Chemotherapy Resistance In Patients Research Articles

A Novel Neutrophil Extracellular Trap Signature Predicts Patient Chemotherapy Resistance and Prognosis in Lung Adenocarcinoma.

Chemoresistance is a key obstacle in the long-term survival of patients with locally and advanced lung adenocarcinoma (LUAD). This study used bioinformatic analysis to reveal the chemoresistance of gene-neutrophil extracellular traps (NETs) associated with LUAD. RNA sequencing data and LUAD expression patterns were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, respectively. The GeneCards database was used to identify NETosis-related genes (NRGs). To identify hub genes with significant and consistent expression, differential analysis was performed using the TCGA-LUAD and GEO datasets. LUAD subtypes were determined based on these hub genes, followed by prognostic analysis. Immunological scoring and infiltration analysis were conducted using NETosis scores (N-scores) derived from the TCGA-LUAD dataset. A clinical prognostic model was established and analyzed, and its clinical applications explored. Twenty-two hub genes were identified, and consensus clustering was used to identify two subgroups based on their expression levels. The Kaplan-Meier (KM) curves demonstrated statistically significant differences in prognosis between the two LUAD subtypes. Based on the median score, patients were further divided into high and low N-score groups, and KM curves showed that the N-scores were more precise at predicting the prognosis of patients with LUAD for overall survival (OS). Immunological infiltration analysis revealed significant differences in the abundances of 10 immune cell infiltrates between the high and low N-score groups. Risk scores indicated significant differences in prognosis between the two extreme score groups. The risk scores for the prognostic model also indicated significant differences between the two groups. The results provide new insights into NETosis-related differentially expressed genes (NRDEGs) associated with chemotherapy resistance in patients with LUAD. The established prognostic model is promising and could help with clinical applications to evaluate patient survival and therapeutic efficiency.

Plasma proteome profiling reveals biomarkers of chemotherapy resistance in patients with advanced colorectal cancer

AbstractColorectal cancer (CRC) is one of the most common cancers. Patients with advanced CRC can only rely on chemotherapy to improve outcomes. However, primary drug resistance frequently occurs and is difficult to predict. Changes in plasma protein composition have shown potential in clinical diagnosis. Thus, it is urgent to identify potential protein biomarkers for primary resistance to chemotherapy for patients with CRC. Automatic sample preparation and high‐throughput analysis were used to explore potential plasma protein biomarkers. Drug susceptibility testing of circulating tumor cells (CTCs) has been investigated, and the relationship between their values and protein expressions has been discussed. In addition, the differential proteins in different chemotherapy outcomes have been analyzed. Finally, the potential biomarkers have been detected via enzyme‐linked immunosorbent assay (ELISA). Plasma proteome of 60 CRC patients were profiled. The correlation between plasma protein levels and the results of drug susceptibility testing of CTCs was performed, and 85 proteins showed a significant positive or negative correlation with chemotherapy resistance. Forty‐four CRC patients were then divided into three groups according to their chemotherapy outcomes (objective response, stable disease, and progressive disease), and 37 differential proteins were found to be related to chemotherapy resistance. The overlapping proteins were further investigated in an additional group of 79 patients using ELISA. Protein levels of F5 and PROZ significantly increased in the progressive disease group compared to other outcome groups. Our study indicated that F5 and PROZ proteins could represent potential biomarkers of resistance to chemotherapy in advanced CRC patients.

Significance of bone marrow immunohistochemical analysis in patients with plasma cell neoplasms

Background. The group of plasma cell neoplasms includes benign and malignant diseases. Sometimes there are difficulties in making a diagnosis. The study of the diagnostic and prognostic significance of immunohistochemical (IHC) markers is of current interest.Aim. To study the significance of IHC markers and histological features of the bone marrow in primary diagnosis in patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS).Materials and methods. The study included 287 patients with plasma cell neoplasms: MGUS (n = 148), MM (n = 139). The observation period was 50 months. All patients have performed an aspiration biopsy and histological examination of the bone marrow with IHC analysis of CD138+, CD56+, CD34+, κ- and λ-chains expression.Results. During the observation period the progression of MGUS to MM was recorded in 8.8 % (n = 13) of cases, the progression of MM was determined in 38.1 % (n = 53) of cases.In patients with MGUS and MM the determined percentage of plasma cells at aspiration biopsy was somewhat lower than at histological examination (p >0.001). Statistically significant differences were determined between the groups MGUS and MM by the type of infiltration (р <0.001). With an increase in the percentage of bone marrow lesions by IHC (<20 % vs. 20–50 % and 20–50 % vs. >50 %), in our study interstitial and diffuse type of lesion with large accumulations was more common compared to the nodular type (p = 0.001).The CD138+ expression (IHC) more than 10 % was associated with a decrease of progression-free survival in patients with MGUS.In MM patients with an interstitial type of bone marrow infiltration and CD138+ over 10 % osteodestructive syndrome was detected by X-ray methods in 82.9 % of cases.Determination of CD56+ and immunoglobulin light chains expression in patients with MM and MGUS indicated an unfavorable prognosis.Resistance to chemotherapy or disease progression in MM patients most often occurred with a combination of IgG and immunoglobulin light chains secretion, with CD138+ plasma cells more than 50 % according to IHC, with a diffuse type of bone marrow lesion with accumulations of plasma cells. MGUS patients progressed more frequently with more than 20 % CD138+ plasma cells according to IHC, interstitial type and diffuse plasma cells accumulation type of bone marrow lesion, secretion of IgG or two immunoglobulins.Conclusion. The significance of the IHC study in the diagnosis of plasma cell neoplasms was confirmed. Markers associated with the disease progression and chemotherapy resistance in patients with MGUS and MM were identified.

Cancer-associated fibroblasts suppress ferroptosis and induce gemcitabine resistance in pancreatic cancer cells by secreting exosome-derived ACSL4-targeting miRNAs

BackgroundPancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic cancer often accompany with dismal prognosis, highlighting the need to investigate mechanisms of drug resistance and develop therapies to overcome chemoresistance. MethodsThis research was filed with the Chinese Clinical Trial Registry (ChiCTR2200061320). In order to isolate primary normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) samples of pancreatic ductal adenocarcinoma (PDAC) and paracancerous pancreatic tissue from individuals diagnosed with PDAC were obtained. The exosomes were obtained using ultracentrifugation, and their characteristics were determined by Western blotting, nanoparticle tracking analysis, and transmission electron microscopy. CAF-derived miRNAs were analyzed by RT-qPCR and high-throughput sequencing. Gemcitabine (GEM) was employed to promote ferroptosis, and ferroptosis levels were determined by monitoring lipid reactive oxygen species (ROS), cell survival, and intracellular Fe2+ concentrations. To assess in vivo tumor response to GEM therapy, a xenograft tumor mouse model was utilized. ResultsExosomes derived from CAFs in PDAC did not exhibit innate GEM resistance. CAFs promoted chemoresistance in PDAC cells following GEM treatment by secreting exosomes, and maintaining signaling communication with cancer cells. Mechanistically, miR-3173–5p derived from CAF exosomes sponged ACSL4 and inhibited ferroptosis after uptake by cancer cells. ConclusionThis work demonstrates a novel mode of acquired chemoresistance in PDAC and identifies the miR-3173–5p/ACSL4 pathway as a promising treatment target for GEM-resistant pancreatic cancer.

METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy

BackgroundSmall cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. Although most patients are initially sensitive to first-line combination chemotherapy with cisplatin and etoposide, chemotherapy drug resistance easily develops and quickly leads to tumour progression. Therefore, understanding the mechanisms of chemotherapy drug resistance and how to reverse it is key to improving the prognosis of patients with SCLC. Moreover, N6-methyladenosine (m6A) is the most abundant mRNA modification and is catalysed by the methyltransferase complex, in which methyltransferase-like 3 (METTL3) is the sole catalytic subunit.MethodsThe effects of METTL3 on chemoresistance in SCLC cells were determined using qRT–PCR, Western blotting, immunohistochemistry, cell counting kit (CCK-8) assays, flow cytometry, and tumorigenicity experiments. Methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP qPCR, immunofluorescence, and drug inhibitor experiments were performed to confirm the molecular mechanism of Decapping Protein 2 (DCP2), which is involved in the chemoresistance of SCLC.ResultsIn the present study, we found that METTL3 is a marker for poor SCLC prognosis, and it is highly expressed in chemoresistant SCLC cells. METTL3 promotes SCLC chemoresistance by positively regulating mitophagy. METTL3 induces m6A methylation of DCP2 and causes the degradation of DCP2, which promotes mitochondrial autophagy through the Pink1-Parkin pathway, leading to chemotherapy resistance. We also found that STM2457, a novel METTL3 inhibitor, can reverse SCLC chemoresistance.ConclusionsThe m6A methyltransferase METTL3 regulates Pink1-Parkin pathway-mediated mitophagy and mitochondrial damage in SCLC cells by targeting DCP2, thereby promoting chemotherapy resistance in patients with SCLC.

The SCF–FBXW7 E3 ubiquitin ligase triggers degradation of histone 3 lysine 4 methyltransferase complex component WDR5 to prevent mitotic slippage

During prolonged mitotic arrest induced by anti-microtubule drugs, cell fate decision is determined by two alternative pathways, one leading to cell death, the other inducing premature escape from mitosis by mitotic slippage. FBWX7, a member of the F-box family of proteins and substrate-targeting subunit of the SCF (SKP1-CUL1-F-Box) E3 ubiquitin ligase complex promotes mitotic cell death and prevents mitotic slippage, but molecular details underlying these roles for FBWX7 are unclear. In this study, we report that WDR5, a component of the mixed lineage leukemia (MLL) complex of Histone 3 Lysine 4 (H3K4) methyltransferases, is a substrate of FBXW7. We determined by co-immunoprecipitation experiments and in vitro binding assays that WDR5 interacts with FBXW7 in vivo and in vitro. SCF-FBXW7 mediates ubiquitination of WDR5 and targets it for proteasomal degradation. Furthermore, we find that WDR5 depletion counteracts FBXW7 loss-of-function by reducing mitotic slippage and polyploidization. In conclusion, our data elucidate a new mechanism in mitotic cell fate regulation which might contribute to prevent chemotherapy resistance in patients after anti-microtubule drug treatment.

Prognostic Factors Associated with hCG Remission and Chemotherapy Resistance in Patients with High-Risk Gestational Trophoblastic Neoplasia

Prognostic Factors Associated with hCG Remission and Chemotherapy Resistance in Patients with High-Risk Gestational Trophoblastic Neoplasia

The influence of lung metastasis on prognosis of previously untreated gestational trophoblastic neoplasia patients

Objective: To investigate the impact of lung metastases on the prognosis of patients with gestational trophoblastic neoplasia (GTN). Methods: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage Ⅰ-Ⅲ GTN receiving primary chemotherapy in Peking Union Medical College Hospital between July 2014 and December 2018 were retrospectively analyzed and divided into group 1 with lung metastasis and group 2 without lung metastasis. The baseline characteristics and treatment outcomes of the two groups were compared. The optimal cut-off values of the diameter of largest lung nodule associated with recurrence were identified by receiver operating characteristic (ROC) curves. Logistic regression analyses were performed to identify risk factors for prognosis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Results: Of the 381 GTN patients enrolled (216 with lung metastases and 165 without lung metastases), the pretreatment β human chorionic gonadotrophin [median: 12 572 IU/L (1 832-51 594 IU/L) vs. 5 614 IU/L (559-26 140 IU/L), P=0.001] and FIGO score [median: 3 (1-6) vs. 2 (1-4), P=0.038] were significantly higher in patients with lung metastases than those without lung metastases. In patients with FIGO score≥5, the emergence of resistance (26.76% vs. 10.26%, P=0.036) and median number of chemotherapy courses to achieve complete remission [6 (6-8) vs. 5 (4-6), P<0.001] were significantly higher than patients with lung metastases. In patients with FIGO score 0-4, no significant difference was found in the treatment outcomes between the two groups(P=0.833). Among all patients with lung metastases, the ROC curve showed a sensitivity and specificity of 62.5% and 78.8%, respectively, for predicting recurrence when the length of the largest lung nodule was 1.6 cm, with an area under the curve (AUC) of 0.711 (95% CI: 0.550, 0.871, P=0.044). Multivariate logistic regression analysis suggested a significantly higher recurrence rate when the largest lung nodule was ≥1.6 cm (OR=7.394, 95% CI: 1.003, 54.520, P=0.049). The 1-year disease-free survival rate was significantly lower in patients with the largest lung nodule ≥1.6 cm than in patients with the nodule <1.6 cm (98.2% vs. 82.4%, P=0.001). Conclusions: Lung metastasis is associated with increased first-line chemotherapy resistance in patients with FIGO scores≥5. The diameter of the largest lung metastatic nodule ≥1.6 cm is an effective factor for predicting recurrence.

STUB1-SMYD2 Axis Regulates Drug Resistance in Glioma cells.

SET and MYND domain-containing protein 2 (SMYD2) is an important epigenetic regulator that methylates histone and non-histone proteins. The study aimed to investigate the oncogenic role of SMYD2 in gliomas and explore its degradation mechanism induced by cisplatin. Tumor tissue microarray of 441 patients with glioma was collected for SMYD2 immunohistochemical staining. Kaplan-Meier survival curves were constructed using the overall survival values. mRNA-sequencing analysis was performed for understanding the downstream mechanisms mediated by SMYD2. The half-inhibitory concentrations (IC50) of temozolomide and cisplatin in AZ505-treated and control cells were calculated. The potential E3 ubiquitin ligase of SMYD2 was predicted in UbiBrowser and confirmed by a knockdown test. The effect of SMYD2 and its E3 ligase on apoptosis and migration of glioma cells was determined via cell-function assays. High SMYD2 expression correlated with a high WHO stage (P = 0.004) and a low survival probability (P = 0.012). The inhibition of SMYD2 suppressed the process of epithelial to mesenchymal transition (EMT) by downregulating the expression of Collagen 1A1 (COL1A1). AZ505 treatment significantly increased the drug sensitivity of glioma cells. SMYD2 expression was markedly reduced by cisplatin treatment via STIP1 Homology And U-Box Containing Protein 1 (STUB1)-mediated degradation. The knockdown of STUB1 could partly reverse the cell function impairment induced by cisplatin. Our findings suggested that SMYD2 could be a potential drug target for the treatment of gliomas, and STUB1-mediated degradation of SMYD2 plays an important role in reversing chemotherapy resistance in patients with gliomas.

Abstract 2331: Metabolic profiling of pre and post treatment ovarian cancer tissues using in situ mass spectrometry imaging

Abstract Chemotherapy resistance represents a major problem in ovarian cancer prognosis and reliable indicators of chemotherapy sensitivity remain an unmet need. Here, we examined metabolic profiles of pre- and post-neoadjuvant chemotherapy (NACT) tumor samples from patients with high-grade serous ovarian cancer (HGSC). We performed spatially resolved, desorption electrospray ionization-mass spectrometry (DESI-MS) on sections from clinically annotated HGSC samples collected according to a laparoscopic triage algorithm from patients pre- and post-NACT. Patients were considered to be either excellent (ER) if they presented complete response or only microscopic disease left at interval surgery, or poor responders (PR) if they presented stable or progressive disease after NACT. Tumor tissues from 50 patients (29 ER and 21 PR, 13 ER matched pre and post NACT, 13 PR matched pre and post-NACT) were eligible for the analyses Data relative to the detected metabolites, were collected from epithelium and stroma separately. We first identified differentially upregulated metabolites in ER and PR groups and performed pathway analysis. The over-represented pathways in the chemo-naïve PR tissues included the nucleotide metabolism pathway in epithelial areas, and degradation of cysteine and homocysteine, metabolism of amino acids and derivatives, as well as sulfur amino acids metabolism in the stromal areas (p values FDR adjusted 0.045). In general, both the epithelium and stroma of PR tissues of chemo-naïve tumors, contained a higher number and a higher variety of lipid species compared with ER tissues. In post-NACT tumor epithelial areas, there was global downregulation of metabolites across all patient samples, compared to the pre-chemo specimens; this was more evident in ER patients. In post-NACT tumors from PR patients, glutathione synthesis and recycling pathway, and sulfite oxidation to sulfate pathway and many glycerolipids species were upregulated in the epithelium, while phosphatidic acids were upregulated in the stroma. Lastly, we evaluated the predictive power of the metabolic data extracted by the epithelial areas of chemo-naïve tissues, in classifying patients as ER or PR. We used 10-fold cross-validation to create a ridge regression model for the classification of ER and PR samples from pre-NACT tumor tissues. This model, based on 78 differentially expressed metabolites (small molecules and lipids), correctly classified patients as ER or PR with an accuracy of 76.2% (sensitivity 84.6% and specificity 62.5%). Our findings indicate altered metabolic pathways in ovarian cancer tissues based on response to NACT. The identification of differentially activated pathways, such as sulfate metabolism and glutathione metabolism in tumors with poor response, suggest novel actionable targets to overcome chemotherapy resistance in patients with HGSC. Citation Format: Sara Corvigno, Meredith Spraldin, Michael Keating, Sunil Badal, Igor Pereira, Elaine Stur, Nicholas Bateman, Waleed Barakat, Thomas Conrads, Sanghoon Lee, George Maxwell, Susan K. Lutgendorf, Premal Thaker, Jinsong Liu, Nicole Fleming, Katheleen Darcy, Livia S. Eberlin, Anil K. Sood. Metabolic profiling of pre and post treatment ovarian cancer tissues using in situ mass spectrometry imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2331.

Albumin/fibrinogen ratio, a predictor of chemotherapy resistance and prognostic factor for advanced gastric cancer patients following radical gastrectomy

BackgroundThe objective of this study was to investigate potential predictors of chemotherapy resistance in patients with advanced gastric cancer (GC) following radical gastrectomy.MethodsEligible stage II/III GC patients with adjuvant chemotherapy after radical gastrectomy were enrolled in this study. A receiver operating characteristic (ROC) curve analysis was performed to assess the predictive and optimal cut-off values of continuous variables for chemotherapy resistance. Potential risk factors for chemotherapy resistance were determined with binary univariate and multivariate analyses. Potential prognostic factors for overall survival (OS) were determined by COX regression analysis. The association between survival and AFR level was examined using the Kaplan–Meier curve analysis.ResultsA total of 160 patients were included in the data analysis, and 41 patients achieved chemotherapeutic resistance with an incidence of 25.6%. Pretreatment albumin/fibrinogen ratio (AFR) (cut-off value: 10.85, AUC: 0.713, P < 0.001) was a predictor for chemotherapeutic resistance by ROC curve analysis. Low AFR (< 10.85) was an independent risk factor of chemotherapeutic resistance as determined by the univariate and multivariate logistic regression analyses (OR: 2.55, 95%CI: 1.21–4.95, P = 0.005). Multivariate COX regression analyses indicated low AFR as a prognostic factor for 5-year OS (HR: 0.36, 95%CI: 0.15–0.73, P = 0.011). Low AFR was associated with poorer 5-year disease-free survival and overall survival.ConclusionsThis study indicated that a low level of pretreatment AFR could serve as an independent predictor of chemotherapy resistance and postoperative prognosis in GC patients following radical gastrectomy.

CircINTS4 Facilitates Chemoresistance of TNBC by Competitively Binding miR-129-5p/POM121 Axis

Objectives To detect the expression of circular RNA (circRNA) circINTS4 in triple-negative breast cancer (TNBC) and to analyze the relationship between the expression of circRNA circINTS4 and the clinicopathological characteristics and chemotherapy resistance of patients with TNBC. Methods Bioinformatics was used to predict that circINTS4 and POM121 could bind to miR-129-5p, and dual luciferase reporter genes proved that circINTS4 could bind to miR-129-5p and miR-129-5p could bind to POM121. RNA immunoprecipitation (RIP) and RNA pull-down experiments confirmed that circINTS4 binds to miR-129-5p. The correlation among circINTS4, miR-129-5p, and POM121 was detected by qRT-PCR. Results In ADR-resistant TNB cells, circINTS4 was significantly up-regulated, miR-129-5p was down-regulated, and POM121 protein expression was significantly up-regulated. Experimental results showed that circINTS4 knockdown inhibited proliferation, migration, invasion, and autophagy. Knocking down miR-129-5p or overexpression of POM121 reversed the inhibitory effect of sh-circints4 on the development of ADR-resistant TNBC cells. In addition, CIRCINTS4 regulates POM121 expression by sponge-adsorbed miR-129-5p. CIRCINTS4 knockdown prevents ADR-resistant tumor growth by regulating the miR-129-5p/POM121 axis in vivo. Conclusions CircRNA circINTS4 may act as the ceRNA of miR-129-5p to regulate the expression of target gene POM121, thereby promoting the progress of TNBC molecular mechanism and providing scientific basis for circINTS4 as a new molecular target for clinical diagnosis and drug resistance therapy of TNBC.

The HSP70 gene predicts prognosis and response to chemotherapy in epithelial ovarian cancer.

BackgroundChemotherapy resistance is an intractable problem in treating patients with epithelial ovarian cancer (EOC). Heat shock proteins (HSPs) act as apoptosis inhibitors and are highly conserved genetically. Most HSPs have strong cytoprotective effects, and their overexpression inhibits apoptosis. This has been demonstrated for HSP70. Heat shock protein 70 (HSP70) expression is abnormally upregulated in malignant cells. Furthermore, HSP70 can inhibit cell death and promote chemotherapeutic resistance. In our study, the relationship between the HSP70 gene and primary chemotherapy resistance and clinical outcome in patients with EOC was explored.MethodsQuantitative real-time polymerase chain (qRT-PCR) was applied to determine HSP70 messenger RNA (mRNA) levels, and immunohistochemistry assay was conducted to determine HSP70 protein level. HSP70 overexpression was assessed to clarify its role on chemotherapy resistance to cisplatin in SKOV3 cell lines.ResultsRT-qPCR assay indicated a strong relationship between HSP70 expression and chemotherapy resistance in patients with EOC. In cultured SKOV3 cells, overexpression of HSP70 inhibited cell sensitivity to cisplatin. Kaplan-Meier analysis demonstrated high HSP70 expression was associated with poor outcome of EOC patients. In multivariate models, high HSP70 expression independently predicted this poor outcome.ConclusionsHSP70 predicts the prognosis and response to chemotherapy in EOC patients.

The hallmarks of ovarian cancer stem cells and niches: Exploring their harmonious interplay in therapy resistance.

The concept of a "cancer stem cell" has evolved over the past decades, and research on cancer stem cell biology has entered into a stage of remarkable progress. Cancer stem cells are a major determining factor contributing to the establishment of phenotypic and functional intratumoral heterogeneity in synchronization with their surrounding "cancer stem cell niches." They serve as the driving force for cancer initiation, metastasis, and therapeutic resistance in various types of malignancies. In verity, reciprocal interplay between ovarian cancer stem cells and their niches involves a complex but ingeniously orchestrated tumor microenvironment within the intraperitoneal milieu and especially contribute to chemotherapy resistance in patients with advanced ovarian cancer. Herein, we review the principles of our current understanding of the biological features of ovarian cancer stem cells, focusing mainly on the precise mechanisms underlying acquired chemotherapy resistance. Furthermore, we highlight the specific roles of various cancer-associated stromal and immune cells in creating possible cancer stem cell niches that regulate ovarian cancer stemness.

Chemotherapeutic efficacy of cucurmosin for pancreatic cancer as an alternative of gemcitabine: a comparative metabolomic study.

As the preferred drug for single chemotherapeutic application in pancreatic cancer, gemcitabine often demonstrated low sensitivity and strong chemotherapy resistance in patients. Therefore, the search for other drugs with high efficiency and low side effects has become of high importance. The aim of this study was to assess the therapeutic effects of cucurmosin on pancreatic cancer as an alternative of gemcitabine and explore its underlying biochemical mechanism. The subcutaneous xenograft mice with pancreatic cancer were treated by high- and low-dose cucurmosin and gemcitabine, respectively. A comparative metabolomic analysis was performed on the serum samples from the different groups by 1H nuclear magnetic resonance (NMR) techniques and then subjected to univariate and multivariate statistical analysis. Cucurmosin demonstrated a dose-dependent inhibition to the pancreatic tumors. High-dose cucurmosin provided similar chemotherapeutic efficacy with gemcitabine by positively regulating pyruvate metabolism, glycolysis or gluconeogenesis, and cysteine and methionine metabolism. Inactivating GFR signaling pathway and further inducing apoptosis of tumor cells are the important mechanism of anti-tumor function of cucurmosin. Cucurmosin is a promising chemotherapeutic drug for pancreatic cancer. However, the dose selection and surface modification should be optimized according to the stage of pancreatic cancer, and an expanded study in both laboratory and clinical regimes needs to be performed.

XGBoost Improves Classification of MGMT Promoter Methylation Status in IDH1 Wildtype Glioblastoma.

Approximately 96% of patients with glioblastomas (GBM) have IDH1 wildtype GBMs, characterized by extremely poor prognosis, partly due to resistance to standard temozolomide treatment. O6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation status is a crucial prognostic biomarker for alkylating chemotherapy resistance in patients with GBM. However, MGMT methylation status identification methods, where the tumor tissue is often undersampled, are time consuming and expensive. Currently, presurgical noninvasive imaging methods are used to identify biomarkers to predict MGMT methylation status. We evaluated a novel radiomics-based eXtreme Gradient Boosting (XGBoost) model to identify MGMT promoter methylation status in patients with IDH1 wildtype GBM. This retrospective study enrolled 53 patients with pathologically proven GBM and tested MGMT methylation and IDH1 status. Radiomics features were extracted from multimodality MRI and tested by F-score analysis to identify important features to improve our model. We identified nine radiomics features that reached an area under the curve of 0.896, which outperformed other classifiers reported previously. These features could be important biomarkers for identifying MGMT methylation status in IDH1 wildtype GBM. The combination of radiomics feature extraction and F-core feature selection significantly improved the performance of the XGBoost model, which may have implications for patient stratification and therapeutic strategy in GBM.

Epigenetic activation of FOXF1 confers cancer stem cell properties to cisplatin‑resistant non‑small cell lung cancer.

The underlying molecular mechanisms of cisplatin resistance in non-small cell lung cancer (NSCLC) are unclear. In this study, a novel differential methylation region located in the upstream regulatory region of the forkhead box F1 (FOXF1) gene was identified. The abnormal hypomethylation of FOXF1 increased the expression of FOXF1, and the high expression of FOXF1 promoted cell proliferation and inhibited cell apoptosis induced by cisplatin, which resulted in cisplatin resistance in NSCLC cells. In addition, FOXF1 promoted the expression of stem cell markers and self-renewal capability, indicating that FOXF1 regulated cisplatin resistance by promoting cancer stem cell properties in NSCLC cells. Moreover, a strong association was observed between FOXF1 upregulation and the presence of platinum-based chemotherapy resistance in patients with NSCLC. On the whole, the findings of this study indicate the regulatory mechanisms of cisplatin resistance by FOXF1 in NSCLC, and suggest that FOXF1 may be used as a prognostic biomarker of platinum-based chemotherapy resistance in NSCLC.

Mitigating temozolomide resistance in glioblastoma via DNA damage-repair inhibition.

Glioblastomas are among the most lethal cancers, with a 5 year survival rate below 25%. Temozolomide is typically used in glioblastoma treatment; however, the enzymes alkylpurine-DNA-N-glycosylase (APNG) and methylguanine-DNA-methyltransferase (MGMT) efficiently mediate the repair of DNA damage caused by temozolomide, reducing treatment efficacy. Consequently, APNG and MGMT inhibition has been proposed as a way of overcoming chemotherapy resistance. Here, we develop a mechanistic mathematical model that explicitly incorporates the effects of chemotherapy on tumour cells, including the processes of DNA damage induction, cell arrest and DNA repair. Our model is carefully parametrized and validated, and then used to virtually recreate the response of heteroclonal glioblastomas to dual treatment with temozolomide and inhibitors of APNG/MGMT. Using our mechanistic model, we identify four combination treatment strategies optimized by tumour cell phenotype, and isolate the strategy most likely to succeed in a pre-clinical and clinical setting. If confirmed in clinical trials, these strategies have the potential to offset chemotherapy resistance in patients with glioblastoma and improve overall survival.

CHEMOTHERAPY ACCORDING TO THE R-mNHL-BFM-90 PROTOCOL IN COMBINATION WITH LENALIDOMIDE AS THE FIRST LINE THERAPY IN PATIENTS WITH MUM1-POSITIVE DIFFUSIVE LARGE B-CELL LYMPHOMA AND FOLLICULAR LYMPHOMA GRADE 3B

Introduction.Diffuse large B-cell lymphoma of postgerminal origin (ABC-DLBCL) and follicular lymphoma grade 3B (FL3B) are characterised by an aggressive course and resistance to chemotherapy (CT). Both diseases are characterised by the activation of genes of the post-terminal stage of B-cell differentiation and high expression of the MUM1 transcriptional protein. Lenalidomide in combination with R-CHOP improved the results of treatment in patients with ABC-DLBCL; however, about 40 % of them remain resistant to the therapy.Aim.The aim of the study was to evaluate the efficacy and toxicity of the R-mNHL-BFM-90 protocol with lenalidomide (R2-mNHL-BFM-90), as well as to analyse possible causes of CT resistance in patients with ABC-DLBCL and FL3B.Patients and methods.Over the period from October 2016 to December 2018, 8 patients with MUM1-positive DLBCL and FL3B were included in the research. All patients underwent a cytogenetic study of tumour samples. A mutational status of the TP53 gene was determined by Sanger sequencing.Results.Patients received combination chemotherapy according to the R2-mNHL-BFM-90 protocol with lenalidomide at a dose of 25 mg/day, from the 1st to the 10th day of each course. Autologous hematopoietic stem cell transplantation was performed as a consolidation in three patients. After the end of the chemotherapy, a complete remission of the disease was achieved in all patients. Relapse developed in 1 patient with a mutation in the TP53 gene. With a median follow-up period of 11 months (1–23), event-free survival was 87 %.Conclusions. The R2-mNHL-BFM-90 protocol has demonstrated a high efficacy and acceptable toxicity in patients with ABC-DLBCL and FL3B. The presence of a mutation in the TP53 gene is established to be an extremely unfavourable prognostic factor even provided intensive treatment protocols, thus requiring the development of alternative approaches to the management of such patients.

Clinical significance of circulating tumor cells in predicting disease progression and chemotherapy resistance in patients with gestational choriocarcinoma.

Gestational choriocarcinoma (GC) is a highly aggressive tumor. In our study, we systematically investigated EpCAM/CD147 expression characteristics in patients with GC and assessed the role of circulating tumor cells (CTCs) in predicting chemotherapy response and disease progression. GC tissues were positive for either epithelial cellular adhesion molecule (EpCAM) or CD147, and all samples exhibited strong human chorionic gonadotropin (HCG) expression. Among all the recruited patients (n = 115), 103 had at least 1 CTC in a 7.5‐mL peripheral blood sample, and the percentage of patients with ≥4 CTCs in a particular FIGO stage group increased with a higher FIGO stage (p < 0.001). Furthermore, the pretreatment CTC count was related to tumor size (r = 0.225, p = 0.015) and the number of metastases (r = 0.603, p < 0.001). A progression analysis showed that among the 115 included patients who qualified for further examination, 52 of the 64 patients defined as progressive had ≥4 pretreatment CTCs, while only 7 of the 51 non‐progressive patients had ≥4 pretreatment CTCs (p < 0.001). In multivariate analysis, CTCs (≥4) remained the strongest predictor of PFS when other prognostic markers, FIGO score and FIGO stage were included. Moreover, based on the chemotherapy response, patients with ≥4 CTCs were more likely to be resistant to chemotherapy than those with <4 CTCs (P < 0.001). These findings demonstrates the feasibility of CTC detection in cases of GC by adopting EpCAM/CD147 antibodies together as capturing antibodies. The CTC count is a promising indicator in the evaluation of biological activities and the chemotherapy response in GC patients.