Objective: This study aimed to predict therapeutic efficacy among diffuse large B-cell lymphoma (DLBCL) after R-CHOP (-like) therapy using baseline 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) radiomics. Methods: A total of 239 patients with DLBCL were enrolled in this study, with 82 patients having refractory/relapsed disease. The radiomics signatures were developed using a stacking ensemble approach. The efficacy of the radiomics signatures, the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI), conventional PET parameters model, and their combinations in assessing refractory/relapse risk were evaluated using receiver operating characteristic (ROC) curves, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and decision curve analysis. Results: The stacking model, along with the integrated model that combines stacking with the NCCN-IPI and SDmax (the distance between the two lesions farthest apart, normalized to the patient's body surface area), showed remarkable predictive capabilities with a high area under the curve (AUC), sensitivity, specificity, PPV, NPV, accuracy, and significant net benefit of the AUC (NB-AUC). Although no significant differences were observed between the combined and stacking models in terms of the AUC in either the training cohort (AUC: 0.992 vs. 0.985, p = 0.139) or the testing cohort (AUC: 0.768 vs. 0.781, p = 0.668), the integrated model exhibited higher values for sensitivity, PPV, NPV, accuracy, and NB-AUC than the stacking model. Conclusion: Baseline PET radiomics could predict therapeutic efficacy in DLBCL after R-CHOP (-like) therapy, with improved predictive performance when incorporating clinical features and SDmax.
Background: Osteosarcoma (OS) is undeniably a formidable bone malignancy characterized by a scarcity of effective treatment options. Reprogramming of amino acid (AA) metabolism has been associated with OS development. The present study was designed to identify metabolism-associated genes (MAGs) that are differentially expressed in OS and to construct a MAG-based prognostic risk signature for this disease. Methods: Expression profiles and clinicopathological data were downloaded from Gene Expression Omnibus (GEO) and UCSC Xena databases. A set of AA MAGs was obtained from the MSigDB database. Differentially expressed genes (DEGs) in GEO dataset were identified using "limma." Prognostic MAGs from UCSC Xena database were determined through univariate Cox regression and used in the prognostic signature development. This signature was validated using another dataset from GEO database. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, single sample gene set enrichment analysis, and GDSC2 analyses were performed to explore the biological functions of the MAGs. A MAG-based nomogram was established to predict 1-, 3-, and 5-year survival. Real-time quantitative polymerase chain reaction, Western blot, and immunohistochemical staining confirmed the expression of MAGs in primary OS and paired adjacent normal tissues. Results: A total of 790 DEGs and 62 prognostic MAGs were identified. A MAG-based signature was constructed based on four MAGs: PIPOX, PSMC2, SMOX, and PSAT1. The prognostic value of this signature was successfully validated, with areas under the receiver operating characteristic curves for 1-, 3-, and 5-year survival of 0.714, 0.719, and 0.715, respectively. This MAG-based signature was correlated with the infiltration of CD56dim natural killer cells and resistance to several antiangiogenic agents. The nomogram was accurate in predictions, with a C-index of 0.77. The expression of MAGs verified by experiment was consistent with the trends observed in GEO database. Conclusion: Four AA MAGs were prognostic of survival in OS patients. This MAG-based signature has the potential to offer valuable insights into the development of treatments for OS.
Background: Acquired multidrug resistance is often blamed for the failure of chemotherapy in patients with malignant tumors, including chronic myeloid leukemia (CML). In this study, the authors investigated the role of circular RNA 0080145 (circ_0080145) in imatinib (IM) resistance of CML. Materials and Methods: Quantitative real-time polymerase chain reaction was applied to measure the expression of circ_0080145, microRNA-326 (miR-326), and PTPRF interacting protein alpha 1 (PPFIA1) mRNA. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to determine the half maximal inhibitory concentration (IC50) of IM and cell proliferation. Flow cytometry analysis was utilized to assess cell apoptosis. The levels of glucose uptake and lactate production were examined using specific kits. Protein levels were detected through Western blot assay. The targeting relationship between miR-326 and circ_0080145 or PPFIA1 was verified by dual-luciferase reporter assay. The murine xenograft model was constructed to investigate the effect of circ_0080145 in vivo. Results: circ_0080145 was upregulated in IM-resistant CML patients and cells. circ_0080145 silencing suppressed IM resistance, cell growth, and glycolysis and induced apoptosis in IM-resistant CML cells in vitro. Moreover, circ_0080145 knockdown blocked tumor growth and IM resistance in vivo. miR-326 was a target of circ_0080145, and miR-326 inhibition restored the effects of circ_0080145 silencing on cell progression and IM resistance. In addition, PPFIA1 was a target gene of miR-326. The suppressive roles in IM resistance, cell growth and glycolysis, and the promotional role in apoptosis mediated by miR-326 were abolished by PPFIA1 overexpression in IM-resistant CML cells. Conclusion: circ_0080145 contributes to IM resistance via modulating miR-326/PPFIA1 axis, which might provide a novel avenue for CML therapy.
This study focuses on acute myeloid leukemia (AML), a condition with a 5-year survival rate below 30% despite various treatment options. Recent strides in targeted therapies have shown promise, leading to better outcomes with minimal toxicity. These advances underscore the importance of discovering new diagnostic and prognostic targets for AML. In this context, the authors investigated the expression of microRNA-106b-5p (miR-106b-5p), Rab10 mRNA, and Rab10 proteins in peripheral blood and bone marrow (BM) samples from both healthy individuals and AML patients at different stages of the disease (initial diagnosis, recurrence, and complete remission). This examination aimed to identify potential biomarkers for AML diagnosis, treatment, and prognosis. From June 2021 to December 2022, they collected 100 BM and peripheral blood samples. The relative expression of miR-106b-5p and Rab10 mRNA in the BM of AML patients was measured using Real-time polymerase chain reaction (qRT-PCR), while the relative expression of Rab10 protein in serum was determined using the ELISA method. The chromosomal karyotype of initially diagnosed patients was analyzed using the R tape. The qRT-PCR results revealed that the expression of miR-106b-5p and Rab10 mRNA were significantly higher in patients at initial diagnosis and recurrence compared with healthy individuals and those in complete remission (p < 0.001). They observed a significant reduction in the expression of miR-106b-5p, Rab10 mRNA, and Rab10 protein in the BM and peripheral blood of patients during complete remission (p < 0.05), as demonstrated by dynamic monitoring of five patients in the initial group. Furthermore, they found a close association between the expression of miR-106b-5p and the number of white blood cells at the initial diagnosis in AML patients (p < 0.05). Spearman correlation analysis revealed a positive correlation among miR-106b-5p, Rab10 mRNA, and Rab10 proteins (p < 0.05). The diagnostic potential of miR-106b-5p and Rab10 proteins was underscored by Receiver Operating Characteristic (ROC) curve analysis, which demonstrated their high accuracy in AML diagnosis (AUC: 0.944 and 0.853, respectively; p < 0.0001). Additionally, Kaplan-Meier survival analysis suggested that lower expression of these markers was associated with better prognoses (p < 0.05). In summary, their findings propose miR-106b-5p and Rab10 proteins as promising biomarkers for AML, offering insights for diagnosis, treatment, and prognosis.
Background: Natural killer (NK) cells are characterized by their antitumor efficacy without previous sensitization, which have attracted attention in tumor immunotherapy. The heterogeneity of osteosarcoma (OS) has hindered therapeutic application of NK cell-based immunotherapy. The authors aimed to construct a novel NK cell-based signature to identify certain OS patients more responsive to immunotherapy. Materials and Methods: A total of eight publicly available datasets derived from patients with OS were enrolled in this study. Single-cell RNA sequencing data obtained from the Gene Expression Omnibus (GEO) database were analyzed to screen NK cell marker genes. Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis was used to construct an NK cell-based prognostic signature in the TARGET-OS dataset. The differences in immune cell infiltration, immune system-related metagenes, and immunotherapy response were evaluated among risk subgroups. Furthermore, this prognostic signature was experimentally validated by reverse transcription-quantitative real-time PCR (RT-qPCR). Results: With differentially expressed NK cell marker genes screened out, a five-gene NK cell-based prognostic signature was constructed. The prognostic predictive accuracy of the signature was validated through internal clinical subgroups and external GEO datasets. Low-risk OS patients contained higher abundances of infiltrated immune cells, especially CD8 T cells and naive CD4 T cells, indicating that T cell exhaustion states were present in the high-risk OS patients. As indicated from correlation analysis, immune system-related metagenes displayed a negative correlation with risk scores, suggesting the existence of immunosuppressive microenvironment in OS. In addition, based on responses to immune checkpoint inhibitor therapy in two immunotherapy datasets, the signature helped predict the response of OS patients to anti-programmed cell death protein 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) therapy. RT-qPCR results demonstrated the roughly consistent relationship of these five gene expressions with predicting outcomes. Conclusions: The NK cell-based signature is likely to be available for the survival prediction and the evaluation of immunotherapy response of OS patients, which may shed light on subsequent immunotherapy choices for OS patients. In addition, the authors revealed a potential link between immunosuppressive microenvironment and OS.
Purpose: In a prior, retrospective study, 76% of patients with advanced neuroendocrine tumors undergoing 177Lu-DOTATOC molecular radiotherapy (MRT) showed their best response within 8 months from the first MRT cycle. In 24% of patients, latency was much greater up to >22 months after the first cycle, and long after near-complete decay of 177Lu from the last cycle. An immune response induced by MRT seems a likely explanation. As a crude measure of immunocompetence, the authors investigated whether blood cell counts (BCCs) may have predictive value for MRT outcome with 177Lu-DOTATOC. Methods: 56 Patients with neuroendocrine tumors (NET) were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) with median radioactivity of 7.0 GBq/cycle at 3-month intervals. Patients' BCCs were evaluated for four responder categories: CR, PR, SD, and PD (RECIST 1.1). Furthermore, baseline BCCs were correlated with progression-free survival (PFS). Finally, BCCs of patients with (PMT+) and without prior medical therapy (PMT-) were compared. Results: Significant differences between responder categories were found for baseline hemoglobin (Hb), erythrocytes, neutrophils, lymphocytes, neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and LEHN-score, integrating lymphocyte, erythrocyte, and neutrophil counts, and Hb level, but not for leukocytes and platelets. LEHN-score yielded an almost complete separation between CR and PD groups. In analogy, PFS times showed significant correlations with baseline Hb, erythrocytes, neutrophils, lymphocytes, NLR, PLR, and LEHN-score, the LEHN-score showing the strongest correlation, but not with leukocytes and platelets. For PMT- patients, median PFS was 34.5 months, compared with 20.8 months in PMT+ patients, with corresponding baseline lymphocyte (32.1 ± 9.6% vs. 24.5 ± 11.6%, p = 0.028) and neutrophil (54.9 ± 11.6% vs. 63.5 ± 13.7%, p = 0.039) counts. Conclusion: These findings emphasize the significance of an immune response to MRT for obtaining optimal therapy efficacy and support concepts to enhance the immune response of less immunocompetent patients before MRT. It seems advisable to avoid prior or concomitant immunosuppressant medical therapy.
Background: Cutaneous squamous cell carcinoma (CSCC) is the most deadly disease among nonmelanoma skin cancers. LINC00641 plays a role in various cancers, but its role in CSCC has not been reported so far. Methods and Materials: The expression of LINC00641 and miR-424 in cells was detected by RT-qPCR. CCK-8 and colony formation assay were used to detect the proliferation of cells. Western blot was used to detect the expression levels of proliferation-, invasion-, and migration-related proteins. Wound Healing and Transwell experiments detected the ability of cell invasion and migration. In animal experiments, a tumor-bearing model was established in nude mice, and tumor volume was measured and photographed. The expression levels of proliferation-, invasion-, and migration-related proteins were detected by Western blot. Results: The expression of LINC00641 was significantly decreased in CSCC cell lines. The overexpression of LINC00641 at the cellular level inhibited the proliferation and migration of CSCC cell line A431 by downregulating the expression of miR-424. The overexpression of LINC00641 in animals inhibited the tumor volume of nude mice by downregulating the expression of miR-424 to inhibit the expression of proliferation- and migration-related proteins. Conclusion: LINC00641 inhibits the development of CSCC by downregulating miR-424.
Background: Adult acute leukemia most commonly manifests as acute myeloid leukemia (AML), a highly heterogeneous malignant tumor of the blood system. The application of genetic diagnostic technology is currently prevalent in numerous clinical sectors. According to recent research, the presence of specific gene mutations or rearrangements in leukemia cells is the primary cause of the disease. As different types of leukemia are caused by atypical mutated genes, testing for these mutations or rearrangements can help diagnose leukemia and identify the disease's molecular targets for treatment. Methods: Using the search fields "WT1," "DNMT3A," "Acute myeloid leukemia," and "survival," the CBM, Cochrane Library, Scopus, EMBASE, and PUBMED databases were separately reviewed. The methodology for evaluating the risk of bias developed by the Cochrane Collaboration was used in conjunction with a methodical evaluation of pertinent literature. Excluded studies with the following characteristics: (1) incomplete and repetitive publications, (2) unable to retrieve or convert data, (3) non-English or Chinese articles. Results: This analysis included 13 studies covering a total of 3478 subjects. The frequency of Wilms' Tumor 1 (WT1) mutations is 6.7%-35.73%, and the frequency of DNMT3A mutations is 12.06%-51.1%. The remission rate of patients with WT1 mutations was less than that of patients without WT1 mutations (OR = 0.22; 95% confidence interval [CI]: 0.14, 0.36; p < 0.00001; I2 = 55%). The DNMT3A mutation has no statistical significance for the prognosis of AML (OR = 1.21; 95% CI: 0.93, 1.58; p = 0.16; I2 = 80%). After removing one study, the heterogeneity of the indicator (mitigation rate) among other studies of DNMT3A mutation was dramatically reduced (OR = 0.63; 95% CI: 0.43, 0.93; p = 0.02; I2 = 0%). Conclusions: Our meta-analysis shows that WT1 mutations hurt the remission rate of AML. Moreover, the impact of DNMT3A mutations on AML needs to be treated with caution. Gene diagnosis is critical for the prognosis and clinical management of AML.
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