PURPOSE:The aim of this study was to evaluate the efficacy of neoadjuvant chemotherapy (albumin-bound paclitaxel + carboplatin) combined with the PD-1 inhibitor tislelizumab in patients with potentially resectable stage II to IVb head and neck squamous cell carcinoma (HNSCC) and explore immune and circulating tumor-related features potentially associated with treatment response. PATIENTS AND METHODS:This was a single-arm phase II trial involving 33 patients with potentially resectable stage II to IVb HNSCC. Participants received two cycles of neoadjuvant therapy followed by surgery. Primary endpoints were pathologic complete response (pCR) rate and major pathologic response (MPR) rate. Safety and exploratory analyses, including circulating tumor cells (CTC), PD-L1 expression, and T-cell senescence, were also assessed. RESULTS:The study demonstrated an objective response rate of 72.7% (24/33) and an R0 resection rate of 93.1% (27/29) in surgical patients. The pCR rate was 44.8%, and the MPR rate was 62.1%. The laryngeal preservation rate was 70.4% (19/27). With a median follow-up of 20.5 months, the 12- and 24-month event-free survival rates were 93.1% (95% confidence interval, 84.3%-100%). Five of six patients with decreased CTC levels achieved MPR (5/6, 83.3%). Among patients whose T-cell senescence decreased, four of six achieved MPR, whereas only two of five with increased T-cell senescence achieved MPR. The pCR rate was significantly higher in patients with PD-L1 combined positive score ≥ 1 compared with those with combined positive score < 1 (55.6% vs. 12.5%). CONCLUSIONS:Neoadjuvant immunochemotherapy improves pathologic response and organ preservation in stage II to IVb HNSCC. Dynamic changes in CTCs and T-cell senescence are associated with treatment efficacy, suggesting their potential as early, noninvasive indicators of response, supporting precision treatment strategies for locally advanced HNSCC.

Radiotherapy is a standard cancer treatment that involves the induction of DNA damage. DNA damage repair (DDR) pathways maintain genomic integrity and make tumors resistant to radiotherapy and certain chemotherapies. In turn, DDR dysfunction results in cumulative DNA damage, leading to increased sensitivity for antitumor treatment. Moreover, radiotherapy has been shown to trigger antitumor immunity. Currently, immunotherapy has become a new and widely used standard strategy for treating a broad spectrum of tumor types. Notably, recent studies have demonstrated that DDR pathways play important roles in driving the response to immunotherapy. Herein, we review and discuss how DDR affects antitumor immunity induced by radiotherapy. Furthermore, we summarize the development of strategies for combining DDR inhibitors with radiotherapy and/or immunotherapy to enhance their efficacy against cancers.

Oxidative stress has been implicated as a pivotal factor in the pathogenesis of numerous malignancies. However, the association between oxidative stress and the prognosis of patients with colorectal cancer liver metastasis (CRCLM) is not well elucidated. We conducted a retrospective analysis of 424 patients with CRCLM who underwent primary resection at the Union Hospital, Tongji Medical College, Wuhan, between July 2013 and September 2018. Patients were randomly divided into a training set (n = 300) and a test set (n = 124) in a 7:3 ratio.To develop the CRCLM-integrated Oxidative Stress Score (CLIOSS) for CRCLM, we utilized individual oxidative stress markers. The overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and the log-rank test was employed to assess prognostic factors.To validate the predictive performance of CLIOSS, we constructed Receiver Operating Characteristic (ROC) curves and calculated the Area Under the Curve (AUC) values. Additionally, Decision Curve Analysis (DCA) and calibration plots were used to evaluate the clinical utility and predictive consistency of the model. The CLIOSS prognostic model was constructed based on the following variables and their corresponding β coefficients: 0.042 × total bilirubin (TBIL, µmol/L) + 0.032 × blood urea nitrogen (BUN, mmol/L) − 0.001 × uric acid (UA, µmol/L). Higher CLIOSS were associated with poorer OS (2.934;95% CI 2.167–3.974;P < 0.001) and DFS(2.707; 95% CI 2.000–3.664; P < 0.001. The 3-year OS AUC values were 0.803 in the training set and 0.851 in the testset, while the 3-year DFS AUC values were 0.892 and 0.898, respectively. Decision curve analysis demonstrated that both predictive models have significant clinical utility in practice. CLIOSS is a comprehensive prognostic index derived from oxidative stress markers, designed to predict long-term survival in patients with CRCLM. Our study shows that higher CLIOSS are significantly associated with poorer outcomes, making it an important tool for assessing patient risk.

Cancer-associated fibroblasts (CAFs) are prominent components of the lung tumor stroma and are known to foster tumor growth, invasion, and metastasis through extracellular matrix (ECM) and tumor stroma remodeling. The interactions of CAFs with cancer cells and other stromal components contribute significantly to the aggressive nature of lung cancer and pose challenges to conventional treatment approaches. Simultaneously, the ECM, which contains numerous proteins and other molecules surrounding cancer cells, serves as more than just a structural scaffold. In lung cancer, alterations in ECM composition and organization not only promote tumor cell proliferation and survival but also impact drug penetration, immune cell infiltration, and therapeutic resistance. Targeting the intricate interplay between CAFs and the dynamic ECM in lung cancer represents a crucial frontier in oncology research. This review aims to delve deeply into the pivotal roles of CAFs and the ECM in the tumorigenesis and progression of lung cancer. Then, the potential of utilizing adjuvants, phytochemicals, and nanoparticles to modulate the functions of CAFs and remodel the ECM in the lung tumor will be reviewed.

Lymphovascular invasion (LVI) is associated with poor prognosis in a variety of malignancies; however, its prognostic value has not been fully defined in patients with colorectal cancer with liver metastases (CRCLM). The aim of this study was to investigate the impact of LVI on long-term postoperative recurrence and survival in patients with CRCLM. Clinicopathologic data were retrospectively collected from patients who underwent primary resection for CRCLM at Wuhan Union Hospital from 2013 to 2018. To reduce potential confounders and selection bias, we used propensity score matching (PSM) to compare the clinicopathologic characteristics and long-term prognostic outcomes of patients in the LVI (+) and LVI (-) groups. Cox unifactorial and multifactorial analyses were used to screen relevant factors affecting patient prognosis, and Kaplan-Meier curves were plotted to compare differences in patient overall survival (OS) and disease-free survival (DFS). The predictive power of independent factors on patients’ long-term prognosis was assessed using receiver operating characteristic ROC) curves and area under the curve (AUC). After PSM, 230 patients were enrolled in the study (n = 115 per group). Multifactorial analysis revealed that LVI was an independent prognostic factor for OS and DFS (hazard ratio [HR], 1.424; 95

The lung tumour microenvironment (TME) is composed of various cell types, including cancer cells, stromal and immune cells, as well as extracellular matrix (ECM). These cells and surrounding ECM create a stiff, hypoxic, acidic and immunosuppressive microenvironment that can augment the resistance of lung tumours to different forms of cell death and facilitate invasion and metastasis. This environment can induce chemo/radiotherapy resistance by inducing anti-apoptosis mediators such as phosphoinositide 3-kinase (PI3K)/Akt, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-κB), leading to the exhaustion of antitumor immunity and further resistance to chemo/radiotherapy. In addition, lung tumour cells can resist chemo/radiotherapy by boosting multidrug resistance mechanisms and antioxidant defence systems within cancer cells and other TME components. In this review, we discuss the interactions and communications between these different components of the lung TME and also the effects of hypoxia, immune evasion and ECM remodelling on lung cancer resistance. Finally, we review the current strategies in preclinical and clinical studies, including the inhibition of checkpoint molecules, chemoattractants, cytokines, growth factors and immunosuppressive mediators such as programmed death 1 (PD-1), insulin-like growth factor 2 (IGF-2) for targeting the lung TME to overcome resistance to chemotherapy and radiotherapy.

Background. Cervical cancer (CC) is one of the most frequent female malignancy. Cancer stem cells (CSCs) positively affect survival outcomes in cancer patients, but in cervical cancer, the mechanism of tumor stem cells is still uncertain. Methods. RNA-seq data and related clinical follow-up of patients suffering from CC were from TCGA. Consensus clustering screened prognostic mRNAsi-related genes and identified molecular subtypes for CC. Based on the overlapping differentially expressed genes (DEGs) in subtypes, we employed LASSO and multivariate Cox regression to screen prognostic-related genes and established the RiskScore system. The patients were grouped by RiskScore, the prognosis was analyzed by the Kaplan-Meier (K-M) curve among the various groups, and the precision of the RiskScore was assessed by the ROC curve. Finally, the potential worth of RiskScore in immunotherapy/chemotherapy response was assessed by evaluating TIDE scores and chemotherapy drug IC(50 )values. Results. We noticed that patients with low mRNAsi had a shorter survival and then identified three molecular subtypes (C1-3), with the C1 having the worst prognosis and the lowest mRNAsi. Finally, we identified 7 prognostic-related genes (SPRY4, PPP1R14A, MT1A, DES, SEZ6L2, SLC22A3, and CXCL8) via LASSO and Cox regression analysis. We established a 7-gene model defined RiskScore to predict the prognosis of CC patients. K-M curve indicated that low RiskScore patients had improved prognosis, and ROC curves indicated that RiskScore could precisely direct the prognostic evaluation for those suffering from the cancer. This was also confirmed in the GSE44001 and GSE52903 external cohorts. Patients were more sensitive to immunotherapy if with low RiskScore, and RiskScore exhibited precise assessment ability in predicting response to immunological therapy in CC patients. Conclusion. CC stemness is associated with patient prognosis, and the RiskScore constructed based on stemness characteristics is an independent prognostic index, which is expected to be a guide for immunotherapy, providing a new idea for CC clinical practice.

Supplementary Figure Legends from ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors

Supplementary Figure 1. Proteomic analysis of ATR-interacting proteins. Supplementary Figure 2. ARID1A interacts with ATR in MDA-MB-231 Cells. Supplementary Figure 3. ARID1A recruitment to I-SceI-induced DSBs analyzed by ChIP assay. Supplementary Figure 4. Schematic diagram of KillerRed system in U2OS TRE cells. Supplementary Figure 5. Expression of ARID1A mutants. Supplementary Figure 6. Knockdown BRG1, BRM, or ARID1A in U2OS cells. Supplementary Figure 7. ARID1A depletion did not affect the number of ATM foci after exposure to IR. Supplementary Figure 8. (A) ARID1A depletion did not affect the presence of DSBs after exposure to IR. Supplementary Figure 9. ARID1A depletion did not affect the expression of DSB end resection factors. Supplementary Figure 10. ARID1A depletion did not affect the expression of ATM and MRN complex. Supplementary Figure 11. (A) ARID1A depletion sensitize MDA-MB-231 cells to PARP inhibitor. Supplementary Figure 12. ARID1A knockdown sensitizes ovarian cancer cell line HOC8 to PARP inhibitor. Supplementary Figure 13. Ovarian cancer cells with lower expression levels of ARID1A are more sensitive to PARP inhibitor treatment than cells with higher ARID1A expression levels. Supplementary Figure 14. Rescuing experiments were conducted with ARID1A wild-type and mutant constructs (deletion mutants/patient-derived mutants). Supplementary Figure 15. ATR inhibitor sensitizes cells to PAPR Inhibitor treatment. Supplementary Figure 16. Proposed model for ARID1A function in DSB End Resection and repair.

The chromatin remodeling gene AT-rich interactive domain 1A (ARID1A), encoding a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is one of the most frequently mutated chromatin regulators across a broad spectrum of cancers. Most of the ARID1A alterations are inactivating, leading to the loss or reduced expression of the protein. Recently, ARID1A has been demonstrated as a tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC), as its inactive alterations attribute to carcinogenesis. Importantly, ARID1A alterations are revealed as predictive biomarkers for the selection of targeted therapy and immune checkpoint blockade (ICB) therapy. In PDAC, the application of ARID1A alterations in stratifying patients for precise treatment has also been widely explored in preclinical and early clinic studies with encouraging preliminary results. Furthermore, the prognostic value of ARID1A mutations in PDAC has been suggested by various studies. In this review, we focus on the functions of ARID1A alterations in PDAC, particularly their functions during carcinogenesis and their predictive value in treatment selection and prognosis, to provide a comprehensive overview on our current understanding of ARID1A alterations in PDAC.

Background Although immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of nasopharyngeal carcinoma (NPC), it is still the second- or third-line treatment after the failure of radiotherapy or chemotherapy. In this study, we aimed to investigate the impact of concurrent chemoradiotherapy (CCRT) on programmed death-ligand 1 (PD-L1) protein expression in NPC patients. Methods We enrolled 24 NPC patients treated with intensity-modulated radiation therapy (IMRT) combined with cisplatin CCRT. PD-L1 expression was evaluated by immunohistochemistry, and next-generation sequencing and annotation were performed to determine the genetic alteration after CCRT. Results Our results showed that patients with a high expression of PD-L1 were more inclined to a complete response (CR) to chemoradiotherapy, as opposed to a partial response (PR) (P<0.05). Moreover, the mean values of the tumor mutation burden (TMB) and the tumor neoantigen burden (TNB) in the PD-L1 positive group were significantly lower than that of the PD-L1 negative group in our cohort. Conclusions We confirmed that the TMB and TNB may be potential clinical indicators in NPC treatment, and PD-L1 expression may be a clinical biomarker in NPC chemoradiotherapy. Finally, through next-generation sequencing and annotation, we found that the most frequent driver gene mutations in NPC were TET2, TP53, and MAPK.

The AT-rich Interactive Domain 1A (ARID1A) is one of the most frequently mutated genes in gastric cancer. Here, we found that genetic variants in noncoding regions of ARID1A associated with altered protein levels by target sequencing. Notably, tumors with ARID1A variants in the 3'untranslated region (3'UTR) exhibited remarkably increased heterogeneity of ARID1A protein. In general, genetic variants and protein deficiency of ARID1A in tumors were associated with a better survival. Strikingly, altered patterns and heterogeneity of ARID1A protein expression were observed in peritumor tissues and carried significant implications in defining tumor immune contexture by multiplex immunohistochemistry. By analyzing the spatial distribution of TILs, we showed that reduced ARID1A protein levels in both tumor and peritumor tissues were significantly correlated with increased density and proximity of TILs to tumor cells. In contrast, high heterogeneity of ARID1A expression was associated with increased TIL density, but reduced proximity of TILs to tumor cells. Collectively, our study characterized ARID1A genetic alterations and its protein expression patterns in EOGC, demonstrating new strategies for clinically assessing its molecular impact on tumor onset and progression, tumor immune response, and patient survival.

The AT-rich interaction domain 1A (ARID1A, also known as BAF250a) is a chromatin remodeling gene, which frequently mutates across a broad spectrum of cancers with loss expression of the ARID1A protein. Recently, the association between ARID1A deficiency and immune checkpoint blockade (ICB) therapy has been reported. ARID1A deficiency contributes to the high microsatellite instability phenotype, increases tumor mutation burden, elevates expression of programmed cell death ligand 1 (PD-L1), and modulates the immune microenvironment, supporting the view that ARID1A loss might serve as a predictive biomarker for ICB. Furthermore, the therapeutic targeting strategies, which show "synthetic lethality" with ARID1A deficiency, exhibit potential synergy with ICB. We collectively reviewed the mechanisms underlying the correlation between ARID1A deficiency and ICB, the predictive function of ARID1A deficiency for ICB, and potential combined strategies of targeting agents, vulnerable for ARID1A deficiency, with ICB in cancer treatment.

Objective. To investigate the effects of HuR protein on the treatment of chronic lymphocytic leukemia (CLL). Methods. LCL lymphoblast cells and B lymphocytes were subjected to HuR overexpression (OV) or interference (IV). Western blot was used to observe the protein expression of human tumor necrosis factor-associated factor 1 (TRAF1), human inhibitor of nuclear factor kappa-B kinase α (IKK-α), NF-κB-inducing kinase (NIK), and p52. Flow cytometry was performed to evaluate apoptosis, and the mRNA expression of TRAF1 was examined by quantitative reverse transcription polymerase chain reaction. Immunofluorescence was carried out to visualize the expression of HuR, and the relationship between HuR and TRAF1 was observed by pull-down test. Cell sensitivity to chlorambucil (CLB) and fludarabine (Flu) was assessed by Cell Counting Kit-8. Results. The expression of HuR and TRAF1 in LCLs was significantly increased compared to that in B lymphocytes. Compared with the control, HuR OV significantly increased the expression of TRAF1 (P<0.05), whereas it was significantly decreased in the IV group (P<0.05). HuR can bind to TRAF1 directly, and the binding rate is positively correlated with HuR expression. After inhibiting HuR, the expression of TRAF1, IKK-α, NIK, p52, pro-Caspase 3, and PARP was significantly upregulated in LCLs and B lymphocytes (P<0.05), while Caspase 3 was downregulated (P<0.05). Compared with the control, the proliferation of LCLs and B lymphocytes treated by CLB and Flu decreased significantly after HuR blockade (P<0.05). Conclusion. HuR may be a key protein regulating CLL resistance. After inhibiting HuR, inflammatory response and apoptosis were significantly increased, and the cell sensitivity to CLB and Flu increased, suggesting that inhibiting HuR activity may be a potential strategy to solve the problem of drug resistance in CLL cells.

Objective Cervical esophageal cancer (CEC) is a relatively rare condition, with limited treatment options. The current study aimed to assess the survival outcomes of patients with CEC who received definitive radiotherapy. Methods In total, 63 consecutive patients with CEC who received definitive radiotherapy between 2010 and 2018 were included in this study. The survival outcomes were analyzed based on statistics. Results The median progression-free survival (PFS) and overall survival (OS) of the patients were 12 and 19 months, respectively. There were no significant differences in terms of survival outcomes between the groups who received radiation doses ≥ 60 and < 60 Gy. Interestingly, in the proximal CEC subgroup, the PFS ( P = 0.039), OS ( P = 0.031), and loco-regional failure-free survival (LRFFS) ( P = 0.005) improved significantly in patients who received a radiation dose ≥ 60 Gy compared with those who received a radiation dose < 60 Gy. However, in the distal CEC subgroup, the PFS, OS, and LRFFS did not significantly improve between patients who received radiation doses ≥ 60 and < 60 Gy. Definitive radiotherapy was well tolerated, and no significant differences were observed in terms of treatment-related toxicities between the groups who received radiation doses ≥ 60 and < 60 Gy. Conclusion The survival outcomes of patients with CEC should be improved. In proximal CEC, a radiation dose ≥ 60 Gy is significantly correlated with better PFS, OS, and LRFFS. However, further research must be performed to validate this finding.

Cysteine oxidation occurs at the active site of deubiquitinases (DUBs) during many biologic signaling cascades. Here we report that hepatocellular carcinoma cells (HCCs) generated higher levels of endogenous reactive oxygen species (ROS). This elevated ROS production was inhibited by NADPH oxidase inhibitor diphenylene iodonium (DPI) and mitochondria electron chain inhibitor rotenone in HCC cells. Moreover, we found that H 2 O 2 could activate NF-κB-dependent inflammatory effect through increased induction of matrix metalloproteinase 2 (MMP2), MMP9, and intercellular adhesion molecule 1 (ICAM1) expression levels. In addition, we found that H 2 O 2 could prolong NF-κB activation by suppressing the negative regulatory functions of Cezanne in HCC cells. Ubiquitin-derived thiol-reactive probe (HA-UbVME) assay and biotin-tagged 1,3-cyclohexadione derivative (DCP-Bio1) assay showed that H 2 O 2 has the capacity to inhibit the catalytic activity of Cezanne, and the reducing agent, DTT, could reactivate the Cezanne deubiquitinating enzyme activity. Taken all together, these findings demonstrated an important role for oxidation of Cezanne by ROS in regulation of the inflammatory effect of hepatocellular carcinoma.

The prognostic roles of neutrophil‐to‐lymphocyte ratio (NLR) and platelet‐to‐lymphocyte ratio (PLR) have been reported in head and neck squamous cell carcinoma (HNSCC), but their results remain controversial.

Dual blockade of phosphoinositide 3-kinase (PI3K) and poly(ADP-ribose) polymerase (PARP) has been revealed to be an effective treatment strategy for breast, ovarian and prostate cancer. However, the efficacy of this combination for the treatment of gastric cancer, and potential predictive therapeutic biomarkers remain unclear. Recent evidence suggests that the deficiency of AT-rich interactive domain containing protein 1A (ARID1A), which is a crucial chromatin remodeling gene, sensitizes tumor cells to PI3K and PARP inhibitors. Herein, we evaluated the therapeutic role of the combined treatment of PI3K inhibitor BKM120 and PARP inhibitor olaparib on gastric cancer cells, and explored ARID1A as a predictive biomarker. The results demonstrated that combined treatment with PI3K and PARP inhibitors effectively inhibited proliferation detected by MTS and clonogenic assay, invasion and migration by Transwell assay, of gastric cancer cells with ARID1A deficiency. Mechanistically, dual blockade of PI3K and PARP in ARID1A-depleted gastric cancer cells significantly increased apoptosis detected by flow cytometry, and induced DNA damage by immunofluorescent staining. Taken together, these data suggest that the combined treatment with PI3K inhibitor BKM120 and PARP inhibitor olaparib may be a promising therapeutic regimen for the treatment of gastric cancer, and ARID1A deficiency could serve as a potential predictive therapeutic biomarker.

Broad specific Notch1 inhibitors suppress glioblastoma multiforme (GBM) growth but have significant gastrointestinal toxicities. Here, we examined Notch1 expression in GBM tissue specimens and its correlation with the overall survival (OS) of GBM patients. Furthermore, using the CRISPR/Cas9 system, we investigated the effects of Notch1 downregulation on clonogenic growth and angiogenesis of GBM cells and xenografts. Immunohistochemistry showed positive Notch1 expression in 71% (49/69) of GBM tissues. Our multivariate Cox regression analysis further revealed that Notch1 expression was an independent adverse prognostic factor for OS. Notch1 downregulation suppressed the growth of GBM cells U87MG and U251. The mean duration to reach 6 x the starting volume was 18.3 days for xenografts with Notch1 downregulation and 13.4 days for the control xenografts. Immunofluorescent staining further disclosed that Notch1 downregulation markedly increased the number of γH2AX foci and radiosensitized GBM cells. Notch1 downregulation also impaired angiogenesis and attenuated VEGF and hypoxic response to irradiation in xenografts. In conclusion, Notch1 ablation inhibited GBM cell proliferation and neovascularization and radiosensitized GBM cells and xenografts, suggesting a pivotal role of Notch1 in tumor growth, angiogenesis, and radioresistance in GBM.

BACKGROUND: Wild-type p53-induced phosphatase (Wip1) is induced in response to stress, DNA damage. Wip1 was frequently overexpressed or amplified in breast cancer, ovarian cancer, neuroblastomas, and was accounted for poor prognosis in glioma patients. Little was known how Wip1 performed when exposed to UVC radiation in human glioblastoma cells. METHODS: Human glioblastoma Cells (U87, U251) were exposed to UVC irradiation with doses of UVC as 0,1,5,25,50 and 100 J J/m2 (J) at 254 nm. Cell proliferation of U87, U251 cells exposed to UVC radiation was investigated. And Cell viability of the U87, U251 cells subjected with CCT007093, specific Wip1 inhibitor, in doses of 0, 5, 25, 50, 100, 200 µM was modulated by CCK-8 assay. Then U87, U251 cells were subjected with 50 J per m2 of UVC irradiation combined with CCT007093, and the expression of p53, Wip1 and p38 was checked. Also the cell invasion and migration exposed to UVC combined with CCT007093 were investigated by transwell and scracth assay. RESULTS: When exposed with doses above 25, the proliferation of U87, U251 cell were inhibited obviously. The exposure to UVC radiation significantly upregulated Wip1 protein level in U87, U251 cells within 24 hours. When subjected to dose of 50 J/m2 UVC combined with 50 µM CCT007093, the protein expression of Wip1, p53 were up-regulated accompany with the downregulation of p38 protein, CCT007093 could block the expression of Wip1 induced by UVC especially in U87 cell. Meanwhile CCT007093 contributed to the inhibition of glioma cell migration and invasion induced by UVC in vitro. CONCLUSIONS: The up-regulation of Wip1 in glioblastoma cells due to UVC damage could be partly attributed to the function of p53. CCT007093, specific Wip1 inhibitor, could synergy UVC irradiation to inhibit cell proliferation, migration and invasion in human glioblastoma cells.