Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.

A Network Meta-Analysis of the Systemic Therapies in Unresectable Head and Neck Squamous Cell Carcinoma.

The current standard treatment for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) comprises concurrent radiotherapy (CRT) alongside platinum-based chemotherapy. However, innovative therapeutic alternatives are being evaluated in phase II/III randomized trials. This study employed a Bayesian network meta-analysis (NMA) using fixed effects to provide both direct and indirect comparisons of all existing treatment modalities for unresectable LASCCHN. METHODS: We referenced randomized controlled trials (RCTs) from January 2000 to July 2023 by extensively reviewing PubMed, EMBASE, and Web of Science databases, adhering to the Cochrane methodology. Relevant data, including summary estimates of overall survival (OS) and progression-free survival (PFS), were extracted from these selected studies and recorded in a predefined database sheet. Subsequently, we conducted a random effects network meta-analysis using a Bayesian framework. RESULTS: Based on the Surface Under the Cumulative Ranking (SUCRA) values, the league table organizes the various treatments for OS in the following order: IC + RT&MTT, MTT-CRT, IC + CRT&MTT, CRT, IC + CRT, MTT-RT, IC + MTT-RT, and RT. In a similar order, the treatments rank as follows according to the league table: IC + CRT&MTT, MTT-CRT, IC + CRT, IC + RT&MTT, CRT, IC + MTT-RT, MTT-RT, and RT. Notably, none of these treatments showed significant advantages over concurrent chemoradiotherapy. CONCLUSION: Despite concurrent chemoradiotherapy being the prevailing treatment for LASCCHN, our findings suggest the potential for improved outcomes when concurrent chemoradiotherapy is combined with targeted therapy or induction chemotherapy.

The current standard treatment for advanced head and neck cancer involves combining radiation therapy with chemotherapy. However, there are ongoing trials exploring alternative therapies. In this study, we conducted a comprehensive analysis of existing treatments using a statistical method called network meta-analysis. Our analysis included data from randomized controlled trials published between January 2000 and July 2023. We focused on overall survival and progression-free survival as key outcome measures. The results of our analysis showed that none of the alternative treatments demonstrated significant advantages over the standard concurrent chemoradiotherapy. Nevertheless, there is potential for improved outcomes when targeted therapy or induction chemotherapy is combined with concurrent chemoradiotherapy.

Comprehensive pan-cancer analysis of 33 human cancers reveals immunotherapeutic value of focal adhesion tyrosine kinase.

The immune environment in tumors is the key factor affecting the survival and immunotherapeutic response of patients. This research aimed to explore the underlying association between focal adhesion tyrosine kinase (FAK/PTK2) and cancer immunotherapy in 33 human cancers. Gene expression data and clinical features of 33 cancers were retrieved from the Cancer Genome Atlas Database. The immunotherapy cohorts included GSE67501, GSE78220, and IMVIGOR210, which were derived from the comprehensive gene expression database or from previous studies. Clinical parameters including patient age, gender, survival rate, and tumor stage were analyzed to evaluate the prognostic value of FAK/PTK2. FAK/PTK2 activity was detected by single-sample gene set enrichment analysis and used to compare the difference between FAK/PTK2 transcriptome and protein expression levels. To better understand the role of FAK/PTK2 in cancer immunotherapy, we analyzed its correlations with tumor microenvironment and with immune processes/elements (e.g., immune cell infiltration, immunosuppressants, and stimulants) and major histocompatible complexes. Potential pathways associated with FAK/PTK2 signaling in cancers were also explored. Correlations between FAK/PTK2 and 2 immunotherapeutic biomarkers (tumor mutation load and microsatellite instability) were studied. Finally, the 3 independent immunotherapy cohorts were used to study the relationship between FAK/PTK2 and immunotherapeutic response. Although FAK/PTK2 is not closely associated with age (13/33), gender (5/33), or tumor stage (5/33) in any of the studied human cancers, it has potential prognostic value for predicting patient survival. Consistency between FAK/PTK2 activity and expression exists in some cancers (3/33). Generally, FAK/PTK2 is robustly correlated with immune cell infiltration, immune modulators, and immunotherapeutic markers. Moreover, high FAK/PTK2 expression is significantly related to immune-relevant pathways. However, FAK/PTK2 is not significantly correlated with the immunotherapeutic response. Research on the immunotherapeutic value of FAK/PTK2 in 33 human cancers provides evidence regarding the function of FAK/PTK2 and its role in clinical treatment. However, given the use of a bioinformatics approach, our results are preliminary and require further validation.

Enzyme-catalyzed electrochemical aptasensor for ultrasensitive detection of soluble PD-L1 in breast cancer based on decorated covalent organic frameworks and carbon nanotubes.

BACKGROUND: Soluble programmed death-ligand 1 (sPD-L1) is critically involved in breast cancer recurrence and metastasis. However, the clinical application of highly sensitive sPD-L1 assays remains a challenge due to its low abundance in peripheral blood. To address this issue, for the first time, an enzyme-catalyzed electrochemical aptasensing platform was devised, incorporating covalent organic frameworks-gold nanoparticles-antibody-horseradish peroxidase (COFs-AuNPs-Ab-HRP) and polyethyleneimine-functionalized multiwalled carbon nanotubes (MWCNTs-PEI-AuNPs) for the highly specific and ultrasensitive detection of sPD-L1. RESULTS: MWCNTs-PEI-AuNPs possessed an extensive specific surface area and exhibited excellent electrical conductivity, facilitating the immobilization of aptamer and amplifying the signal. COFs modified with AuNPs not only amplified the electrical signal but also proffered a loading platform for the Ab and HRP. The favorable biocompatibility of COFs contributed to the preservation of enzyme activity and stability. HRP acted in synergy with hydrogen peroxide (H2O2) to catalyze the oxidation of hydroquinone (HQ) to benzoquinone (BQ). Subsequently, BQ underwent electrochemical reduction to HQ, inducing an enzymatic redox cycle that amplified the electrochemical signal and enhanced the sensitivity and selectivity of the detection method. The developed aptasensor displayed a liner range for sPD-L1 identification from 1 pg mL-1 to 100 ng mL-1 and the detection limit reached 0.143 pg mL-1 (S/N = 3). SIGNIFICANCE: Paving the way for clinical application, this strategy detected differences in sPD-L1 in cell supernatants and peripheral blood of breast cancer patients with higher sensitivity compared to commercial sPD-L1 ELISA kit. This work demonstrates significant potential in offering reference information for early diagnosis and disease surveillance of breast cancer.

circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a prevalent malignant tumor worldwide. Circular RNA (circRNA) is of great value in tumorigenesis progression. However, the mechanism of circFNDC3B in ESCC remains to be clarified. METHODS: Firstly, the circular characteristics of circFNDC3B were evaluated by Actinomycin D and RNase R measurements. The functions of circFNDC3B in ESCC cells were examined by CCK-8, EdU and flow cytometry. Subsequently, the molecular mechanism of circFNDC3B was explained using luciferase reporter gene detection. Finally, we constructed xenograft model to prove the role of circFNDC3B in vivo. RESULTS: Our study revealed that circFNDC3B was more stable than its linear RNA and prominently upregulated in ESCC. Functional findings suggested that silencing of circFNDC3B reduced the proliferation and enhanced apoptosis of ESCC cells in vitro. Meanwhile, knockdown of circFNDC3B attenuated tumor progression in vivo. Next, miR-370-3p/miR-136-5p was discovered to bind circFNDC3B. miR-370-3p/miR-136-5p reversed the promotive effect on cell proliferation and the inhibitory effect on cell apoptosis of circFNDC3B. MYO5A was a downstream target of miR-370-3p/miR-136-5p. CircFNDC3B served as a sponge for miR-370-3p/miR-136-5p and alleviated the prohibitory effect of miR-370-3p/miR-136-5p on MYO5A, which accelerated ESCC progression. CONCLUSION: circFNDC3B positively adjusted the MYO5A expression via spongy miR-370-3p/miR-136-5p, hence achieving the cancer-promoting effect on ESCC. circFNDC3B was a prospective diagnosis marker for ESCC.

Neoadjuvant chemoradiotherapy with capecitabine based regimen in locally advanced rectal cancer: A retrospective study.

Capecitabine-based neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer. The objective of this study is to analyze overall survival (OS), disease-free survival (DFS) and prognostic factors of patients with stage II to III rectal cancer treated with nCRT in our institution. Between March 2014 to June 2020, 121 locally advanced rectal cancer patients were retrospectively reviewed and analyzed. All of the enrolled patients were treated with capecitabine-based nCRT (pelvic radiotherapy: 45-50.4 Gy, 1.8 Gy/d plus concomitant capecitabine-based chemotherapy), total mesorectal excision surgery (surgery was carried out 8-12 weeks after the end of CRT), and capecitabine-based adjuvant chemotherapy. We examined the pathological complete response rate, 3-year OS, 3-year DFS and the other prognostic factors. Kaplan-Meier method and Log-rank test were used to estimate and compare survival rate. With a median follow-up of 36 months, 3-year DFS and 3-year OS was 74.4% and 83.2%, respectively. Among the 121 patients, 24 achieved pathological complete remission (19.8%). After multivariate analysis, ypTNM stage (TNM stage after neoadjuvant therapy) was significantly associated with DFS. Positive mesorectal fasciae (MRF) status on magnetic resonance imaging and ypTNM stage were significantly related to OS. CRT with capecitabine based regimen provides high rates of survival and sphincter preservation with acceptable toxicity. YpTNM stage was significantly associated with DFS; magnetic resonance imaging MRF status and ypTNM stage were significant factors for OS after multivariate analysis. Distant metastasis is the dominant mode of treatment failure, and it is crucial to optimize systemic treatment for newly diagnosed patients.

Predictive values of the hemoglobin, albumin, lymphocyte and platelet score (HALP) and the modified -Gustave Roussy immune score for esophageal squamous cell carcinoma patients undergoing concurrent chemoradiotherapy.

The hemoglobin, albumin, lymphocyte and platelet (HALP) score and the Gustave Roussy immune score (GRIm⁃Score) are prognostic markers in several types of malignant tumors. The prognostic values of HALP score and GRIm⁃Score in concurrent chemoradiotherapy for unresectable esophageal cancer remain unknown. METHODS: We enrolled 150 esophageal squamous cell carcinoma (ESCC) patients who underwent concurrent chemoradiotherapy in our institution between 2013 and 2018. The cutoff values for HALP, and GRIm⁃Score were defined by using receiver's operating characteristic curves. Survival was analyzed with the Kaplan- Meier method, with differences analyzed with the log-rank test. Multivariate Cox proportional-hazards models were used to evaluate the prognostic significance of HALP and GRIm for ESCC. RESULTS: HALP was significantly associated with the Zubrod ECOG WHO performance status, tumor location, and the clinical tumor, node, metastasis stage. Modified GRIm (mGRIm) was only significantly associated with metastasis / recurrence before radiotherapy (χ2 = 6.25). Univariate Cox regression analysis showed that higher mGRIm (HR 1.9 95%CI 1.3-2.9) and lower HALP (HR 2.4 95%CI 1.6-3.7) were all associated with worse OS. Multivariate COX analysis found that higher mGRIm score (HR 1.7 95%CI 1.1-2.6), and lower HALP score (HR 2 95%CI 1.3-3.2) were both independent risk factors of overall survival. The nomogram c-index in inside validation was 0.66. CONCLUSION: Both HALP and mGRIm are independent prognostic factors for patients with unresectable ESCC.

Necrotic related-lncRNAs: Prediction of prognosis and differentiation between cold and hot tumors in head and neck squamous cell carcinoma.

Treatment of head and neck squamous cell carcinoma (HNSCC) is a substantial clinical challenge due to the high local recurrence rate and chemotherapeutic resistance. This project seeks to identify new potential biomarkers of prognosis prediction and precision medicine to improve this condition. A synthetic data matrix for RNA transcriptome datasets and relevant clinical information on HNSCC and normal tissues was downloaded from the Genotypic Tissue Expression Project and The Cancer Genome Atlas (TCGA). The necrosis-associated long-chain noncoding RNAs (lncRNAs) were identified by Pearson correlation analysis. Then 8-necrotic-lncRNA models in the training, testing and entire sets were established through univariate Cox (uni-Cox) regression and Lasso-Cox regression. Finally, the prognostic ability of the 8-necrotic-lncRNA model was evaluated via survival analysis, nomogram, Cox regression, clinicopathological correlation analysis, and receiver operating characteristic (ROC) curve. Gene enrichment analysis, principal component analysis, immune analysis and prediction of risk group semi-maximum inhibitory concentration (IC50) were also conducted. Correlations between characteristic risk score and immune cell infiltration, immune checkpoint molecules, somatic gene mutations, and anti-cancer drug sensitivity were analyzed. Eight necrosis-associated lncRNAs (AC099850.3, AC243829.2, AL139095.4, SAP30L-AS1, C5orf66-AS1, LIN02084, LIN00996, MIR4435-2HG) were developed to improve the prognosis prediction of HNSCC patients. The risk score distribution, survival status, survival time, and relevant expression standards of these lncRNAs were compared between low- and high-risk groups in the training, testing and entire sets. Kaplan-Meier analysis showed the low-risk patients had significantly better prognosis. The ROC curves revealed the model had an acceptable predictive value in the TCGA training and testing sets. Cox regression and stratified survival analysis indicated that the 8 necrosis-associated lncRNAs were risk factors independent of various clinical parameters. We recombined the patients into 2 clusters through Consensus ClusterPlus R package according to the expressions of necrotic lncRNAs. Significant differences were found in immune cell infiltration, immune checkpoint molecules, and IC50 between clusters, suggesting these characteristics can be used to evaluate the clinical efficacy of chemotherapy and immunotherapy. This risk model may serve as a prognostic signature and provide clues for individualized immunotherapy for HNSCC patients.

Identification and verification of aging-related lncRNAs for prognosis prediction and immune microenvironment in patients with head and neck squamous carcinoma.

Aging is highly associated with tumor formation and progression. However, little research has explored the association of aging-related lncRNAs (ARLs) with the prognosis and tumor immune microenvironment (TIME) of head and neck squamous cell carcinoma (HNSCC). RNA sequences and clinicopathological data of HNSCC patients and normal subjects were downloaded from The Cancer Genome Atlas. In the training group, we used Pearson correlation, univariate Cox regression, least absolute shrinkage/selection operator regression analyses, and multivariate Cox regression to build a prognostic model. In the test group, we evaluated the model. Multivariate Cox regression was done to screen out independent prognostic factors, with which we constructed a nomogram. Afterward, we demonstrated the predictive value of the risk scores based on the model and the nomogram using time-dependent receiver operating characteristics. Gene set enrichment analysis, immune correlation analysis, and half-maximal inhibitory concentration were also performed to reveal the different landscapes of TIME between risk groups and to predict immuno- and chemo-therapeutic responses. The most important LINC00861 in the model was examined in HNE1, CNE1, and CNE2 nasopharyngeal carcinoma cell lines and transfected into the cell lines CNE1 and CNE2 using the LINC00861-pcDNA3.1 construct plasmid. In addition, CCK-8, Edu, and SA-ß-gal staining assays were conducted to test the biofunction of LINC00861 in the CNE1 and CNE2 cells. The signature based on nine ARLs has a good predictive value in survival time, immune infiltration, immune checkpoint expression, and sensitivity to multiple drugs. LINC00861 expression in CNE2 was significantly lower than in the HNE1 and CNE1 cells, and LINC00861 overexpression significantly inhibited the proliferation and increased the senescence of nasopharyngeal carcinoma cell lines. This work built and verified a new prognostic model for HNSCC based on ARLs and mapped the immune landscape in HNSCC. LINC00861 is a protective factor for the development of HNSCC.

Effectiveness of S-1-Based Chemoradiotherapy in Patients 70 Years and Older With Esophageal Squamous Cell Carcinoma: A Randomized Clinical Trial.

Importance: Double-agent intravenous chemotherapy concurrent with radiotherapy is the standard of care for patients with inoperable esophageal cancer. However, patients tend to tolerate intravenous chemotherapy less well with age and comorbidities. It is essential to find a better treatment modality that improves survival outcomes without reducing the quality of life. Objective: To evaluate the effectiveness of simultaneous integrated boost radiotherapy (SIB-RT) with concurrent and consolidated oral S-1 chemotherapy for patients aged 70 years and older with inoperable esophageal squamous cell carcinoma (ESCC). Design, Setting, and Participants: This multicenter, phase III randomized clinical trial was conducted between March 2017 and April 2020 in 10 centers in China. Patients with inoperable, locally advanced, clinical stage II to IV ESCC were enrolled and randomized to receive SIB-RT concurrent with and followed by oral S-1 chemotherapy (CRTCT group) or SIB-RT alone (RT group). Data analysis was completed on March 22, 2022. Interventions: In both groups, the planning gross tumor volume was administered with radiation dose of 59.92 Gy and the planning target volume was administered with radiation dose of 50.4 Gy, in 28 fractions each. In the CRTCT group, concurrent S-1 was administered on radiotherapy days, and consolidated S-1 was administered at 4 to 8 weeks after SIB-RT. Main Outcomes and Measures: The primary end point was overall survival (OS) of the intent-to-treat population. Secondary end points were progression-free survival (PFS) and toxicity profile. Results: A total of 330 patients (median [IQR] age, 75.5 [72-79] years; 220 [66.7%] male patients) were included, with 146 patients randomized to the RT group and 184 randomized to the CRTCT group. A total of 107 patients (73.3%) in the RT group and 121 patients (67.9%) in the CRTCT group were clinically diagnosed with stage III to IV disease. At the time of analysis of the 330 patients in the intent-to treat-population (March 22, 2022), OS was improved in the CRTCT group compared with the RT group at 1 year (72.2% vs 62.3%) and 3 years (46.2% vs 33.9%; log-rank P = .02). PFS was similarly improved in the CRTCT group compared with the RT group at 1 year (60.8% vs 49.3%) and 3 years (37.3% vs 27.9%; log-rank P = .04). There was no significant difference in the incidence of treatment-related toxic effects higher than grade 3 between the 2 groups. Grade 5 toxic effects occurred in each group, including 1 patient who experienced myelosuppression and 4 patients with pneumonitis in the RT group and 3 patients with pneumonitis and 2 patients with fever in the CRTCT group. Conclusions and Relevance: These findings suggest that oral S-1 chemotherapy administered with SIB-RT should be considered as an alternative treatment option for patients aged 70 years and older with inoperable ESCC, since it improved survival outcomes without additional treatment-related toxic effects compared with SIB-RT alone. Trial Registration: ClinicalTrials.gov Identifier: NCT02979691.

MRI-based clinical radiomics nomogram may predict the early response after concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma.

Objective: Tumor residue after concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients often predicts poor prognosis. Thus, the objective of this retrospective study is to develop a nomogram that combines magnetic resonance (MRI) radiomics features and clinical features to predict the early response of locally advanced nasopharyngeal carcinoma (LA-NPC). Methods: A total of 91 patients with LA-NPC were included in this study. Patients were randomly divided into training and validation cohorts at a ratio of 3:1. Univariate and multivariate analyses were performed on the clinical parameters of the patients to select clinical features to build a clinical model. In the training cohort, the Least Absolute Shrinkage and Selection Operator (LASSO) regression model was used to select radiomics features for construction of a radiomics model. The logistic regression algorithm was then used to combine the clinical features with the radiomics features to construct the clinical radiomics nomogram. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were drawn to compare and verify the predictive performances of the clinical model, radiomics model, and clinical radiomics nomogram. Results: Platelet lymphocyte ratio (PLR) and nasopharyngeal tumor volume were identified as independent predictors of early response in patients with locally advanced nasopharyngeal carcinoma. A total of 5502 radiomics features were extracted, from which 25 radiomics features were selected to construct the radiomics model. The clinical radiomics nomogram demonstrated the highest AUC in both the training and validation cohorts (training cohort 0.975 vs 0.973 vs 0.713; validation cohort 0.968 vs 0.952 vs 0.706). The calibration curve and DCA indicated good predictive performance for the nomogram. Conclusion: A clinical radiomics nomogram, which combines clinical features with radiomics features based on MRI, can predict early tumor regression in patients with LA-NPC. The performance of the nomogram is superior to that of either the clinical model or radiomics model alone. Therefore, it can be used to identify patients without CR at an early stage and provide guidance for personalized therapy.

Immune characteristics and genetic markers of esophageal cancer by single-cell analysis: implications for immunotherapy.

Background: Esophageal cancer (EC) is one of the most common cancers worldwide. The prognoses for patients with the same stage of EC can vary substantially. The progress of single-cell analysis technology has furthered the understanding of tumor heterogeneity. This paper aimed to apply single-cell analysis to explore the characteristics of the tumor environment of EC and provide a basis for personalized treatment. Methods: The latest gene expression data and clinical follow-up information of single-cell sequencing results of EC samples were downloaded from The Cancer Genome Atlas (TCGA) Genomic Data Commons (GDC) Application Programming Interface (API). A differential gene function analysis of the immune infiltration signature agents in the tumor microenvironment (TME) was performed using bioinformatics analytical methods, and potential molecular targets were sought. Results: We identified specific cell subsets in the EC and paracancerous samples, including panel cells, natural killer (NK) cells, exhausted cluster of differentiation (CD)8+ T cells, CD8+ memory T (Tcm) cells, and effector memory T (Tem) cells, including B cell enrichment in the cancer samples. Differences were detected between B cells and monocytes in stage II and III tumors, which may be related to RNA transcription and degradation. The CXCL8 protein was identified as a valid potential prognostic marker. Conclusions: Cell groups with homogenous cell surface markers exhibit intercellular variations that exert a considerable effect on cell function. Our study will contribute to the understanding of the TME and cellular heterogeneity in EC patients and serve as a valuable resource for in-depth exploration of the pathogenesis of EC and the identification of potential therapeutic targets in the future.

Psychological Burden of Patients with Head and Neck Cancer Undergoing Radiotherapy and Their Family Caregivers: A Cross-Sectional Survey.

Background: The consequences of Head and neck cancer (HNC) affect both the person who receives the diagnosis and their family caregivers (FCs). Objective: To investigate the psychological status of patients and their FCs, and the burden of the FCs during radiotherapy. Methods: This cross-sectional study was conducted with a questionnaire survey by convenience sampling method. Patients with HNC and their caregivers (both N = 85) from the radiotherapy department of our hospital were recruited between March 2021 and March 2022. The Hospital Anxiety and Depression Scale (HADS), the Chinese version of the Connor and Davidson Resilience Scale (CD-RISC), and the Zarit Burden Interview (ZBI) were used to assess the symptoms of anxiety and depression, psychological resilience, and the impact of care work, emotions and social lives of participants. Pearson's correlation analysis and a Mann-Whitney test were used to analyse the association between the HADS and the CD-RISC scores of the patients. Results: About half of the patients (56.47%) and the caregivers (62.35%) have had anxiety. The average HADS-Anxiety scores, HADS-Depression scores, and CD-RISC scores of the patients with HNC were 7.4±1.9, 6.4±2.2, and 56.8±12.6. The "Strength" and "Resilience" scores of the patients were inversely related to their HADS anxiety scores (p < 0.05). The "Resilience" and "optimism" scores of them were inversely related to HADS depression scores (p < 0.05). The average ZBI score of the caregivers was 23.8±10.1; HADS anxiety scores and HADS depression scores of the caregivers were positively associated with total ZBI scores and individual burden scores (p < 0.05). Conclusion: More than half of patients with HNC undergoing radiotherapy have anxiety, and about a third have depression. The anxiety and depression status of the FCs of patients with HNC undergoing radiotherapy is related to caregiver burden, deserving the attention of clinical medical staff.

FoxM1 knockdown enhanced radiosensitivity of esophageal cancer by inducing apoptosis.

Radioresistance is a main reason for local recurrence of esophageal squamous cell carcinoma (ESCC). Forkhead box M1 (FoxM1) is implicated in cancer progression and chemoresistance. This study aims to determine the role of FoxM1 in ESCC radioresistance. We found that FoxM1 protein was upregulated in ESCC tissues compared with adjacent normal tissues. In vitro assays revealed that following irradiation, Eca-109, TE-13, and KYSE-150 cells had increased levels of FoxM1 protein. FoxM1 knockdown resulted in significantly reduced colony formation and increased cell apoptosis following irradiation. Moreover, FoxM1 knockdown induced ESCC cells to accumulate in the radiosensitive G2 /M phase and impeded the repair of radiation-induced DNA damage. Mechanistic studies indicated that radiosensitization of ESCC enhanced by FoxM1 knockdown was associated with increased BAX/BCL2 ratio as well as downregulated Survivin and XIAP, followed by the activation of both extrinsic and intrinsic apoptosis pathways. In xenograft mouse model, the combination of radiation and FoxM1-shRNA led to a synergistic anti-tumor effect. In conclusion, FoxM1 is a promising target to enhance radiosensitivity of ESCC.

Prognostic value of modified-Gustave-Roussy Immunity Score in resectable proximal gastric cancer.

The prognostic evaluation of GRIm score has been confirmed in many tumor species. The purpose of this study is to clarify the value of GRIm score in the prognostic evaluation of patients with resectable proximal gastric cancer. A single center retrospective study was conducted in 174 patients with proximal gastric cancer who underwent radical total gastrectomy. An in-depth analysis was carried out to explore the prognostic differences between high and low GRIm, and the influencing factors of disease-free survival rates and overall survival rates were analyzed by Cox regression model and Kaplan-Meier method. A total of 174 patients were divided into two groups: 135 patients were marked in L-mGRIm and 39 patients in H-mGRIm groups respectively. The median OS of the H-mGRIm and L-mGRIm groups were 23.2 and 38.6 months, respectively. The median DFS of the H-mGRIm and L-mGRIm groups was 16.9 and 31.7 months, respectively. Both DFS and OS were significantly different between groups (P = .000, P = .000). In multivariate analysis, ZPS (2 vs 0-1: HR 1.99 95% CI 1.05-3.76 P = .035), LDH (≥193 vs <193:HR 0.6; 95% CI 0.38-0.95 P = .028), mGRIm score (2-3 vs 0-1: HR 2.4; 95% CI 1.09-5.23 P = .029) was independent risk factors of OS. The age (>65 vs ≤65 years HR 0.63; 95% CI 0.4-0.95 P = .003), LDH (>193 U/L vs ≤193 U/L: HR 0.55; 95% CI 0.37-0.82 P = .004) and mGRIm score (2-3 vs 0-1: HR 4.74; 95% CI 2.24-9.9 P = .000) as an independent risk factor for DFS. mGRIm score is a novel, simple and effective index for prognosis evaluation of resectable cardiac cancer and can be used as a part of the risk stratification process.

Immune mechanisms of group B coxsackievirus induced viral myocarditis.

Viral myocarditis is known to be a primary cause of dilated cardiomyopathy (DCM) that can lead to heart failure and sudden cardiac death and is invariably caused by myocardial viral infection following active inflammatory destruction of the myocardium. Although acute viral myocarditis frequently recovers on its own, current chronic myocarditis therapies are unsatisfactory, where the persistence of viral or immunological insults to the heart may play a role. Cellular and mouse experimental models that utilized the most prevalent Coxsackievirus group B type 3 (CVB3) virus infection causing myocarditis have illustrated the pathophysiology of viral myocarditis. In this review, immunological insights into the different stages of development of viral myocarditis were discussed, concentrating on the mechanisms of innate and adaptive immunity in the development of CVB3-induced myocarditis.

Combined use of NK cells and radiotherapy in the treatment of solid tumors.

Natural killer (NK) cells are innate lymphocytes possessing potent tumor surveillance and elimination activity. Increasing attention is being focused on the role of NK cells in integral antitumor strategies (especially immunotherapy). Of note, therapeutic efficacy is considerable dependent on two parameters: the infiltration and cytotoxicity of NK cells in tumor microenvironment (TME), both of which are impaired by several obstacles (e.g., chemokines, hypoxia). Strategies to overcome such barriers are needed. Radiotherapy is a conventional modality employed to cure solid tumors. Recent studies suggest that radiotherapy not only damages tumor cells directly, but also enhances tumor recognition by immune cells through altering molecular expression of tumor or immune cells via the in situ or abscopal effect. Thus, radiotherapy may rebuild a NK cells-favored TME, and thus provide a cost-effective approach to improve the infiltration of NK cells into solid tumors, as well as elevate immune-activity. Moreover, the radioresistance of tumor always hampers the response to radiotherapy. Noteworthy, the puissant cytotoxic activity of NK cells not only kills tumor cells directly, but also increases the response of tumors to radiation via activating several radiosensitization pathways. Herein, we review the mechanisms by which NK cells and radiotherapy mutually promote their killing function against solid malignancies. We also discuss potential strategies harnessing such features in combined anticancer care.

Progression-free survival as surrogate endpoint of overall survival in esophageal squamous cell carcinoma: a real-world data and literature-based analysis.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal squamous cell carcinoma (ESCC) remains unelucidated. This study aimed to determine the validity of PFS as a surrogate endpoint for OS in ESCC patients treated with definitive radiotherapy or definitive chemoradiotherapy (dRT/dCRT), as well as characterize the prognostic factors and survival of such patients. Methods: A total of 3662 patients from 10 cancer centers were enrolled. One-, 2-, and 3-year PFS (PFS12, PFS24, and PSF36, respectively) were used as time points for analysis. At each time point, ESCC-specific mortality and OS were characterized using competing risk and conditional survival models, while correlation between PFS and OS was evaluated by linear regression. Results: At PFS12, PFS24, and PFS36, a progressive decrease in 5-year ESCC-specific mortality (35.2%-13.4%) and increase in 5-year OS (46.6%-62.9%) were observed. Regardless, the OS of patients remained markedly lower than those of the age- and sex-matched Chinese general population. TNM stage remained a significant prognostic factor at PFS36. Strong correlation was found between 3-year PFS and 5-year OS, which was further externally validated. Conclusions: Three-year PFS may act as a potential surrogate endpoint for 5-year OS. TNM stage was considered a significant prognostic factor for OS, and may represent the optimal prognostic tool to guide clinical decision-making and post-treatment follow-up.

CBX4 contributes to radioresistance by regulating autophagic activity in esophageal squamous cell carcinoma.

Background: The function of Chromobox 4 (CBX4) function has attracted attention in many cancer types due to its unique biological role; however, its mechanism in esophageal squamous cell carcinoma (ESCC) under radiotherapeutic treatment has not yet been investigated. Methods: Silencing of CBX4 was carried out in TE-13 and KYSE-150 cell lines. Cell proliferation, radiosensitivity, DNA damage, apoptosis, and cell cycle distribution were determined by Cell Counting Kit-8 (CCK-8), colony formation assay, immunofluorescence, flow cytometry, and immunoblot in vitro. In vivo xenograft models were also used to assess tumor cell growth and radioresistance. The underpinning mechanisms were explored based on pathway analysis and confirmed by rescue experiments, detecting cellular autophagy. Results: Knockdown of CBX4 resulted in reduced tumor growth and enhanced radio-response in vivo and in vitro. Down-regulating CBX4 increased DNA damage, apoptotic rate, and G2/M arrest induced by radiation in ESCC cell lines. Gene Set Enrichment Analysis (GSEA) revealed that CBX4 was associated with cellular autophagy regulation. Enhanced radiosensitivity in ESCC cells silenced for CBX4 was partially blocked by autophagy inhibition (P<0.05). Beclin 1 was upregulated at the gene and protein levels in ESCC cells with CBX4 knockdown after irradiation, and overexpressing Beclin 1 reversed the radiosensitivity of ESCC cells with CBX4 knockdown (P<0.05). Conclusions: By regulating autophagic activity, CBX4 contributes to radioresistance. Targeting CBX4 might constitute an efficient approach for increasing radiosensitivity in ESCC.

Identification of Immune and Hypoxia Risk Classifier to Estimate Immune Microenvironment and Prognosis in Cervical Cancer.

Purpose: Cervical cancer (CC) is one of the most common gynecologic neoplasms. Hypoxia is an essential trigger for activating immunosuppressive activity and initiating malignant tumors. However, the determination of the role of immunity and hypoxia on the clinical outcome of CC patients remains unclear. Methods: The CC independent cohort were collected from TCGA database. Consensus cluster analysis was employed to determine a molecular subtype based on immune and hypoxia gene sets. Cox relevant analyses were utilized to set up a risk classifier for prognosis assessment. The underlying pathways of classifier genes were detected by GSEA. Moreover, we conducted CIBERSORT algorithm to mirror the immune status of CC samples. Results: We observed two cluster related to immune and hypoxia status and found the significant difference in outcome of patients between the two clusters. A total of 251 candidate genes were extracted from the two clusters and enrolled into Cox relevant analyses. Then, seven hub genes (CCL20, CXCL2, ITGA5, PLOD2, PTGS2, TGFBI, and VEGFA) were selected to create an immune and hypoxia-based risk classifier (IHBRC). The IHBRC can precisely distinguish patient risk and estimate clinical outcomes. In addition, IHBRC was closely bound up with tumor associated pathways such as hypoxia, P53 signaling and TGF ß signaling. IHBRC was also tightly associated with numerous types of immunocytes. Conclusion: This academic research revealed that IHBRC can be served as predictor for prognosis assessment and cancer treatment estimation in CC.