Although neoadjuvant therapy has achieved higher levels of resectability and improved the survival outcomes of pancreatic carcinoma patients, cancer cells' resistance to conventional cell death has limited its clinical efficiency. Thus, developing an optimal sequence of novel neoadjuvant therapy modalities to boost cancer cell death is urgently needed. The current work addresses this issue by developing a combination of radiotherapy with metformin as a novel neoadjuvant therapy and investigating its optimal sequencing treatment to boost cancer cell ferroptosis. Of the three treatment regimens investigated, the sequential treatment with RT followed by metformin (i.e. as opposed to metformin followed by RT, or simultaneous treatment with both RT and metformin) was most effective in eliciting ferroptosis in vitro and in animal models. Mechanically, RT followed by metformin is dependent on the inhibition of the AMPK-GOT1 axis, which further leads to the arrest of cancer cells in G1/S phase, and ultimately ferroptosis. Moreover, using a combination of patient samples and mouse models, RT followed by metformin enhanced the anti-tumor immune cells (IFNγ+CD8+T cells, DC cells, and M1 macrophage) infiltration and cytokines (IFN-γ and IL-2) level, inhibited the pro-tumor immune cells (PD-1+TIM3+ CD8+T cells and M2 macrophage) infiltration and cytokines (TGF-β and IL-10) level. Overall, the study developed an optimal sequencing of neoadjuvant therapy modality that induced superior cancer cell ferroptosis and boosted anti-tumor immunity, which presented a promising therapeutic approach for refractory tumors.

This study investigates the efficacy and safety of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) in treating hormone receptor-positive (HR +), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. A systematic review of randomized clinical trials (RCTs) from 2015 to 2024 was conducted using databases such as PubMed, Google Scholar, Embase, and Cochrane. Data were collected on treatment outcomes, including complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), overall response rate (ORR), and treatment-related adverse events (TRAEs). Analysis was performed using Review Manager 5.4.1, following PRISMA guidelines, with registration in the PROSPERO database (ID: CRD42023471168). 1223 studies screened, 13 met inclusion criteria. CDK4/6i + ET significantly reduced PD rates and increased SD compared to ET + chemotherapy. No significant differences were observed in CR, PR, or SD between the groups. CDK4/6i + ET demonstrated a favorable safety profile with fewer high-grade TRAEs but had a higher incidence of grade 3–4 adverse events than ET alone. CDK4/6i combined with ET improves disease control by decreasing progression and increasing stability, though it shows a lower PR rate than ET + chemotherapy in HR + /HER2 − advanced breast cancer. These findings underscore the need to balance efficacy with tolerability when selecting treatment strategies.

The identification of affordable and easily accessible indicators to predict overall survival is important for tumor immunotherapy. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which promote tumor immune escape in the tumor microenvironment (TME). This study aimed to determine whether peripheral blood MDSCs could determine their potential as predictors of survival in tumor patients with immunotherapy. Flow cytometry was used to detect peripheral blood monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic myeloid-derived suppressor cells (G-MDSCs) in 126 patients. Multivariate Cox regression analysis was conducted to examine the associations between peripheral blood MDSCs and patient survival. The receiver operating characteristic (ROC) curve determined the optimal cutoff value for peripheral blood MDSCs and grouped the indicators. The relationship between peripheral blood M-MDSCs and the prognosis and treatment outcome of tumor patients was explored. The proportion of peripheral blood M-MDSCs was associated with the prognosis of patients with tumors, as were tumor metastasis, the red blood cell count, absolute neutrophil count, absolute monocyte count, and BMI. Multivariate Cox regression analysis revealed that M-MDSCs, absolute lymphocyte value, and tumor metastasis were independent risk factors affecting the prognosis of patients with tumors. Detection of peripheral blood M-MDSCs obtained high sensitivity and specificity for tumor diagnosis. Patients with high M-MDSCs percentage demonstrated reduced survival durations and diminished responses to immunotherapy compared to those with low M-MDSCs percentage. Peripheral blood M-MDSCs may be used to predict overall survival and immunotherapy efficacy outcomes. This study provides a putative predictive biomarker for clinicians to choose from to predict tumor patients’ survival and the selection of receiving immunotherapy regimens.

BACKGROUND:This study aimed to explore the predictive value of pretreatment peripheral blood immune cell subsets in analyzing the outcomes of patients who underwent radiation therapy for esophageal cancer at their first visit. PATIENTS AND METHODS:This study included 72 patients with esophageal cancer (EC) treated at Jiangsu University Hospital from December 2021 to December 2023. Among them, 48 were males and 24 were females, with a median age of 64 years (range: 52-98 years). Comprehensive clinical data, laboratory results, and imaging findings were collected to analyze survival differences. The log-rank test was used for univariate analysis to assess the sensitivity of these patients to radiotherapy. The statistically significant and clinically relevant factors identified from the univariate analysis were subsequently incorporated into a Cox proportional hazards regression model for multivariate analysis to investigate the associations between pretreatment peripheral blood immune cell subsets and patient survival. RESULTS:Univariate Cox regression analysis revealed that the Eastern Cooperative Oncology Group (ECOG) score, CD4+ T-cell ratio, neutrophil-to-CD4+ T-cell ratio (N/CD4), neutrophil-to-CD8+ T-cell ratio (N/CD8), and neutrophil-to-B-cell ratio (N/B) were significantly correlated with survival outcomes in patients receiving radiotherapy for tumors. Furthermore, multivariate Cox regression analysis identified N/CD4+ T cells and N/CD8+ T cells as critical prognostic indicators for these patients. Receiver operating characteristic curve analysis was employed to evaluate the work characteristics of the subjects, resulting in area under the curve values of 0.763 for both N/CD4 and N/CD8. The analysis also revealed that the optimal cutoff values for N/CD4+ T cells and N/CD8+ T cells were 0.01053329 and 0.01184294, respectively. CONCLUSIONS:N/CD4 and N/CD8 have emerged as viable prognostic predictors for patients undergoing radiotherapy for EC, offering valuable insights for clinicians to strategize further treatment options. However, the retrospective nature of this study introduces potential bias in assessment, underscoring the necessity for large-scale, prospective, randomized controlled trials to substantiate and validate these findings.

BACKGROUND:Ferroptosis is a distinct form of cell death characterized by unique morphology, biochemistry, and genetics, playing a crucial role in the initiation, progression, prognosis, and therapeutic strategies of tumors. However, the impact of ferroptosis-related genes (FRGs) on the tumor microenvironment (TME) remains unclear. This study may advance the existing knowledge of FRGs in gastric cancer, and push ahead with more effective prognostic assessment and the development of more effective immunotherapy approaches.METHODS:FRGs were acquired from the FerrDb database and a consensus clustering technique was adopted to categorize patients with GC into groups in line with the expression profiles of 44 FRGs in order to further investigate the expression properties of these proteins. Assessment of the immune status, microsatellite instability (MSI) and cancer stem cell (CSC) index between the high- and low- risk groups to assess the proportion of TIICs in the TME, ssGSVA was adopted to detect the abundance of infiltrating immune cells from the low-risk and high-risk groups. Expression levels of eight ferroptosis-related genes of prognostic signature in GC tissues and adjacent normal tissues was detected by RT-PCR.RESULTS:In the GC cohort, TP53 has the highest mutation frequency (44 %), and was shown to be highly linked with the expression levels of 11 FRGs. In accordance with the Kaplan-Meier curve, the overall survival time of patients with subtype A (Low FRG-score) discernibly exceeded that of patients with subtype B (High FRG-score).In addition, there is a significant difference in the infiltration of most immune cells between subtype A and subtype B, and some important immune checkpoints (CTLA4, PDCD1, CD274, LAG3, PDCD1LG2, and HAVCR2) have higher expression in cluster A. Finally, low FRG-scores were significantly associated with MSI-H status, while high FRG-scores were significantly associated with microsatellite stable status (MSS). FRG-score is negatively related to the cancer stem cell (CSC).CONCLUSION:Low FRG-score, due to its high microsatellite instability (MSI-H), high mutational load and immune activation, indicates the possible advantage of OS. In addition, the FRG-score was closely related to the cancer stem cell (CSC) index and the sensitive degree of chemotherapeutic drug.

Radiotherapy is an important means of tumor treatment, but radiotherapy resistance has been a difficult problem in the comprehensive treatment of clinical tumors. The mechanisms of radiotherapy resistance include the repair of sublethal damage and potentially lethal damage of tumor cells, cell repopulation, cell cycle redistribution, and reoxygenation. These processes are closely related to the regulation of epigenetic modifications. Histone deacetylases (HDACs), as important regulators of the epigenetic structure of cancer, are widely involved in the formation of tumor radiotherapy resistance by participating in DNA damage repair, cell cycle regulation, cell apoptosis, and other mechanisms. Although the important role of HDACs and their related inhibitors in tumor therapy has been reviewed, the relationship between HDACs and radiotherapy has not been systematically studied. This article systematically expounds for the first time the specific mechanism by which HDACs promote tumor radiotherapy resistance in vivo and in vitro and the clinical application prospects of HDAC inhibitors, aiming to provide a reference for HDAC-related drug development and guide the future research direction of HDAC inhibitors that improve tumor radiotherapy resistance.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that a large number of data panels showing cell migration and invasion assay data in Figs. 3C and 5 contained overlapping sections, such that data that were intended to show results obtained under different experimental conditions may have been derived from a smaller number of original sources. In addition, certain of the data in this pair of figures were strikingly similar to data that were submitted for publication in another journal at around the same time as the above paper was submitted to Oncology Reports. Finally, regarding the western blotting data shown in Fig. 4B, an obvious splice in the gel strip was noticed for the FBXW7 bands, whereas no equivalent splice was present in the associated GADPH loading control, suggesting that these data originated from different gels. Owing to the fact that the contentious data in the above article were under consideration for publication at around the time that this was submitted to Oncology Reports, in addition the other features of concern regarding the data, the Editor has decided that this paper should be retracted from the Journal on account of a lack of confidence in the presented data. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 3030‑3038, 2017; DOI: 10.3892/or.2017.5995].

目的:观察阿伐曲泊帕对化疗相关血小板降低症(CIT)患者的临床效果.方法:选取2019年6月～2021年6月在本院确诊的50例化疗后3级及以上CIT患者临床资料进行回顾性分析,其中27例患者采用重组人血小板生成素(rhTPO)治疗作为对照组,23例患者采用阿伐曲泊帕联合rhT PO治疗作为观察组.比较两组患者血小板开始升高时间、血小板恢复时间、血小板极值、凝血和肝肾功能.记录治疗期间不良反应的发生情况.结果:治疗后观察组血小板开始升高时间、血小板计数升高至50×109/L、75×109/L、100×109/L的时间及部分凝血活酶时间(APTT)均明显短于对照组(均P<0.05),凝血酶时间(TT)和血小板最高值明显高于对照组(均P<0.05).治疗前后两组患者丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、尿素氮(BUN)、血肌酐(Scr)水平、不良反应发生率无明显差异(均P>0.05).结论:阿伐曲泊帕能快速升高CIT患者血小板计数,提高疗效的同时未明显增加不良反应发生率,无肝肾毒害性.

Inflammatory bowel disease (IBD) remains one of the most prevalent gastrointestinal diseases worldwide. Purinergic signaling has emerged as a promising therapeutic target of inflammation-associated diseases. However, little is known about the specific roles of purinergic receptors in IBD. In the present study, expression profile of purinergic receptors was screened in the public Gene Expression Omnibus (GEO) datasets, and we found that expression of P2RX1 was significantly upregulated in inflamed colon tissues. Then, purinergic receptor P2RX1 was genetically ablated in the background of C57BL/6 mice, and dextran sulfate sodium (DSS) was used to induce mice colitis. RNA sequencing results of colon tissues showed that genetic knockout of P2RX1 suppressed the inflammation responses in DSS-induced mice colitis. Flow cytometry indicated that neutrophil infiltration was inhibited in P2RX1 ablated mice. 16S ribosomal DNA sequencing revealed major differences of intestinal microbiota between WT and P2RX1 ablated mice. Functional metagenomics prediction indicated that the indole alkaloid biogenesis pathway was upregulated in P2RX1 gene ablated mice. Further studies revealed that microbiota metabolites (indole alkaloid)-involved aryl hydrocarbon receptor (AhR)/IL-22 axis was associated with the beneficial effects of P2RX1 ablation. Finally, we found that a specific P2RX1 inhibitor succeeded to improve the therapeutic efficiency of anti-TNF-α therapy in DSS-induced mice colitis. Therefore, our study suggests that targeting purinergic receptor P2RX1 may provide novel therapeutic strategy for IBD.

In the tumor microenvironment, inflammatory cells and molecules influence almost every process; among them, interleukin-23 (IL-23) is a pro-inflammatory molecule that exhibits pro- or anti-tumor properties, but both activities remain poorly understood. In this study, we investigated the effect of extracellular IL-23 in IL-23 receptor-positive (IL-23R+) esophageal squamous cell carcinoma (ESCC) and explored the mechanisms underlying this effect. We analyzed ESCC tumor tissues by immunohistochemical and immunofluorescence staining and found that IL-23, which was highly expressed, co-localized with Oct-4A in IL-23R+ ESCC cells. In addition, IL-23 treatment significantly increased the accumulation of CD133+ cells and activated the Wnt and Notch signaling pathways in CD133−IL-23R+ ESCC cell lines. Consistently, CD133−IL-23R+ cells pretreated with IL-23 showed stronger anti-apoptosis activity when exposed to radiation and higher survival than untreated groups. Moreover, the inhibition of Wnt/Notch signaling by a small-molecule inhibitor or siRNA abolished the effect of IL-23-induced dormancy and consequent radioresistance. Taken together, these results suggested that IL-23 facilitates radioresistance in ESCC by activating Wnt/Notch-mediated G0/1 phase arrest, and attenuating these detrimental changes by blocking the formation of dormancy may prove to be an effective pretreatment for radiotherapy.

Objective To investigate the effect of acetyl coenzyme A synthase 2 (ACSS2) on the migration and invasion induced by nutrient stress (NS) in cervical cancer cells. Methods Immunohistochemistry was used to detect the expression and distribution of ACSS2 protein in 20 pairs of cervical tumors and their adjacent normal tissues. Cervical cancer HeLa cells and the normal cervical epithelial HCvEpC cells were cultured, and serum content in culture medium was reduced from 100 to 10 mL/L as NS treatment. Western blot analysis was performed to detect the expression of ACSS2, GSK-3β, p-GSK-3β, β-catenin, β-actin, E-cadherin, vimentin. Small interfering RNA (siRNA) was used to down-regulate the expression of ACSS2. Cell migration was assessed by wound healing test, and cell invasion was tested by TranswellTM assay. Results The expression level of ACSS2 in 20 cervical tumors was significantly higher as compared with the adjacent normal tissues. The levels of ACSS2 in HeLa cells could be significantly up-regulated by NS, while no marked change was seen in HCvEpC cells. The treatment of NS promoted the epithelial mesenchymal transformation (EMT) of HeLa cells, which could be effectively reversed by siRNA-ACSS2. The scratch results showed that NS increased the healing rate of HeLa cells, which could be blocked by ACSS2 silencing. Coincidently, the number of invasive cells was elevated after NS treatment, which could be partly reversed by siRNA-ACSS2. The expression of ACSS2, p-GSK-3β and nuclear β-catenin was up-regulated in HeLa cells treated with NS for 48 hours, while siRNA-ACSS2 down-regulated their expression. Conclusion Silencing ACSS2 expression inhibits migration and invasion of cervical cancer cells induced by NS, which is related to down-regulated Wnt/β-catenin signaling pathway activity.

Increasing evidence suggests that miR-25 can function as an oncogene in different types of human malignancies, whereas little is known concerning the role of miR-25 in esophageal squamous cell carcinoma (ESCC). The aim of the present study was to investigate the role of miR-25 in ESCC and to determine the molecular mechanisms underlying its function. The expression level of miR-25 was detected in primary ESCC tissues and cell lines by real-time quantitative PCR. We also assessed whether knockdown of miR-25 influences in vitro cell invasion and migration. Western blot analysis was used to detect the influence of miR-25 on a target gene, and Pearson analysis was used to calculate the correlation between the expression of a target gene and miR-25 in ESCC tissues. The results revealed that the relative level of miR-25 expression was significantly upregulated in ESCC tissues and cell lines. Expression of miR-25 in ESCC tissues was positively associated with depth of tumor invasion and tumor stage. Moreover, high miR-25 expression conferred poorer overall survival (OS), and a multivariate analysis revealed that miR-25 was an independent risk factor for OS. In addition, knockdown of miR-25 in ESCC cells significantly suppressed cell migration and invasion. Furthermore, we identified F-box and WD repeat domain-containing 7 (FBXW7) protein as a direct functional target of miR-25 in ESCC. In conclusion, the present study supports the potential of miR-25 as a prognostic predictor with its high expression in cancer tissues and its association with tumor progression by targeting FBXW7 in ESCC.

Parasite-derived molecules with immunomodulatory properties, which have been optimised during host-parasite co-evolution, exhibit potential applications as novel immunotherapeutics. We have previously demonstrated that Schistosoma japonicum HSP60-derived peptide SJMHE1 induces CD4+CD25+ regulatory T-cells (Tregs) and that adoptively transferred SJMHE1-induced CD4+CD25+ Tregs inhibit delayed-type hypersensitivity (DTH) in mice. However, multiple concerns regarding this method render this treatment unsuitable. To gain further insights into the potential effects of SJMHE1, we used ovalbumin (OVA)-induced DTH and evaluated the effect of SJMHE1 on DTH mice.

The PI3K/Akt/mTOR pathway is activated in a variety of human tumors including B-cell non-Hodgkin lymphoma (B-NHL). Targeting this pathway has been validated in solid and hematological tumors. In the present study, we demonstrated that PF-04691502, a novel PI3K/mTOR inhibitor has potent activity in a panel of aggressive B-NHL cell lines including diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). MTS analysis showed that PF-04691502 effectively inhibited cell proliferation with IC50 values ranging from 0.12 to 0.55 µM. Cells treated with PF-04691502 exhibited decreased phosphorylation of Akt and S6 ribosomal protein confirming the mechanism of action of a PI3K/mTOR inhibitor. Also, treatment of B-NHL cell lines with PF-04691502 induced apoptosis in a dose- and time-dependent manner. Moreover, PF-04691502 significantly induced G1 cell cycle arrest associated with a decrease in cyclin D1 which contributed to suppression of cell proliferation. Finally, rituximab enhanced apoptosis induced by PF-04691502. Taken together, our findings provide for the first time that PF-04691502 inhibits the constitutively activated PI3K/mTOR pathway in aggressive B-cell NHL cell lines associated with inhibition of cell cycle progression, cell proliferation and promotion of apoptosis. These findings suggest that PF-04691502 is a novel therapeutic strategy in aggressive B-cell NHL and warrants early phase clinical trial evaluation with and without rituximab.

OBJECTIVE:This study aims to detect the expression level of interleukin-23 (IL-23) in tongue squamous cell carcinoma tissues and its relationship with clinical prognosis, as well as explore the anti-apoptotic and drug resistance of the tongue squamous cell line-SCC9 before and after treatment with IL-23.METHODS:The expression of IL-23 in tumor tissues from 28 tongue cancer patients was analyzed by immunohistochemistry assay. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Wingless-related integration site (Wnt)1 and c-myc in SCC9 cells treated with different IL-23 concentrations. After interferencing the β-catenin with small interfering RNA (siRNA), the expression of β-catenin, B-cell lymphoma-2 (Bcl-2), ATP-binding cassette sub-family G member 2 (ABCG2), and permeability-glycoprotein (P-gp) in SCC9 was measured by Western blot analysis. The effect of IL-23 on the apoptotic resistance of SCC9 to cisplatin was examined by methyl thiazolyl tetrazolium test.RESULTS:The expression of IL-23 in tongue cancer tissues was correlated with lymphatic metastasis, nerve invasion, and the recurrence after therapy (P<0.05). After dealing with IL-23, SCC9 showed the upregulation effect of Bcl-2, ABCG2 and P-gp expressions. IL-23 was closely related to the activation level of the Wnt pathway and significantly strengthened the resistance to cisplatin (P<0.01).CONCLUSION:IL-23 activates the Wnt pathway in tongue squamous cell carcinoma, thereby enhancing its resistance to apoptosis and drug.

Objective:To detect the progress of epithelial-mesenchymal transition(EMT) in esophageal squamous carcinoma cells(ESCC) TE-1 which was treated with ionizing radiation,and explore the underlying mechanisms.Methods:After treated with different intensity of ionizing radiation (0,2,4,8 Gy),realtime PCR was used to detect the mRNA expression of Snail 1 and AP-1 in TE-1 cells.Western blot was used to measure the protein expressions of Snail 1,Slug,E-cadherin and Vimentin.The protein levels of Ecadherin and Vimentin was verified by immunofluorescence.The ability of migration was measured by wound healing test and Transwell inserts.Dealing with ionizing radiation (4 Gy) and/or DAPT the inhibitor of Notch signaling pathway,the expression levels of Notch 1,NICD,Hes 1 and MMP-9 proteins were measured by Western blot.Results:After treated with ionizing radiation,TE-1 cells showed the up-regulation effect of the transcription factors of EMT(Snail 1,Slug,AP-1),mesenchymal marker(Vimentin) and metastasis related protein (MMP-9),meanwhile the down-regulation effect of epithelial marker(E-cadherin).and when dealing with 4 Gy radiation,the changes was significant (P ＜0.01).Ionizing radiation accelerated the transfer ability of TE-1 (P ＜ 0.05).By up-regulating the expression levels of Notch 1/NICD/Hes 1 signaling pathway,ionizing radiation promoted EMT related protein expressions (P ＜ 0.01).Conclusion:The ionizing radiation strengthens EMT,thereby induces metastasis,by activating Notch signaling pathway.

OBJECTIVES:To compare the cytokine profile in RA patients and healthy control by using two methods-FlowCytomix assay and traditional ELISA.METHODS:Cytokine levels were evaluated by FlowCytomix assay and ELISA in serum and supernatants of peripheral blood mononuclear cells (PBMC) cultures with and without stimulation by phytohaemagglutinin (PHA).RESULTS:The levels of IL-6, IL-1β, and TNF-α were significantly higher in sera of RA patients than those of healthy controls. The levels of IL-22, IL-6, IL-1β, TNF-α, and IL-10 were higher in unstimulated PBMC culture supernatant of RA patients than those of healthy controls. PHA stimulation significantly increased the production of proinflammatory cytokines from PBMC with RA patients. Compared with detectable cytokine levels in sera, cytokine concentration in the supernatant of PBMCs was remarkably higher. FlowCytomix and ELISA showed significant correlation in detecting cytokines. However, the FlowCytomix assay detected more cytokines than ELISA.CONCLUSION:The supernatant of PBMCs provide a fine condition for the study of cytokine production because of the lack of interference factors in sera. The FlowCytomix assay is more sensitive than ELISA in detecting cytokines from RA patients. Multiple cytokine signatures using FlowCytomix assay may represent a more realistic approach in the future of personalized medicine in RA.

As the eighth most common malignant tumour worldwide, oesophageal cancer (OC) is often diagnosed during the metastasis of its advanced stage. Interleukin (IL)-23 is an immunomodulatory cytokine that has recently been identified as a cancer-associated factor. However, the role of IL-23 in the evolution of OC remains unclear. In the present study, we found that IL-23 was significantly expressed in the tumours of OC patients suffering metastasis and demonstrated that IL-23 contributed to epithelial-mesenchymal transition (EMT) through the Wnt/β-catenin pathway, promoting the migration and invasion of OC cells. In conclusion, IL-23 plays a pivotal role in the development of OC via EMT.