Efficacy and safety of intrapleural perfusion with hyperthermic chemotherapy for malignant pleural effusion: a meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of intrapleural perfusion with hyperthermic chemotherapy (IPHC) in treating malignant pleural effusion (MPE). METHODS: PubMed, Embase, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), VIP Chinese Science and Technology Journal Full-text Database (VP-CSJFD), and Wanfang database were searched by computer from database establishment to January 17, 2024. Relevant randomized controlled articles with IPHC as the observational group and intrapleural perfusion chemotherapy (IPC) as the control group for MPE were included. Then, the methodological quality of the included articles was evaluated and statistically analyzed using Stata 16.0. RESULTS: Sixteen trials with 647 patients receiving IPHC and 661 patients receiving IPC were included. The meta-analysis found that MPE patients in the IPHC group had a more significant objective response rate [RR = 1.31, 95%CI (1.23, 1.38), P < 0.05] and life quality improvement rate [RR = 2.88, 95%CI (1.95, 4.24), P < 0.05] than those in the IPC group. IPHC and IPC for MPE patients had similar incidence rates of asthenia, thrombocytopenia, hepatic impairment, and leukopenia. CONCLUSION: Compared with IPC, IPHC has a higher objective response rate without significantly increasing adverse reactions. Therefore, IPHC is effective and safe. However, this study is limited by the quality of the literature. Therefore, more high-quality, multi-center, large-sample, rigorously designed randomized controlled clinical studies are still needed for verification and evaluation.

PathExpSurv: pathway expansion for explainable survival analysis and disease gene discovery.

BACKGROUND: In the field of biology and medicine, the interpretability and accuracy are both important when designing predictive models. The interpretability of many machine learning models such as neural networks is still a challenge. Recently, many researchers utilized prior information such as biological pathways to develop neural networks-based methods, so as to provide some insights and interpretability for the models. However, the prior biological knowledge may be incomplete and there still exists some unknown information to be explored. RESULTS: We proposed a novel method, named PathExpSurv, to gain an insight into the black-box model of neural network for cancer survival analysis. We demonstrated that PathExpSurv could not only incorporate the known prior information into the model, but also explore the unknown possible expansion to the existing pathways. We performed downstream analyses based on the expanded pathways and successfully identified some key genes associated with the diseases and original pathways. CONCLUSIONS: Our proposed PathExpSurv is a novel, effective and interpretable method for survival analysis. It has great utility and value in medical diagnosis and offers a promising framework for biological research.

Highly Expressing SCARA5 Promotes Proliferation and Migration of Esophageal Squamous Cell Carcinoma.

Background: Thrombospondin type 1 domain-containing 7A (THSD7A) was reported to play a procancer role in esophageal squamous cell carcinoma (ESCC). The aim of the study was to screen the downstream functional genes of THSD7A and explore their functions in ESCC, based on the reported research into THSD7A function and on gene microarrays. Methods: We adopted quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Celigo high-content screening (HCS) technology to screen the downstream genes of THSD7A. The expression level of target genes was examined by PCR, western blot, and immunohistochemistry (IHC). The effects of these target genes on ESCC malignant biological behavior were performed in vivo and in vitro. The Kaplan-Meier (K-M) survival analysis and Cox regression were used to analyze the prognostic significance of target genes in ESCC patients. Experiments in the literature on liver cancer (LC) were repeated to verify the functions of these genes in different tumors. We further explored the cancer-promoting mechanism of target genes in ESCC by sequencing of the genes' exons. Results: Scavenger receptor class A member 5 (SCARA5) was proved to be the downstream driving gene of THSD7A. SCARA5 promoted cell proliferation and migration but inhibited apoptosis in ESCC. IHC results confirmed that SCARA5 expression in ESCC exceeded that in normal tissues. The K-M survival analysis indicated that SCARA5 expression quantity was not related to prognosis, but tumor volume and T classification were both the independent prognostic factors. Repetition of experiments in LC in the literature confirmed that SCARA5 had exactly opposite functions in EC and LC. Conclusion: SCARA5 was related to the development and occurrence of ESCC. Our findings suggested that it was a potentially diagnostic individualized therapeutic target for ESCC in the future and that its application could possibly be combined with that of upstream THSD7A gene.

Open Search-Based Proteomics Reveals Widespread Tryptophan Modifications Associated with Hypoxia in Lung Cancer.

The tryptophan residue has a large hydrophobic surface that plays a unique role in the folded protein conformation and functions. Tryptophan modifications are presumably to be readily detected in proteins due to the vulnerability of the indole structure to electrophilic attacks. In this study, we report a systematic identification of sequence variations at tryptophan, termed tryptophan variants, from the proteome of patients with nonsmall cell lung cancer (NSCLC). Using shotgun proteomics and a modified open search algorithm, 25 tryptophan variants on 2481 sites in over 858 proteins were identified. Among these, 6 tryptophan variants are previously identified, 15 are newly annotated, and 4 are still unknown, most of which are involved in the cascade of oxidation in the blood microparticle. Remarkably, Trp313 of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was up-oxidized whereas Trp16 and Trp38 of hemoglobin (HBB) were down-oxidized in NCSLC tissues. The results were further supported by an independent cohort of 103 lung adenocarcinoma samples, reflecting a negative feedback and potential detoxification mechanism against tumor glycolysis and hypoxia. Overall, the study reports a quick approach to explore tryptophan variants at the proteomic scale. Our findings highlight the predominant role of tryptophan oxidation in regulating the redox balance of cancer cells and its potential role as prognostic biomarker for patients with NSCLC.

Identification of key classification features of early cervical squamous cell carcinoma.

Despite the tremendous progress in molecular analysis of pan-cancer, little is known regarding molecular classification of cervical squamous cell carcinoma. In this study, we adopted a multi-omics approach to identify potential key classification features of cervical squamous cell carcinoma. Specifically, we analyzed mRNA, and microRNA (miRNA) expression data, as well as DNA methylation and copy number variation in cervical squamous cell carcinoma cases, using datasets obtained from The Cancer Genome Atlas (TCGA). Moreover, we identified molecules in each dimension, as well as integrated and clustered filtered classification features, and used them to distinguish different subtypes. The resulting key classification features were used to establish a classification model for cervical squamous cell carcinoma. Our results revealed two cervical squamous cell carcinoma subtypes, with significant differences across clinical survival levels, as well as 8 key classification features of cervical squamous cell carcinomas. These findings are expected to provide important references for early classification of cervical squamous cell carcinoma and identification of classification markers.

Lipid alterations and subtyping maker discovery of lung cancer based on nontargeted tissue lipidomics using liquid chromatography-mass spectrometry.

High morbidity and mortality are still associated with lung cancer, especially non-small cell lung cancer (NSCLC). Although several studies showed abnormality in lung cancer lipidome, the underlying mechanism remains unclear. Therefore, a marker for early diagnosis of NSCLC is highly needed. In this study, a nontargeted lipidomics approach based on liquid chromatography-mass spectrometry was used to analyze the lung tumor tissue (LCT) lipidome to investigate the characteristics of lipid metabolism alterations in lung cancer tissues and find suitable lipid markers for lung cancer and its subtypes. Our results revealed that the most prominent alterations in LCT were the decrease of free fatty acid (FFA) and increase of triglyceride compared with distal noncancerous tissue (DNT). We also identified and verified the combinational lipid markers which can discriminate malignant from benign tissue as well as different NSCLC subtypes. These results not only provide hints in the lipid metabolism dysregulations between malignant and benign tissues but also define the combinational lipid markers to aid clinical diagnosis of lung cancer and its subtypes.

Association between TP53 gene deletion and protein expression in esophageal squamous cell carcinoma and its prognostic significance.

The aim of the present study was to investigate the association between tumor protein 53 (TP53) gene deletion and protein expression and clinical features in esophageal squamous cell carcinoma (ESCC), and to evaluate the predictive value of these two characteristics in the prognosis of ESCC. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were performed to detect the expression of p53 protein and gene deletion in ESCC tissue samples from different ethnic groups in Xinjiang, in order to analyze their association with clinicopathological characteristics and patient prognosis, as well as the sensitivity and specificity of the two methods. In addition, the results were further validated by tissue microarray from a different region. The positive rate of p53 protein expression was 54.5% (201/369) in the multi-ethnic group, and was significantly different between sex (P=0.026) and between tumor differentiation groups (P=0.032). FISH demonstrated that the TP53 gene deletion rate was 31.8% (68/214), which was significantly different between different tumor differentiation (P=0.002), lymph node metastasis (P=0.005) and vascular invasion (P<0.001) groups. The survival rate of patients with TP53 gene deletion was significantly lower than those without TP53 gene deletion (P<0.05). The positive rate of p53 protein expression in the tissue microarray was 58.1% (68/117), which was significantly different between the depth of invasion groups (P=0.011). The TP53 gene deletion rate was 47.9% (56/117), which significantly differed according to lymph node metastasis (P=0.003) and TNM stage (P=0.01). In addition, the total concordance rates of the two methods were 60.3 and 64.1%, respectively. There were also significant differences in the positive rate of TP53 gene deletion and protein expression in different stages of ESCC (P<0.05), which increased gradually with the progression of ESCC. The deletion of the TP53 gene in esophageal cancer was associated with poor prognosis and may be an important biomarker for evaluating the prognosis of patients with ESCC. The combination of FISH and IHC methods could significantly improve the detection rate of TP53 gene abnormalities and the accuracy of prognostic assessment of ESCC.

[Pulmonary nodule detection method based on convolutional neural network].

A method was proposed to detect pulmonary nodules in low-dose computed tomography (CT) images by two-dimensional convolutional neural network under the condition of fine image preprocessing. Firstly, CT image preprocessing was carried out by image clipping, normalization and other algorithms. Then the positive samples were expanded to balance the number of positive and negative samples in convolutional neural network. Finally, the model with the best performance was obtained by training two-dimensional convolutional neural network and constantly optimizing network parameters. The model was evaluated in Lung Nodule Analysis 2016(LUNA16) dataset by means of five-fold cross validation, and each group's average model experiment results were obtained with the final accuracy of 92.3%, sensitivity of 92.1% and specificity of 92.6%.Compared with other existing automatic detection and classification methods for pulmonary nodules, all indexes were improved. Subsequently, the model perturbation experiment was carried out on this basis. The experimental results showed that the model is stable and has certain anti-interference ability, which could effectively identify pulmonary nodules and provide auxiliary diagnostic advice for early screening of lung cancer.

High MLL2 expression predicts poor prognosis and promotes tumor progression by inducing EMT in esophageal squamous cell carcinoma.

BACKGROUND: MLL2 has been identified as one of the most frequently mutated genes in a variety of cancers including esophageal squamous cell carcinoma (ESCC). However, its clinical significance and prognostic value in ESCC has not been elucidated. In the present study, we aimed to investigate the expression and role of MLL2 in ESCC. METHODS: Immunohistochemistry (IHC) and qRT-PCR were used to examine the expression profile of MLL2. Kaplan-Meier survival analysis and univariate and multivariate Cox analyses were used to investigate the clinical and prognostic significance of MLL2 expression in Kazakh ESCC patients. Furthermore, to evaluate the biological function of MLL2 in ESCC, we applied the latest gene editing technique CRISPR/Cas9 to knockout MLL2 in ESCC cell line Eca109. MTT, colony formation, flow cytometry, scratch wound-healing and transwell migration assays were performed to investigate the effect of MLL2 on ESCC cell proliferation and migration. The correlation between MLL2 and epithelial-mesenchymal transition (EMT) was investigated by Western blot assay in vitro and IHC in ESCC tissue, respectively. RESULTS: Both mRNA and protein expression levels of MLL2 were significantly overexpressed in ESCC patients. High expression of MLL2 was significantly correlated with TNM stage (P = 0.037), tumor differentiation (P = 0.032) and tumor size (P = 0.035). Kaplan-Meier survival analysis showed that patients with low MLL2 expression had a better overall survival than those with high MLL2 expression. Multivariate Cox analysis revealed that lymph node metastasis and tumor differentiation were independent prognostic factors. Knockout of MLL2 in Eca109 inhibited cell proliferation and migration ability, induced cell cycle arrest at G1 stage, but it had no significant effect on apoptosis. In addition, knockout of MLL2 could inhibit EMT by up-regulation of E-Cadherin and Smad7 as well as down-regulation of Vimentin and p-Smad2/3 in ESCC cells. In cancer tissues, the expression of E-Cadherin was negatively correlated with MLL2 expression while Vimentin expression was positively correlated with MLL2 expression. CONCLUSION: Our results indicate that overexpression of MLL2 predicts poor clinical outcomes and facilitates ESCC tumor progression, and it may exert oncogenic role via activation of EMT. MLL2 may be used as a novel prognostic factor and therapeutic target for ESCC patients.

RNF113A promotes the proliferation, migration and invasion, and is associated with a poor prognosis of esophageal squamous cell carcinoma.

Ring finger protein 113A (RNF113A) possesses a C3HC4 zinc finger domain and this domain is found in E3 ubiquitin ligase and is involved in tumorigenesis. To date, and at least to the best of our knowledge, there are no studies available which have investigated RNF113A in cancer. Thus, this study aimed to explore the role of RNF113A in the development of esophageal squamous cell carcinoma (ESCC). For this purpose, paraffin-embedded samples from 117 patients with ESCC were selected, as well as 41 pairs of fresh-frozen ESCC and adjacent normal tissue samples. RNF113A expression was examined by immunohistochemistry and reverse transcription-quantitative PCR (RT-qPCR). RNF113A was overexpressed or silenced in the EC9706 and Eca109 cells. The cells were examined for cell cycle progression, apoptosis, invasiveness and migration. Xenograft tumors were also created in mice using the Eca109 cells. Tumor differentiation (P=0.008) and T classification (P<0.001) were found to be significantly associated with RNF113A expression. No statistically significant association was observed between RNF113A expression and sex, age, histological type, tumor location and lymph node metastasis (N classification). Kaplan-Meier analysis revealed that the patients with ESCC with ahigh expression of RNF113A had a lower survival rate than those with a low expression (P=0.002). Multivariate analysis revealed that RNF113A expression (HR=2.406; 95% CI, 1.301-4.449, P=0.005) was independently associated with overall survival in patients with ESCC. The overexpression of RNF113A promoted proliferation, migration, and invasiveness of ESCC cell lines in vitro, and RNF113A silencing reversed these malignant behaviors. RNF113A knockdown inhibited tumor growth in vivo. Thus, these results indicate that RNF113A promotes the proliferation, migration and invasiveness of ESCC cell lines. RNF113A expression in ESCC is this associated with a poor prognosis of affected patients.

Expression, prognosis and functional role of Thsd7a in esophageal squamous cell carcinoma of Kazakh patients, Xinjiang.

Thsd7a (Thrombospondin type 1 domain containing 7a) is a critical transmembrane protein. Studies have indicated that Thsd7a was associated with cytoskeletal organization, cell migration and filopodia formation. However, the involvement of Thsd7a remains elusive in human Esophageal Squamous Cell Carcinoma (ESCC). Consequently, immunohistochemistry and reverse transcription-polymerase chain reaction were utilized to study the correlation between the expression of Thsd7a and clinical-pathological characteristics. The influence of Thsd7a on apoptosis, cell proliferating activity, cell cycle, migratory and invasive capacity was determined in Eca 109 and EC 9706 cell lines in vitro. And the influence on proliferating activity was testified using naked mice model in vivo. In addition, the potential molecular mechanism was tested by microarray. It was discovered that there is a certain correlation between Thsd7a and the Kazakh ESCC. By knocking out Thsd7a, the invasion, migration and proliferation could be decreased. And it could also arrest the cell cycle at G1 phase and increase the apoptosis rate. It was further verified that Thsd7a had obvious effect on proliferation in naked mice with xenograft of Eca109 cells. Finally, it was uncovered by microarray analysis that a variety of tumor genes and pathways related to Thsd7a. Together, it was demonstrated that Thsd7a might have a certain degree of carcinogenesis in ESCC.

Metabolomic profiling reveals potential biomarkers in esophageal cancer progression using liquid chromatography-mass spectrometry platform.

Esophageal cancer (EC) is one of the most common malignancies with poor prognosis. Metabolomics has been shown to be a powerful approach to discover the potential biomarkers for cancer diagnosis and prognosis. The goal of this study is to screen potential biomarkers for early diagnosis and prognosis. In this study, 40 tissue samples and the corresponding control samples from the same esophageal squamous cell carcinoma (ESCC) patients were analyzed by liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. 20 potential diagnostic biomarkers were selected. Moreover, 9 metabolites were found to be closely correlated with the pathological feature such as local invasion, lymphatic metastasis and postoperative survival time. Glutamate was correlated with local invasion of tumor, and oleic acid, LysoPC(15:0), uracil, inosine and choline were closely related with the lymphatic metastasis, while glutamine, kynurenine, serine and uracil were related with postoperative survival time. The results indicated that the potential biomarkers discovered by metabolomics could reflect the metabolic characterization of ESCC, and offers a novel approach for early diagnosis, assessment and prognosis of the disease.

Partition-Defective 3 (PARD3) Regulates Proliferation, Apoptosis, Migration, and Invasion in Esophageal Squamous Cell Carcinoma Cells.

BACKGROUND Altered expression of partition-defective 3 (PARD3), a polarity-related gene associated with oncogenesis, has been identified in some cancers, but the role of PARD3 in esophageal squamous cell carcinoma (ESCC) remains unclear. MATERIAL AND METHODS PARD3 expression in Eca109 cells was silenced using siRNA and overexpressed using an expression vector. We investigated the role of PARD3 in ESCC growth and motility to evaluate its potential role in ESCC. Transwell assay was used to evaluated cell migration and invasion. PARD3 protein expression was assessed by Western blot. RESULTS PARD3 overexpression promoted apoptosis, impaired proliferation, and inhibited cell migration and invasion in Eca109 cells, while PARD3 silencing promoted proliferation and increased migration and invasion. Overexpression of PARD3 exerted its antitumor activity in vitro by impairing cell proliferation, inducing apoptosis, and inhibiting migration and invasion of Eca109 cells, suggesting that PARD3 might play a tumor suppressor role in ESCC. CONCLUSIONS Overexpression of PARD3 could be a promising new therapeutic intervention against ESCC.