American journal of cancer research最新文献

Approximately 10% of breast cancer cases are hereditary and associated with germline BRCA1/2 mutations. To characterize the somatic alteration landscape and HRD-related genomic features, we analyzed next-generation sequencing and clinical data from 1,243 breast cancer patients treated at Tianjin Cancer Hospital Airport Hospital between October 2021 and November 2024. We compared mutation patterns and clinicopathological features between patients with and without germline BRCA (gBRCA) mutations and further assessed somatic alterations and homologous recombination deficiency (HRD) in those carrying pathogenic variants. PIK3CA mutations were significantly more frequent in the Non-Germline and non-gBRCA groups than in the Germline and gBRCA groups (49% vs. 6%; 47% vs. 0%; both P < 0.001), indicating mutual exclusivity with gBRCA mutations. Conversely, PTEN alterations co-occurred in 30% of gBRCA cases, while TP53 mutations were mutually exclusive with MDM2 and FGFR1. HER2 amplification was identified in 10% of gBRCA-mutated tumors, and somatic alterations in non-gBRCA tumors were enriched in endocrine-resistance pathways. HRD scores were markedly higher in gBRCA patients than in non-gBRCA patients (median 59 vs. 24.5, P = 0.015), driven by significant increases in large-scale state transitions (LST) and telomeric allelic imbalance (TAI). The overall gBRCA1/2 mutation frequency was 15.61%, and two previously unreported variants, BRCA1 NM_007294.3:c.4185G>A and BRCA2 NM_000059.3:c.439C>A, were identified in the Chinese population. These findings provide a biological rationale to explore AKT1/HER2-targeted combinations with PARP inhibition in future studies for gBRCA-mutated breast cancer and provide the first evidence of PIK3CA-gBRCA mutual exclusivity in Chinese patients. The elevated HRD scores further underscore the presence of homologous recombination deficiency in the gBRCA group.

To identify mitochondria related genes involved in intervertebral disc degeneration (IDD) and to investigate the potential molecular mechanism. The GSE124272 and GSE56081 datasets were used in this study. First, intersecting genes were screened by overlapping key module genes obtained from weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs). Functional enrichment analyses were performed to explore the functions of intersecting genes. Subsequently, candidate IDD-associated genes were screened using Mendelian randomization (MR) based on the intersecting genes. Thereafter, machine learning algorithm was applied to identify biomarkers, and their diagnostic performance was assessed using receiver operating characteristic (ROC) curves. Single-gene gene set enrichment analysis (GSEA) was utilized to investigate the molecular mechanisms of the identified biomarkers. Meanwhile, correlations between the biomarkers and immune cell infiltration were investigated. In addition, the transcription factor (TF)-mRNA and competing endogenous RNA (ceRNA) networks were constructed. Finally, the mRNA-drug interaction network was established. A total of 827 intersecting genes were screened, and 31 differentially expressed mitochondria-related genes were obtained. Functional enrichment results revealed that these genes were primarily involved in the positive regulation of cytokine production and the cell cycle. Four candidate genes were obtained by MR analysis based on intersecting genes. Finally, two biomarkers (PTGS1 and PPBP) were screened, both of which demonstrated decent diagnostic performance. Single-gene GSEA enrichment results indicated that these two biomarkers were mainly enriched in the ribosome and neuroactive ligand receptor interaction. Correlation analysis showed strongest positive correlation between PTGS1 and mast cells, and the highest negative association between PPBP and activated CD4 T cells. The mRNA-TF regulatory network included 2 mRNAs, 12 TFs, and 15 pairs of regulatory interactions. Furthermore, the ceRNA regulatory network included 2 biomarkers, 45 miRNAs, and 67 long non-coding RNA (lncRNAs). Finally, a total of 70 potential drugs targeting these biomarkers were predicted. In conclusion, PTGS1 and PPBP were identified as key mitochondria-related genes associated with IDD, providing novel insights into the diagnosis and treatment of IDD.

Leukemia with MLL rearrangement (MLL-r) always exhibited a poor prognosis. Targeting ferroptosis was believed to be a novel strategy for the treatment of leukemia. However, the ferroptosis inducer, RSL3 (GPX4 inhibitor), was not clinically available due to its potential off-target effects and toxicity. This study aimed to explore whether the additional matrine (MAT) could yield superior therapeutic outcomes with ferroptosis inducer. Herein, we explored that MAT can synergistically induce ferroptosis with non-toxic dosage of RSL3 in MOLM-13 and MV4-11 cells. The underlying mechanism was investigated via western blot, quantitative RT-PCR (qRT-PCR) analysis, enzyme-linked immunosorbent assay (ELISA) and Flow cytometry. We found that the combination of MAT and non-toxic-dose RSL3 significantly increased levels of intracellular ferrous ion (IFI) and lipid ROS, decreased mitochondrial membrane potential and glutathione (GSH) levels, as well as down-regulated the expression of SLC7A11 and GPX4. Systematic bioinformatic analysis results have indicated that MAT may potentiate the efficacy of RSL3 through modulation of the p53 signaling pathway. Further experiments showed that knocking down p53 reduced the synergistic effect of MAT and RSL3 in inducing ferroptosis. In addition, the combination of MAT and RSL3 can dramatically reduce the population of bone marrow CD45+ cells in AML xenograft mouse. In conclusion, MAT can synergistically promote non-toxic-dose RSL3 induced ferroptosis by modulating the p53 pathway in AML with MLL translocation, which may potentially enable the clinical application of ferroptosis inducers in further.

TMEM121 is a six-pass transmembrane protein consisting of an N-terminal transmembrane domain (TD; residues 1-284) and a C-terminal polyproline sequence (PP; residues 284-319). In this study, publicly accessible databases were utilized to ascertain that TMEM121 correlates with various cytokines associated with the MAPK signaling pathway in cervical cancer. Furthermore, TMEM121 expression was negatively correlated with ERK expression in cervical cancer tissues. Protein interaction prediction using AlphaFold3 suggested an interaction between TMEM121 and ERK1/2, which was experimentally validated through Co-immunoprecipitation and immunofluorescence analyses. Both full-length TMEM121 and the TD truncator interacted with ERK and downregulate p-ERK1/2 protein levels, thereby inhibiting the proliferation and invasion of cervical cancer cells. In contrast, the PP truncator did not exhibit these effects. RNA-seq analysis further confirmed a significant association between TMEM121 and the MAPK signaling pathway in cervical cancer. Additionally, flow cytometry analysis showed that the ERK inhibitor PD98059 reversed the S phase cell cycle arrest induced by TMEM121 overexpression. Collectively, these findings suggest that TMEM121 exerts its inhibitory effects on the growth, proliferation, and invasion of cervical cancer cells through its interaction with ERK, providing a theoretical basis for the development of novel diagnostic and therapeutic strategies for cervical cancer.

To compare the clinical efficacy, safety, and cost-effectiveness of bispecific antibody teclistamab and chimeric antigen receptor T-cell (CAR-T) therapy in relapsed/refractory multiple myeloma (RRMM) to guide individualized treatment. This retrospective study enrolled 67 RRMM patients (excluded 6 of 73) hospitalized at Xinxiang Central Hospital (December 2024-May 2025), divided into teclistamab (n=32) and CAR-T (n=35) groups. Primary outcomes included overall response rate (ORR) and progression-free survival (PFS). Secondary outcomes comprised complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) negativity rate, overall survival (OS), adverse events (AEs), hospital stays, direct medical costs, and cost-effectiveness ratio (CER). The CAR-T group showed higher CRR (P=0.011), ORR (P=0.029), MRD negativity rate (P=0.027), longer median DOR [HR: 3.35 (1.838, 6.10), P<0.001], PFS [HR: 4.407 (1.994, 9.74), P<0.001], and better OS (HR: 3.204 (1.015, 10.1), P=0.021) than the teclistamab group. However, the CAR-T group had higher incidences of cytokine release syndrome (P=0.033) and hematological AEs (P=0.040), longer hospital stays, higher direct costs, and higher CER (all P<0.001). Prior treatment lines were independent prognostic factors (P=0.036). CAR-T therapy outperforms teclistamab in efficacy and survival outcomes but has higher AEs and costs. Teclistamab demonstrates superior safety and shorter hospital stays, supporting individualized clinical selection.

This study aimed to assess the impact of Graves' disease (GD) on the clinicopathological characteristics and prognosis of patients with differentiated thyroid cancer (DTC) undergoing initial radioactive iodine (RAI) therapy, as well as to identify factors influencing RAI therapy outcomes. A retrospective analysis was conducted on 959 DTC patients who received initial RAI therapy at the Department of Nuclear Medicine, First Affiliated Hospital of Nanchang University, between January 2021 and December 2023. Patients were divided into two groups based on a history of GD: the GD group (n = 60) and the non-GD group (n = 899). Data on demographics, laboratory tests, clinicopathological features, and RAI-related parameters were collected. Univariate analysis was performed to identify variables associated with treatment response, followed by multivariate logistic regression to determine independent predictors of outcomes after initial RAI therapy. The distribution of treatment responses across the four categories was as follows: in the GD group, excellent response (ER) occurred in 71.67%, indeterminate response (IDR) in 16.67%, biochemical incomplete response (BIR) in 6.67%, and structural incomplete response (SIR) in 5.00%; in the non-GD group, the respective rates were 39.60% (ER), 29.37% (IDR), 17.80% (BIR), and 13.24% (SIR). Statistically significant differences were observed in dichotomous outcomes - ER versus non-excellent response (N-ER), and ideal/acceptable response versus incomplete response - between the two groups (both P < 0.01). Multivariate analysis identified several independent factors associated with favorable RAI outcomes, including younger age, GD (P < 0.001; OR = 0.16; 95% CI: 0.07-0.35), shorter interval between surgery and ¹³¹I administration, fewer metastatic lymph nodes, negative pre-ablation thyroglobulin antibody (pa-TgAb), lower pre-treatment stimulated thyroglobulin (sTg) levels, and higher ¹³¹I dose (all P < 0.05). In contrast, Hashimoto's thyroiditis (HT), maximum diameter of metastatic lymph nodes, body mass index (BMI), tumor multifocality, maximum tumor diameter, tumor location, and ATA recurrence risk stratification were not significantly associated with treatment response (all P > 0.05). Compared to non-GD DTC patients, those with GD exhibited more favorable pathological features and significantly better short-term prognosis following initial RAI therapy, with an 84% reduced likelihood of N-ER. Key predictors of favorable RAI response included GD status, younger age, shorter surgery-to-RAI interval, lower metastatic lymph node burden, pa-TgAb negativity, lower sTg levels, and higher ¹³¹I dose. HT, metastatic lymph node size, BMI, tumor multifocality, tumor size, and tumor location did not significantly influence treatment outcomes.

[This corrects the article on p. 2180 in vol. 15, PMID: 40520866.].

Mantle cell lymphoma (MCL) is a rare type of mature B-cell lymphoma. This multicenter retrospective cohort study aimed to analyze the epidemiological characteristics, treatment patterns, and survival outcomes of patients with MCL in Taiwan. We collected baseline information, treatment modalities, and response evaluation of patients with MCL. A total of 204 patients who were diagnosed with mantle cell lymphoma between November 2001 and July 2022 were included. When divided into low, intermediate, and high-risk groups according to the Mantle Cell Lymphoma International Prognostic Index, their median overall survival times were 83.7 (95% confidence interval [CI]: 77.7-NR), 72.7 (95% CI: 30.7-NR), and 19.3 (95% CI: 14.2-45.6) months, respectively. In this multicenter retrospective cohort, first line rituximab containing regimens, higher chemotherapy intensity, and ASCT were associated with longer PFS/OS, although the magnitude and statistical significance varied after adjustment and by transplant eligibility. Given potential confounding by indication, era effects, and missing data, these findings should be interpreted as observational associations rather than causal effects. Prospective or target trial emulation studies are warranted.

Trichilemmal carcinoma (TC) is a rare malignant cutaneous appendage neoplasm originating from the epithelium of the outer root sheath of hair follicles. TC is generally non-invasive, causing only localized damage, and can be successfully managed with wide excision. Although recurrence and metastasis are rare, such cases often exhibit high malignancy, necessitating regular follow-up. Here, a retrospective study was conducted to review the clinical and histopathological features, diagnosis, and treatment of TC. Seven TC patients were enrolled in this study with 3 female and 4 male patients. The average age was 56.14±20.72 years old and the average year of lesion onset to clinic visit was 3.91±5.07 years. All patients received enlarged excision therapy. Six of Seven patients were followed for at least two years. Only one reported lesion relapse one year after surgery with 0.5 cm enlarged margin. In conclusion, surgery is a great method for TC treatment with at least 1 cm margin. Long-term post operative follow-up is necessary to screening recurrence.