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Background: There is inconclusive evidence to suggest that the expression of programmed cell death ligand 1 (PD-L1) is a putative predictor of response to EGFR-TKI therapy in advanced EGFR-mutant non-small cell lung cancer (NSCLC). We evaluated the heterogeneity in PD-L1 expression in the primary lung site and metastatic lymph nodes to analyze the association between PD-L1 expression and response for patients treated with EGFR-TKI., Methods: This study reviewed 184 advanced NSCLC patients with EGFR mutations who received first-generation EGFR-TKI as first-line treatment from 2020 to 2021 at Shanghai Chest Hospital. The patients were divided into the primary lung site group (n = 100) and the metastatic lymph nodes group (n = 84) according to the biopsy site. The patients in each group were divided into TPS < 1%, TPS 1-49%, and TPS ≥ 50% groups according to PD-L1 expression., Results: The median PFS was 7 (95% CI: 5.7-8.3) months, and the median OS was 26 (95% CI: 23.5-28.5) months for all patients. No correlation existed between PFS or OS and PD-L1 expression. The median PFS in the primary lung site group was 11 months (95% CI: 9.6-12.4) in the TPS < 1% group, 8 months (95% CI: 6.6-9.4) in TPS 1-49% group, and 4 months (95% CI: 3.2-4.8) in TPS ≥ 50% group, with statistically significant differences (p = 0.000). The median OS of the TPS < 1% group and TPS ≥ 50% group showed a statistically significant difference (p = 0.008) in the primary lung site group. In contrast, PD-L1 expression in the lymph nodes of EGFR-mutant patients was unrelated to PFS or OS after EGFR-TKI therapy., Conclusion: PD-L1 expression from the primary lung site might predict clinical benefit from EGFR-TKI, whereas PD-L1 from metastatic lymph nodes did not., Trial Registration: This retrospective study was approved by the Ethics Committee of Shanghai Chest Hospital (ID: IS23060) and performed following the Helsinki Declaration of 1964 (revised 2008)., (© 2024. The Author(s).)

Background: Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of telomerase enzyme, which adds nucleotides to telomeres and counteracts their length shortening. The development of a telomere maintenance mechanism represents a hallmark of cancer. On the other hand, idiopathic pulmonary fibrosis (IPF) is associated with mutations in telomerase genes and shorter telomeres. IPF is frequently complicated with lung cancer., Aim: To investigate the expression of hTERT in lung cancer with co-existing IPF and to compare with lung cancer without fibrosis., Methods: Diagnostic lung cancerous biopsies were retrieved from 18 patients with lung cancer and concomitant IPF, as well as 18 age and gender matched controls with lung cancer without pulmonary fibrosis. The expression of hTERT was studied with immunohistochemistry. ImajeJ software was used to quantitate subcellular stain intensity. Immunohistochemical investigation of two senescence-associated markers, p16 and p21, was also performed in all 36 cases., Results: Both groups highly expressed hTERT, without significant difference (100% vs 95%, p = 0.521). Evaluation of p16 and p21 immunostaining revealed negative to minimal immunoreactivity in both groups. hTERT localization exhibited higher median nuclear intensity in the group of lung cancer with IPF (0.62 vs 0.45, p = 0.016), while cytoplasmic intensity did not differ significantly (0.17 vs 0.15, p = 0.463). Higher median nuclear intensity was also correlated with small cell lung cancer subtype in the whole study sample (0.69 vs 0.45, p = 0.09)., Conclusion: hTERT is highly expressed in lung cancer with concomitant IPF, but with differential localization compared to lung cancer without IPF, implying differences in pathogenicity and requiring further investigation., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer‑specific biomarkers. The application of three membrane‑bound receptors, namely urokinase‑type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)‑positive and 48 HPV‑negative groups, the IHC‑determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow‑up data, overall survival (OS) and recurrence‑free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log‑rank test following Kaplan‑Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor‑specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92‑4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor‑specific expression pattern.

Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) might be involved in the activation of important pathways related to tumor immune escape, along with programmed death-ligand 1 (PD-L1). Here, we aimed to investigate the correlation between the expression of Siglec-15 and PD-L1 in nasopharyngeal carcinoma (NPC) patients. We determined the expression of PD-L1 via immunohistochemical staining and that of Siglec-15 via immunofluorescence staining in 182 NPC tissue samples. A significant correlation was identified between the PD-L1 and Siglec-15 expression (P = 0.000). Moreover, Kaplan-Meier survival curves showed that PD-L1 expression was associated with improved overall survival (OS) (P = 0.025) and Siglec-15 expression was associated with improved distant failure-free survival (D-FFS) (P = 0.048). Moreover, multivariate Cox analysis showed that PD-L1 and Siglec-15 were independent predictors of OS (P = 0.020) and D-FFS (P = 0.047), respectively. The results of the log-rank test and Cox regression analyses showed that patients exhibiting no PD-L1/Siglec-15 expression had significant advantages regarding OS, compared to other groups (P = 0.037). PD-L1 and Siglec-15 may represent novel biomarkers for predicting the prognosis of NPC patients. Siglec-15 may be considered as a potential target for the development of therapeutics for NPC treatment in the future., (© 2022. The Author(s).)

Purpose: To find a useful disease marker for early diagnosis of gastric cancer, we tried to explore the expression of serum miR-181, miR-652, and carbohydrate antigen 72-4 (CA72-4)., Patients and Methods: According to clinical pathologic stages, 112 patients with gastric cancer were divided into early gastric cancer group (n = 60) and advanced gastric cancer group (n = 52), stage I-II (n = 65), and stage III-IV (n = 47). Another 50 cases of gastric benign lesions and 40 healthy controls were also selected. Real-time quantitative PCR together with chemiluminescence were applied to detect expression levels. ROC curve was applied to judge their diagnostic efficiency. Pearson's correlation analysis was put into use to investigate the relevance of three indicators., Results: Compared with benign lesions group and control group, significantly higher expression levels were found in patients of gastric cancer (all p < 0.001). Similarly, compared with early gastric cancer group, significantly higher expression levels were found in advanced gastric cancer group (all p < 0.001). The same result was also found in stage III-IV (all p < 0.001). The best cutoff values were 0.93, 2.38, and 16.94 U/ml, respectively. The area under the curve (0.917, 95%CI: 0.856-0.975) of the three combined diagnosis of early gastric cancer was the largest, and its sensitivity and specificity were 92.5% and 86.8%. And miR-181 and miR-652 were positively correlated with CA72-4 (r = 0.772, p < 0.001, r = 0.853, p < 0.001)., Conclusion: Serum miR-181, miR-652, and CA72-4 are closely linked to the occurrence and development of gastric cancer. Combination of three indicators has diagnostic value for early gastric cancer., (© 2022 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

The accurate identification of different components in testicular germ cell tumors (GCT) is essential for tailoring treatment and informing the clinical prognosis. PRAME (preferentially expressed antigen in melanoma), a member in the family of cancer testis antigens, plays critical roles in regulating pluripotency and suppressing somatic/germ cell differentiation in seminomas (SEM). To investigate the potential diagnostic value of PRAME in testicular GCT, here we comparatively examined the expression patterns of PRAME and SOX17 by immunohistochemistry in both pure and mixed GCT. Tissue microarrays constructed from 66 pure or mixed GCT were examined, including 25 seminomas (13 pure and 12 mixed), 35 embryonal carcinomas (EC; 7 pure and 28 mixed), 23 teratomas (TER; 10 pure and 13 mixed), 15 yolk sac tumors (YST; 1 pure and 14 mixed), and 5 choriocarcinomas (CC; 1 pure and 4 mixed), with 11 germ cell neoplasia in situ (GCNIS) and 6 normal testicular tissue as controls. The expression levels of PRAME or SOX17 were evaluated by a scoring system counting for intensity and extent of staining. PRAME nuclear expression was present in 92% (23/25) of SEM, including all 13 pure SEM, and 10 out of 12 seminomatous component of mixed GCT. In contrast, all EC and TER were completely negative for PRAME, and focal expression was demonstrated in 33.3% of YST and 20% of CC. As for SOX17, 96% of SEM and 73% of YST stained positively, whereas EC and CC were negative. Focal nuclear positivity was identified in the epithelial cell component of 17.4% (4/23) of TER. We found the sensitivity of PRAME to detect SEM to be comparable to SOX17, although SOX17 staining is more diffuse and stronger in the majority of cases. The specificity of PRAME for SEM appeared to be superior to that of SOX17 (92% versus 81%). In conclusion, PRAME is preferentially expressed in SEM or within the seminomatous component of mixed GCT with only focal variable expression in YST and CC, but shows no expression in EC and TER. These findings suggest that PRAME can be explored as a diagnostic marker for SEM., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Reliable biomarkers to predict the outcome and treatment response of estrogen receptor (ER)-negative breast cancer (BC) are urgently needed. Since immune-related signaling plays an important role in the tumorigenesis of ER-negative BC, we asked whether Notch genes, alone or in combination with other immune genes, can be used to predict the clinical outcome and immune checkpoint blockade (ICB) for this type of cancer., Methods: We analyzed transcriptome data of 6918 BC samples from five independent cohorts, 81 xenograft triple-negative BC tumors that respond differently to ICB treatment and 754 samples of different cancer types from patients treated with ICB agents., Results: We found that among four Notch genes, the expression levels of NOTCH1 and NOTCH4 were positively associated with recurrence of ER-negative BC, and that combined expression of these two genes (named Notch14) further enhanced this association, which was comparable with that of the Notch pathway signature. Analysis of 1182 immune-related genes revealed that the expression levels of most HLA genes, particularly HLA-DMA and -DRA, were reversely associated with recurrence in ER-negative BC with low, but not high Notch14 expression. A combined expression signature of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA was more prognostic for ER-negative and triple-negative BCs than previously reported immune-related signatures. Furthermore, we found that the expression levels of these four genes were also synergistically associated with T cell exclusion score, infiltration of specific T cells and ICB efficacy in ER-negative BC, thereby providing a potential molecular mechanism for the synergistic effect of these genes on BC., Conclusions: Our data indicate that a gene signature composed of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA may serve as a potential promising biomarker for predicting ICB therapy efficacy and recurrence in ER-negative/triple-negative BCs., (© 2022. Springer Nature Switzerland AG.)

Background: This study aimed to investigate the expression pattern and prognostic significance of HOXB13 in rectal cancer., Methods: HOXB13 expression in rectal cancer and normal adjacent tissues was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, and its clinicopathological characteristics and prognosis were statistically tested. Furthermore, we evaluated the association between tumor immune infiltrating cells and HOXB13 using the tumor immune estimation resource (TIMER) database. The potential biological mechanism associated with HOXB13 overexpression was investigated by gene set enrichment analysis (GSEA)., Results: The expression of HOXB13 messenger RNA and protein in human rectal cancer tissues were significantly higher than those in the normal adjacent tissues ( P  < 0.05). HOXB13 expression was significantly correlated with depth of invasion, lymphatic invasion, lymph node metastasis, distant metastasis, and pathological tumor node metastasis stage ( P  < 0.05). Kaplan-Meier survival curves confirmed that HOXB13 overexpression was correlated negatively with overall survival and disease-free survival in rectal cancer ( P  < 0.05). Also, multivariate Cox regression analysis demonstrated that HOXB13 expression, age, and lymphatic invasion were independent prognostic factors in rectal cancer ( P  < 0.05). Plus, the results from the TIMER database indicated that HOXB13 expression has a significant association with several immune cell infiltrates. Finally, the GSEA results indicated that HOXB13 participated in the various immune-associated processes, including natural killer cell-mediated cytotoxicity and the T-cell receptor signaling pathway., Conclusion: Our study showed an essential role of HOXB13 in rectal cancer immunity and prognosis. Significantly, the overexpression of HOXB13 leads to the worse prognosis for patients with rectal cancer, which will contribute to understanding molecular mechanisms associated with tumor pathogenesis and prognosis in this disease.

Purpose: The authors aimed to evaluate the prognostic and predictive value of androgen receptor (AR) expression in patients with luminal/human EGFR2 negative (HER2-) T1N0 breast cancer. Methods: The cohort in this retrospective study comprised 471 patients with luminal/HER2- T1N0 breast cancer who had undergone surgery between 2013 and 2017 in the authors' center. Results: AR+ tumors were associated with favorable characteristics. AR+ patients had better 5-year recurrence-free survival rates and the risk of recurrence was greater for AR- than for AR+ patients. AR- status predicted the failure of adjuvant endocrine therapy with aromatase inhibitors and of adjuvant chemotherapy with docetaxel plus cyclophosphamide. Conclusion: AR+ expression is significantly related to a better prognosis. AR expression may be an additional biomarker for both endocrine and chemotherapy responsiveness.

Background: Colorectal cancer (CRC) is the third most common of cancer-related deaths. Nucleolar protein 14 (NOP14) is known to play different roles in diverse types of cancers. However, little is known about its roles in CRC. Here, we assessed the prognostic value and functions of NOP14 in CRC using the data from The Cancer Genome Atlas (TCGA) and validated them based on the data from Gene Expression Omnibus (GEO)., Methods: NOP14 mRNA and protein data in CRC was obtained from the TCGA, GEO, human protein atlas (HPA), and UALCAN databases. Survival and Cox regression analysis was performed to assess the prognostic value of NOP14 in CRC patients. Next, to evaluate the potential functions of NOP14, a protein-protein interaction (PPI) network was constructed and gene set enrichment analysis (GSEA) of differential expression genes (DEGs) associated with dysregulated NOP14 was performed. Finally, to investigate the immune response associated with NOP14 expression in CRC, we analyzed the correlations between immune cells infiltration and NOP14 expression level. Additionally, the correlations between immune molecule expression levels with NOP14 expression level were analyzed., Results: High NOP14 mRNA expression was observed in CRC tissues based on the data from TCGA and GEO datasets. Similarly, high NOP14 protein levels were found in CRC tissues according to the immunohistochemical images from HPA. Interestingly, high NOP14 expression level was associated with an improved prognosis in CRC patients. Univariate and multivariate Cox regression analysis indicated that high NOP14 expression level was an independent protective factor for CRC patients. With the support of PPI network analysis, we found several risk genes interacted with NOP14. GSEA revealed that high NOP14 expression inhibited several signal pathways involved in tumor formation and development. Additionally, high NOP14 expression was positively associated with most kinds of immune cell infiltrations and the expression levels of some molecules related to immune activation., Conclusion: Altogether, these results indicated that high NOP14 expression leads to improved prognosis in CRC patients by inhibiting the signaling pathways involved in tumor growth and promoting the immune responses., (© 2022. The Author(s).)

Assessment of programmed death-ligand 1 (PD-L1) expression and CD8+ lymphocyte infiltrates in triple-negative breast carcinoma (TNBC) can provide valuable prognostic and predictive information. Knowledge of clinical and pathological factors that predict the status of these two markers is needed to better select patients likely to respond to immunotherapy. We aim to assess the association between histological subtypes of TNBC and tumor microenvironment type, defined here as each tumor's PD-L1 status and the percentage of CD8+ cells in its tumor-associated lymphocyte population. Tissue microarrays consisting of 72 TNBC cases (28 conventional invasive ductal carcinomas (IDCs), 21 basal-like IDCs, 18 apocrine carcinomas, and five metaplastic carcinomas) were evaluated for PD-L1 expression using the SP142 and 22C3 immunohistochemical (IHC) assays. The percentages of CD8+ and CD4+ intra-tumoral stromal lymphocytes in each case were analyzed using QuPath (open-source software platform) on CD8 and CD4 IHC-stained digital slides of the TMAs. Tumor-infiltrating lymphocytes (TILs) were also assessed on representative H&E-stained whole-tissue sections and compared to CD8+ and CD4+ lymphocyte percentages, and to the CD4/CD8 ratio of intra-tumoral lymphocytes for each case. Cases were then separated into four tumor microenvironment groups (PD-L1+/CD8+, PD-L1+/CD8-, PD-L1-/CD8+, and PD-L1-/CD8-). Basal-like IDCs were most often PD-L1-/CD8- (71.4%/61.9% of cases with SP142/22C3, respectively), while conventional IDCs were more distributed among PD-L1+ and PD-L1- microenvironments (35.7% PD-L1+/CD8+ and 42.9% PD-L1-/CD8- with the 22C3 assay). Apocrine carcinomas tended to be PD-L1-/CD8- (83.3% of cases with both SP142 and 22C3 antibodies). Metaplastic carcinomas were PD-L1-/CD8- in 60% of cases with both 22C3 and SP142. A CD8+ lymphocyte percentage ≥5% strongly predicted PD-L1 positivity (positive predictive value using the 22C3 assay: 0.75). Our data suggest that some histological subtypes of TNBC are predictive of PD-L1 status and CD8+ T-cell infiltrate levels., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: This study evaluated the association of mucinous metaplasia (MM) with tumor cell proliferation, androgen receptor (AR) expression and invasiveness in Pten conditional knockout mice and the prognostic value of MM markers for patients with PCa., Main Methods: Prostatic lobes samples from genetic engineered mouse model Pten f/f and Pb-Cre4/Pten f/f were submitted for histopathological analysis and tissue expression of AR, the proliferation marker Ki67, alpha-smooth muscle actin, and laminin. RNAseq data of prostatic lobes samples were analyzed searching for MM gene expression patterns. We also investigated gene and protein expression related to MM in human PCa public databases., Key Findings: All knockout animals analyzed showed at least one area of stroma-invading MM, which was absent in the control animals. The tumoral regions of MM showed a proliferative index 5 times higher than other tumoral areas and low expression of the AR (less than 20% of the cells were AR-positive). Disrupted basement membrane areas were observed in MM. The mouse and human PCa transcriptomes exhibited increased expression of the MM markers such as MUC1, MUC19, MUC4, MUC5AC, MUC5B, and TFF3. Gene expression profile was associated with castration-resistant prostate cancer (CRPC) and with a lower probability of freedom from biochemical recurrence., Significance: The expression of goblet cell genes, such as MUC1, MUC5AC, MUC5B, and TFF3 have significant prognostic value for PCa patients and represent another class of potential therapeutic targets., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Paclitaxel (PTX) resistance contributes to mortality in epithelial ovarian cancer (EOC). Aerobic glycolysis is elevated in the tumor environment and may influence resistance to PTX in EOC. KH domain-containing, RNA-binding signal transduction-associated protein 3 (KHDRBS3) is an RNA binding protein that is up-regulated in EOC, but its underlying mechanism in EOC is unclear. Here, we investigate the role of KHDRBS3 in glycolysis and increased resistance to PTX. Expression of KHDRBS3 and Claudin (CLDN6) were measured in EOC tissue and cells by quantitative real-time PCR, western blotting and immunohistochemistry. The biological functions of KHDRBS3, MIR17HG and CLDN6 were examined using MTT, colony formation, apoptosis and seahorse assays in vitro. For in vivo experiments, a xenograft model was used to investigate the effects of KHDRBS3 and MIR17HG in EOC. Here, we investigate the role of KHDRBS3 in glycolysis and increased resistance to PTX. The expression of KHDRBS3 was up-regulated in PTX-resistant cells. KHDRBS3 knockdown restrained the IC 50 of PTX, cell proliferation, colony formation and glycolysis in SKOV3-R and A2780-R cells in vitro and enhanced PTX sensitivity in a xenograft mouse model in vivo. KHDRBS3 interacts with lncRNA MIR17HG, which is down-regulated in EOC tissue and cells. The effect of KHDRBS3 overexpression on PTX resistance and glycolysis was rescued by MIR17HG overexpression. Additionally, MIR17HG interacts with the 3'UTR of CLDN6 and negatively regulates CLDN6 expression. MIR17HG overexpression suppressed the IC 50 of PTX and glycolysis by targeting CLDN6. Our results reveal a KHDRBS3-MIR17HG-CLDN6 regulatory axis that contributes to enhanced glycolysis in EOC and represents a potential target for therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Transcriptional enhanced associate domain (TEAD) transcription factor family, a very important family in the hippo signaling pathway, has been found to play oncogenic functions in the occurrence of various malignant tumors. However, the expression of TEADs in pan-cancer and the important role of TEAD4 in clear cell renal cell carcinoma (ccRCC) have not been analyzed. Herein, we aim to evaluate the expression of TEADs in pan-cancer, and focus on analyzing the role of TEAD4 in the progression of ccRCC., Main Methods: Data from the Cancer Genome Atlas (TCGA) was used to analyze the expression of TEADs in pan-cancer and its clinical correlation. TEAD4 expression in ccRCC tissues, biological functions in vitro and in vivo were analyzed by immunohistochemistry (IHC), western blotting, RNAi and Xenograft assay. Mircode, BioGRID and g: Profiler website were used to build a ceRNA network and downstream pathway prediction., Key Findings: TEAD1, TEAD2, TEAD3 and TEAD4 were highly expressed in 3, 6, 5, and 12 types of cancer tissues, respectively, indicating that TEAD4 is most closely related to tumor progression. Among the cancers with high TEAD4 expression, the expression of TEAD4 has the greatest correlation with the poor prognosis of ccRCC. We also found the malignant phenotypes of ccRCC cells in vitro and vivo have been significantly suppressed by silencing TEAD4., Significance: TEADs, especially TEAD4, were overexpressed in many human tumors. This study is the first to show that TEAD4 acts as an oncogene in ccRCC and may be an important factor in progress of ccRCC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Low human epidermal growth factor receptor 2 (HER2) expression is emerging as an actionable biomarker for the treatment of breast cancer (BC) with novel anti-HER2 drugs. However, the evolution of this biomarker during the course of disease is still poorly characterised, and controversial data exist on its prognostic implications., Methods: We reviewed data of patients with HER2-negative BC according to the latest ASCO/CAP guidelines referred between January 2014 and December 2020. We grouped patients based on the immunohistochemistry (IHC) expression of HER2, HER2-zero (IHC 0) and HER2-low subgroup (IHC 1+ or 2+/ISH-negative) and evaluated the evolution of HER2 expression between the primary tumour and the first biopsy collected in the advanced setting. Disease-free survival, overall survival and progression-free survival were compared between patients with HER2-zero and HER2-low expression on the primary tumour., Results: 232 patients were included in the analysis. Among the overall population, there was a relevant discordance in HER2 expression between the primary tumour and the matched biopsy (K = 0.33, 95%CI 0.21-0.44): 44% of the HER2-zero primary tumour showed an increased HER2 score on biopsy, and 22% of the HER2-low primary tumours turned into HER2-IHC 0. The findings in the sub-populations of hormone-receptors positive (K = 0.32, 95%CI 0.19-0.45) and triple-negative tumours (K = 0.18, 95%CI -0.09-0.46) were consistent with the primary analysis. No difference in survival outcomes was observed between HER2-low and HER2-zero primary tumours., Conclusions: HER2-low expression is dynamic in BC and may be enriched in the advanced-stage setting. No prognostic significance was demonstrated for HER2-low expression., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PT has served as an advisor/consultant to AstraZeneca. GC received honoraria for speaker, consultancy or advisory role from AstraZeneca, Roche, Pfizer, Novartis, Seattle Genetics, Lilly, Ellipses Pharma, Foundation Medicine, Daiichi Sankyo and Samsung. CC received honoraria for consulting/advisory role/speaker bureau from Novartis, Eli-Lilly, Pfizer, and Roche. GV received honoraria for consulting, advisory role, speaker bureau, travel, accommodation, expenses, and/or research funding from MSD Oncology, Pfizer, Dako, Roche/Genetech, Astellas Pharma, Novartis, Bayer, Daiichi Sankyo, Menarini, Ventana Medical Systems Dako/Agilent Technologies, Cepheid, and Celgene. Other authors declare no conflict of interest to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Diffuse large B-cell lymphoma (DLBCL) is the main pathological type of non-Hodgkin lymphoma (NHL). Chromobox (CBX) family proteins are classical components of polycomb group (PcG) complexes in many cancer types, resulting in accelerated carcinogenesis. Nevertheless, the prognostic, functional and expression significance of these CBX family members in DLBCL remain unclear and elusive., Methods: CBX transcriptional levels were confirmed using Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA) and Cancer Cell Line Encyclopedia (CCLE) databases. The protein levels of CBX family members were analysed using The Human Protein Atlas (HPA) database. Information on the PPI network, functional enrichment, drug sensitivity, prognostic value, miRNA network, protein structure, genetic alteration and immune cell infiltration were generated using the GeneMANIA, Metascape, GSCALite, GEPIA, PDB, cBioPortal, and TIMER databases, and the correlation of these factors with CBX expression levels in DLBCL was assessed., Results: CBX1/2/3/5/6/8 mRNA levels were significantly enhanced in DLBCL tissues compared to corresponding normal tissues. CBX1/3/4/5/8 protein expression levels were obviously increased, whereas CBX7 was obviously decreased. This difference might be attributed to miRNA regulation based on the miRNA network. Overall survival (OS) analysis showed that CBX levels were not correlated with prognosis in DLBCL patients, indicating that CBXs are not good biomarkers for DLBCL patients. Furthermore, functional enrichment analyses indicated that CBXs were closely related to DNA duplex unwinding, covalent chromatin modification, and histone lysine methylation. The levels of CBXs were also significantly associated with diverse immune cell infiltration in DLBCL., Conclusions: This study reveals that dysregulated CBXs are involved in DLBCL development and might represent potential therapeutic targets for DLBCL., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Recent studies have shown that nicotinamide adenosine dinucleotide phosphate oxidase 4 (NOX4) is related to cancer development, proliferation, invasion, epithelial-to-mesenchymal transition, and metastasis. The prognostic value of NOX4 expression although has been reported in various cancers, it remains unclear as several studies have reported conflicting results. Therefore, the purpose of this study was to systematically investigate the prognostic value of NOX4 expression in cancer patients., Method: Appropriate studies were collected by searching the PubMed, EMBASE, and Cochrane library databases, and the prognostic value of NOX4 expression in cancer patients was assessed through a meta-analysis., Results: Nine eligible studies involving 2675 cancer patients were included in this meta-analysis. We found that NOX4 expression is related to prognosis in cancer patients. In particular, high expression of NOX4 was significantly associated with overall survival in patients with gastrointestinal cancer (hazard ratio [HR]: 1.83, 95% confidence interval [CI]: 1.39-2.42, p < 0.001)., Conclusion: NOX4 expression is significantly correlated with overall survival in patients with gastrointestinal cancer, indicating that it could be a potential prognostic marker., Competing Interests: The authors declare no competing financial interests., (Copyright © 2022 Hyun Min Koh et al.)

Sustained proliferative signaling and resisting cell death are hallmarks of cancer. Zinc finger protein 277 (ZNF277; murine Zfp277), a transcription factor regulating cellular senescence, is overexpressed in colon cancer, but its actions in intestinal homeostasis and neoplasia are unclear. Using human and murine intestine, human colon cancer cells, and ApcMin/+ mice with dysregulated β-catenin signaling and exuberant intestinal neoplasia, we explored the actions of ZNF277/Zfp277 and defined the underlying mechanisms. In normal human and murine intestine, ZNF277/Zfp277 was expressed uniquely in early stem cell progenitors, undifferentiated transit-amplifying cells (TACs). Zfp277 was overexpressed in the ApcMin/+ mouse colon, implicating ZNF277/Zfp277 as a transcriptional target of β-catenin signaling. We confirmed this by showing β-catenin knockdown reduced ZNF277 expression and, using chromatin IP, identified 2 β-catenin binding sites in the ZNF277 promoter. Zfp277 deficiency attenuated intestinal epithelial cell proliferation and tumor formation, and it strikingly prolonged ApcMin/+ mouse survival. RNA-Seq and PCR analyses revealed that Zfp277 modulates expression of genes in key cancer pathways, including β-catenin signaling, the HOXD family that regulates development, and p21WAF1, a cell cycle inhibitor and tumor suppressor. In both human colon cancer cells and the murine colon, ZNF277/Zfp277 deficiency induced p21WAF1 expression and promoted senescence. Our findings identify ZNF277/Zfp277 as both a TAC marker and colon cancer oncogene that regulates cellular proliferation and senescence, in part by repressing p21WAF1 expression.

In a quest for prognostic biomarkers in early-stage colorectal cancer, we investigated NNMT (nicotinamide N-methyltransferase) in large cohorts of patients. Immunohistochemical examination of 679 patients illustrates that NNMT protein is predominantly expressed in the cancer stroma at varying levels, and about 20% of cancer tissues overexpress NNMT when compared to levels observed in normal colorectal mucosa. Clinical correlation analyses of 572 patients with early-stage cancers reveal that NNMT protein overexpression is significantly associated with shorter overall and disease-free survival, but no such correlation is found in late-stage colorectal cancer. Analyses of TCGA and CPTAC colorectal cancer cohorts show that NNMT mRNA expression is positively correlated with protein levels, is significantly higher in CIMP-high or MSI subtypes than in CIMP-low or MSS subtypes, and is positively correlated with its paralog INMT but not with its interaction partners such as PNMT, ADK, APP, ATF6, BMF, BRD4, CDC37, or CRYZ. In early-stage cancers, NNMT expression is higher in BRAF-mutated than in BRAF wild type tumors but is not affected by KRAS or PIK3CA mutation status. As a cancer stromal protein with important roles in metabolism and cancer epigenetics, NNMT is emerging as a promising biomarker for risk stratification of early-stage cancers., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) such as PD1/PD-L1 blockers are an established treatment for many solid cancers. There are currently no approved ICIs for sarcomas, but satisfactory results have been seen in some patients with disseminated disease in certain histological types. Most studies on PD-L1 in sarcoma have used small specimens and there are no clear cutoff values for scoring. We investigated PD-L1 immunoreactivity in high-grade chondrosarcomas (CS), abdominal liposarcoma (LS) and undifferentiated pleomorphic sarcomas (UPS). In total, 230 tumors were stained with SP142 and SP263 assays and evaluated by two clinical pathologists. Immunoreactivity in tumor and immune cells was correlated with clinical outcome. Overall, ≥1% PD-L1 immunoreactivity in tumor cells was found in 11 CS, 26 LS and 59 UPS (SP142 assay) and in 10 CS, 26 LS and 77 UPS (SP263 assay). Most tumors exhibited ≤10% PD-L1 immunoreactivity, but a subset across all three subtypes had >50%. Kaplan-Meier survival analysis showed no significant difference in metastasis-free or overall survival in relation to PD-L1 immunoreactivity in tumor or immune cells for any subtype. As there is a lack of clinical data regarding PD-L1/PD-1 status and therapy response, it is not currently possible to establish clear cutoff values. Patients with high (>50%) PD-L1 immunoreactivity in tumor cells (TC) with the SP263 assay would be a logical group to investigate for potentially beneficial PD1/PD-L1-targeted treatment.

Standard radiation therapy (RT) does not reliably provide locoregional control for women with multinode-positive breast cancer and triple-negative breast cancer (TNBC). We hypothesized that CDK4/6 inhibition (CDK4/6i) would increase the radiosensitivity not only of estrogen receptor-positive (ER+) cells, but also of TNBC that expresses retinoblastoma (RB) protein. We found that CDK4/6i radiosensitized RB WT TNBC (n = 4, radiation enhancement ratio [rER]: 1.49-2.22) but failed to radiosensitize RB-null TNBC (n = 3, rER: 0.84-1.00). RB expression predicted response to CDK4/6i + RT (R2 = 0.84), and radiosensitization was lost in ER+/TNBC cells (rER: 0.88-1.13) after RB1 knockdown in isogenic and nonisogenic models. CDK4/6i suppressed homologous recombination (HR) in RB WT cells but not in RB-null cells or isogenic models of RB1 loss; HR competency was rescued with RB reexpression. Radiosensitization was independent of nonhomologous end joining and the known effects of CDK4/6i on cell cycle arrest. Mechanistically, RB and RAD51 interact in vitro to promote HR repair. CDK4/6i produced RB-dependent radiosensitization in TNBC xenografts but not in isogenic RB1-null xenografts. Our data provide the preclinical rationale for a clinical trial expanding the use of CDK4/6i + RT to difficult-to-control RB-intact breast cancers (including TNBC) and nominate RB status as a predictive biomarker of therapeutic efficacy.

Cancer stem cell is considered as an important cause to exacerbate the prognosis. NANOG and POU5F1 are markers for cancer stem cells. The associations between NANOG and POU5F1 expressions with the sorafenib anticancer effects in primary cultured hepatocellular carcinoma (HCC) cells were investigated. Eight primary cultured HCC parent cell lines and 13 subgroups established by flow cytometric sorting using NANOG and POU5F1 as targets were investigated with clinically achievable sorafenib plasma concentrations (5 and 10 μg/mL). Sorafenib showed obvious downregulation of RAF/MEK/ERK signaling pathways and dose-dependent anti-proliferative effects only on s003 parent cell line, which showed the lowest expression of NANOG among all tested cell lines except one downregulated NANOG with upregulated POU5F1 s020 subgroup. Sorafenib also inhibited proliferation in this s020 subgroup but promoted proliferation in its parent cell line. For the only one downregulated NANOG alone s015 subgroup, sorafenib which had no influence on its parent cell line inhibited proliferation in this subgroup. Only the above three cell lines could demonstrate sorafenib antiproliferative effects. On the contrary, sorafenib promoted proliferation in three (s003, s015, s071) out of four upregulated NANOG alone subgroups. On the other hand, Sorafenib showed diverse influence on proliferation among four upregulated POU5F1 alone subgroups. In conclusion, NANOG rather than POU5F1 expression is a critical marker for the anticancer effects of sorafenib on HCC. The sorafenib anticancer effects on HCC cells with high NANOG expression were limited. Sorafenib should be combined with other drug able to target cancer cells with high NANOG expression., (© 2021 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Purpose: The International Federation of Gynecology and Obstetrics (FIGO) stage remains the standard staging system for the assessment of endometrial cancer (EC) prognosis. Thus, we aim to identify the significant genes or biomarkers associated with the stage of endometrial cancer, which may also help reveal the mechanism of EC progression and assess the prognosis of patients with EC., Materials and Methods: We compared the mRNA expression levels of EC patients with stages I and II as well as stages III and IV in the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) of EC patients at different stages were selected by volcano plot and Venn analysis. Gene Ontology (GO) and Pathways were applied to analyze the identified genes. Protein protein interaction (PPI) network was employed to identify the correlation. The survival analyses based on TCGA database were conducted for further screening. The Human Protein Atlas, quantitative PCR and immunohistochemistry were utilized to confirm the differences in expression of DEGs in endometrial cancer samples at different FIGO stages., Results: CKMT1A was identified as a candidate gene. Through survival analyses, we found that CKMT1A may be a poor prognostic factor in the overall survival of endometrial cancer patients. GO and Pathways revealed that CKMT1A is closely associated with the metabolic process. More importantly, Human Protein Atlas and quantitative PCR confirmed the differences in expression of CKMT1A in endometrial cancer samples at different FIGO stages., Conclusion: In summary, this study shows that CKMT1A is a newly identified essential tumor progression regulator of endometrial cancer, which may give rise to novel therapeutic strategies in the management of endometrial cancer patients to prolong its prognosis and prevent tumor progression., Competing Interests: The authors declare no conflicts of interest.

Lung adenocarcinoma (LUAD) and squamous carcinoma (LUSC) are two major subtypes of non-small cell lung cancer with distinct pathologic features and treatment paradigms. The heterogeneity can be attributed to genetic, transcriptional, and epigenetic parameters. Here, we established a multi-omics atlas, integrating 52 single-cell RNA sequencing and 2342 public bulk RNA sequencing. We investigated their differences in genetic amplification, cellular compositions, and expression modules. We revealed that LUAD and LUSC contained amplifications occurring selectively in subclusters of AT2 and basal cells, and had distinct cellular composition modules associated with poor survival of lung cancer. Malignant and stage-specific gene analyses further uncovered critical transcription factors and genes in tumor progression. Moreover, we identified subclusters with proliferating and differentiating properties in AT2 and basal cells. Overexpression assays of ten genes, including sub-cluster markers AQP5 and KPNA2, further indicated their functional roles, providing potential targets for early diagnosis and treatment in lung cancer., (© 2021. The Author(s).)

Background: This study is aimed at constructing a risk signature to predict survival outcomes of ORCA patients., Methods: We identified differentially expressed autophagy-related genes (DEARGs) based on the RNA sequencing data in the TCGA database; then, four independent survival-related ARGs were identified to construct an autophagy-associated signature for survival prediction of ORCA patients. The validity and robustness of the prognostic model were validated by clinicopathological data and survival data. Subsequently, four independent prognostic DEARGs that composed the model were evaluated individually., Results: The expressions of 232 autophagy-related genes (ARGs) in 127 ORCA and 13 control tissues were compared, and 36 DEARGs were filtered out. We performed functional enrichment analysis and constructed protein-protein interaction network for 36 DEARGs. Univariate and multivariate Cox regression analyses were adopted for searching prognostic ARGs, and an autophagy-associated signature for ORCA patients was constructed. Eventually, 4 desirable independent survival-related ARGs ( WDR45 , MAPK9 , VEGFA , and ATIC ) were confirmed and comprised the prognostic model. We made use of multiple ways to verify the accuracy of the novel autophagy-related signature for survival evaluation, such as receiver-operator characteristic curve, Kaplan-Meier plotter, and clinicopathological correlational analyses. Four independent prognostic DEARGs that formed the model were also associated with the prognosis of ORCA patients., Conclusions: The autophagy-related risk model can evaluate OS for ORCA patients independently since it is accurate and stable. Four prognostic ARGs that composed the model can be studied deeply for target treatment., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2022 Hongjun Fei and Xiongming Chen.)

Background: Papillary thyroid carcinoma (PTC) is one of the common clinical tumors, where LncRNA plays an important role in tumorigenesis and its development. The purpose of this study was to explore the role of DIO3OS in PTC., Method: Firstly, this study verified the expression of DIO3OS in PTC through the public database. Then, the differences in DIO3OS expression between the PTC group and paracancerous tissues were verified using the qRT-PCR. A series of in vitro experiments were conducted to verify the function of DIO3OS in PTC, while its involvement in possible pathways was analyzed by the GSEA. The ssGSEA algorithm estimated the immune status using the queue transcriptome graph derived from the TCGA database. Further, the correlation analysis was used to confirm the relationship between DIO3OS and the immune genes., Result: The results showed that the expression of DIO3OS was low in PTC. The same results were also confirmed by qRT-PCR analysis (P= 0.0077). In vitro, DIO3OS was localized within the cytoplasm and exosomes. Overexpression of DIO3OS hindered the proliferation, invasion, and migration of PTC cells. According to the degree of immune cell infiltration, the tumor group was divided into high immune cell infiltration group, medium immune cell infiltration group, and low immune cell infiltration group. The results showed that the DIO3OS was highly expressed in the high immune cell infiltration group (P < 0.001), which was positively correlated with the immune cell infiltration and also correlated with multiple immune genes., Conclusion: In summary, this study illustrated the expression pattern of DIO3OS in PTC, which may be involved in the immune-inflammatory pathway. Hence, our results may provide new diagnostic biomarkers and therapeutic targets for PTC., (Copyright © 2021 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: The aim of the study was to perform mRNA-miRNA regulatory network analyses to identify a miRNA panel for molecular subtype identification and stratification of high-risk patients with pancreatic ductal adenocarcinoma (PDAC)., Background: Recent transcriptional profiling effort in PDAC has led to the identification of molecular subtypes that associate with poor survival; however, their clinical significance for risk stratification in patients with PDAC has been challenging., Methods: By performing a systematic analysis in The Cancer Genome Atlas and International Cancer Genome Consortium cohorts, we discovered a panel of miRNAs that associated with squamous and other poor molecular subtypes in PDAC. Subsequently, we used logistic regression analysis to develop models for risk stratification and Cox proportional hazard analysis to determine survival prediction probability of this signature in multiple cohorts of 433 patients with PDAC, including a tissue cohort (n = 199) and a preoperative serum cohort (n = 51)., Results: We identified a panel of 9 miRNAs that were significantly upregulated (miR-205-5p and -934) or downregulated (miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p, and 1251-5p) in PDAC molecular subtypes with poor survival [squamous, area under the receiver operating characteristic curve (AUC) = 0.90; basal, AUC = 0.89; and quasimesenchymal, AUC = 0.83]. The validation of this miRNA panel in a tissue clinical cohort was a significant predictor of overall survival (hazard ratio = 2.48, P < 0.0001), and this predictive accuracy improved further in a risk nomogram which included key clinicopathological factors. Finally, we were able to successfully translate this miRNA predictive signature into a liquid biopsy-based assay in preoperative serum specimens from PDAC patients (hazard ratio: 2.85, P = 0.02)., Conclusion: We report a novel miRNA risk-stratification signature that can be used as a noninvasive assay for the identification of high-risk patients and potential disease monitoring in patients with PDAC., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

We have previously revealed the overexpression of Wilms' tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4 + /CD8 + tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3 + or CD8 + T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4 + T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Lung cancer is the primary cause of cancer-related deaths worldwide. The human lung serves as a niche to a unique and dynamic bacterial community that is related to the development of multiple diseases. Here, we investigated the differences in the lung microbiomes of patients with lung cancer., Methods: 16S rRNA sequencing was performed to evaluate the respiratory tract microbiome present in the bronchoalveolar lavage fluid. Patients were stratified based on programmed death-ligand 1 (PD-L1) expression levels and immunotherapy responses., Results: In total, 84 patients were prospectively analyzed, of which 59 showed low (< 10%), and 25 showed high (≥ 10%) PD-L1 expression levels. The alpha and beta diversities did not significantly differ between the two groups. Veillonella dispar was dominant in the high-PD-L1 group; the population of Neisseria was significantly higher in the low-PD-L1 group than in the high-PD-L1 group. In the immunotherapy responder group, V. dispar was dominant, while Haemophilus influenzae and Neisseria perflava were dominant in the non-responder group., Conclusion: The abundances of Neisseria and V. dispar differed significantly in relation to PD-L1 expression levels and immunotherapy responses., (© 2021. The Author(s).)

Histone demethylase JMJD4 is a burgeoning tumor marker, which has been proven to be associated with colon cancer, but the role it plays in kidney cancer has not yet been investigated. In the present study, we evaluated whether JMJD4 can be a prognostic marker of patients with clear cell renal cell carcinoma (ccRCC) using data from public platform and in vitro experiments. Our results revealed that the expression of JMJD4 is higher in cancerous tissue than in normal tissues ( p < 0.001). High expression of JMJD4 is associated with a poor overall survival (OS) of ccRCC as compared with low expression of JMJD4 ( p = 0.015). JMJD4 showed significant relevance with M stage ( p = 0.016), gender ( p = 0.003), OS (0.018), disease-specific survival (DSS) (0.007), and percussion free interval (PFI) (0.041). Univariate and multivariate Cox analyses demonstrated that high JMJD4 expression had independent predictive value for OS in ccRCC patients (hazard ratio (HR) = 1.563, 95%confidence interval (CI) = 1.055-2.316, and p = 0.026). Besides, in vitro experiments confirmed that high expression of JMJD4 can significantly promote the invasion ability ( p < 0.001), cloning ability ( p < 0.001), and proliferation ( p < 0.001) of renal cell carcinoma. In summary, high JMJD4 expression may be a prognostic marker in patients with kidney cancer., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Hao Yan et al.)

The PPARδ gene codes protein that belongs to the peroxisome proliferator-activated receptor (PPAR) family engaged in a variety of biological processes, including carcinogenesis. Specific biological and clinical roles of PPARδ in non-small cell lung cancer (NSCLC) is not fully explained. The association of PPARα with miRNA regulators (e.g. miRNA-17) has been documented, suggesting the existence of a functional relationship of all PPARs with epigenetic regulation. The aim of the study was to determine the PPARδ and miR-17 expression profiles in NSCLC and to assess their diagnostic value in lung carcinogenesis. PPARδ and miR-17 expressions was assessed by qPCR in NSCLC tissue samples (n = 26) and corresponding macroscopically unchanged lung tissue samples adjacent to the primary lesions served as control (n = 26). PPARδ and miR-17 expression were significantly lower in NSCLC than in the control (p = 0.0001 and p = 0.0178; respectively). A receiver operating characteristic (ROC) curve analysis demonstrated the diagnostic potential in discriminating NSCLC from the control with an area under the curve (AUC) of 0.914 for PPARδ and 0.692 for miR-17. Significant increase in PPARδ expression in the control for current smokers vs. former smokers (p = 0.0200) and increase in miR-17 expression in control tissue adjacent to adenocarcinoma subtype (p = 0.0422) were observed. Overexpression of miR-17 was observed at an early stage of lung carcinogenesis, which may suggest that it acts as a putative oncomiR. PPARδ and miR-17 may be markers differentiating tumour tissue from surgical margin and miR-17 may have diagnostic role in NSCLC histotypes differentiation., (© 2021. The Author(s).)

Aims: Discs large-associated protein 5 (DLGAP5), a kinetochore fibers-binding protein, functions as a oncoprotein in many cancers. However, its expression patterns in pan-cancer including clear cell renal cell carcinoma (ccRCC) are not analyzed. Herein, we aimed to evaluate its expression in more common cancers, especially in ccRCC., Main Methods: Data from Genotype-Tissue Expression, The Cancer Genome Atlas, and Tumor Immune Estimation Resource were used to analyze the DLGAP5 expression in normal tissues, cancer cell lines, and cancer tissues, as well as the immune infiltration levels. The analysis results were verified with ccRCC cell lines via RNAi, western blotting, and the cytological analysis., Key Findings: Low DLGAP5 expression in 31 types of normal tissues, the upregulation in 21 cancer cell lines, and the significant elevated expression in 26 types of cancers, were found, Surprisingly, kidney cancer including ccRCC, DLGAP5 exhibited a slightly elevated but statistically significant expression among 26 types of cancers. In addition, elevated DLGAP5 expression was significantly positive correlated with immune infiltration level in ccRCC. The survival probability of some cancers including kidney cancer, clinical TNM stage of ccRCC patients were significantly related to upregulated DLGAP5 expression. The experiments results showed DLGAP5 upregulation in ccRCC tissues and the cell lines, its knockdown inhibited the cells viability and proliferation, and compromised the cells migration and invasion., Significance: Elevated DLGAP5 expression occurred in common cancers. However, its slightly upregulated expression is related with ccRCC progression, it is therefore a prognostic risk factor for ccRCC, but not an independent factor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Emerging evidence shows that Homeobox ( HOX ) genes are important in carcinogenesis, and their dysregulation has been linked with metastatic potential and poor prognosis. This review (PROSPERO-CRD42020190953) aims to systematically investigate the role of HOX genes as biomarkers in CRC and the impact of their modulation on tumour growth and progression. The MEDLINE, EMBASE, Web of Science and Cochrane databases were searched for eligible studies exploring two research questions: (a) the clinicopathological and prognostic significance of HOX dysregulation in patients with CRC and (b) the functional role of HOX genes in CRC progression. Twenty-five studies enrolling 3003 CRC patients, showed that aberrant expression of HOX proteins was significantly related to tumour depth, nodal invasion, distant metastases, advanced stage and poor prognosis. A post-hoc meta-analysis on HOXB9 showed that its overexpression was significantly associated with the presence of distant metastases (pooled OR 4.14, 95% CI 1.64-10.43, I 2 = 0%, p = 0.003). Twenty-two preclinical studies showed that HOX proteins are crucially related to tumour growth and metastatic potential by affecting cell proliferation and altering the expression of epithelial-mesenchymal transition modulators. In conclusion, HOX proteins may play vital roles in CRC progression and are associated with overall survival. HOXB9 may be a critical transcription factor in CRC.

Cervical lymph node metastasis is the leading cause of poor prognosis in oral tongue squamous cell carcinoma and also occurs in the early stages. The current clinical diagnosis depends on a physical examination that is not enough to determine whether micrometastasis remains. The transcriptome profiling technique has shown great potential for predicting micrometastasis by capturing the dynamic activation state of genes. However, there are several technical challenges in using transcriptome data to model patient conditions: (1) An Insufficient number of samples compared to the number of genes, (2) Complex dependence between genes that govern the cancer phenotype, and (3) Heterogeneity between patients between cohorts that differ geographically and racially. We developed a computational framework to learn the subnetwork representation of the transcriptome to discover network biomarkers and determine the potential of metastasis in early oral tongue squamous cell carcinoma. Our method achieved high accuracy in predicting the potential of metastasis in two geographically and racially different groups of patients. The robustness of the model and the reproducibility of the discovered network biomarkers show great potential as a tool to diagnose lymph node metastasis in early oral cancer., (© 2021. The Author(s).)

Myasthenia gravis (MG) is a complex neurological autoimmune disease with a pathogenetic mechanism that has yet to be elucidated. Emerging evidence has revealed that genes, non-coding RNAs and genetic variants play significant roles in the pathogenesis of MG. However, the molecular mechanisms of single nucleotide polymorphisms (SNPs) located on lncRNAs could disturb lncRNA-mediated ceRNA regulatory functions still unclear in MG. In this study, we collated 276 experimentally confirmed MG risk genes and 192 MG risk miRNAs. We then constructed a lncRNA-mediated ceRNA network for MG based on multi-step computational strategies. Next, we systematically integrated risk pathways and identified candidate SNPs in lncRNAs for MG based on data acquired from public databases. In addition, we constructed a pathway-based lncRNA-SNP mediated network (LSPN) that contained 128 lncRNAs targeting 8 MG risk pathways. By analyzing network, we propose a latent mechanism for how the "lncRNA-SNP-mRNA-pathway" axis affects the pathogenesis of MG. Moreover, 25 lncRNAs and 51 SNPs on lncRNAs were extracted from the "lncRNA-SNP-mRNA-pathway" axis. Finally, functional analyses demonstrated lncRNA-SNPs mediated ceRNA regulation pairs associated with MG participated in the MAPK signaling pathway. In summary, we constructed MG-specific lncRNA-SNPs mediated ceRNA regulatory networks based on pathway in the present study, which was helpful to elucidate the roles of lncRNA-SNPs in the pathogenesis of MG and provide novel insights into mechanism of lncRNA-SNPs as potential genetic risk biomarkers of MG., (© 2021. The Author(s).)

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 - 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 - 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sbiera, Kircher, Altieri, Lenz, Hantel, Fassnacht, Sbiera and Kroiss.)

Background: Breast cancer is the most common female cancer worldwide. DNA methylation is a common modification in epigenetics and affects the prognosis of breast cancer by changing gene expression. In the present study, we aim to investigate the role of DNA methylation in TMEM130 gene expression, and the function of TMEM130 in breast cancer cell migration., Methods: The transcriptional expression of TMEM130 was detected by qRT-PCR in breast cancer cell lines and tissues. Bisulfite sequencing PCR (BSP) was used to confirm the methylation status of TMEM130 promoter. Then, TMEM130 was transfected in breast cancer cell lines and to explore its role in cell migration by Transwell and western blot., Results: TMEM130 mRNA expression was decreased in breast cancer cell lines and tissues, and consistent with the data in The Cancer Genome Atlas (TCGA). The promoter of TMEM130 was hypermethylated in breast cancer and the expression of TMEM130 could be restored by the methyltransferase inhibitor. Overexpression of TMEM130 could inhibit cell migration ability in breast cancer cell lines., Conclusion: Taken together, these results indicate TMEM130 downregulation and hypermethylation might contribute to breast cancer migration and TMEM130 might be a promising biomarker for breast cancer., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Gastric cancer (GC) is one of the most common and lethal cancers worldwide. The Nudix hydroxylase (NUDT) genes have been reported to play notable roles in tumor progression. However, the role of NUDT10 in GC has not been reported. In this study, we investigated the expression of NUDT10 in GC and its association with clinicopathological characteristics. Quantitative real-time polymerase chain reaction and analyses of The Cancer Genome Atlas and Human Protein Atlas databases were performed to determine NUDT10 mRNA and protein expression. Receiver operating characteristic curve analysis was used to assess the diagnostic value of NUDT10 in patients with GC. We used Cox regression and the Kaplan-Meier method to assess the correlations between clinicopathological factors and survival outcomes of patients with GC. Gene set enrichment analysis (GSEA) was performed to identify the underlying signaling pathways. NUDT10 mRNA and protein expression was significantly lower in GC tissues compared to normal tissues. Interestingly, higher NUDT10 expression was correlated with advanced tumor stage, deeper local invasion, and worse survival outcomes. Patients with higher NUDT10 expression had a significantly worse prognosis than those with lower NUDT10 expression. Multivariate analysis showed that high NUDT10 expression was an independent predictor of survival outcome. Several pathways, including mismatch repair, nucleotide excision repair, extracellular matrix receptor interaction, and cancer signaling, were identified as enriched pathways in GC through GSEA. To our knowledge, this study is the first to characterize NUDT10 expression in GC. Our study demonstrates that NUDT10 is a promising independent biomarker for GC prognosis.

Background: Approximately 10% to 15% of patients with solitary fibrous tumors of the pleura (SFTP) have recurrence after resection. Many are not candidates for reresection and lack effective treatments. We explored the expression of programmed death ligand 1 (PD-L1) as a biomarker for candidacy for treatment with immune checkpoint inhibitors., Methods: We reviewed the medical records of 52 patients with primary SFTP and 5 with recurrent SFTP. We performed immunohistochemistry on tumor tissue to determine the expression of PD-L1 and infiltration by cluster of differentiation 8 (CD8)-positive immune cells., Results: Any PD-L1 expression was observed in 11 primary SFTP (21.2%). Overall, PD-L1 expression level was less than 1% in 10 patients (19.2%) and greater than 1% in 1 (1.9%). Tumor infiltration by CD8-positive immune cells was absent or rare in 13 patients (25%), less than 5% in 31 (59.6%), and 5% to 25% in 8 (15.4%). There were no associations between PD-L1 expression or immune cell infiltrates and known risk factors for recurrence or a prognostic risk score classification. Time to recurrence was strongly associated with the risk score classification (P < .001), but it was not associated with PD-L1 expression (P = .296) or immune cell infiltrates (P = .619). In recurrent SFTP, PD-L1 was expressed in 4 of 10 tumors (40%; all <1% expression). There was no correlation in PD-L1 expression between primary and recurrent SFTP samples., Conclusions: A small subset of SFTP express PD-L1 at low levels (<1%) but exhibit colocalization of CD8-positive immune cells suggesting an inducible expression mechanism. The role of PD-L1 merits exploration in the clinical setting in patients with advanced SFTP when alternative treatments or clinical trials are considered., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

N 6 -methyladenosine (m 6 A) has been involved in diverse biological processes in cancer, but its function and clinical value in clear cell renal cell carcinoma (ccRCC) remain largely unknown. In this study, we found that 1453 m 6 A-modified differentially expressed genes (DEGs) of ccRCC were mainly enriched in cell cycle, PI3K-AKT, and p53 signaling pathways. Then we constructed a co-expression network of the 1453 m 6 A-modified DEGs and identified a most clinically relevant module, where NUF2, CDCA3, CKAP2L, KIF14, and ASPM were hub genes. NUF2, CDCA3, and KIF14 could combine with a major RNA m 6 A methyltransferase METTL14, serving as biomarkers for ccRCC. Real-time quantitative PCR assay confirmed that NUF2, CDCA3, and KIF14 were highly expressed in ccRCC cell lines and ccRCC tissues. Furthermore, these three genes were modified by m 6 A and negatively regulated by METTL14. This study revealed that NUF2, CDCA3, and KIF14 were m 6 A-modified biomarkers, representing a potential diagnostic, prognostic, and therapeutic target for ccRCC. Abbreviations: m 6 A: N 6 -methyladenosine; ccRCC: clear cell renal cell carcinoma; DEGs: differentially expressed genes; NUF2: NUF2 component of NDC80 kinetochore complex; CDCA3: cell division cycle associated 3; CKAP2L: cytoskeleton associated protein 2 like; KIF14: kinesin family member 14; ASPM: assembly factor for spindle microtubules; METTL14: methyltransferase 14; OS: overall survival; FPKM: fragments per kilobase million; GEO: gene expression omnibus; TCGA: the Cancer Genome Atlas; RMA: robust multi-array average expression measure; WGCNA: weighted gene co-expression network analysis; GO: gene ontology; KEGG: kyoto encyclopedia of genes and genomes; ROC: receiver operating characteristic curve; AUC: area under the curve; RIP: RNA immunoprecipitation; qPCR: real-time quantitative PCR.

FRG1 has a role in tumorigenesis and angiogenesis. Our preliminary analysis showed that FRG1 mRNA expression is associated with overall survival (OS) in certain cancers, but the effect varies. In cervix and gastric cancers, we found a clear difference in the OS between the low and high FRG1 mRNA expression groups, but the difference was not prominent in breast, lung, and liver cancers. We hypothesized that FRG1 expression level could affect the functionality of the correlated genes or vice versa, which might mask the effect of a single gene on the OS analysis in cancer patients. We used the multivariate Cox regression, risk score, and Kaplan Meier analyses to determine OS in a multigene model. STRING, Cytoscape, HIPPIE, Gene Ontology, and DAVID (KEGG) were used to deduce FRG1 associated pathways. In breast, lung, and liver cancers, we found a distinct difference in the OS between the low and high FRG1 mRNA expression groups in the multigene model, suggesting an independent role of FRG1 in survival. Risk scores were calculated based upon regression coefficients in the multigene model. Low and high-risk score groups showed a significant difference in the FRG1 mRNA expression level and OS. HPF1, RPL34, and EXOSC9 were the most common genes present in FRG1 associated pathways across the cancer types. Validation of the effect of FRG1 mRNA expression level on these genes by qRT-PCR supports that FRG1 might be an upstream regulator of their expression. These genes may have multiple regulators, which also affect their expression, leading to the masking effect in the survival analysis. In conclusion, our study highlights the role of FRG1 in the survivability of cancer patients in tissue-specific manner and the use of multigene models in prognosis., (© 2021. The Author(s).)

Zinc-finger proteins are transcription factors with a "finger-like" domain that are widely involved in many biological processes. The zinc-finger protein 677 (ZNF677) belongs to the zinc-finger protein family. Previous reports have highlighted the tumor suppressive role of ZNF677 in thyroid and lung cancer. However, its role in colorectal cancer (CRC) has not been explored. ZNF677 protein expression was analyzed by immunohistochemistry in a large cohort of 1158 CRC patients. ZNF677 loss of expression was more frequent in CRC tissues (45.3%, 525/1158), when compared to that of normal tissue (5.1%, 11/214) (p < 0.0001) and was associated with mucinous histology (p = 0.0311), advanced pathological stage (p < 0.0001) and lymph node (LN) metastasis (p = 0.0374). Further analysis showed ZNF677 loss to be significantly enriched in LN metastatic CRC compared to overall cohort (p = 0.0258). More importantly, multivariate logistic regression analysis showed that ZNF677 loss is an independent predictor of LN metastasis in CRC (Odds ratio = 1.41; 95% confidence interval 1.05-1.87; p = 0.0203).The gain- and loss-of-function studies in CRC cell lines demonstrated that loss of ZNF677 protein expression prominently increased cell proliferation, progression of epithelial-mesenchymal transition and conferred chemoresistance, whereas its overexpression reversed the effect. In conclusion, loss of ZNF677 protein expression is common in Middle Eastern CRC and contributes to the prediction of biological aggressiveness of CRC. Therefore, ZNF677 could not only serve as a marker in predicting clinical prognosis in patient with CRC but also as a potential biomarker for personalized targeted therapy., (© 2021. The Author(s).)

Human papillomavirus (HPV)-induced anal intraepithelial neoplasia (AIN, graded 1-3) is highly prevalent in HIV-positive (HIV+) men who have sex with men (MSM), but only a minority of lesions progresses to cancer. Our study aimed to characterise comprehensively anal tissue samples from a cross-sectional series (n = 104) of HIV+ MSM and longitudinal series (n = 40) of AIN2/3 progressing to cancer using different biomarkers. The cross-sectional series consisted of 8 normal, 26 AIN1, 45 AIN2, 15 AIN3 and 10 anal squamous cell carcinoma. Tissue sections were immunohistochemically (IHC) stained for p16 (viral transformation marker), Ki-67 (cellular proliferation marker) and HPV-E4 (viral production marker). We evaluated the expression of IHC markers and compared it with DNA methylation, a marker for malignant transformation. E4 positivity decreased, whereas p16 and Ki-67 scores and methylation marker positivity increased (P values < .001) with increasing severity of anal lesions. Within AIN2, a heterogeneous biomarker pattern was observed concerning E4, p16 and methylation status, reflecting the biological heterogeneity of these lesions. In the longitudinal series, all AIN2/3 and carcinomas showed high p16 and Ki-67 expression, strong methylation positivity and occasional E4 positivity. We earlier showed that high methylation levels are associated with progression to cancer. The observed E4 expression in some AIN2/3 during the course of progression to cancer and absence of E4 in a considerable number of AIN1 lesions make the potential clinical significance of E4 expression difficult to interpret. Our data show that IHC biomarkers can help to characterise AIN; however, their prognostic value for cancer risk stratification, next to objective methylation analysis, appears to be limited., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

FAM159B is a so-called adaptor protein. These proteins are essential components in numerous cell signalling pathways. However, little is known regarding FAM159B expression in normal and neoplastic human tissues. The commercially available rabbit polyclonal anti-human FAM159B antibody HPA011778 was initially characterised for its specificity using Western blot analyses and immunocytochemistry and then applied to a large series of formalin-fixed, paraffin-embedded normal and neoplastic human tissue samples. Confirmation of FAM159B's predicted size and antibody specificity was achieved in BON-1 cells, a neuroendocrine tumour cell line endogenously expressing FAM159B, using targeted siRNA. Immunocytochemical experiments additionally revealed cytoplasmic expression of the adaptor protein. Immunohistochemical staining detected FAM159B expression in neuronal and neuroendocrine tissues such as the cortex, the trigeminal ganglia, dorsal root and intestinal ganglia, the pancreatic islets and the neuroendocrine cells of the bronchopulmonary and gastrointestinal tract, but also in the syncytiotrophoblasts of the placenta. FAM159B was also expressed in many of the 28 tumour entities investigated, with high levels in medullary and anaplastic thyroid carcinomas, parathyroid adenomas, lung and ovarian carcinomas, lymphomas and neuroendocrine tumours of different origins. The antibody HPA011778 can act as a useful tool for basic research and identifying FAM159B expression in tissue samples.

Background: lncRNAs are modulatory factors with critical function in the tumorigenesis pathways, introducing them as promising therapeutic and diagnostic biomarkers for different cancers. This study is thus aimed to evaluate the differences in PVT1 and ZFAS1 gene expression in tumorous tissues as compared with adjacent healthy non-tumorous biopsies of gastric cancer cases., Methods: One hundred two pairs of tumorous and adjacent non-tumorous biopsies of GC cases were sampled. RNA isolation and cDNA production were carried out. The qRT-PCR was performed to evaluate the expression of PVT1 and ZFAS1 genes. Moreover, the associations between PVT1 or ZFAS1 and clinicopathological characteristics as well as the biomarker roles of the lncRNAs were assessed., Results: The PVT1 and ZFAS1 expressions showed a significant increase and decrease in GC samples as compared with non-cancerous tissues, respectively. PVT1 expression was significantly associated with and lymph-node involvement (p = 0.0007). Moreover, ZFAS1 expression demonstrated a significant association with lymph-node involvement (p = 0.0005), and tumor size >5 cm (p = 0.003). The findings of the ROC curve revealed that PVT1 and ZFAS1 may act as a possible biomarker with AUC of 0.71 and 0.79, specificity of 78.43% and 79.41%, and sensitivity of 55.88% and 64.71%., Conclusions: Regarding upregulation of PVT1 and downregulation of ZFAS1 in human GC samples, these genes may respectively act as oncogenic and tumor-suppressive factors in GC cases. Furthermore, PVT1 and ZFAS1 can be considered as possible biomarkers for the detection and treatment of GC cases., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Aim: A comprehensive meta-analysis was carried out to evaluate the association between high PARP1 expression and clinical outcomes in diverse types of cancers. Materials & methods: The electronic databases for all articles about PARP1 expression and cancers were searched. Additionally, bioinformatics analysis was utilized to validate the results of the meta-analysis. Results: Fifty-two studies with a total of 7140 patients were included in the current meta-analysis. High PARP1 expression was found to be significantly associated with poor overall survival and recurrence in various cancers, which were further strengthened and complemented by the results of bioinformatic analysis. Furthermore, increased PAPR1 expression was also related to clinicopathological features. Conclusion: Our findings confirmed that PARP1 might be a promising biomarker for prognosis in human cancers.

Objective: This study aimed to conduct a genomewide transcriptomic profiling to develop a microRNA (miRNA)-based signature for the identification of peritoneal metastasis (PM) in patients with gastric cancer (GC)., Summary Background Data: Even though PM in patients with GC has long been recognized to associate with poor prognosis, currently there is lack of availability of molecular biomarkers for its robust diagnosis., Methods: We performed a systematic biomarker discovery by analyzing miRNA expression profiles in primary tumors from GC patients with and without PM, and subsequently validated the expression of candidate miRNA biomarkers in 3 independent clinical cohorts of 354 patients with advanced GC., Results: Five miRNAs (miR-30a-5p, -134-5p, -337-3p, -659-3p, and -3917) were identified during the initial discovery phase; three of which (miR-30a-5p, -659-3p, and -3917) were significantly overexpressed in the primary tumors from PM-positive patients in the testing cohort (P = 0.002, 0.04, and 0.007, respectively), and distinguished patients with versus without peritoneal metastasis with the value of area under the curve (AUC) of 0.82. Furthermore, high expression of these miRNAs also associated with poor prognosis (hazard ratio = 2.18, P = 0.04). The efficacy of the combination miRNA signature was subsequently validated in an independent validation cohort (AUC = 0.74). Finally, our miRNA signature when combined together with the macroscopic Borrmann's type score offered a much superior diagnostic in all 3 cohorts (AUC = 0.87, 0.76, and 0.79, respectively)., Conclusions: We have established an miRNA-based signature that have a potential to identify peritoneal metastasis in GC patients., Competing Interests: The authors report no conflicts of interest to disclose., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The prognostic role of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM) is incompletely understood. Our objectives were to evaluate the evidence for tumor PD-L1 as a prognostic biomarker in MPM through meta-analysis and to determine whether tumor PD-L1 expression is associated with survival in MPM patients undergoing macroscopic complete resection., Methods: Meta-analysis was performed to determine the association of PD-L1 with overall survival in MPM (n = 1655) from 14 studies containing overall survival and tumor PD-L1 expression. Univariable and multivariable analyses tested the relationship of tumor PD-L1 with overall survival and recurrence-free survival in an institutional cohort of MPM patients treated by macroscopic complete resection (n = 75). To validate the association of PD-L1 with overall survival, we utilized two independent MPM cohorts (n = 284)., Results: Meta-analysis demonstrated that high tumor PD-L1 expression was associated with poor overall survival. Among 75 patients undergoing macroscopic complete resection, 49 tumors (65%) expressed PD-L1 (1% or more), and high PD-L1 (50% or greater) was more commonly expressed on nonepithelial (29%) compared with epithelial tumors (14%). High tumor PD-L1 expression was independently associated with poor overall survival (P < .001, hazard ratio 5.67) and recurrence-free survival (P = .003, hazard ratio 3.28). The association of PD-L1 overexpression with unfavorable survival was more significant in epithelial MPMs than nonepithelial MPMs. These findings were validated in RNA sequencing analyses in two independent cohorts. Exploratory transcriptome analysis revealed that MPM tumors with PD-L1 overexpression displayed coexpression of other immune regulatory molecules, programmed cell death 1 ligand 2 and T-cell immunoglobulin mucin receptor 3., Conclusions: Tumor PD-L1 expression is a prognostic biomarker in patients undergoing surgical resection for MPM and may be useful in perioperative decision making., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) remains one of the most prevalent human malignancies with high mortality. Increasing studies have revealed microRNAs (miRNAs) play crucial roles in the tumorigenesis and progression of cancers. The current study investigated the expression levels of miR-1229-3p and its potential role in HCC. This study enrolled 121 HCC patients. The expression of miR-1229-3p was measured using RT-qPCR in HCC tissue samples and cell lines. The association of miR-1229-3p expression with clinical parameters and patients' prognosis was analyzed by χ 2 test, Kaplan-Meier, and multivariate Cox regression analyses, respectively. The functions of miR-1229-3p in HCC cells were explored by CCK-8 assay, Transwell migration, and invasion assays. miR-1229-3p was upregulated in HCC tissue samples and cell lines. The upregulation of miR-1229-3p was related to positive lymph node metastasis and advanced TNM stages and predicted with patients' poor prognosis. Overexpression of miR-1229-3p facilitated cell viability and metastasis of HCC cells while knockdown of miR-1229-3p suppressed cell viability and metastasis of HCC cells in vitro. miR-1229-3p may function as an oncogenic role in HCC via promoting cell viability and metastasis. Moreover, miR-1229-3p may be a predictive marker for tumor development and prognosis of HCC patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background and Aim: The thymosin beta 10 (TMSB10) was originally identified from the thymus, which plays a key role in the development of many cancers. However, the underlying molecular mechanisms of TMSB10 involved in GC have not been understood., Methods: We sought to determine the expression of TMSB10 in human GC tissues and illustrate whether it is correlated with the clinical pathologic characteristics and prognosis in GC patients. Its roles and potential mechanisms in regulating tumor growth, invasion, and angiogenesis were evaluated by TMSB10 knockdown/overexpression of GC cells in vitro and ex vivo., Results: Marked overexpression of TMSB10 protein expression was observed in GC cells and tissues, which was associated with the advanced tumor stage and lymph nodes (LN) metastasis of GC patients. Furthermore, prognostic analysis showed that GC patients with high TMSB10 expression had a remarkably shorter survival and acted as an important factor for predicting poor overall survival in GC patients. Moreover, TMSB10 overexpression promoted, while TMSB10 knockdown the proliferation, EMT process, and angiogenesis of GC cells., Conclusion: The study highlights that TMSB10 may hold promise as potential prognosis prediction biomarker for the diagnosis of GC and a potential therapeutic target, which will facilitate the development of a novel therapeutic strategy against GC., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)