Targeting RBM39 through indisulam induced mis-splicing of mRNA to exert anti-cancer effects in T-cell acute lymphoblastic leukemia.

BACKGROUND: Despite the use of targeted therapeutic approaches, T-cell acute lymphoblastic leukemia (T-ALL) is still associated with a high incidence of complications and a poor prognosis. Indisulam (also known as E7070), a newly identified molecular glue compound, has demonstrated increased therapeutic efficacy in several types of cancer through the rapid degradation of RBM39. This study aimed to evaluate the therapeutic potential of indisulam in T-ALL, elucidate its underlying mechanisms and explore the role of the RBM39 gene. METHODS: We verified the anticancer effects of indisulam in both in vivo and in vitro models. Additionally, the construction of RBM39-knockdown cell lines using shRNA confirmed that the malignant phenotype of T-ALL cells was dependent on RBM39. Through RNA sequencing, we identified indisulam-induced splicing anomalies, and proteomic analysis helped pinpoint protein changes caused by the drug. Comprehensive cross-analysis of these findings facilitated the identification of downstream effectors and subsequent validation of their functional roles. RESULTS: Indisulam has significant antineoplastic effects on T-ALL. It attenuates cell proliferation, promotes apoptosis and interferes with cell cycle progression in vitro while facilitating tumor remission in T-ALL in vivo models. This investigation provides evidence that the downregulation of RBM39 results in the restricted proliferation of T-ALL cells both in vitro and in vivo, suggesting that RBM39 is a potential target for T-ALL treatment. Indisulam's efficacy is attributed to its ability to induce RBM39 degradation, causing widespread aberrant splicing and abnormal translation of the critical downstream effector protein, THOC1, ultimately leading to protein depletion. Moreover, the presence of DCAF15 is regarded as critical for the effectiveness of indisulam, and its absence negates the ability of indisulam to induce the desired functional alterations. CONCLUSION: Our study revealed that indisulam, which targets RBM39 to induce tumor cell apoptosis, is an effective drug for treating T-ALL. Targeting RBM39 through indisulam leads to mis-splicing of pre-mRNAs, resulting in the loss of key effectors such as THOC1.

CT-based radiomics combined with clinical features for invasiveness prediction and pathological subtypes classification of subsolid pulmonary nodules.

Purpose: To construct optimal models for predicting the invasiveness and pathological subtypes of subsolid nodules (SSNs) based on CT radiomics and clinical features. Materials and Methods: This study was a retrospective study involving two centers. A total of 316 patients with 353 SSNs confirmed as atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) were included from January 2019 to February 2023. Models based on CT radiomics and clinical features were constructed for classification of AAH/AIS and MIA, MIA and IAC, as well as lepidic-predominant adenocarcinoma (LPA) and acinar-predominant adenocarcinoma (APA). Receiver operating characteristic (ROC) curve was used to evaluate the model performance. Finally, the nomograms based on the optimal models were established. Results: The nomogram based on the combined model (AAH/AIS versus MIA) consisting of lobulation, the GGN-vessel relationship, diameter, CT value, consolidation tumor ratio (CTR) and rad-score performed the best (AUC=0.841), while age, CT value, CTR and rad-score were the significant features for distinguishing MIA from IAC, the nomogram based on these features performed the best (AUC=0.878). There were no significant differences in clinical features between LPA and APA, while the radiomics model based on rad-score showed good performance for distinguishing LPA from APA (AUC=0.926). Conclusions: The nomograms based on radiomics and clinical features could predict the invasiveness of SSNs accurately. Moreover, radiomics models showed good performance in distinguishing LPA from APA.

Distribution, traceability, and risk assessment of organophosphate flame retardants in agricultural soils along the Yangtze River Delta in China.

Severe pollution threatens the ecosystem and human health in the Yangtze River Delta (YRD) in China because of the rapid development of industry in this area. This study examines the types, distribution, concentration, and origin of fourteen typical organophosphate flame retardants (OPFRs) in agricultural soils within the YRD region to offer insights for pollutant control and policy-making. The total concentration of OPFRs (ΣOPFRs) varied between 79.19 and 699.58 µg/kg dry weight (dw), averaging at 209.61 µg/kg dw. Among the OPFRs detected, tributoxyethyl phosphate (TBEP) was identified as the main congener, followed by tri-n-butyl phosphate (TnBP), tris(2-chloroisopropyl) phosphate (TCPP), and trimethyl phosphate (TMP). Source analysis, conducted through correlation coefficients and PCA, indicated that OPFRs in agricultural soils within the YRD region mainly originate from emissions related to plastic products and transportation. The health risk exposure to ΣOPFRs in agricultural soil was considered negligible for farmers, with values below 1.24 × 10-2 and 1.76 × 10-9 for noncarcinogenic and carcinogenic risks, respectively. However, the ecological risk of ΣOPFRs in all the samples ranged from 0.08-1.08, indicating a medium to high risk level. The results offer a comprehensive understanding of OPFR pollution in agricultural soils in the YRD region and can be useful for pollution control that mitigates ecological and health risks in this region.

Development and Validation of a Nomogram Based on DCE-MRI Radiomics for Predicting Hypoxia-Inducible Factor 1α Expression in Locally Advanced Rectal Cancer.

RATIONALE AND OBJECTIVES: The expression levels of hypoxia-inducible factor 1 alpha (HIF-1α) have been identified as a pivotal marker, correlating with treatment response in patients with locally advanced rectal cancer (LARC). This study aimed to develop and validate a nomogram based on dynamic contrast-enhanced MRI (DCE-MRI) radiomics and clinical features for predicting the expression of HIF-1α in patients with LARC. MATERIALS AND METHODS: A total of 102 patients diagnosed with locally advanced rectal cancer were divided into training (n = 71) and validation (n = 31) cohorts. The expression statuses of HIF-1α were histopathologically classified, categorizing patients into high and low expression groups. The intraclass correlation coefficient (ICC), minimum redundancy maximum relevance (mRMR), and the least absolute shrinkage and selection operator (LASSO) were employed for feature selection to construct a radiomics signature and calculate the radiomics score (Rad-score). Univariate and multivariate analyses of clinical features and Rad-score were applied, and the clinical model and the nomogram were constructed. The predictive performance of the nomogram incorporating clinical features and Rad-score was assessed using Receiver Operating Characteristics (ROC) curves, decision curve analysis (DCA), and calibration curves. RESULTS: Seven radiomics features from DCE-MRI were used to build the radiomics signature. The nomogram incorporating CEA, Ki-67 and Rad-score had the highest AUC values in the training cohort and in the validation cohort (AUC: 0.918 and 0.920). Decision curve analysis showed that the nomogram outperformed the clinical model and radiomics signature in terms of clinical utility. In addition, the calibration curve for the nomogram demonstrated good agreement between prediction and actual observation. CONCLUSION: The nomogram based on DCE-MRI radiomics and clinical features showed favorable predictive efficacy and might be useful for preoperatively discriminating the expression of HIF-1α.

METTL14 promotes neuroblastoma formation by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism.

Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5' UTR, were specifically recognized by the m6A "reader" protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Machine learning models based on quantitative dynamic contrast-enhanced MRI parameters assess the expression levels of CD3+, CD4+, and CD8+ tumor-infiltrating lymphocytes in advanced gastric carcinoma.

Objective: To explore the effectiveness of machine learning classifiers based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in predicting the expression levels of CD3+, CD4+, and CD8+ tumor-infiltrating lymphocytes (TILs) in patients with advanced gastric cancer (AGC). Methods: This study investigated 103 patients with confirmed AGC through DCE-MRI and immunohistochemical staining. Immunohistochemical staining was used to evaluate CD3+, CD4+, and CD8+ T-cell expression. Utilizing Omni Kinetics software, radiomics features (Ktrans, Kep, and Ve) were extracted and underwent selection via variance threshold, SelectKBest, and LASSO methods. Logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost) are the four classifiers used to build four machine learning (ML) models, and their performance was evaluated using 10-fold cross-validation. The model's performance was evaluated and compared using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value, and negative predictive value. Results: In terms of CD3+, CD4+, and CD8+ T lymphocyte prediction models, the random forest model outperformed the other classifier models in terms of CD4+ and CD8+ T cell prediction, with AUCs of 0.913 and 0.970 on the training set and 0.904 and 0.908 on the validation set, respectively. In terms of CD3+ T cell prediction, the logistic regression model fared the best, with AUCs on the training and validation sets of 0.872 and 0.817, respectively. Conclusion: Machine learning classifiers based on DCE-MRI have the potential to accurately predict CD3+, CD4+, and CD8+ tumor-infiltrating lymphocyte expression levels in patients with AGC.

MZ1, a BRD4 inhibitor, exerted its anti-cancer effects by suppressing SDC1 in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a relatively prevalent primary tumor of the central nervous system in children, characterized by its high malignancy and mortality rates, along with the intricate challenges of achieving complete surgical resection. Recently, an increasing number of studies have focused on the crucial role of super-enhancers (SEs) in the occurrence and development of GBM. This study embarks on the task of evaluating the effectiveness of MZ1, an inhibitor of BRD4 meticulously designed to specifically target SEs, within the intricate framework of GBM. METHODS: The clinical data of GBM patients was sourced from the Chinese Glioma Genome Atlas (CGGA) and the Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the gene expression data of tumor cell lines was derived from the Cancer Cell Line Encyclopedia (CCLE). The impact of MZ1 on GBM was assessed through CCK-8, colony formation assays, EdU incorporation analysis, flow cytometry, and xenograft mouse models. The underlying mechanism was investigated through RNA-seq and ChIP-seq analyses. RESULTS: In this investigation, we made a noteworthy observation that MZ1 exhibited a substantial reduction in the proliferation of GBM cells by effectively degrading BRD4. Additionally, MZ1 displayed a notable capability in inducing significant cell cycle arrest and apoptosis in GBM cells. These findings were in line with our in vitro outcomes. Notably, MZ1 administration resulted in a remarkable decrease in tumor size within the xenograft model with diminished toxicity. Furthermore, on a mechanistic level, the administration of MZ1 resulted in a significant suppression of pivotal genes closely associated with cell cycle regulation and epithelial-mesenchymal transition (EMT). Interestingly, our analysis of RNA-seq and ChIP-seq data unveiled the discovery of a novel prospective oncogene, SDC1, which assumed a pivotal role in the tumorigenesis and progression of GBM. CONCLUSION: In summary, our findings revealed that MZ1 effectively disrupted the aberrant transcriptional regulation of oncogenes in GBM by degradation of BRD4. This positions MZ1 as a promising candidate in the realm of therapeutic options for GBM treatment.

Remote ischemic postconditioning alleviates cerebral ischemic injury through SERCA2/endoplasmic reticulum stress-mediated apoptosis.

Remote ischemic postconditioning (RIPostC) alleviates brain ischemic injury through several pathways, including endoplasmic reticulum (ER) stress modulation. Sarco endoplasmic reticulum Ca2+ -ATPase(SERCA2) which plays vital role in calcium homeostasis regulation could modulate ER stress logically. This study aimed to investigate whether RIPostC exerts its neuroprotective effect by reducing ER stress mediated by SERCA2. Male SD rats underwent transient middle cerebral artery occlusion (tMCAO) for 2 h followed by reperfusion, with the RIPostC group undergoing 3 cycles of bilateral femoral artery clamping and reperfusion at the beginning of reperfusion. Stroke outcome was assessed based on infarct volume and neurological function evaluation. Protein levels of SERCA2 and other ER stress markers were measured using Western blotting, immunofluorescence, and immunohistochemistry techniques. Compared to the sham group, we observed that RIPostC can effectively reduce cerebral infarct volume after I/R (34.55%: 21.03%; p = .004) and improve neurological function deficit (9.67:12.5; p = .029). Additionally, RIPostC increased SERCA2 protein expression and decreased the protein level of glucose-regulated protein 78 (GRP78), phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) and CCAAT/EBP homologous protein (CHOP). Furthermore, B-cell lymphoma-2 (Bcl-2) expression was increased, while Bcl-2-associated X protein (Bax) and cleaved-caspase-3 was decreased in response to application of RIPostC. Our results suggest that RIPostC improves the prognosis of tMCAO rats, possibly by inhibiting the ER stress mediated by SERCA2, facilitating apoptosis downregulation. The significance of this study is to provide a theoretical basis for further exploring the protective mechanism of ischemic stroke by RIPostC. RESEARCH HIGHLIGHTS: Our results suggest that RIPostC improves the prognosis of tMCAO rats, possibly by inhibiting the ER stress mediated by SERCA2, facilitating apoptosis downregulation, thus achieving a neuroprotective effect.

[Effects of Exogenous Plant Hormone Spraying on the Phytoremediation by Bidens pilosa L. in Cadmium-contaminated Soil].

To explore the effect of exogenous plant hormone spraying on the absorption of heavy metals by hyperaccumulated plants, Bidens pilosa L. was selected as the tested plant owing to the large biomass, short growth cycle, and high accumulation efficiency. Here, the effect of foliar spraying 6-benzylaminopurine (6-BA), salicylic acid (SA), and 24-epi-brassinosteroid (24-EBR) on the remediation of cadmium (Cd)-contaminated soil by B. pilosa L. was examined. The results showed:① the efficiency of the remediation in Cd-contaminated soil by B. pilosa L. was effectively enhanced after the spraying of all three kinds of exogenous plant hormones with appropriate concentrations. The spraying of the three exogenous plant hormones could promote the cadmium concentration in the leaves of B. pilosa L. to increase by 4.21%, 31.79%, and 14.89%; promote the translocation factor (TF) to increase by 9.67%, 18.83%, and 17.85%; promote the phytoextraction rates (PR) to increase by 15.36%, 32.33%, and 64.38%, respectively. ② The growth of B. pilosa L. was significantly promoted after the spraying of the three kinds of exogenous plant hormones with appropriate concentrations. The spraying of the three exogenous plant hormones could promote plant growth under cadmium stress, and the dry weight of the plant root, stem, and leaf was increased by 37.53%, 74.50%, and 104.02%, respectively. ③ The photosynthesis of B. pilosa L. was significantly enhanced after the spraying of the three kinds of exogenous plant hormones with appropriate concentrations. The chlorophyll concentration of the plant was significantly increased after foliar spraying with plant hormones, and the concentration of chlorophyll a was increased by 79.31%, 92.27%, and 51.12%; the photochemical quenching coefficient (qP) was increased by 11.32%, 89.16%, and 78.43%; and the non-photochemical quenching coefficient (NPQ) was increased by 51.71%, 241.12%, and 27.85%, respectively, after foliar spraying with appropriate concentrations of 6-BA, SA, and 24-EBR. ④ The antioxidant capacity of B. pilosa L. was significantly strengthened after the spraying of the three kinds of exogenous plant hormones with appropriate concentrations. The malondialdehyde (MDA) concentration of the plant was reduced by 62.41%, 68.67%, and 46.76% after the application of 6-BA, SA, and 24-EBR, respectively. Meanwhile, superoxide dismutase (SOD) was increased by 68.33%, 10.28%, and 6.17%, and catalase (CAT) was increased by 31.43%, 37.87%, and 37.31%, respectively. Generally, the spraying of exogenous 6-BA, SA, and 24-EBR with the appropriate concentration under Cd stress could significantly increase the biomass of B. pilosa L. and promote the accumulation of heavy metals in the plant, improve the photosynthetic ability of the plant, reduce the oxidative damage of the plant under heavy metal stress, enhance the antioxidant capacity, and improve the absorption and tolerance of plants to Cd. It also could promote the transfer of Cd from roots to shoots, improve the phytoextraction rates of Cd from the plant, and effectively strengthen the phytoremediation efficiency. Among them, 30 mg·L-1 SA foliar spraying had the best effect.

Ketoprofen exposure perturbs nitrogen assimilation and ATP synthesis in rice roots: An integrated metabolome and microbiome analysis.

Ketoprofen, a commonly used non-steroidal anti-inflammatory drug (NSAID), can enter farmland environments via sewage irrigation and manure application and is toxic to plants. However, there have been relatively few studies on the association of ketoprofen with nitrogen (N) assimilation and metabolic responses in plants. Accordingly, the goal of this study was to investigate the effects of ketoprofen on ATP synthesis and N assimilation in rice roots. The results showed that with increasing ketoprofen concentration, root vitality, respiration rate, ATP content, and H+-ATPase activity decreased and plasma membrane permeability increased. The expressions of OSA9, a family III H+-ATPase gene, and OSA6 and OSA10, family IV genes, were upregulated, indicating a response of the roots to ketoprofen. Nitrate, ammonium, and free amino acids content decreased with increased ketoprofen. The levels of enzymes involved in N metabolism, namely nitrate reductase, nitrite reductase, glutamine synthetase, glutamate synthetase, and glutamate dehydrogenase, also decreased under ketoprofen treatment. Principal component analysis revealed that ketoprofen treatment can significantly affect energy synthesis and nitrogen assimilation in rice roots, while these effects can be alleviated by the antioxidant response. Most of the metabolite contents increased, including amino acids, carbohydrates, and secondary metabolites. Key metabolic pathways, namely substance synthesis and energy metabolism, were found to be disrupted. Microbiome analysis showed that community diversity and richness of rice root microorganisms in solution increased with increasing levels of ketoprofen treatment, and the microbial community structure and metabolic pathways significantly changed. The results of this study provides new insights into the response of rice roots to ketoprofen.

Super Enhancer Regulatory Gene FYB1 Promotes the Progression of T Cell Acute Lymphoblastic Leukemia by Activating IGLL1.

Background: Arising from T progenitor cells, T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignant tumor, accounting for 15% of childhood ALL and 25% of adult ALL. Composing of putative enhancers in close genomic proximity, super enhancer (SE) is critical for cell identity and the pathogenesis of multiple cancers. Belonging to the cytosolute linker protein group, FYB1 is essential for TCR signaling and extensively studied in terms of tumor pathogenesis and metastasis. Dissecting the role of FYN binding protein 1 (FYB1) in T-ALL holds the potential to improve the treatment outcome and prognosis of T-ALL. Methods: In this study, SEs were explored using public H3K27ac ChIP-seq data derived from T-ALL cell lines, AML cell lines and hematopoietic stem and progenitor cells (HSPCs). Downstream target of FYB1 gene was identified by RNA-seq. Effects of shRNA-mediated downregulation of FYB1 and immunoglobulin lambda-like polypeptide 1 (IGLL1) on self-renewal of T-ALL cells were evaluated in vitro and/or in vivo. Results: As an SE-driven gene, overexpression of FYB1 was observed in T-ALL, according to the Cancer Cell Line Encyclopedia database. In vitro, knocking down FYB1 led to comprised growth and enhanced apoptosis of T-ALL cells. In vivo, downregulation of FYB1 significantly decreased the disease burden by suppressing tumor growth and improved survival rate. Knocking down FYB1 resulted in significantly decreased expression of IGLL1 that was also an SE-driven gene in T-ALL. As a downstream target of FYB1, IGLL1 exerted similar role as FYB1 in inhibiting growth of T-ALL cells. Conclusion: Our results suggested that FYB1 gene played important role in regulating self-renewal of T-ALL cells by activating IGLL1, representing a promising therapeutic target for T-ALL patients.

BRD4 PROTAC degrader MZ1 exhibits anti-B-cell acute lymphoblastic leukemia effects via targeting CCND3.

INTRODUCTION: B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent malignant tumor affecting children. While the majority of B-ALL patients (90%) experience successful recovery, early relapse cases of B-ALL continue to exhibit high mortality rates. MZ1, a novel inhibitor of Bromodomains and extra-terminal (BET) proteins, has demonstrated potent antitumor activity against hematological malignancies. The objective of this study was to examine the role and therapeutic potential of MZ1 in the treatment of B-ALL. METHODS: In order to ascertain the fundamental mechanism of MZ1, a sequence of in vitro assays was conducted on B-ALL cell lines, encompassing Cell Counting Kit 8 (CCK8) assay, Propidium iodide (PI) staining, and Annexin V/PI staining. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to examine protein and mRNA expression levels. Transcriptomic RNA sequencing (RNA-seq) was utilized to screen the target genes of MZ1, and lentiviral transfection was employed to establish stably-expressing/knockdown cell lines. RESULTS: MZ1 has been observed to induce the degradation of Bromodomain Containing 4 (BRD4), Bromodomain Containing 3 (BRD3), and Bromodomain Containing 2 (BRD2) in B-ALL cell strains, leading to inhibited cell growth and induction of cell apoptosis and cycle arrest in vitro. These findings suggest that MZ1 exhibits cytotoxic effects on two distinct molecular subtypes of B-ALL, namely 697 (TCF3/PBX1) and RS4;11 (MLL-AF4) B-ALL cell lines. Additionally, RNA-sequencing analysis revealed that MZ1 significantly downregulated the expression of Cyclin D3 (CCND3) gene in B-ALL cell lines, which in turn promoted cell apoptosis, blocked cell cycle, and caused cell proliferation inhibition. CONCLUSION: Our results suggest that MZ1 has potential anti-B-ALL effects and might be a novel therapeutic target.

The RNA polymerase II subunit B (RPB2) functions as a growth regulator in human glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor with a poor prognosis. The growth of GBM cells depends on the core transcriptional apparatus, thus rendering RNA polymerase (RNA pol) complex as a candidate therapeutic target. The RNA pol II subunit B (POLR2B) gene encodes the second largest subunit of the RNA pol II (RPB2); however, its genomic status and function in GBM remain unclear. Certain GBM data sets in cBioPortal were used for investigating the genomic status and expression of POLR2B in GBM. The function of RPB2 was analyzed following knockdown of POLR2B expression by shRNA in GBM cells. The cell counting kit-8 assay and PI staining were used for cell proliferation and cell cycle analysis. A xenograft mouse model was established to analyze the function of RPB2 in vivo. RNA sequencing was performed to analyze the RPB2-regulated genes. GO and GSEA analyses were applied to investigate the RPB2-regulated gene function and associated pathways. In the present study, the genomic alteration and overexpression of the POLR2B gene was described in glioblastoma. The data indicated that knockdown of POLR2B expression suppressed tumor cell growth of glioblastoma in vitro and in vivo. The analysis further demonstrated the identification of the RPB2-regulated gene sets and highlighted the DNA damage-inducible transcript 4 gene as the downstream target of the POLR2B gene. The present study provides evidence indicating that RPB2 functions as a growth regulator in glioblastoma and could be used as a potential therapeutic target for the treatment of this disease.

Association between radiomics features of DCE-MRI and CD8+ and CD4+ TILs in advanced gastric cancer.

Objective: The aim of this investigation was to explore the correlation between the levels of tumor-infiltrating CD8+ and CD4+ T cells and the quantitative pharmacokinetic parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced gastric cancer. Methods: We retrospectively analyzed the data of 103 patients with histopathologically confirmed advanced gastric cancer (AGC). Three pharmacokinetic parameters, Kep, Ktrans, and Ve, and their radiomics characteristics were obtained by Omni Kinetics software. Immunohistochemical staining was used to determine CD4+ and CD8+ TILs. Statistical analysis was subsequently performed to assess the correlation between radiomics characteristics and CD4+ and CD8+ TIL density. Results: All patients included in this study were finally divided into either a CD8+ TILs low-density group (n = 51) (CD8+ TILs < 138) or a high-density group (n = 52) (CD8+ TILs ≥ 138), and a CD4+ TILs low-density group (n = 51) (CD4+ TILs < 87) or a high-density group (n = 52) (CD4+ TILs ≥ 87). ClusterShade and Skewness based on Kep and Skewness based on Ktrans both showed moderate negative correlation with CD8+ TIL levels (r = 0.630-0.349, p < 0.001), with ClusterShade based on Kep having the highest negative correlation (r = -0.630, p < 0.001). Inertia-based Kep showed a moderate positive correlation with the CD4+ TIL level (r = 0.549, p < 0.001), and the Correlation based on Kep showed a moderate negative correlation with the CD4+ TIL level, which also had the highest correlation coefficient (r = -0.616, p < 0.001). The diagnostic efficacy of the above features was assessed by ROC curves. For CD8+ TILs, ClusterShade of Kep had the highest mean area under the curve (AUC) (0.863). For CD4+ TILs, the Correlation of Kep had the highest mean AUC (0.856). Conclusion: The radiomics features of DCE-MRI are associated with the expression of tumor-infiltrating CD8+ and CD4+ T cells in AGC, which have the potential to noninvasively evaluate the expression of CD8+ and CD4+ TILs in AGC patients.

Transcriptome sequencing identifies novel EVX fusions involved in transcriptional activation of HOX family genes in pediatric immature T-cell acute lymphoblastic leukemia: two cases reports and a literature review.

Driver genomic alterations in pediatric immature T-cell acute lymphoblastic leukemia are not fully known. We report two cases of novel EVX fusions involved in the transcriptional activation of HOX family genes, ETV6::EVX2 and MSI2::EVX1/HOXA13, which activate HOXD and HOXA cluster genes transcription through enhancer hijacking. HOXA and HOXD were the only key transcription factors activated in these cases, which indicates their important roles in leukemogenesis. Our findings elucidate potential drivers for development of T-cell lymphoblastic leukemia, and are valuable for diagnosis and risk stratification of pediatric T-ALL in the era of precision medicine.

Visualization of Phototherapy Evolution by Optical Imaging.

Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is a non-invasive and effective approach used for cancer treatment, in which phototherapeutic agents are irradiated with an appropriate light source to produce cytotoxic reactive oxygen species (ROS) or heat to ablate cancer cells. Unfortunately, traditional phototherapy lacks a facile imaging method to monitor the therapeutic process and efficiency in real time, usually leading to severe side effects due to high levels of ROS and hyperthermia. To realize precise cancer treatment methods, it is highly desired to develop phototherapeutic agents possessing an imaging ability to evaluate the therapeutic process and efficacy in real time during cancer phototherapy. Recently, a series of self-reporting phototherapeutic agents were reported to monitor PDT and PTT processes by combining optical imaging technologies with phototherapy. Due to the real-time feedback provided by optical imaging technology, therapeutic responses or dynamic changes in the tumor microenvironment could be evaluated in a timely manner, thereby achieving personalized precision treatment and minimizing toxic side effects. In this review, we focus on the advances in the development of self-reporting phototherapeutic agents for a cancer phototherapy evaluation based on optical imaging technology to realize precision cancer treatments. Additionally, we propose the current challenges and future directions of self-reporting agents for precision medicine.

New insight into desorption behavior and mechanism of oil from aged oil-contaminated soil in microemulsion.

The intractable nature of oil-contaminated soil (OS) constitutes the chief limiting factor for its remediation. Herein, the aging effect (i.e., oil-soil interactions and pore-scale effect) was investigated by analyzing the properties of aged OS and further demonstrated by investigating the desorption behavior of the oil from the OS. XPS was performed to detect the chemical environment of N, O, and Al, indicating the coordination adsorption of carbonyl groups (oil) on the soil surface. Alterations in the functional groups of the OS were detected using FT-IR, indicating that the oil-soil interactions were enhanced via wind-thermal aging. SEM and BET were used to analyze the structural morphology and pore-scale of the OS. The analysis revealed that aging promoted the development of the pore-scale effect in the OS. Moreover, the desorption behavior of oil molecules from the aged OS was investigated via desorption thermodynamics and kinetics. The desorption mechanism of the OS was elucidated via intraparticle diffusion kinetics. The desorption process of oil molecules underwent three stages: film diffusion, intraparticle diffusion, and surface desorption. Owing to the aging effect, the latter two stages constituted the major steps for controlling oil desorption. This mechanism provided theoretical guidance to apply microemulsion elution for remedying industrial OS.

The frequencies of lymphocyte subsets on "day 30″ correlate with the clinical outcome of pediatric hematopoietic stem cell transplantation.

We aimed to determine the relationship between lymphocyte subsets on day 30 (D30) and prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children. We retrospectively examined the clinical outcomes and lymphocyte subsets on D30 after allo-HSCT in 115 pediatric patients at the Children's Hospital of Soochow University between January 2016 and June 2019. Measurements were performed using flow cytometry on D30. Lymphocyte subsets were compared among the umbilical cord blood (UCB) (n = 22), HLA-matched sibling donor (MSD) (n = 14), haploidentical donor transplantation (HID) (n = 57), and unrelated donor transplantation (UD) (n = 22) groups. The relationships between the frequencies and counts of lymphocyte subsets and clinical outcomes were analyzed. T and B cell counts were the highest in the MSD group compared to the other groups, and natural killer cell counts were the highest in the UCB group. Lymphocyte subsets on D30 after allo-HSCT were correlated with the occurrence of acute (aGVHD) and chronic graft versus host disease (cGVHD). A high frequency of B cells (≥4.65%) was associated with the development of severe aGVHD. High frequencies of CD4+T (≥10.25%) were correlated with extensive cGVHD. Moreover, a high frequency of CD4+T cells (≥9.80%) was correlated with GVHD-free and failure-free survival (GFFS) after allo-HSCT. However, on D30, there were no statistically significant correlations between viral infections and lymphocyte subsets. The frequencies of lymphocyte subsets on D30 after allo-HSCT are good indicators of prognosis after allo-HSCT in children.

Metabolomic analysis reveals the impact of ketoprofen on carbon and nitrogen metabolism in rice (Oryza sativa L.) seedling leaves.

Pharmacologically active compounds (PACs) are becoming common pollutants in the natural environment, posing potential risks to crop quality; however, the toxic effects and metabolic changes that they cause in agricultural plants remain unclear. Here, we investigated the effects of ketoprofen on respiration rate, ATP synthesis, carbon and nitrogen metabolism, and metabolomics in rice seedling leaves. The results showed that ketoprofen treatment adversely affected the respiration rate, ATP content, H+-ATPase activity and induced changes in the contents of carbon assimilation products (soluble sugar, reducing sugar, sucrose, and starch) and the activities of key enzymes in carbon metabolism (sucrose synthase (SS), sucrose phosphate synthase (SPS), and sucrose invertase (InV)). The contents of nitrate, ammonium, and free amino acids, and the activities of key enzymes involved in nitrogen metabolism (nitrate reductase (NR), nitrite reductase (NiR), glutamine synthetase (GS), glutamate synthase (GOGAT), and glutamate dehydrogenase (GDH)) were also affected in a concentration-dependent manner. Metabolomics analysis showed that ketoprofen disturbed the type and content of metabolites (amino acids, carbohydrates, and secondary metabolites) to varying degrees and perturbed key metabolic pathways (substance synthesis and energy metabolism), ultimately resulting in the reduction of rice seedling biomass. This study provides important information and a useful reference for the accurate assessment of the environmental risks of PACs.