American journal of cancer research最新文献

Betel nut chewing, common in several Asian populations, is linked to increased cancer risk, including oral, esophageal, gastric, and hepatocellular carcinoma. Aspirin shows potential as a chemopreventive agent. This study investigates the association between aspirin use and cancer risk among betel nut chewers. Betel nut chewers aged 18 and older were included, with aspirin use defined as at least 28 cumulative defined daily doses (cDDDs). Propensity score matching and Cox proportional hazards models, adjusted for time-varying covariates, were used to assess cancer risk. The study included 46,302 betel nut chewers, equally divided between aspirin users and non-users. Aspirin use was associated with a 31% reduction in overall cancer risk (adjusted hazard ratio [aHR], 0.69; 95% confidence interval [CI], 0.66 to 0.73; P<0.0001). A dose-response relationship was observed, with higher cDDDs of aspirin corresponding to greater reductions in cancer risk. The highest quartile of aspirin use (Quartile 4) showed a 62% reduction in cancer risk (aHR, 0.38; 95% CI, 0.34 to 0.41; P<0.0001). Daily aspirin intensity was also associated with a significant reduction in cancer risk, with doses greater than 1 DDD showing an aHR of 0.54 (95% CI, 0.47 to 0.61; P<0.0001) compared to 1 DDD or less. Aspirin use significantly reduces cancer risk among betel nut chewers in a dose-dependent manner. These findings suggest aspirin as a potential chemopreventive agent in high-risk populations, warranting further investigation.

Objective: To analyze the clinical characteristics and molecular biomarkers of adult T-cell lymphoblastic lymphoma (T-LBL) to identify prognostic factors, and to evaluate the efficacy of different chemotherapy regimens, providing a basis for optimizing treatment strategies for T-LBL.

Methods: A total of 89 Patients aged 18-72 years with T-LBL, confirmed via histopathological examination of lymph nodes, extranodal tissues, or bone marrow, were retrospectively included. Clinical data, treatment details, and mutational profiles were collected. Prognostic factors were assessed based on clinical and molecular characteristics, and the efficacy and safety of two chemotherapy regimens were compared. Descriptive statistics were used to analyze the disease spectrum.

Results: Most patients (84.00%) presented with advanced disease (stages III-IV). Mediastinal invasion was observed in 63 patients (70.80%), and 59 patients (66.30%) exhibited B symptoms. Bone marrow involvement occurred in 19 patients (21.20%), and bulky mediastinum (>10 cm) was present in 50 patients (56.18%). Mutations were detected in 29 patients, with NOTCH1 being the most frequently mutated gene, followed by PHF-6, JAK-1, JAK-3, IL-7R, and TP53. The complete response (CR) rate was 51.69%. The 3-year overall survival (OS) and progression-free survival (PFS) rates were 74.9% and 58.80%, respectively. Multivariate analysis identified female sex, lack of CR, and elevated lactate dehydrogenase (LDH) levels (>2× normal) as independent predictors of poor OS (58.25%). Chemotherapy regimens, LDH levels, and sex were independent prognostic factors for PFS (21.24%).

Conclusion: T-LBL is characterized by high-frequency gene mutations across multiple signaling pathways. Mediastinal invasion (70.80%) and extranodal involvement (39.33%) were prevalent in Chinese patients and were associated with poor prognosis. Combined assessment of clinical and molecular features allows for improved prognostic stratification and facilitates the development of targeted therapies for high-risk patients.

Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-associated cancer, and immune checkpoint inhibitors (ICIs) have shown efficacy in its treatment. The combination of chemotherapy and ICIs represents a new trend in the standard care for metastatic NPC. In this study, we aim to clarify the immune cell profile and related prognostic factors in the ICI-based treatment of metastatic NPC. Programmed cell death ligand 1 (PD-L1) expression was measured in 81 metastatic tissue samples that had not received prior ICI treatment. The combined positive score (CPS) was positive in 58.0% of the samples, with a statistically significant correlation to median overall survival (OS) (CPS ≥ 1 vs. CPS < 1: 28 vs. 16 months, P = 0.004). For the combination treatment of metastatic NPC, 62 patients were enrolled in a retrospective analysis, yielding a median OS of 39.3 months. The objective response rate for this combination therapy was 71%, with a complete response rate of 45.2%. With a cutoff value of 4.8 for the pre-treated neutrophil-lymphocyte ratio (NLR) in peripheral blood (PB), the difference in median OS was statistically significant (P = 0.021). Thirty-seven patients received local treatment following the combination therapy of ICIs and chemotherapy, which provided additional survival benefits. Most hyper-responders exhibited a prolonged low NLR (< 3), a high total lymphocyte count, and an undetectable or stable EBV DNA load in PB during treatment. Peripheral blood mononuclear cells (PBMCs) from most patients receiving the combination treatment were rich in PD-1+CD8+ lymphocytes, which showed high expression of both IFN-γ and Granzyme B, demonstrating the ability to kill the EBV-positive NPC cell line and xenografts in vitro and in vivo. Responders also displayed increased levels of CD4+CD45RA-CCR7-CD28+CD57- cells (effector memory cell subset) in peripheral blood. These results indicate that in the context of combined chemotherapy and ICIs, high PD-L1 expression in pre-treated metastatic tumor tissue, a low NLR before treatment, a decrease in NLR after treatment, and local treatment can provide significant benefits for patients with metastatic NPC.

Gastric cancer is a common malignant tumor with high incidence and mortality. The overexpression of Human epidermal growth factor receptor 2 (HER2) is associated with increased metastatic potential and poor clinical outcome in gastric cancer. Despite the proven clinical response rates of approved HER2-targeted therapies, including Trastuzumab combined with chemotherapy, their limited long-term clinical benefits and inevitable disease progression still pose significant challenges to the clinical treatment of gastric cancer. Hence, exploring novel strategies to enhance therapeutic outcomes for HER2-positive patients is extremely crucial and urgent. Here, we reported that DX126-262, a novel HER2-targeted antibody-drug conjugate, generated by conjugating a potent Tubulysin B analogue (Tub-114) to humanized anti-HER2 monoclonal antibody, exhibited a significant synergistic inhibitory effect with both Cisplatin and 5-FU in HER2-positive gastric cancer NCI-N87 cells. Moreover, the triple-drug combination strategy of DX126-262 combined with Cisplatin and 5-FU showed much better in vitro and in vivo therapeutic efficacy than monotherapy or double-drug combination (Cisplatin plus 5-FU) or first-line standard-of-care (SOC, Herceptin plus Cisplatin and 5-FU), and comparable or even superior in vivo efficacy than third-line SOC (DS-8201a) in NCI-N87 cells and xenograft models. Meanwhile, the triple-drug combination therapy did not exhibit superimposed toxicity. Taken together, our findings provide compelling evidence that DX126-262 in combination with Cisplatin and 5-FU exerts synergistic antitumor activity and is a promising strategy to improve the clinical efficacy of HER2-positive advanced or metastatic gastric cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among American men. The development of metastatic castration resistant PCa (mCRPC) is the current clinical challenge. Antiandrogens such as Enzalutamide (ENZ) are commonly used for CRPC treatment. However, patients with androgen receptor (AR)-negative tumors do not respond to ENZ, while AR-positive tumors frequently develop resistance, limiting the long-term efficacy of this therapy. This study investigates the efficacy of neutral sphingomyelinase 2 (n-SMase2) inhibition by DPTIP, both alone and in combination with ENZ, as a therapeutic strategy for mCRPC. In vitro assays were conducted to determine the half-maximal inhibitory concentration (IC₅₀) of DPTIP and ENZ in mCRPC cells. The effect of these treatments on cell proliferation, migration, and colony formation was assessed. The antitumor effect of DPTIP was also evaluated in a preclinical PCa mouse model. Elevated n-SMase2 expression was observed in PCa patients compared to normal subjects at both mRNA and protein levels. In CWR-R1ca and PC-3 cells, DPTIP had IC₅₀ values of 10.31 and 14.57 µM, while ENZ had IC₅₀ values of 33.7 and 81 µM, respectively. Combined treatment significantly suppressed cell proliferation, colony formation, and migration of mCRPC cells. Mechanistically, the ERK1/2 activity and the expression of nSMase2 and NF-kB p65 were inhibited by DPTIP. The in vivo combination of DPTIP and ENZ reduced tumor size and weight more effectively than either drug alone, without significant changes in body weight. This study highlights the therapeutic potential of targeting n-SMase2 for mCRPC. Inhibition of n-SMase2 using DPTIP, both as a standalone treatment and in combination with ENZ, effectively suppressed the growth and migration of mCRPC cells. These findings suggest a promising novel approach to treating mCRPC and warrant further investigation in clinical settings.

Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the main cause of mortality in lung cancer. This study aimed to investigate the roles of neuropilin 1 (NRP1) in non-small cell lung cancer (NSCLC). NRP1 expression was assessed in tumor tissues from patients with osimertinib-resistant (OR) NSCLC and osimertinib-responsive NSCLC as well as in patients with paracancerous NSCLC tissues who did not undergo radiotherapy or chemotherapy. In vitro experiments were conducted using five cell lines: BEAS-2B, HCC827, and PC9 cells, and the constructed OR cell lines, HCC827-OR and PC9-OR. HCC827-OR cells showing significant differences in osimertinib IC₅₀ were selected for further study. After investigating the effects of altering NRP1 expression on cell sensitivity to osimertinib, NRP1 expression was inhibited to further investigate changes in cell viability, proliferation, migration, invasion, and apoptosis in OR cells. Additionally, bioinformatics techniques were used to detect targets (Integrin β3) and signaling pathways (PI3K/AKT) downstream of NRP1; subsequent cell experiments verified their interactivity. Finally, an orthotopic mouse tumor model was constructed using HCC827-OR cells treated with a PI3K/AKT signaling pathway activator (740Y-P), allowing exploration of the role played by the PI3K/AKT signaling pathway via NRP1 regulation on NSCLC resistance both in vivo and in vitro. Results showed that NRP1 expression was significantly increased in the cells of patients with NSCLC-OR, and increased NRP1 expression reduced HCC827 cell sensitivity to osimertinib. Both in vitro and in vivo experiments showed that NRP1 deficiency mediated by NRP1 inhibitors inhibited HCC827-OR cell proliferation, migration, and invasion, promoted tumor cell apoptosis, and enhanced osimertinib efficacy. In contrast, 740Y-P partially inhibited the effects of NRP1 inhibitors combined with osimertinib on the PI3K/AKT signaling pathway and on tumor growth in vivo and in vitro. Cellular experimental results showed that NRP1 positively regulates the Integrin β3 expression and activation of the PI3K/AKT signaling pathway. Bioinformatics analysis showed that both NRP1 and Integrin β3 may jointly participate in regulating the PI3K/AKT signaling pathway. In conclusion, our findings suggest that elevated NRP1 expression in NSCLC tumor tissues may promote NSCLC resistance to osimertinib by activating the PI3K/AKT signaling pathway, and integrin β3 potentially being involved in this process. These insights may provide a novel strategy for combination therapy for OR NSCLC.

The combination of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAb) and doublet chemotherapy is the standard first-line treatment for patients with wild-type RAS/BRAF metastatic colorectal cancer (mCRC). Some patients may require secondary resection after first-line treatment. However, it remains unclear whether targeted therapy should be continued after liver resection. To investigate whether targeted therapy can be spared after secondary resection, we retrospectively analyzed data from the Taiwan National Health Insurance Research Database for patients with wild-type KRAS mCRC who received first-line anti-EGFR mAb plus doublet chemotherapy. Between 2013 and 2018, 5694 mCRC patients were screened, with 174 meeting the eligibility criteria and being enrolled in this study. Among them, 153 patients continued anti-EGFR mAb after secondary resection. These patients demonstrated a significant improvement in overall survival (OS) but not in time to treatment failure. Postresection anti-EGFR mAb conferred OS benefits compared to no anti-EGFR mAb (43.17 vs. 31.41 months; P = 0.0064). When stratified by assessment period, OS was longer in patients assessed between 2016 and 2018 than in those assessed between 2012 and 2015 (not reached vs. 39.87 months; P = 0.1819). However, no significant difference was observed in time to treatment failure when stratified by assessment period or primary tumor location. A multivariate analysis revealed that postresection anti-EGFR mAb was an independent predictor of prolonged OS. In conclusion, for mCRC patients who have undergone secondary resection after first-line anti-EGFR mAb plus doublet chemotherapy, continuing anti-EGFR mAb may significantly extend OS, regardless of the primary tumor location.

N staging systems are paramount clinical features for colorectal cancer (CRC). In N1 stage (N1) CRC, patients present with a limited number of metastatic lymph nodes, yet their prognoses vary widely. The tumor invasion proportion of lymph nodes (TIPLN) has gained attention, but its prognostic value in N1 CRC remains unclear. We retrospectively analyzed 416 N1 CRC patients who underwent radical surgery from January 2014 to December 2018, reviewing 713 hematoxylin and eosin (H&E)-stained slides to assess TIPLN. Overall survival was the primary outcome in our study. Using restricted cubic splines, we explored the relationship between TIPLN and prognosis, with Cox regression and subgroup analyses adjusting for potential confounders. We found that increased TIPLN was associated with an unfavorable prognosis. At a cut-off value of 50%, patients with high-TIPLN exhibiting poorer outcomes than their low-TIPLN counterparts (hazard ratio: 3.77, P < 0.001). Furthermore, high-TIPLN was confirmed as an independent risk factor for overall survival (hazard ratio: 3.12, P < 0.001) after adjusting for clinical confounders. Notably, TIPLN could also enhance risk stratification within the T and N stages, where patients with low-risk (T1-3 stage) and high-TIPLN demonstrated poorer overall survival compared to those with high-risk (T4 stage) and low-TIPLN (hazard ratio: 2.54, P = 0.021). In conclusion, TIPLN is a promising prognostic indicator for N1 CRC patients that complements traditional N staging system for a more comprehensive evaluation. Integrating TIPLN into the TNM staging system could enhance risk stratification and guide treatment decisions.

The tumor immune microenvironment (TIME) plays a critical role in cancer development and response to immunotherapy. Immune checkpoint inhibitors aim to reverse the immunosuppressive effects of the TIME, but their success has been limited. Immunotherapy directed at PD-1/PD-L1 has been widely employed, yielding positive results. Unfortunately, the gradual emergence of resistance to PD-1/PD-L1 inhibition has diminished the effectiveness of this immunotherapy in cancer patients, emphasizing the need for new compounds that will be more effective in managing immunotherapy. This study investigated the effect of the natural compound cardamonin on PD-L1 expression and its ability to modulate the TIME, which could overcome immunotherapy resistance in triple-negative breast cancer (TNBC). This investigation used two genetically distinct triple-negative breast cancer cell lines, MDA-MB-231 (MDA-231) and MDA-MB-468 (MDA-468). The results show that TNBC cell treatment with cardamonin inhibited PD-L1 expression and reduced JAK1 and STAT3 levels in MDA-231 cells, while it increased JAK1 expression in MDA-468 cells. Also, cardamonin increased the expression of Nrf2 in both cell lines. In addition, cardamonin decreased MUC1, NF-κB1, and NF-κB2 expression in MDA-MB-231 cells and selectively reduced NF-κB1 expression in MDA-468 cells. Furthermore, cardamonin very potently reduced the inflammatory cytokine CCL2 levels. The decrease in CCL2 release reduces the chemoattraction of macrophages in the tumor microenvironment, which may increase the effectiveness of PD-1/PD-L1 inhibition and allow T-cell infiltration. These findings suggest that the cardamonin modulation of TIME holds promise in reversing resistance of PD-1/PD-L1 inhibition when it is used along with immunotherapy in TNBC treatment.

Cancer cell overexpresses numerus proteins, however, how these up-regulated proteins, especially those enzymatically opposite kinases and phosphatases, act together to promote oncogenesis is unknown. Here, we reported that protein tyrosine phosphatase H1 (PTPH1) is a scaffold protein for receptor tyrosine kinase (HER2) to potentiate breast tumorigenesis. PTPH1 utilizes its PDZ domain to bind HER2, p38γ, PBK, and YAP1 and to increase HER2 nuclear translocation, stemness, and oncogenesis. PTPH1 de-phosphorylates HER2 and reciprocally increases HER2 protein expression dependent on cellular content. PTPH1 itself can be phosphorylated at S459 by redundant kinases p38γ and/or PBK, thereby distinctively regulating expression and/or turnover of scaffold proteins. Moreover, PTPH1 and HER2 cooperate to increase PBK and Yap1 transcription thus acting as an additional mechanism to activate the scaffold. PTPH1 protein levels are higher in HER2⁺ breast cancer in which their phosphorylated forms are inversely correlated, indicating an integrated oncogenic activity through coordinated PTPH1 phosphorylation and HER2 de-phosphorylation. Combinational, but not individual, application of scaffold-kinases' inhibitors suppresses xenograft growth in mice. Thus, a PDZ-coupled and phosphorylation-driven scaffold can integrate proliferative signaling of enzymatically distinct proteins as a super-oncogene and as a target for combination therapy.