American journal of cancer research最新文献

A novel reduced-toxicity conditioning (RTC) regimen of busulfan, fludarabine, cyclophosphamide, and antithymocyte globulin (Bu/Flu/Cy/ATG) followed by haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients with hematologic malignancies has been reported and the results was encouraging. However, the safety and efficacy of this regimen was unknown in older myelodysplastic neoplasms (MDS) patients. From January 2018 to December 2021, 68 consecutive older patients (aged over 50) using the RTC regimen for T-cell replete haplo-HSCT (RTC group) at our center were eligible, 68 patients aged under 50 using modified busulfan, cyclophosphamide plus antithymocyte globulin regimen (Bu/Cy/ATG) (Bu/Cy/ATG group) were randomly selected from 223 MDS patients during the same period in a 1:1 ratio matched-pair analysis for patient sex, World Health Organization (WHO) category, international prognostic scoring system (IPSS) risk group, time from diagnosis to HSCT, chemotherapy in advanced, response after chemotherapy, donor sex, infused mononuclear cells and the CD34-positive cell count. The transplant outcomes were also compared between the RTC group and the matched sibling donor (MSD) haploidentical stem cell transplantation (HSCT) with the busulfan and cyclophosphamide (Bu/Cy) conditioning regimen. The cumulative incidences of grade II-IV acute graft versus host disease (aGVHD) in the RTC group were significantly lower than that in the Bu/Cy/ATG group. The 3-year cumulative incidences of treatment related mortality (TRM) in the two groups were 12.3% versus 14.7% (P=0.613). The cumulative incidences of relapse, disease-free survival (DFS) and overall survival (OS) were comparable between the two groups. The outcomes were better in RTC group than those patients received MSD transplant, with lower incidence of TRM, and higher OS and DFS. The advantages were still significant when comparing patients receiving children donors HSCT in RTC group with MSD transplant in survival and TRM. Children donor with the RTC regimen could be a better choice than the MSD HSCT with Bu/Cy regimen for the elderly MDS patients. The encouraging results suggest that the RTC regimen followed by haplo-HSCT is a potentially promising method for older MDS patients. The trail number of the prospective study is "NCT03412409" and the trial URL is "https://clinicaltrials.gov/study/NCT03412409?term=NCT03412409&rank=1".

Radiation-induced bone injury (RBI) has a multifaceted mechanism of occurrence, is influenced by various factors, and is difficult to prevent. Clinicopathologic features and manifestations of disease progression were observed in two patients with distinct fractures: one with a left-sided fourth rib fracture after postoperative radiotherapy for lung cancer, and the other with a right-sided intertrochanteric femur fracture following accidental exposure to a ¹⁹²Ir radiation source 5 years prior. These two clinical case reports discussed the clinicopathologic features of RBI and disease progression and utilized transcriptome sequencing to explore potential new targets for treating this type of RBI. Both patients exhibited similar incurable osteolytic bone destruction and fatty infiltration in their pathology. It is proposed that XIST, the most significantly upregulated gene identified by transcriptome sequencing analysis, maybe a potential target for understanding these molecular mechanisms.

This study aimed to construct multi-site magnetic nanospheres to capture circulating tumor cells (CTCs) from peripheral blood specimens of laryngopharyngeal head and neck tumors. Separated CTCs were used to measure downstream molecular markers and to detect and analyze the disease status. A stable CTC multisite nano-enrichment system was used to determine changes in CTCs levels in Programmed Death-Ligand-1 (PD-L1)-positive patients and to assess the extent of real-time changes in CTCs over the course of the disease in correlation with clinicopathological indicators. The results demonstrated that the constructed immunomagnetic spheres could effectively capture CTCs and that the constructed lipid nanoparticles exhibited high capture efficiency and low cytotoxicity. The results of the concordance or complementarity analyses of PD-L1 expression at the CTC and tissue levels indicated good concordance between the two at up to 70%. The analysis of PD-L1 expression and the changes in CTCs in PD-L1-positive cells plays an auxiliary role in clinical diagnosis and can be used as a dynamic detection index for the course of head, neck, and throat tumor treatment and as a predictor of recurrence risk.

Osteosarcoma (OS) is a highly malignant bone tumor with poor prognosis and limited therapeutic options. Recent studies have highlighted the critical role of RNA modifications, particularly N6-methyladenosine (m6A) methylation, in cancer progression. This study aimed to investigate the role of ALKBH1, a m6A demethylase, in the proliferation and metastasis of OS through the regulation of TRAF1. Our findings showed that lower ALKBH1 expression correlates with poorer overall survival in OS patients. Knockdown of ALKBH1 significantly enhanced the proliferation, migration, and clonogenicity of OS cell lines (MG63 and HOS cells), while overexpression had the opposite effects. Transcriptomic analysis revealed that ALKBH1 regulates the expression of key oncogenes, including TRAF1, through m6A methylation. m6A-RIP and qPCR assays further confirmed that overexpression of ALKBH1 significantly decreased the m6A methylation and expression of TRAF1 in both MG63 and HOS cells, and ALKBH1 knockdown had the opposite roles. Combined knockdown of ALKBH1 and TRAF1 further reduced the oncogenic properties of osteosarcoma cells compared to individual knockdown for ALKBH1. In conclusion, ALKBH1 silence promotes osteosarcoma proliferation and metastasis by regulating TRAF1 expression through m6A methylation. Targeting the ALKBH1-TRAF1 axis may provide a novel therapeutic strategy for osteosarcoma.

Vitamin A (VA, retinol) and its metabolites, including retinoic acid (RA), play a major role in the maintenance of cell populations in the adult pancreas. Pancreatic ductal adenocarcinomas (PDACs) contain lower amounts of VA and express lower levels of retinoic acid receptors (RARs) compared to normal human pancreatic tissues. Our goal was to determine if VA signaling directly impacts molecular events underlying pancreatic carcinogenesis using cell-type specific genetic approaches in mice. We knocked out retinoic acid receptor beta (RAR-β) selectively in pancreatic cells by tamoxifen treatment after crossing these adult RAR-β^fl/fl mice with Pdx1/CreER (PC^er) and lox-stop-lox KRas^G12D transgenic mice. Our data show that the rounds of tamoxifen we used were able to induce the knockout of the RAR-β gene in pancreatic cells in this PC^er;KRas;RAR-β^fl/fl transgenic model. We detected increases in proteins involved in RA metabolism (CYP26A1, RBP1, and ALDH1A2) in the PC^er;RAR-β^D/wt pancreata, but the levels of RBP1 and ALDH1A2 were decreased in PC^er;RAR-β^D (both RAR-β alleles deleted) compared to PC^er;KRas;RAR-β^D and wild-type pancreata. Ki67 and vimentin proteins exhibited lower levels in the PC^er;KRas;RAR-β^D and PC^er;RAR-β^D pancreata compared to wild-type, indicating that deletion of RAR-β reduced cell proliferation in acinar cells. Expression of SOX9, a key protein required for formation and maintenance of PDAC, was higher in PC^er;RAR-β^D/wt and PC^er;RAR-β^D pancreata compared to wild-type, indicating that deletion of RAR-β increases SOX9 levels even without the KRas activating mutation. In summary, lack of RAR-β in pancreatic acinar cells reduced cell proliferation and increased SOX9 protein levels in this transgenic model.

This review investigates the role of amino acid metabolism in the tumor microenvironment of colorectal cancer (CRC) and explores potential targeted therapeutic strategies. The paper synthesized current research on amino acid metabolism in the colorectal cancer tumor microenvironment, focusing on amino acids such as tryptophan, methionine, glutamine, and arginine. It examined their impact on tumor growth, immune evasion, and patient prognosis, as well as the metabolic reprogramming of tumor cells and complex tumor microenvironment interactions. Aberrant amino acid metabolism was a hallmark of colorectal cancer, influencing tumor proliferation, survival, and invasiveness. Key findings included: Tryptophan metabolism via the kynurenine and serotonin pathways significantly affected immune response and tumor progression in CRC. Methionine influenced T cell function and DNA methylation, playing a critical role in tumor development. Glutamine was extensively used by tumor cells for energy metabolism and supported immune cell function. Arginine metabolism impacted CD8+ T cell functionality and tumor growth. The review also discussed the dual roles of immune cells in the tumor microenvironment and the potential of targeting amino acid metabolic pathways for CRC treatment. In conclusion, amino acid metabolism significantly impacts the colorectal cancer tumor microenvironment and immunity. Understanding these metabolic pathways provides valuable insights into CRC pathogenesis and identifies potential therapeutic targets. Future research should focus on developing treatments that disrupt these metabolic processes to improve patient outcomes in CRC.

This study aims to explore a new approach to reduce the recurrence risk and improve the prognosis of ovarian cancer (OC) patients with abdominal metastasis by analyzing the clinical characteristics and prognostic factors. A total of 292 OC patients with abdominal metastasis, treated at Henan Provincial People's Hospital between 2021 and 2023 were included in this retrospective study. Follow-up was conducted for one year to observe the recurrence, with 285 patients completing the observation. The patients were then categorized into relapsing and non-relapsing groups based on whether they experienced a relapse within one-year follow-up. Independent sample t-tests and χ ² tests were used for inter-group comparison. Both univariate and multivariate logistic regression analyses were utilized to screen factors affecting recurrence. The variance inflation factor (VIF) was used to analyze whether the variables in the model had multicollinearity. Receiver Operating Characteristic (ROC) curves and nomographs were used to construct models for predicting one-year recurrence in OC patients with abdominal metastasis. Area under curve (AUC) of ROC and Hosmer-Lemeshow goodness of fit test were used to evaluate the accuracy of the model. The prediction model was verified by internal verification and external verification. The number of pregnancies, the number of births, diabetes mellitus, tumor diameter, tumor reduction combined with intraperitoneal chemotherapy, CA-125, HE-4, NLR, PLR, MLR showed association with patient recurrence. Logistic regression analysis revealed that lower pregnancy frequency and elevated levels of CA-125, HE-4, PLR and MLR were independent risk factors for increased risk of recurrence. In addition, the nomogram-based model demonstrated strong predictive accuracy for one-year recurrence. OC patients with abdominal metastasis present diverse clinical manifestations, among which fewer pregnancies and elevated levels of CA-125, HE-4, PLR, and MLR may be independent risk factors for increased risk of recurrence. Individualized interventions based on these prognostic factors are essential to reduce risk and enhance patient quality of life.

Pancreatic ductal adenocarcinoma (PDAC) has an immunosuppressed, apoptosis-resistant phenotype. TLY012 is pegylated recombinant Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL), an orphan drug for chronic pancreatitis and systemic sclerosis. Innate immune TRAIL signaling suppresses cancer. We hypothesized that the combination of immune checkpoint-blocking anti-PD-1 antibody and TLY012 would have synergistic anti-tumor efficacy in immune-competent PDAC-bearing mice. PDAC tumor-bearing C57Bl/6 mice treated with 10 mg/kg anti-mouse PD-1 antibody twice weekly and 10 mg/kg TLY012 three times weekly had reduced tumor growth and tumor volume at 70 days compared to either drug alone (all P < 0.005). B-cell activating factor (BAFF), which promotes PDAC tumors, decreased to 44% of control mice with dual treatment at 7 days and remained decreased at 3 months. Long-term dual treatment showed the highest plasma levels of proinflammatory cytokines interferon-gamma (average 5.6 times control level, P=0.046), CCL5 (average 14.1 times control level, P=0.048), and interleukin-3 (IL-3, average 71.1 times control level, P=0.0053). Flow cytometry showed trends toward decreased circulating regulatory T cells, increased NK cells, and a higher proportion of CD8+ T cells within tumors in the dual treatment group. In summary, the combination of anti-PD-1 and TLY012 prevented the growth of PDAC in an immunocompetent mouse model while increasing tumor-infiltrating CD8+ T cells, decreasing circulating T-regulatory cells and altering plasma cytokine expression of CCL5, interferon-gamma, and IL-3 to promote proinflammatory, antitumor effects. Combining TLY012 and anti-mouse PD-1 modifies immune cell and cytokine levels to induce a more proinflammatory immune environment that contributes to decreased PDAC tumor growth.

Mastocytosis is characterized by an abnormal accumulation of mast cells (MC) in various organs. In most patients, the disease is driven by the KIT D816V mutation, leading to activation of the KIT receptor and subsequent downstream signaling, including the JAK/STAT pathway. In recent years, KIT-targeting tyrosine kinase inhibitors (TKI) have emerged for the treatment of systemic mastocytosis; however, the overall response rate is often not sufficient. In this study, we investigated whether targeting the JAK/STAT pathway might be a novel treatment approach in mastocytosis. Using human MC lines carrying the KIT D816V mutation and human primary cord blood-derived MC, we examined the effects of different JAK inhibitors. Our findings revealed that the JAK inhibitors fedratinib and gandotinib decreased viability, reduced proliferation, and induced apoptosis in KIT D816V-positive MC lines (HMC-1.2 and ROSA ^{KIT D816V}). In contrast, ruxolitinib, baricitinib, upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with fedratinib, gandotinib and the two TKI avapritinib and midostaurin was more effective than treatment with TKI alone. Fedratinib also induced apoptosis and enhanced the efficacy of TKI in primary cord blood-derived MC. These results indicate that fedratinib and gandotinib, but not the other JAK inhibitors used in this study, can suppress viability and induce apoptosis in KIT D816V-mutant and KIT WT MC and increase effects of TKI. These findings suggest to explore fedratinib and gandotinib as novel treatment option in mastocytosis.

Tumor metastasis is the leading cause of death in cancer patients. Epithelial cell adhesion molecule (EpCAM) is abundantly expressed in various malignant tumors and plays a crucial role in cell adhesion, metastasis, proliferation, and differentiation. This study investigated the effects of hinokitiol, a natural tropolone compound known for its antiviral, anti-inflammatory, and antibacterial properties, on tumor growth and metastasis. Specifically, the study focused on the expression of EpCAM in mouse tumor cells treated with hinokitiol. Hinokitiol was administered to mouse melanoma cells (B16F10) and mouse colorectal carcinoma cells (CT26), resulting in a significant decrease in EpCAM expression. Additionally, the protein levels involved in the protein kinase-B/mammalian target of rapamycin (AKT/mTOR) signaling pathway were reduced following hinokitiol treatment. Using wound healing and Transwell assays, the study demonstrated that hinokitiol effectively inhibits cancer cell migration. In vivo experiments were conducted using mice, which were injected intravenously with B16F10 or CT26 cells to induce tumor metastasis. The tumor cells were either treated with hinokitiol or left untreated. The results showed that tumor cells treated with hinokitiol exhibited significantly reduced tumor size and weight in the lungs, as well as prolonged survival, compared to untreated tumor cells. This study concludes that hinokitiol inhibits tumor migration by downregulating EpCAM via the AKT/mTOR signaling pathway and exhibits positive effects in vivo.