a prevalent cancer worldwide, still requiring efficient therapeutic agents and approaches. 20-Hydroxyecdysone (20-HE), a steroid hormone, can be found in insects and few plants and mediate numerous biological events to control the progression of varying diseases; however, its impacts on bladder cancer remain unclear. In the study, we found that 20-HE treatments effectively inhibited the viability and proliferation of bladder cancer cells and induced apoptosis by activating Caspase-3. The migratory and invasive potential of bladder cancer cells was markedly repressed by 20-HE in a dose-dependent manner. The inhibitory effects of 20-HE on bladder cancer were confirmed in an established xenograft mouse model, as indicated by the markedly reduced tumor growth rates and limited lung and lymph node metastasis. High-throughput RNA sequencing was performed to explore dysregulated genes in bladder cancer cells after 20-HE treatment. We identified ubiquitin-specific protease 21 (USP21) as a key deubiquitinating enzyme for bladder cancer progression and a positive correlation between USP21 and nuclear factor-κB (NF-κB)/p65 in patients. Furthermore, 20-HE treatments markedly reduced USP21 expression, NF-κB/p65 mRNA, stability and phosphorylated NF-κB/p65 expression levels in bladder cancer cells, which were validated in animal tumor tissues. Mechanistic studies showed that USP21 directly interacted with and stabilized p65 by deubiquitinating its K48-linked polyubiquitination in bladder cancer cells, which could be abolished by 20-HE treatment, contributing to p65 degradation. Finally, we found that USP21 overexpression could not only facilitate the proliferation, migration, and invasion of bladder cancer cells, but also significantly eliminated the suppressive effects of 20-HE on bladder cancer. Notably, 20-HE could still perform its anti-tumor role in bladder cancer when USP21 was knocked down with decreased NF-κB/p65 expression and activation, revealing that USP21 suppression might not be the only way for 20-HE during bladder cancer treatment. Collectively, all our results clearly demonstrated that 20-HE may function as a promising therapeutic strategy for bladder cancer treatment mainly through reducing USP21/p65 signaling expression.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer with high aggressive phenotype and poor prognosis. Accumulating evidence suggests that circRNAs have been identified as pivotal mediators in cancers. However, the role of circRNAs in ccRCC progression remains elusive. Methods The differentially expressed circRNAs in 4 paired human ccRCC and adjacent noncancerous tissues ccRCC were screened using circRNA microarrays and the candidate target was selected based on circRNA expression level using weighted gene correlation network analysis (WGCNA) and the gene expression omnibus (GEO) database. CircPDHK1 expression in ccRCC and adjacent noncancerous tissues (n = 148) were evaluated along with clinically relevant information. RT-qPCR, RNase R digestion, and actinomycin D (ActD) stability test were conducted to identify the characteristics of circPDHK1. The subcellular distribution of circPDHK1 was analyzed by subcellular fractionation assay and fluorescence in situ hybridization (FISH). Immunoprecipitation-mass spectrometry (IP-MS) and immunofluorescence (IF) were employed to evaluate the protein-coding ability of circPDHK1. ccRCC cells were transfected with siRNAs, plasmids or lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPDHK1 and its encoded peptide PDHK1-241aa. RNA-sequencing, western blot analysis, immunoprecipitation (IP) and chromatin immunoprecipitation (ChIP) assays were further employed to identify the underlying mechanisms regulated by PDHK1-241aa. Results CircPDHK1 was upregulated in ccRCC tissues and closely related to WHO/ISUP stage, T stage, distant metastasis, VHL mutation and Ki-67 levels. CircPDHK1 had a functional internal ribosome entry site (IRES) and encoded a novel peptide PDHK1-241aa. Functionally, we confirmed that PDHK1-241aa and not the circPDHK1 promoted the proliferation, migration and invasion of ccRCC. Mechanistically, circPDHK1 was activated by HIF-2A at the transcriptional level. PDHK1-241aa was upregulated and interacted with PPP1CA, causing the relocation of PPP1CA to the nucleus. This thereby inhibited AKT dephosphorylation and activated the AKT-mTOR signaling pathway. Conclusions Our data indicated that circPDHK1-encoded PDHK1-241aa promotes ccRCC progression by interacting with PPP1CA to inhibit AKT dephosphorylation. This study provides novel insights into the multiplicity of circRNAs and highlights the potential use of circPDHK1 or PDHK1-241aa as a therapeutic target for ccRCC.

Abstract Objective To investigate the relationship between pro‐gastrin‐releasing peptide (ProGRP) and the clinical characteristics of patients with medullary thyroid carcinoma (MTC) and the value of ProGRP in surgical treatment monitoring. Patients and Methods A total of 347 patients with MTC and non‐MTC malignant and benign thyroid diseases were enrolled. The concentrations of neuron‐specific enolase (NSE), carcinoembryonic antigen (CEA), calcitonin (CT), and ProGRP were determined by Elecsys® assays. The NSE, CEA, CT, and ProGRP levels in different thyroid disease groups were compared, and ProGRP levels in different clinicopathological feature groups pre and postoperatively were further compared. Results The CT, CEA, NSE, and ProGRP levels were upregulated in the MTC group compared to those in the non‐MTC malignant and benign thyroid disease groups. The area under the receiver operating characteristic curve (AUC) of ProGRP for the diagnosis of MTC was 0.832(0.787–0.871), similar to that of CT and CEA. The sensitivity and specificity were 71.4% and 92.7%, respectively, and the optimal cut‐off value was 61.8 pg/mL. The AUC of ProGRP combined with CT or CEA for the diagnosis of MTC was 0.933 (0.900–0.958) and 0.922 (0.886–0.949), respectively, which were higher than those of a single index. ProGRP levels were higher in patients with lymph nodes and distant metastases than in patients without metastases. The postoperative level of ProGRP was lower than that before treatment. Conclusion ProGRP is comparable to CEA and CT as an MTC biomarker with broad prospects. It has potential application value in the progression of MTC assessment and the evaluation of surgical intervention effects.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, with a highly aggressive phenotype and poor prognosis. RNA binding proteins (RBPs) play crucial roles in post-transcriptional gene regulation and have been implicated in tumorigenesis. RBPs have the potential to become a new therapeutic target for ccRCC. In this study, we screened and validated that insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) as an RBP, was down-regulated in ccRCC tissues and cell lines. Functionally, we verified that IGF2BP2 significantly suppressed the migration and invasion ability of ccRCC in vitro and in vivo. Mechanistically, RIP-seq and actinomycin D experiments results showed that IGF2BP2 enhanced the expression of Creatine Kinase B (CKB) by binding to CKB mRNA and enhancing its mRNA stability. Thus, IGF2BP2 inhibited ccRCC metastasis through enhancing the expression of CKB. Taken together, these finding suggests that IGF2BP2 is a novel metastasis suppressor of ccRCC and may serve as a potential therapeutic target.

Abstract Background Gastric cancer (GC) is one of the most common malignant tumors in China. Circular RNAs (circRNAs) are novel non-coding RNAs with important regulatory roles in cancer progression. IGF2BP3 has been found to play oncogenic roles in various cancers including GC, while the exact mechanism of IGF2BP3 is largely unknown. Methods The expression of IGF2BP3 in GC was evaluated by Western Blot and bioinformatics analysis. CircRNA expression profiles were screened via IGF2BP3 RIP-seq in GC. Sanger sequencing, RNase R digestion, nucleo-plasmic separation and RNA-FISH assays were used to detect the existence and expression of circARID1A. RNA ISH assay was employed to test the expression of circARID1A in paraffin-embedded GC tissues. Moreover, the function of circARID1A on cellular proliferation was assessed by CCK-8, plate colony formation, EdU assays and GC xenograft mouse model in vivo. Furthermore, the location or binding of circARID1A, IGF2BP3 protein and SLC7A5 in GC was evaluated by RNA-FISH/IF or RNA pull-down assays. Results We identified a novel circRNA, circARID1A, that can bind to IGF2BP3 protein. CircARID1A was significantly upregulated in GC tissues compared with noncancerous tissues and positively correlated with tumor length, tumor volume, and TNM stage. CircARID1A knockdown inhibited the proliferation of GC cells in vitro and in vivo and circARID1A played an important role in the oncogenic function of IGF2BP3. Mechanistically, circARID1A served as a scaffold to facilitate the interaction between IGF2BP3 and SLC7A5 mRNA, finally increasing SLC7A5 mRNA stability. Additionally, circARID1A was able to directly bind SLC7A5 mRNA through complementary base-pairing and then formed the circARID1A-IGF2BP3-SLC7A5 RNA–protein ternary complex and promoted the proliferation of GC via regulating AKT/mTOR pathway. Conclusions Altogether, our data suggest that circARID1A is involved in the function of IGF2BP3 and GC proliferation, and the circARID1A-IGF2BP3-SLC7A5 axis has the potential to serve as a novel therapeutic target for GC.

AimsTo investigate the changes in lung cancer-related serum tumor markers in patients with chronic kidney disease (CKD) and determine the upper reference limit for patients with different stages.MethodsIncluded inpatients diagnosed with CKD who did not receive dialysis temporarily in our hospital from March to September 2020. Changes in serum CA125, HE4, CYFRA21-1, SCCA, NSE and ProGRP in CKD patients were analyzed. The non-parametric method was used to estimate the upper reference limit of the above indicators in patients with CKD stages 2-5.ResultsThe serum levels of HE4, CYFRA21-1, SCCA, and ProGRP in the CKD group were significantly higher than those in the healthy control group; CA125 and NSE levels were not statistically different. The false positives of SCC, CYFRA21-1, ProGRP, and HE4 increased significantly with the CKD stage. Still, NSE and CA125 did not show a significant increasing trend. Both HE4 and ProGRP have independent upper reference limits from CKD2 to CKD5 stage, namely 220.8 pmol/l and 101.4 pg/ml in the CKD2 stage, 496.7 pmol/l and 168.63 pg/ml in CKD3 stage, 4592.4 pmol/l and 272.8 pmol/l for CKD4 stage, CKD5 stage was 4778.2 pmol/l and 491.6 pmol/l.ConclusionThis study preliminarily determined the upper reference limits of Lung cancer-related tumor markers in patients with different CKD stages and provided laboratory support for the rational use and interpretation of Lung cancer-related tumor markers in special populations.

Abstract Transcriptional factor nuclear factor κB (NF-κB) can be activated by various intracellular or extracellular stimuli and its dysregulation leads to pathological conditions, such as neurodegenerative disorders, infection, and cancer. The carboxyl terminus of HSC70-interacting protein (CHIP), a pathogenic gene of spinocerebellar autosomal recessive 16 (SCAR16), plays an important roles in protein degradation, trafficking, and multiple signaling transductions. It has been reported that CHIP participates in the regulation of NF-κB signaling, and the mutant of CHIP (p.T246M) leads to the occurrence of SCAR16. However, the detailed mechanism of CHIP and CHIP (p.T246M) in the regulation of NF-κB signaling in neurological disorders remains unclear. Here, we found that CHIP promoted the activation of NF-κB signaling, while the knockdown had the opposite effect. Furthermore, CHIP interacted with TAK1 and targeted it for K63-linked ubiquitination. Finally, CHIP enhanced the interaction between TAK1 and NEMO. However, CHIP (p.T246M) couldn’t upregulate NF-κB signaling, potentiate the ubiquitination of TAK1, and enhance the interactions. Taken together, our study demonstrated for the first time that CHIP positively regulates NF-κB signaling by targeting TAK1 and enhancing its K63-linked ubiquitination.

Abstract Background Accumulating evidence indicates that miRNAs are involved in multiple cellular functions and participate in various cancer development and progression, including breast cancer. Methods We aimed to investigate the role of miR-381-3p in breast cancer. The expression level of miR-381-3p and EMT transcription factors was examined by quantitative real-time PCR (qRT-PCR). The effects of miR-381-3p on breast cancer proliferation and invasion were determined by Cell Counting Kit-8 (CCK-8), colony formation, and transwell assays. The regulation of miR-381-3p on its targets was determined by dual-luciferase analysis, qRT-PCR, and western blot. Results We found that the expression of miR-381-3p was significantly decreased in breast cancer tissues and cell lines. Overexpression of miR-381-3p inhibited breast cancer proliferation and invasion, whereas knockdown of miR-381-3p promoted cell proliferation and invasion in MDA-MB-231 and SKBR3 cells. Mechanistically, overexpression of miR-381-3p inhibited breast cancer epithelial–mesenchymal transition (EMT). Both Sox4 and Twist1 were confirmed as targets of miR-381-3p. Moreover, transforming growth factor-β (TGF-β) could reverse the effects of miR-381-3p on breast cancer progression. Conclusions Our observation suggests that miR-381-3p inhibits breast cancer progression and EMT by regulating the TGF-β signaling via targeting Sox4 and Twist1.

Abstract Background Whether patients with non-small cell lung cancer (NSCLC) with unexpected pleural dissemination (UPD) could get survival benefit from tumor resection remained controversial. Methods Totally, 169 patients with NSCLC with UPD were included between 2012 and 2016. Patients were divided into the tumor resection and open-close group. Progression-free survival (PFS) and overall survival (OS) were compared with a log-rank test. The multivariable Cox analysis was applied to identify prognostic factors. Results Sixty-five patients received open-close surgery and 104 patients underwent main tumor and visible pleural nodule resection. Tumor resection significantly prolonged OS (hazard ratio [HR]: 0.408, P < 0.001), local PFS (HR: 0.283, P < 0.001), regional PFS (HR: 0.506, P = 0.005), and distant metastasis (HR: 0.595, P = 0.032). Multivariable Cox analysis confirmed that surgical method was an independent prognostic factor for OS, local PFS and regional PFS, except distant metastasis. Subgroup analyses indicated that tumor resection could not improve OS in the patients who received targeted therapy (HR: 0.649, P = 0.382), however, tumor resection was beneficial for the patients who received adjuvant chemotherapy alone (HR: 0.322, P < 0.001). In the tumor resection group, lobectomy (HR: 0.960, P = 0.917) and systematic lymphadenectomy (HR: 1.512, P = 0.259) did not show survival benefit for OS. Conclusions Main tumor and visible pleural nodule resection could improve prognosis in patients with UPD who could not receive adjuvant targeted therapy. Sublobar resection without systematic lymphadenectomy may be the optimal procedure.

Background: Primary localized mediastinal mesothelioma is a rare tumour which accounts for about 0.7% of all mesotheliomas. The mesothelial cells lining of the pericardium are suggested as the most probable cells of origin. Mediastinal pleural mesothelioma are distinctly uncommon, which has only been reported in a single case. Case presentation: We report a case of a 57 years old man with primary mediastinal pleural mesothelioma involving middle and posterior upper mediastinum, one months following surgery, the patient is alive with good performance status. Chest plain scan and contrast-enhanced computer tomography（CT）scan showed a 43 mm×36 mm×36 mm tumor，with a CT value of about 41.5 HU, an arterial phase CT value of about 59.8HU and a venous phase CT value of about 77.5HU during the contrast-contrast-enhanced scan.Patients underwent thoracotomy.The pathological diagnosis was derived from malignant pleural mesothelioma(MPM) growing from the chest wall into the mediastinum. Conclusions Imaging manifestations of tumors have rarely been described in the literature. A short review of literature on MPM is given and summarize the imaging characteristics.

N6-methyladenosine (m6A) is an epigenetic modification that widely exists in long noncoding RNAs (lncRNAs) and is involved in the regulation of oncogenes or tumor suppressor genes that form complex enzymes to affect the occurrence of tumors. The abnormal modification of m6A methylation can alter the overall m6A level and thus contribute to the malignant biological behaviors of hepatocellular carcinoma (HCC). LncRNAs related to m6A methylation are involved in lipogenesis, the proliferation, migration and invasion of HCC cells, the stemness of tumor cells and sorafenib resistance. In this review, we systematically elaborated the occurrence mechanism of lncRNA and m6A methylation modification in HCC and the effect of m6A methylation modification of lncRNA on the occurrence of HCC, suggesting that the combination of m6A methylation modification and lncRNA will be more meaningful as molecular markers or prognostic markers. It is helpful to provide further ideas for exploring the pathogenesis of HCC and identifying new targets for HCC treatment and diagnosis and achieve precise individual treatment of liver cancer.

N6-methyladenosine (m6A) is the most abundant internal modification on eukaryotic mRNAs. There is increasing evidence that m6A plays a key role in tumor progression, so it is important to analyze m6A modifications within the transcriptome-wide in lung adenocarcinoma (LUAD). Three pairs of LUAD samples and tumor-adjacent normal tissues were obtained from the South University of Science and Technology Hospital. And then methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were used to identify differential m6A modifications between tumor and tumor-adjacent normal tissues. We identified 4041 aberrant m6A peaks, of which 1192 m6A peaks were upregulated and 2849 m6A peaks downregulated. It was found that genes with the dysregulated m6A peaks were enriched in the pathways in cancer, Rap1 signaling pathway, and insulin resistance. Additionally, 612 genes with abnormal regulation of m6A peaks and RNA expression were identified by combining MeRIP-seq and RNA-seq data. Through KEGG analysis, the 612 genes were enriched in cancer-related signaling pathways, such as the cGMP-PKG signaling pathway, and the Rap1 signaling pathway. What’s more, GSEA enrichment analysis showed these genes were enriched in cell cycle phase transition, cell division, cellular response to DNA damage stimulus, and chromosome organization. To further explore the relationship between differential m6A modified genes and clinical parameters of LUAD patients, we searched The Cancer Genome Atlas (TCGA) and identified 2 genes (FCRL5 and GPRIN1) that were associated with the prognosis and diagnosis of LUAD patients. Furthermore, we found a positive correlation between GPRIN1 and m6A reader YTHDF1 in the GEPIA2 database. It was verified that YTHDF1 binds to GPRIN1 mRNA and regulates its expression. Our study results suggest that m6A modification plays important role in the progression and prognosis of LUAD and maybe a potential new therapeutic target for LUAD patients in the future.

Abstract The correlations between microbiota dysbiosis and cancer have gained extensive attention and been widely explored. As a leading cancer diagnosis worldwide, lung cancer poses a great threat to human health. The healthy human lungs are consistently exposed to external environment and harbor a specific pattern of microbiota, sharing many key pathological and physiological characteristics with the intestinal tract. Although previous findings uncovered the critical roles of microbiota in tumorigenesis and response to anticancer therapy, most of them were focused on the intestinal microbiota rather than lung microbiota. Notably, the considerable functions of microbiota in maintaining lung homeostasis should not be neglected as the microbiome dysbiosis may promote tumor development and progression through production of cytokines and toxins and multiple other pathways. Despite the fact that increasing studies have revealed the effect of microbiome on the induction of lung cancer and different disease status, the underlying mechanisms and potential therapeutic strategies remained unclear. Herein, we summarized the recent progresses about microbiome in lung cancer and further discussed the role of microbial communities in promoting lung cancer progression and the current status of therapeutic approaches targeting microbiome to alleviate and even cure lung cancer.

Long-term survival benefit has been noticed in non-small-cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), such as PD-1 inhibitors. However, it is still controversial whether patients with EGFR-activating mutations may benefit from ICIs. Recently, in stage IIIA NSCLC, chemo-immunotherapy has led to significant pathological response, yet patients with the presence of known EGFR mutations were excluded from some randomized trials of neoadjuvant therapy. Herein, we report a case of a 50-year-old female patient, who was initially diagnosed as stage IIIA lung squamous cell carcinoma. Immunohistochemistry analysis showed that the patient presented with high PD-L1 expression. Then, chemo-immunotherapy was given to the patient but the disease progressed quickly with distant metastasis. A re-biopsy revealed a poorly differentiated lung adenocarcinoma together with EGFR p.L858R mutation. Then the patient received gefitinib, which resulted in significant regression of primary lung lesion. A detailed examination of pre-treatment tumor sections demonstrated rare infiltration of CD8+ T cells, indicating that the current patient presented with an “immune-cold” microenvironment, which might explain the primary resistance to chemo-immunotherapy. Taken together, our case indicated that comprehensive detection of PD-L1 expression, driver gene status, together with tumor immune microenvironment, may offer a better prediction of treatment efficacy.

Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.

Immune checkpoint inhibitors have brought long-term survival benefit in advanced non-small cell lung cancer patients without driver gene mutations. Even after withdrawal of immunotherapy for a maximum of two years, some patients still benefit from this therapy and the reason is not fully clear. Results from several neoadjuvant trials indicated that in resectable lung cancer patients, neoadjuvant immunotherapy or chemo-immunotherapy led to major or complete pathological responses in a high proportion of tumors. Here we report a case of a brain-metastatic lung squamous cell carcinoma patient who received supratentorial tumor resection and thoracic surgery after chemo-immunotherapy, and achieved a pathological complete response (pCR) in both lesions. This case indicated that pCR can also happen in advanced-stage lung cancer patients receiving chemo-immunotherapy, which may be the reason for long-term benefit of those patients.

Background Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive and lethal cancers lacking valid prognostic biomarkers. As an essential component of a large ribonucleoprotein complex, U Three Protein 14a (UTP14a) might play important roles in human tumorigenesis. However, the clinical significance and functions of UTP14a in ESCC still remain unclear. Methods From September 2009 to August 2015, 210 patients with ESCC of the thoracic esophagus underwent thoracoscopic esophagectomy in our institute. The corresponding 210 tissue samples and 30 cancer‐distant mucosa (CDM) samples were tested for UTP14a expression by immunohistochemical staining. The long‐term survival was analyzed by the Kaplan–Meier method and Cox proportional hazards regression analyses. CCK8, cell colony formation, cell cycle, apoptosis, cell invasion, and wound healing assays were carried out with ECA109 cells to evaluate the effects of UTP14a on ESCC in vitro. Results UTP14a was positively expressed in 88.1% (185/210) of the ESCC samples. UTP14a expression in ESCC was significantly higher than in CDM, as further confirmed by Western blot analysis. High expression of UTP14a in ESCC correlated significantly with tumor invasive depth (pT stage), which predicts poor disease‐free survival and disease‐specific survival, as indicated by the log‐rank test and Cox proportional hazards regression analysis. Additionally, our in vitro experiments further demonstrated that knockdown of UTP14a inhibits cell proliferation and invasion in ECA109 cells. Conclusions Our results suggest that UTP14a is aberrantly expressed in ESCC, plays a critical role in cancer progression and could be a potential prognosis predictor of ESCC.

BackgroundIt has been shown that circular RNAs (circRNAs) play a vital role in the progression of glioma. Recently, hsa_circ_0001836 was found to be upregulated in glioma tissues, but the role of hsa_circ_0001836 in glioma remains unclear.MethodsEdU staining and flow cytometry assays were used to measure the viability and death of glioma cells. In addition, scanning electron microscopy (SEM) was used to observe the morphology of cells undergoing cell death.ResultsHsa_circ_0001836 expression was upregulated in U251MG and SHG-44 cells. In addition, hsa_circ_0001836 knockdown significantly reduced the viability and proliferation of U251MG and SHG-44 cells. Moreover, hsa_circ_0001836 knockdown markedly induced the pyroptosis of U251MG and SHG-44 cells, evidenced by the increased expressions of NLRP1, cleaved caspase 1 and GSDMD-N. Meanwhile, methylation specific PCR (MSP) results indicated that hsa_circ_0001836 knockdown epigenetically increased NLRP1 expression via mediating DNA demethylation of NLRP1 promoter region. Furthermore, downregulation of hsa_circ_0001836 notably induced pyroptosis and inhibited tumor growth in a mouse xenograft model of glioma.ConclusionCollectively, hsa_circ_0001836 knockdown could induce pyroptosis cell death in glioma cells in vitro and in vivo via epigenetically upregulating NLRP1 expression. These findings suggested that hsa_circ_0001836 may serve as a potential therapeutic target for the treatment of glioma.

In the present study, we aimed to investigate immune-related signatures and immune infiltration in melanoma. The transcriptome profiling and clinical data of melanoma were downloaded from The Cancer Genome Atlas database, and their matched normal samples were obtained from the Genotype-Tissue Expression database. After merging the genome expression data using Perl, the limma package was used for data normalization. We screened the differentially expressed genes (DEGs) and obtained immune signatures associated with melanoma by an immune-related signature list from the InnateDB database. Univariate Cox regression analysis was used to identify potential prognostic immune genes, and LASSO analysis was used to identify the hub genes. Next, based on the results of multivariate Cox regression analysis, we constructed a risk model for melanoma. We investigated the correlation between risk score and clinical characteristics and overall survival (OS) of patients. Based on the TIMER database, the association between selected immune signatures and immune cell distribution was evaluated. Next, the Wilcoxon rank-sum test was performed using CIBERSORT, which confirmed the differential distribution of immune-infiltrating cells between different risk groups. We obtained a list of 91 differentially expressed immune-related signatures. Functional enrichment analysis indicated that these immune-related DEGs participated in several areas of immune-related crosstalk, including cytokine-cytokine receptor interactions, JAK–STAT signaling pathway, chemokine signaling pathway, and Th17 cell differentiation pathway. A risk model was established based on multivariate Cox analysis results, and Kaplan-Meier analysis was performed. The Kruskal-Wallis test suggested that a high risk score indicated a poorer OS and correlated with higher American Joint Committee on Cancer-TNM (AJCC-TNM) stages and advanced pathological stages (P

Background: PTPRG antisense RNA 1 has been well-documented to exert an oncogenic role in diverse neoplasms. However, the precise role of PTPRG antisense RNA 1 in regulating radiosensitivity of nonsmall cell lung cancer cells remains largely elusive. Methods: Expression levels of PTPRG antisense RNA 1 and miR-200c-3p in nonsmall cell lung cancer tissues and cells were detected by quantitative real-time polymerase chain reaction, while transcription factor 4 expression was examined by immunohistochemistry and Western blot. After nonsmall cell lung cancer cells were exposed to X-ray with different doses in vitro , Cell Counting Kit - 8 assay and colony formation assay were conducted to determine the influence of PTPRG antisense RNA 1 on cell viability. Interaction between miR-200c-3p and PTPRG antisense RNA 1 as well as transcription factor 4 was investigated by dual luciferase reporter assay. Result: In nonsmall cell lung cancer tissues, the expressions of PTPRG antisense RNA 1 and transcription factor 4 were significantly upregulated, whereas the expression of miR-200c-3p was downregulated. It was also proved that PTPRG antisense RNA 1 and 3′-untranslated region of transcription factor 4 can bind to miR-200c-3p. Under X-ray irradiation, overexpressed PTPRG antisense RNA 1 could promote the viability and enhance the radioresistance of nonsmall cell lung cancer cells, and this effect was partially weakened by miR-200c-3p mimics. Transcription factor 4 was identified as a target gene of miR-200c-3p, which could be positively regulated by PTPRG antisense RNA 1. Conclusion: PTPRG antisense RNA 1 reduces the radiosensitivity of nonsmall cell lung cancer cells via modulating miR-200c-3p/TCF4 axis.

Abstract Background Mast cells are prominent components of solid tumors and exhibit distinct phenotypes in different tumor microenvironments. However, the nature, regulation, function, and clinical relevance of mast cells in human gastric cancer (GC) are presently unknown. Methods Flow cytometry analyses were performed to examine level and phenotype of mast cells in samples from 114 patients with GC. Multivariate analysis of prognostic factors for overall survival was performed using the Cox proportional hazards model. Kaplan-Meier plots for patient survival were performed using the log-rank test. Mast cells, T cells and tumor cells were isolated or generated, stimulated and/or cultured for in vitro and in vivo function assays. Results Patients with GC showed a significantly higher mast cell infiltration in tumors. Mast cell levels increased with tumor progression and independently predicted reduced overall survival. These tumor-infiltrating mast cells accumulated in tumors by CXCL12-CXCR4 chemotaxis. Intratumoral mast cells expressed higher immunosuppressive molecule programmed death-ligand 1 (PD-L1), and mast cells induced by tumors strongly express PD-L1 proteins in both time-dependent and dose-dependent manners. Significant correlations were found between the levels of PD-L1+ mast cells and pro-inflammatory cytokine TNF-α in GC tumors, and tumor-derived TNF-α activated NF-κB signaling pathway to induce mast cell expression of PD-L1. The tumor-infiltrating and tumor-conditioned mast cells effectively suppressed normal T-cell immunity through PD-L1 in vitro, and tumor-conditioned mast cells contributed to the suppression of T-cell immunity and the growth of human GC tumors in vivo; the effect could be reversed by blocking PD-L1 on these mast cells. Conclusion Thus, our results illuminate novel immunosuppressive and protumorigenic roles of mast cells in GC, and also present a novel mechanism in which PD-L1 expressing mast cells link the proinflammatory response to immune tolerance in the GC tumor milieu.

Abstract Background Patients with metastatic or relapsed gallbladder cancer generally have a poor prognosis. Therefore, targeting metastasis is one arm of therapeutic strategies to treat gallbladder cancer. Methods Levels of translationally controlled tumor protein (TCTP) were measured in samples of gallbladder cancer by immunohistochemical staining. Wound healing, migration and invasion assays were used to investigate the motility of cells. Western blot assay was used to investigate the levels of TCTP and other proteins. Liver metastasis models and lung metastasis models were established to investigate the inhibitory effect of Dihydroartemisinin on gallbladder cancer metastasis. Results TCTP is aberrantly expressed in gallbladder cancer patients and associated with metastasis and a poor prognosis. Depleting TCTP significantly inhibited gallbladder cancer cell migration and invasion. We found that Dihydroartemisinin as a potent inhibitor of TCTP inhibited TCTP-dependent cell migration and invasion by reducing cell division control protein 42 homolog (Cdc42) activation. In addition, in mice with xenografted tumors, treatment with Dihydroartemisinin decreased gallbladder cancer cell metastases and improved survival. Conclusions These findings provide new insights into the therapeutic activity of Dihydroartemisinin as a treatment for gallbladder cancer metastasis.

Mannan binding lectin (MBL), initially known to activate the complement lectin pathway and defend against infection, was recently shown to be potentially involved in the development of several types of cancer; however, its exact role in cancers, especially its effect on tumor microenvironment remain largely unknown. Here, using a murine hepatocellular carcinoma (HCC) model, we showed that MBL was a component of liver microenvironment and MBL-deficient (MBL–/–) mice exhibited an enhanced tumor growth compared with wild-type (WT) mice. This phenomenon was associated with elevation of myeloid derived suppressed cells (MDSCs) in tumor tissue of MBL–/– mice. MBL deficiency also resulted in an increase of activated hepatic stellate cells (HSCs), which showed enhanced cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production. Pharmacological inhibition of COX-2 in vivo partially abrogated the MBL deficiency-promoted tumor growth and MDSC accumulation. Mechanistic studies revealed that MBL could interact directly with HSCs and inhibit HCC-induced HSCs activation via downregulating the extracellular signal-regulated kinase (ERK)/COX-2/PGE2 signaling pathway. Furthermore, MBL-mediated suppression of HCC is validated by administration of MBL-expressing, liver-specific adeno-associated virus (AAV), which significantly inhibited HCC progression in MBL–/– mice. Taken together, these data reveal that MBL may impact on tumor development by shaping the tumor microenvironment via its interaction with the local stromal cells, and also suggests its potential therapeutic use for the treatment of HCC.

In the original publication of this article [1], there are mistakes in Fig. 3A and Fig. 3D.