Chemotherapy remains the main approach conserving vision during the treatment of retinoblastoma, the most prevalent eye cancer in children. Unfortunately, the development of chemoresistance stands as the primary reason for treatment failure. Within this study, we showed that prolonged exposure to vincristine led to heightened expression of JAK1 and JAK2 in retinoblastoma cells, while the other members of the JAK family exhibited no such changes. Employing a genetic intervention, we demonstrated the efficacy of depleting either JAK1 or JAK2 in countering vincristine-resistant retinoblastoma cells. In addition, the dual depletion of both JAK1 and JAK2 produced a more potent inhibitory outcome compared to the depletion of either gene alone. We further demonstrated that ruxolitinib, a small molecular inhibitor of JAK1/2, effectively reduced viability and colony formation in vincristine-resistant retinoblastoma cells. It also acts synergistically with vincristine in retinoblastoma cells regardless of inherent cellular and genetic heterogeneity. The effectiveness of ruxolitinib as standalone treatment against chemoresistant retinoblastoma, as well as its combination with vincristine, was validated in multiple retinoblastoma mouse models. Importantly, mice exhibited favorable tolerance to ruxolitinib administration. We confirmed that the underlying mechanism of ruxolitinib's action in chemoresistant retinoblastoma cells is the inhibition of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Our study reveals that the underlying mechanism driving ruxolitinib's impact on chemoresistant retinoblastoma cells is the inhibition of JAK/STAT signaling. This study reveals the contribution of JAK1/2 to the development of chemoresistance in retinoblastoma and underscores the effectiveness of targeting JAK1/2 as a strategy to sensitize retinoblastoma to chemotherapy.

Chemotherapy failure and resistance are the leading causes of mortality in patients with acute myeloid leukemia (AML). However, the role of m6A demethylase FTO and its inhibitor rhein in AML and AML drug resistance is unclear. Therefore, this study aimed to investigate the antileukemic effect of rhein on AML and explore its potential mechanisms underlying drug resistance. Bone marrow fluid was collected to assess FTO expression in AML. The Cell Counting Kit 8 reagent was used to assess cell viability. Migration assays were conducted to assess the cell migration capacity. Flow cytometry was used to determine the apoptotic effects of rhein and western blot analysis was used to detect protein expression. Online SynergyFinder software was used to calculate the drug synergy scores. The in-vivo antileukemic effect of rhein was assessed in an AML xenograft mouse model. We analyzed different types of AML bone marrow specimens to confirm that FTO is overexpressed in AML, particularly in cases of multidrug resistance. Subsequently, we conducted in-vivo and in-vitro investigations to explore the pharmacological activity and mechanism of rhein in AML and AML with multidrug resistance. The findings demonstrated that rhein effectively suppressed the proliferation and migration of AML cells in a time- and dose-dependent manner and induced apoptosis. Rhein targets FTO, inhibits the AKT/mTOR pathway, and exhibits synergistic antitumor effects when combined with azacitidine. This study elucidates the significant role of FTO and its inhibitor rhein in AML and AML with multidrug resistance, providing new insights for overcoming multidrug resistance in AML.

To study the diagnostic value of mRNA expression in urinary exocrine body in bladder cancer. From February 2022 to December 2022, 60 patients diagnosed with bladder cancer by pathology in the Department of Urology, Affiliated Hospital of Chengde Medical University were selected as the case group. In total, 40 healthy subjects receiving physical examinations were selected as the control group. 100 mL of morning urine samples were collected from the subjects in both groups based on the same standard. Three subjects were randomly selected from each group. Urinary exosomes were extracted by differential ultracentrifugation. High-throughput sequencing (RNA-seq) was used to detect mRNA expression profiles in urinary exosomes and identify differentially expressed genes. Bioinformatic analysis was performed to predict major biological functions of differentially expressed genes and related signaling pathways. RT-PCR validated expression levels of differentially expressed genes in urinary exosomes between the two groups. ROC curves evaluated the diagnostic value of differential genes for bladder cancer. Spearman's correlation analysis determined correlations between differentially expressed genes and the occurrence of bladder cancer. ROC curves speculated the diagnostic value of using combined differentially expressed genes. Compared with normal subjects, there were 189 significantly differentially expressed genes in urinary exosomes of bladder cancer patients, including 33 up-regulated and 156 down-regulated. According to go and kyoto encyclopedia of genes and genomes (KEGG) analysis, the above differentially expressed genes may participate in the occurrence and development of bladder cancer through the MAPK pathway, PPAP signaling pathway, PI3K Akt signaling pathway and Hippo signaling pathway, affect protein and lipid metabolism, RNase activity, polysaccharide synthesis, signal transduction and other biological processes, and participate in cell proliferation, death, movement and adhesion, as well as cell differentiation and signal transduction. RT-PCR verified that the expression of tmeff1, SDPR, ACBD7, SCG2 and COL6A2 in the two groups of samples was statistically significant ( P < 0.05). The ROC curve showed that the area under curve area under the curve of the five differential genes were 0.6934, 0.7746, 0.7239, 0.6396 and 0.6610, respectively. The sensitivity was 42.11%, 64.86%, 47.37%, 73.53% and 76.47%, and the specificity was 90%, 81.36%, 96.36%, 61.02% and 58.18%, respectively. Spearman correlation analysis showed that tmeff1, SDPR and acbd7 were associated with the occurrence of bladder cancer. The ROC curve of the combined diagnosis of the three and the two combined diagnoses suggested that the area under the curve of the combined diagnosis of SDPR and acbd7 was 0.7945, the sensitivity was 89.09%, and the specificity was 60.53%. The gene expression profile in urinary exosomes of bladder cancer patients has changed significantly, and the differential genes may play an important biological role in the occurrence and development of bladder cancer. The combined detection of urinary exosome SDPR and ACBD7 has a certain diagnostic value for bladder cancer.

It is well known that immune cells including macrophages within the tumor microenvironment play an essential role in tumor progression. Here, we studied how NFATc2 regulated macrophage properties in lung adenocarcinoma. Higher expression of NFATc2 was observed in the lung adenocarcinoma tissues than in the normal lung tissues. Positive relationships were found between NFATc2 and genes associated with hypoxia and glycolysis in lung adenocarcinoma from the TCGA dataset. According to single-cell sequence data, NFATc2 was closely associated with infiltrating immune cells and was related to macrophage polarization. As a transcription factor, NFATc2 binding to the USP17 promoter region, that enhanced cell migration and lactate level in lung adenocarcinoma cells, and M2 polarization in macrophages. Furthermore, the NFATc2 inhibitor suppressed lactate and M2 macrophage polarization induced by NFATc2 and USP17. In conclusion, NFATc2 promotes lactate level and M2 macrophage polarization by transcriptionally regulating USP17 in lung adenocarcinoma.

Gastric cancer is a kind of malignant tumor that seriously endangers human life and health. Its incidence rate and mortality rate are among the highest in the global malignant tumors. Therefore, this study explored the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the progression of gastric cancer and its underlying mechanism. Patients with gastric cancer were collected, and human GC cell lines (stomach gastric carcinoma 7901, stomach gastric carcinoma 823 , human gastric carcinoma cell line 803 and adenocarcinoma gastric stomach) were used in this study. We utilized glucose consumption, cell migration, and ELISA assay kits to investigate the function of GC. To understand its mechanism, we employed quantitative PCR (qPCR), western blot, and m6A methylated RNA immunoprecipitation assay. FKFB3 protein expression levels in patients with gastric cancer were increased. The induction of PFKFB3 mRNA expression levels in patients with gastric cancer or gastric cancer cell lines. Gastric cancer patients with high PFKFB3 expression had a lower survival rate. PFKFB3 high expression possessed the probability of pathological stage, lymph node metastasis or distant metastasis in patients with gastric cancer. PFKFB3 upregulation promoted cancer progression and Warburg effect progression of gastric cancer. PFKFB3 upregulation reduced pyroptosis and suppressed nucleotidebinding domain, leucinerich repeat containing protein 3-induced pyroptosis of gastric cancer. M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability. Taken together, the M6A-forming enzyme methyltransferase-like 3 increased PFKFB3 stability and reduced pyroptosis in the model of gastric cancer through the Warburg effect. The PFKFB3 gene represents a potential therapeutic strategy for the treatment of gastric cancer.

The treatment strategy for nonsmall cell lung cancer (NSCLC) has always been a hot topic of concern, and its treatment strategies are also emerging. This experiment wants to know the effects of apolipoprotein C1 (APOC1) in immunotherapy of NSCLC. APOC1 mRNA and protein expression were upregulated in lung cancer tissue of patients with NSCLC. programmed cell death protein 1 (PD-1) mRNA expression was negatively correlated with PD-1 mRNA expression in patients. The survival rate of APOC1 high expression was lower than that of low expression in patients with NSCLC. APOC1 gene reduced the transformation of M2 into M1 macrophages (TMMM). APOC1 gene promoted cell growth, and the gene reduced ferroptosis of NSCLC. APOC1-induced nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway. Sh-APOC1 gene reduced cell growth in mice of NSCLC through the inhibition of NRF2/HO-1 signaling pathway. The inhibition of NRF2 reduced the TMMM by APOC1. The activation of NRF2 reduced the TMMM by si-APOC1. In conclusion, APOC1 reduced anti-PD-1 immunotherapy of NSCLC via the TMMM by ferroptosis by NRF2/HO-1, suggesting that targeting this mechanism of APOC1 may be a feasible strategy for anti-PD-1 immunotherapy for NSCLC.

Biliary tract cancers are solid tumors with poor prognosis and over 70% of patients present in advanced stages. The efficacy of second-line treatment for patients who progressed on GC chemotherapy is limited. Median OS of these patients is less than 1 year with palliative treatment. Despite the success of anti-HER2 therapy in HER2-positive breast cancer, the targeted therapy of HER2 mutations in BTCs is still being explored. This case report is the first report suggesting a 15-month PFS and partial response of pyrotinib in HER2-positive BTC. We report a 64-year-old female with HER2-positive biliary tract cancer. She was diagnosed with AJCC clinical stage IV (cT3N1M1) intrahepatic biliary tract cancer and got PD after 3 cycles of systemic chemotherapy of gemcitabine plus cisplatin. Due to the HER2-positive signature, pyrotinib (400 mg daily in 21-day cycles), an oral irreversible pan-ErbB TKI was prescribed in September 2021, with her informed consent. The tumor shrank significantly after this treatment and imaging assessments conducted on 24 September 2022 showed PR. Until the writing of the case draft, the patient had achieved 15 months of PFS. The present case suggests that Pyrotinib might be a potential effective treatment for HER2-positive advanced BTC.

Several rare anaplastic lymphoma kinase (ALK) fusions have been identified in patients with non-small cell lung cancer (NSCLC); however, their treatment is not currently uniform. alectinib has been commonly used to treat rare ALK fusions in patients with NSCLC. This is the first study to report the occurrence of a uridine diphosphate-glucose pyrophosphorylase 2 (UGP2)-ALK fusion in a patient with NSCLC. The patient, who was hospitalized because of shortness of breath lasting 20 days, showed hydrothorax of the left lung under a computerized tomography chest scan. Pathological histology revealed lung adenocarcinoma in the patient. The UGP2-ALK mutation was found by next-generation sequencing. Subsequently, the patient was administered alectinib, and thereafter, the tumor lesion was observed to gradually shrink over the follow-up period. Progression-free survival reached 10 months as of the follow-up date, with no adverse events detected. This case report provides valuable insights into the clinical management of NSCLC patients with UGP2-ALK fusions. Moreover, alectinib is confirmed to be an appropriate therapeutic agent for such patients.

To evaluate the relationship between the use of proton pump inhibitors (PPI) and the risk of gastric cancer and colorectal cancer by using meta-analysis. Computer search PUBMED, EMBASE, Cochrane Library, CNKI and Wanfang database to obtain relevant literature on the use of PPI and the risk of gastric cancer and colorectal cancer, extract relevant data, and use Stata14.0 for Meta-analysis. A total of 24 articles were included, including 12 articles for gastric cancer and 12 articles for colorectal cancer. A total of 5 313 749 persons were included in the study and analysis. Meta-analysis results showed that the risk of gastric cancer in PPI users was significantly increased [risk ratio (RR) = 2.04, 95% confidence interval (CI) (1.33-2.75)], and the regional subgroup analysis results showed that in Europe [RR = 2.01, 95% CI (0.92, 3.09), P < 0.05] and Asia [RR = 2.15, 95% CI (1.16, 3.14), P < 0.05] This risk is higher, and Asia is higher than Europe. The risk of colorectal cancer is slightly increased [RR = 1. 22, 95% CI (1.03, 1.40, P < 0.05], and the regional subgroup analysis results show that in Europe [RR = 1.05 95% CI (0.98, 1.12), P < 0.05] and Asia [RR = 1.18, 95% CI (1.10, 1.27), P < 0.05]. This risk is low, but Asia is higher than Europe. The use of PPI significantly increases gastric cancer However, the risk of colorectal cancer is not significantly increased. The risk of gastric cancer and colorectal cancer in the population using PPI in Asia is higher than that in Europe.

Cisplatin-based chemotherapy plays a vital role in the management of muscle-invasive bladder cancer (MIBC); however, off-tumor toxicity and resistance often lead to cancer recurrence and eventual treatment failure. The loss of function of the nucleotide excision repair gene excision repair cross-complementing rodent repair deficiency gene 2 ( ERCC2 ) in cancer cells correlates with sensitivity to cisplatin, while its overexpression causes cisplatin resistance. Small interfering RNA (siRNA) knockdown of ERCC2 combined with cisplatin treatment may improve therapeutic outcomes in patients with bladder cancer. Here, we aimed to develop macrophage-derived mimetic nanovesicles (MNVs) as a nanoplatform for the simultaneous delivery of cisplatin and ERCC2 siRNA for enhancing the efficacy of bladder cancer chemotherapy. The cellular uptake, gene down-regulation, tumor inhibition effects, and biosafety of the synthesized nanodrugs (MNV-Co) as a synergistic therapeutic strategy for MIBC were evaluated in vitro and in vivo . The results indicated high efficacy of MNV-Co against MIBC and low off-tumor toxicity. Furthermore, by down-regulating ERCC2 mRNA and protein levels, MNV-Co improved chemosensitivity, promoted cancer cell apoptosis, and effectively suppressed tumor growth. This study presents a potential approach for delivering cisplatin and ERCC2 siRNA concurrently to treat bladder cancer using a biomimetic nanosystem.