Effectiveness and safety of combined nimotuzumab and S-1 chemotherapy with concurrent radiotherapy for locally advanced esophageal cancer in malnourished and elderly patients: A prospective phase II study.

Objective: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal cancer. However, this treatment is associated with substantial toxicity, and most malnourished or elderly patients are unable to complete this therapy. Therefore, there is a need for a more suitable radiotherapy combination regimen for this population. This study was aimed to evaluate the efficacy and safety of a combination regimen comprising chemotherapy with nimotuzumab and S-1 and concurrent radiotherapy for patients with fragile locally advanced esophageal cancer with a high Nutritional Risk Screening 2002 (NRS-2002) score. Methods: Eligible patients with unresectable esophageal carcinoma who had an NRS-2002 score of 2 or higher were enrolled. They were treated with S-1 and nimotuzumab with concurrent radiotherapy, followed by surgery or definitive radiotherapy. The primary endpoint was the locoregional control (LRC) rate. Results: A total of 55 patients who met the study criteria were enrolled. After completion of treatment, surgery was performed in 15 patients and radiotherapy was continued in 40 patients. The median follow-up period was 33.3 [95% confidence interval (95% CI), 31.4-35.1)] months. The LRC rate was 77.2% (95% CI, 66.6%-89.4%) at 1 year in the entire population. The overall survival (OS) rate and event-free survival (EFS) rate were 57.5% and 51.5% at 3 years, respectively. Surgery was associated with better LRC [hazard ratio (HR)=0.16; 95% CI, 0.04-0.70; P=0.015], OS (HR=0.19; 95% CI, 0.04-0.80; P=0.024), and EFS (HR=0.25; 95% CI, 0.08-0.75; P=0.013). Most adverse events were of grade 1 or 2, and no severe adverse events occurred. Conclusions: For malnourished or elderly patients with locally advanced esophageal cancer, radiotherapy combined with nimotuzumab and S-1 is effective and has a good safety profile.

[TRIP13 Enhances Radioresistance of Lung Adenocarcinoma Cells 
through the Homologous Recombination Pathway].

BACKGROUND: Radiation therapy is one of the most common treatments for non-small cell lung cancer (NSCLC). However, the insensitivity of some tumor cells to radiation is one of the major reasons for the poor efficacy of radiotherapy and the poor prognosis of patients, and exploring the underlying mechanisms behind radioresistance is the key to solving this clinical challenge. This study aimed to identify the molecules associated with radioresistance in lung adenocarcinoma (LUAD), identified thyroid hormone receptor interactor 13 (TRIP13) as the main target initially, and explored whether TRIP13 is related to radioresistance in LUAD and the specific mechanism, with the aim of providing theoretical basis and potential targets for the combination therapy of LUAD patients receiving radiotherapy in the clinic. METHODS: Three datasets, GSE18842, GSE19188 and GSE33532, were selected from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (|log FC|>1.5, P<0.05) in each of the three datasets using the R 4.1.3 software, and then Venn diagram was used to find out the differentially expressed genes common to the three datasets. The screened differential genes were then subjected to protein-protein interaction (PPI) analysis and module analysis with the help of STRING online tool and Cytoscape software, and survival prognosis analysis was performed for each gene with the help of Kaplan-Meier Plotter database, and the TRIP13 gene was identified as the main molecule for subsequent studies. Subsequently, the human LUAD cell line H292 was irradiated with multiple X-rays using a sub-lethal dose irradiation method to construct a radioresistant cell line, H292DR. The radioresistance of H292DR cells was verified using cell counting kit-8 (CCK-8) assay and clone formation assay. The expression levels of TRIP13 in H292 and H292DR cells were measured by Western blot. Small interfering RNA (siRNA) was used to silence the expression of TRIP13 in H292DR cells and Western blot assay was performed. The clone formation ability and migration ability of H292DR cells were observed after TRIP13 silencing, followed by the detection of changes in the expression levels of proteins closely related to homologous recombination, such as ataxia telangiectasia mutated (ATM) protein. RESULTS: Screening of multiple GEO datasets, validation of external datasets and survival analysis revealed that TRIP13 was highly expressed in LUAD and was associated with poor prognosis in LUAD patients who had received radiation therapy. And the results of gene set enrichment analysis (GSEA) of TRIP13 suggested that TRIP13 might be closely associated with LUAD radioresistance by promoting homologous recombination repair after radiation therapy. Experimentally, TRIP13 expression was found to be upregulated in H292DR, and silencing of TRIP13 was able to increase the sensitivity of H292DR cells to radiation. CONCLUSIONS: TRIP13 is associated with poor prognosis in LUAD patients treated with radiation, possibly by promoting a homologous recombination repair pathway to mediate resistance of LUAD cells to radiation.

S-1-based concurrent chemoradiotherapy plus nimotuzumab in patients with locally advanced esophageal squamous cell carcinoma who failed neoadjuvant therapy: a real-world prospective study.

PURPOSE: This prospective study in a real-world setting investigated the feasibility and safety of S-1 plus nimotuzumab (S-1-Nimo) based concurrent chemoradiotherapy (CCRT) in locally advanced esophageal squamous cell carcinoma (LA-ESCC) patients who failed to neoadjuvant chemotherapy or chemoimmunotherapy. METHODS: LA-ESCC patients who failed to converse to resectable disease after neoadjuvant chemotherapy or chemoimmunotherapy were enrolled to receive the 4-week S-1-Nimo regimen of radiotherapy (40 Gy in 20 fractions, 5 days per week), S-1 chemotherapy, and nimotuzumab. Then, after surgical assessments, patients evaluated as resectable disease received surgery; patients with unresectable disease continued to receive definitive radiotherapy (50-60 Gy in 25-30 fractions, 5 days per week) concurrently with S-1-Nimo. The primary endpoint was event-free survival (EFS). RESULTS: Sixty-four patients were enrolled and evaluated. The median follow-up time was 23.2 months. Median EFS was 9.6 (95% confidence interval [CI], 7.1-14.0) months, with an estimated 2-year EFS rate of 24.2%. The median overall survival (OS) and the estimated OS rate at 2 years were 13.4 (95% CI, 10.3-17.5) months and 31.2%, respectively. Twelve underwent surgery, with a surgical conversion rate of 18.8% and an R0 resection rate of 100.0%. Subgroup analysis identified the significantly prolonged EFS and OS in patients who experienced radical surgery (median EFS, not reached vs. 8.7 months; p = .0117. median OS, 24.9 vs. 10.6 months; p = .0205) as compared to those treated with CCRT. Of 64 patients, grade 3 adverse events mainly included radiation esophagitis (4.7%), anemia (1.6%), and thrombocytopenia (1.6%). CONCLUSION: The study demonstrated the reasonable efficacy and promising safety of the S-1-Nimo-based CCRT in LA-ESCC patients with failure to neoadjuvant chemotherapy or chemoimmunotherapy.

Relationship between NUDT21 mediated alternative polyadenylation process and tumor.

Alternative polyadenylation (APA) is a molecular process that generates diversity at the 3' end of RNA polymerase II transcripts from over 60% of human genes. APA and microRNA regulation are both mechanisms of post-transcriptional regulation of gene expression. As a key molecular mechanism, Alternative polyadenylation often results in mRNA isoforms with the same coding sequence but different lengths of 3' UTRs, while microRNAs regulate gene expression by binding to specific mRNA 3' UTRs. Nudix Hydrolase 21 (NUDT21) is a crucial mediator involved in alternative polyadenylation (APA). Different studies have reported a dual role of NUDT21 in cancer (both oncogenic and tumor suppressor). The present review focuses on the functions of APA, miRNA and their interaction and roles in development of different types of tumors.NUDT21 mediated 3' UTR-APA changes can be used to generate specific signatures that can be used as potential biomarkers in development and disease. Due to the emerging role of NUDT21 as a regulator of the aforementioned RNA processing events, modulation of NUDT21 levels may be a novel viable therapeutic approach.

CTCs Detection and Whole-exome Sequencing Might Be Used to Differentiate Benign and Malignant Pulmonary Nodules.

BACKGROUND: Low-density computed tomography (LDCT) improved early lung cancer diagnosis but introduces an excess of false-positive pulmonary nodules data. Hence, accurate diagnosis of early-stage lung cancer remains challenging. The purpose of the study was to assess the feasibility of using circulating tumour cells (CTCs) to differentiate malignant from benign pulmonary nodules. METHODS: 122 patients with suspected malignant pulmonary nodules detected on chest CT in preparation for surgery were prospectively recruited. Peripheral blood samples were collected before surgery, and CTCs were identified upon isolation by size of epithelial tumour cells and morphological analysis. Laser capture microdissection, MALBAC amplification, and whole-exome sequencing were performed on 8 samples. The diagnostic efficacy of CTCs counting, and the genomic variation profile of benign and malignant CTCs samples were analysed. RESULTS: Using 2.5 cells/5 mL as the cut-off value, the area under the receiver operating characteristic curve was of 0.651 (95% confidence interval: 0.538-0.764), with a sensitivity and specificity of 0.526 and 0.800, respectively, and positive and negative predictive values of 91.1% and 30.3%, respectively. Distinct sequence variations differences in DNA damage repair-related and driver genes were observed in benign and malignant samples. TP53 mutations were identified in CTCs of four malignant cases; in particular, g.7578115T>C, g.7578645C>T, and g.7579472G>C were exclusively detected in all four malignant samples. CONCLUSIONS: CTCs play an ancillary role in the diagnosis of pulmonary nodules. TP53 mutations in CTCs might be used to identify benign and malignant pulmonary nodules.

Impact of the Extent of Thyroidectomy on Quality of Life in Differentiated Thyroid Cancer Survivors: A Propensity Score Matched Analysis.

PURPOSE: As most thyroid cancer patients survive for more than ten years, it has become increasingly important to understand whether the different surgery types have any effect on the quality of life (QoL) of patients. PATIENTS AND METHODS: Using observational data from head and neck surgery at the Sichuan Cancer Hospital in China, three scoring methods - sum scoring, domain-based scoring and IRT-based scoring, were employed to measure the QoL in differentiated thyroid cancer (DTC) patients and a propensity score matched analysis performed to explore the impact of surgery type on QoL as measured by the Treatment of Cancer Quality of Life core Questionnaire version 3.0 (EORTC QLQ-C30) and a disease-specific health-related quality of life questionnaire (THYCA-QoL). RESULTS: No statistically significant patient QoL differences were found between the two surgery types regardless of which questionnaire was used and which scoring method was used (, using the EORTC QLQ-C30 and the sum scoring; , using the EORTC QLQ-C30 and the domain-based scoring; and , using the EORTC QLQ-C30 and the IRT-based scoring; , using the THYCA-QoL and the sum scoring; , using the THYCA-QoL and the domain-based scoring; and , using the THYCA-QoL and the IRT-based scoring). CONCLUSION: This study confirmed that the surgery type (hemithyroidectomy or total thyroidectomy) for DTC patients did not appear to influence their general QoL.

A clinicopathologic analysis of microscopic extension in small cell lung cancer and lung adenocarcinoma: Determination of clinical target volume with precise radiotherapy.

PURPOSE: The identification of the clinical target volume (CTV) is particularly important in the precise radiotherapy of lung cancer. The purpose of this study was to determine the extension margin from gross tumor volume (GTV) to CTV in primary small cell lung cancer (SCLC) and lung adenocarcinoma (ADC) by microscopic extension (ME). MATERIAL AND METHODS: The data of 25 cases of SCLC and 29 cases of ADC from August 2015 to August 2020 were analyzed. The measurement of tumor size between preoperative thoracic computed tomography (CT) and postoperative macroscopic specimens was compared, and the ME range of tumor cells was measured under a microscope to determine its correlation with clinical features and pathological manifestations. RESULTS: A total of 217 slides were examined, corresponding to 103 slides for SCLC and 114 slides for ADC. The radiologic sizes of the tumors in SCLC and ADC were 12.8 and 7.9 mm, respectively (p = 0.09), and the macroscopic sizes were 12.5 and 8.5 mm, respectively (p = 0.07). There was a significant correlation between the radiologic and macroscopic size of the same tumor sample (r = 0.886). Compared with ADC, more SCLC tumor cells infiltrated through vascular or lymphatic dissemination (16% vs. 9%, p = 0.047). The mean ME value was 2.81 mm for SCLC and 2.02 mm for ADC (p = 0.012). To take into account 95% of the ME, a margin of 8 and 7.7 mm must be expanded for SCLC and ADC, respectively. The ME value of the tumor was related to the presence of atelectasis, the location of the tumor, and the Ki-67 cell proliferation index. CONCLUSION: The GTV of the tumor was contoured according to CT images, which was basically consistent with the actual tumor size. The GTVs of SCLC and ADC should be expanded by 8 and 7.7 mm, respectively, to fully cover the subclinical lesions in 95% of cases.

High Expression of Cancer-IgG Is Associated With Poor Prognosis and Radioresistance via PI3K/AKT/DNA-PKcs Pathway Regulation in Lung Adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is the dominant type of lung neoplasms, and radiotherapy is its mainstay treatment, yet poor prognosis caused by radioresistance remains problematic. Cancer-derived immunoglobulin G (cancer-IgG) has been detected in multiple cancers and plays important roles in carcinogenesis. This study aimed to demonstrate that cancer-IgG is associated with poor prognosis of LUAD and to identify its role in radioresistance. METHODS: Cancer-IgG expression was detected by immunohistochemistry from 56 patients with stage III LUAD and by western blot and immunofluorescence in LUAD cell lines and in a human bronchial epithelial cell line. The effects of cancer-IgG silencing on the proliferation and apoptosis of PC9 and H292 cells were evaluated by plate cloning and apoptosis assay; the effects of cancer-IgG silencing on DNA damage repair ability and radiosensitivity were evaluated by colony-forming assay, γH2AX immunofluorescence, and neutral comet assay. Finally, we used the protein phosphorylation microarray and western blot to explore mechanisms involving cancer-IgG that increased radioresistance. RESULTS: Cancer-IgG is widely expressed in stage III LUAD, and the overall survival and disease-free survival of patients with positive expression are notably lower than those of patients with negative expression, indicating the associations between cancer-IgG and poor prognosis as well as radioresistance. The expression of cancer-IgG in the four LUAD cell lines was located mainly on the cell membrane and cytoplasm and not in the normal lung epithelial cell. Knockdown of cancer-IgG in PC9 and H292 cells resulted in increased apoptosis and negatively affected cancer cell proliferation. After irradiation, silencing of cancer-IgG showed a decrease in colonies as well as increases in the Olive tail moment and γH2AX foci in nucleus, indicating that the knockdown of cancer-IgG resulted in a decrease in the damage repair ability of DNA double-strand breaks in LUAD cells and an enhanced radiosensitivity. The expression of p-AKT, p-GSK3ß, and p-DNA-PKcs decreased in the knockdown group after radiotherapy, suggesting that cancer-IgG could affect radiotherapy resistance by mediating double-strand breaks damage repair in LUAD cells through the PI3K/AKT/DNA-PKcs pathway. CONCLUSIONS: This study revealed that cancer-IgG regulates PI3K/AKT/DNA-PKcs signaling pathways to affect radioresistance of LUAD and associated with poor prognosis.

A signature of tumor DNA repair genes associated with the prognosis of surgically-resected lung adenocarcinoma.

BACKGROUND: Lung cancer has the highest morbidity and mortality of cancers worldwide. Lung adenocarcinoma (LUAD) is the most common pathological subtype of lung cancer and surgery is its most common treatment. The dysregulated expression of DNA repair genes is found in a variety of cancers and has been shown to affect the origin and progression of these diseases. However, the function of DNA repair genes in surgically-treated LUAD is unclear. METHODS: We sought to determine the association between the signature of DNA repair genes for patients with surgical LUAD and their overall prognosis. We obtained gene expression data and corresponding clinical information of LUAD from The Cancer Genome Atlas (TCGA) database. The differently expressed DNA repair genes of surgically-treated LUAD and normal tissues were identified using the Wilcoxon rank-sum test. We used uni- and multivariate Cox regression analyses to shrink the aberrantly expressed genes, which were then used to construct the prognostic signature and the risk score formula associated with the independent prognosis of surgically-treated LUAD. We used Kaplan-Meier and Cox hazard ratio analyses to confirm the diagnostic and prognostic roles. Two validation sets (GSE31210 and GSE37745) were downloaded from the Gene Expression Omnibus (GEO) and were used to externally verify the prognostic value of the signature. OSluca online database verifies the hazard ratio for the DNA repair genes by which the signature was constructed. We investigated the correlation between the signature of the DNA repair genes and the clinical parameters. The potential molecular mechanisms and pathways of the prognostic signature were explored using Gene Set Enrichment Analysis (GSEA). RESULTS: We determined the prognostic signature based on six DNA repair genes (PLK1, FOXM1, PTTG1, CCNO, HIST3H2A, and BLM) and calculated the risk score based on this formula. Patients with surgically-treated LUAD were divided into high-risk and low-risk groups according to the median risk score. The high-risk group showed poorer overall survival than the low-risk group; the signature was used as an independent prognostic indicator and had a greater prognostic value in surgically-treated LUAD. The prognostic value was replicated in GSE31210 and GSE37745. OSluca online database analysis shows that six DNA repair genes were associated with poor prognosis in most lung cancer datasets. The prognostic signature risk score correlated with the pathological stage and smoking status in surgically-treated LUAD. The GSEA of the risk signature in high-risk patients showed pathways associated with the cell cycle, oocyte meiosis, mismatch repair, homologous recombination, and nucleotide excision repair. CONCLUSIONS: A six-DNA repair gene signature was determined using TCGA data mining and GEO data verification. The gene signature may serve as a novel prognostic biomarker and therapeutic target for surgically-treated LUAD.

[Expression and Clinical Significance of Cancer-derived Immunoglobulin G in Non-small Cell Lung Cancer by Bioinformatics and Immunohistochemistry].

BACKGROUND: It was believed that immunoglobulin G (IgG) was synthesized only by B cells. However, in recent years, researchers have found that a variety of cancer cells can also synthesize IgG (cancer-IgG) which promote the development of tumors. This study analyzed the expression and clinical significance of cancer-IgG in non-small cell lung cancer (NSCLC), and initially explored its mechanism. METHODS: The expression of IgG1 heavy chain gamma 1 (IGHG1) and cancer-IgG were detected by bioinformatics and immunohistochemistry in NSCLC; The gene set enrichment analysis (GSEA) method was used to explore the signaling pathways involved in IGHG1 regulation. RESULTS: The expression level of cancer-IgG in NSCLC was significantly higher than that in normal tissues. The high expression group had a poor prognosis and was associated with clinical stage (P=0.042), T stage (P=0.044) and metastasis (P=0.007). GSEA analysis showed that IGHG1 was associated with cell adhesion, cytokine interaction and chemokine signaling pathway. CONCLUSIONS: High expression of cancer-IgG in NSCLC is a poor prognosis factor, which may be related to the promotion of tumor invasion and metastasis.

Optoelectronic and magnetic properties of Mn-doped and Mn-C co-doped Wurtzite ZnS: a first-principles study.

In order to meet the requirement of spintronic and optoelectronic, we have systematically investigated the effect of Mn doping and co-doping of Mn with C on the electronic, magnetic and optical properties of wurtzite zinc sulfide (ZnS) using first principle calculations. Our results find that single Mn doping alters the non-magnetic ZnS to a magnetic one and keeps its semiconducting and a semiconductor to half-metal transition is observed for Mn-C co-doping. Furthermore, an antiferromagnetic (AFM) and ferromagnetic (FM) ground states are favorable for Mn-doped and Mn-C co-doped system, respectively. Additionally, the optical properties of our studied configuration have been calculated in terms of real and imaginary parts of the complex dielectric function, absorption coefficient, and reflectivity. The absorption edge shifts slightly toward lower energy and intensity of the main peak become weak for single Mn doping, and a sharp peak at low energy is observed for the Mn-C co-doping. The analysis of optical absorption of Mn ions doped system shows the blue- and red-shifts of the d-d transition in the AFM and FM coupled of Mn ions doped configuration, respectively which is in good agreement with the experimental observations. The improved magnetic and optical properties of Mn-C co-doped ZnS shed light on the future application of such kind of materials in spintronic and optoelectronic devices such as remote sensing and photovoltaics.

Ab initio study of optoelectronic and magnetic properties of Mn-doped ZnS with and without vacancy defects.

The effect of vacancy defects on optoelectronic and magnetic properties of Mn-doped ZnS have been systematically investigated using first principle approaches. A single Mn substitution at Zn site induces a spin-polarized ground state in pure ZnS with total magnetization 5 [Formula: see text]. Our results for magnetic coupling show that the coupling between Mn spins in pure Mn doped ZnS is antiferromagnetic under the super-exchange mechanism. The existence of native defects has a great influence on the magnetic ground state of Mn-doped ZnS. In particular, a p -type defect such as Zn vacancy play a crucial role in stabilizing ferromagnetic ground state while n-type defect, such as S vacancy, has no effect on the magnetic ground state i.e. the interaction between two Mn spins with S-vacancy remain antiferromagnetic. Furthermore, optical properties such as dielectric functions, absorption coeffiecients, reflectivity and transmissitivity for Mn doped systems with and without vacancy defect were also studied, and we found that an absorption peak was obtained in the infrared region which is attributed to the defect states introduced by Zn vacancy in the system. In a S-vacancy defect system, the peaks in the near infrared and visible region are due to donor states introduced by S vacancy defect and these peaks are produced by electrons flipping from a spin up state to a spin down state. Finally, we also correlated the magnetic interactions with the d-d optical transition in pure Mn-doped ZnS and found that the d-d transitions during optical absorptions are red shifted and blue shifted in FM and AFM coupled Mn ions pair, which is in good agreement with the experimental observations. This study may help to understand the behavior of optical and magnetic properties of DMS under vacancy defects.

Dual-Color Lasing Lines from EMPs in Diluted Magnetic Semiconductor CdS:NiI Structure.

Have one ever seen a semiconductor that can issue two-color lasing lines? The diluted magnetic semiconductor (DMS) can do this. Here, we have observed dual lasing lines of 530 nm and 789 nm from a DMS structure of CdS:NiI, in which the excitonic magnetic polaron (EMP) and localized excitonic magnetic polaron (LEMP) are excitations out of ferromagnetic (NiS) x nanocluster and NiI2 nanoclusters within CdS lattice; both of them could lead to the collective EMP state at high excitation and therein produce coherent emission lines simultaneously. This occurrence is due to the superposition of EMP near CdS bandedge and the combination of the charge-transfer band of (NiI) n cluster with the LEMP within CdS lattice by overcoming the strong electron correlation of NiI cluster in a DMS structure, evidenced also by ab initio calculation. This finding opens a way to understand the collective behaviour of spin-coupled excitons in DMS and to find novel applications in the spin-related quantum technology.