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Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy. Temozolomide resistance in glioblastoma is associated with MGMT overexpression. Here, the authors identify a lncRNA that is a competitive endogenous RNA for miR-20b-3p, which causes c-Met activation to modulate acetylation of histone H3 on MGMT promoter through Stat3/p300 complex to increase MGMT expression and temozolomide resistance.

Activation of receptor tyrosine kinase (RTK) protein is frequently observed in malignant progression of gliomas. In this study, the crosstalk activation of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling pathways is demonstrated to contribute to temozolomide (TMZ) resistance, resulting in an unfavorable prognosis for patients with glioblastoma. To simultaneously mitigate EGFR and MET activation, a dual functionalized brain-targeting nanoinhibitor, BIP-MPC-NP, is developed by conjugating Inherbin3 and cMBP on the surface of NHS-PEG 8 -Mal modified MPC-nanoparticles. In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma. In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ. These results demonstrate the promise of this nanoinhibitor as a feasible strategy overcoming TMZ resistance in glioma. Receptor tyrosine kinases are often activated in malignant gliomas. Here, the authors develop a dual functionalized brain targeting nano-inhibitor to simultaneously target EGFR and MET pathways, and show this can overcome temozolomide resistance in glioma.

Neutrophil extracellular traps (NETs) produced by tumor-infiltrating neutrophils (TINs) are associated with poor prognosis in patients with several types of cancer. However, the mechanisms underlying the involvement of NETs in glioma progression remain largely unknown. This study aimed to elucidate the roles of NETs in biological processes that drive the crosstalk between glioma progression and the tumor microenvironment. Neutrophil infiltration and NETs formation were investigated in glioma tissue through immunohistochemistry, and their relationships with clinicopathological features and outcomes were statistically evaluated. The effects of NETs on glioma cell progression were studied in a co-culture system. and experiments validated the reactive oxygen species activity and cytokine production of TINs, as well as the ERK signaling pathway activation and the metastasis of gliomas. Neutrophil infiltration and NETs formation were induced in high-grade glioma compared with low-grade glioma. NETs induced by TINs were determined to be an oncogenic marker of high-grade gliomas and to be involved in cell proliferation and invasion. NETs overproduction promoted glioma cell proliferation, migration, and invasion. Furthermore, HMGB1 was found to bind to RAGE and activate the NF-κB signaling pathway . In addition, NETs stimulated the NF-κB signaling pathway, thus promoting IL-8 secretion in glioblastoma. Subsequently, IL-8 recruited neutrophils which in turn mediated NETs formation the PI3K/AKT/ROS axis in TINs. Our results suggest that NETs produced by TINs mediate the crosstalk between glioma progression and the tumor microenvironment by regulating the HMGB1/RAGE/IL-8 axis. Targeting NETs formation or IL-8 secretion may be an effective approach to inhibit glioma progression.

A brain organoid is a self-organizing three-dimensional tissue derived from human embryonic stem cells or pluripotent stem cells and is able to simulate the architecture and functionality of the human brain. Brain organoid generation methods are abundant and continue to improve, and now, an in vivo vascularized brain organoid has been encouragingly reported. The combination of brain organoids with immune-staining and single-cell sequencing technology facilitates our understanding of brain organoids, including the structural organization and the diversity of cell types. Recent publications have reported that brain organoids can mimic the dynamic spatiotemporal process of early brain development, model various human brain disorders, and serve as an effective preclinical platform to test and guide personalized treatment. In this review, we introduce the current state of brain organoid differentiation strategies, summarize current progress and applications in the medical domain, and discuss the challenges and prospects of this promising technology.

Introduction Empathy is considered the ability to understand or feel others emotions or experiences. As an important part of medical education, empathy can affect medical students in many ways. It is still lacking a comprehensive evaluation of the existing articles on empathy’s impact on medical students, despite the existence of many articles on the topic. Objectives To summarize the impact of empathy on medical students during medical education from four perspectives: mental health, academic performance, clinical competence, and specialty preference. Methods The search terms used for retrieval were “empathy”, “medical student”, “mental health”, “depression”, “anxiety”, “burnout”, “examinations”, “academic performance”, “clinical competence”, “specialty preference” on PubMed, EBSCO, and Web of Science before January 2024. The search was carried out by two reviewers. Titles and abstracts were screened independently and reviewed based on inclusion/exclusion criteria. A consensus was drawn on which articles were included. Results Our results indicated that high empathy was a positive factor for mental health, However, students with high affective empathy were more likely to suffer from depression, anxiety, and burnout. Empathy was found to be unrelated to academic performance, but positively correlated with clinical competence, particularly in terms of communication skills. Medical students with high levels of empathy tended to prefer people-oriented majors. Conclusions Medical students who score higher on the self-reported empathy scales often have better mental health, better communication skills, and tend to choose people-oriented specialties. But empathy is not related to academic performance. Additionally, the different dimensions of empathy have different impacts on medical students. It is necessary to design targeted courses and training for medical students to enhance their empathy.

The aim of this study was to investigate the roles of the transcription factor Snail and adhesion factor epithelial-cadherin (E-cadherin) in clear cell renal cell carcinoma (CCRCC) and evaluate their correlation with tumor pathological grading, clinical stage, invasion and metastases. The expression of Snail and E-cadherin protein in 69 samples of CCRCC tissue, 58 samples of para-cancerous mucosa and 10 samples of normal renal tissue were detected using the immunohistochemical streptavidin-peroxidase method. The positivity rate of Snail in CCRCC was 82.61%, which was significantly higher than that in para-cancerous mucosa (43.10%, P<0.001). The positivity rate of E-cadherin in CCRCC was 31.88%, which was significantly lower than that in para-cancerous mucosa (91.38%, P<0.001). The expression of E-cadherin and Snail correlated significantly with tumor differential degree, clinical stage and the depth of tumor invasion and distant metastasis (P<0.05). There was a negative correlation between the expression of E-cadherin and Snail in CCRCC. The overexpression of Snail and reduced expression of E-cadherin may be important biological markers for the invasion and metastasis of CCRCC. The combined detection of E-cadherin and Snail has far-reaching significance for the prediction of CCRCC invasion and metastasis.

Background The treatments for refractory leptomeningeal metastasis (RLM) of non-small cell lung cancer (NSCLC) are limited, and response assessment is complex and challenging. This clinical trial aimed to evaluate the efficacy of intrathecal pemetrexed (IP) and response assessment using cerebrospinal fluid (CSF) tumor marker in RLM. Methods This was a single-center, single-arm, phase II adaptive clinical trial. Patients with RLM of NSCLC were eligible for inclusion. Patients were assigned to receive 30 mg of IP every 3 weeks for a total of 6 cycles. The primary endpoint was overall survival (OS). The secondary endpoints included progression-free survival (PFS) evaluated according to EANO-ESMO response assessment, disease control rate, the concordance of CSF tumor marker response with EANO-ESMO response assessment, and safety. Results A total of 29 patients were enrolled in the trial. The median PFS was 10.03 months (95% CI, 6.42–13.64), and the median OS was 20.37 months (95% CI, 14.86–25.88), respectively. A ± 35% threshold for CSF tumor marker level change (TML) yielded the optimal predictive performance, with AUCs of 0.890 (95% CI, 0.833–0.947), 0.911 (95% CI, 0.870–0.951), and 0.784 (95% CI, 0.717–0.850) for EANO-ESMO response, progression, and stable, respectively. Most patients (93.1%) experienced grade 1–2 treatment-related adverse events. Conclusions Our therapeutic regimen of IP provided a practical, survival-extending, and tolerant option for RLM patients. CSF tumor marker response was correlated with EANO-ESMO response assessment, offering an effective tool for response monitoring of RLM. Trial registration Chinese Clinical Trial Register (ChiCTR) ChiCTR2200057235. Registered on March 1, 2022. Date of the first patient enrollment: April 29, 2022.

Glioblastoma multiform (GBM) is the most common malignant primary brain tumor in adults. Radiotherapy plus concomitant and adjuvant TMZ chemotherapy is the current standard of care for patients with GBM. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, are key modulators of tumor invasion and metastasis due to their ECM degradation capacity. The aim of the present study was to identify the most informative MMP member in terms of prognostic and predictive ability for patients with primary GBM. The mRNA expression profiles of all MMP genes were obtained from the Chinese Glioma Genome Atlas (CGGA), the Repository for Molecular Brain Neoplasia Data (REMBRANDT) and the GSE16011 dataset. MGMT methylation status was also examined by pyrosequencing. The correlation of MMP9 expression with tumor progression was explored in glioma specimens of all grades. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the association of MMP9 expression with survival and response to temozolomide. MMP9 was the only significant prognostic factor in three datasets for primary glioblastoma patients. Our results indicated that MMP9 expression is correlated with glioma grade (p<0.0001). Additionally, low expression of MMP9 was correlated with better survival outcome (OS: p = 0.0012 and PFS: p = 0.0066), and MMP9 was an independent prognostic factor in primary GBM (OS: p = 0.027 and PFS: p = 0.032). Additionally, the GBM patients with low MMP9 expression benefited from temozolomide (TMZ) chemotherapy regardless of the MGMT methylation status. Patients with primary GBMs with low MMP9 expression may have longer survival and may benefit from temozolomide chemotherapy.

NoncoRNA ( http://www.ncdtcdb.cn:8080/NoncoRNA/ ) is a manually curated database of experimentally supported non-coding RNAs (ncRNAs) and drug target associations that aim to potentially provide a high-quality data resource for exploring drug sensitivity/resistance-related ncRNAs in various human cancers. ncRNA are RNA molecular that do not encode proteins, but are involved in gene regulation and cellular functions in variety of human diseases, including neurodegenerative diseases and cancers. Here, we developed NoncoRNA which contained 8233 entries between 5568 ncRNAs and 154 drugs in 134 cancers. Each entry in the NoncoRNA contains detailed information on the ncRNAs, drugs, and cancers, the ncRNA expression pattern and experimental detection techniques, drug response and other targets, literature references, and other information. NoncoRNA offers a user-friendly, open access web interface to easily browse, search, and download data. NoncoRNA also provides a submission page for researchers to submit newly validated ncRNA-drug-cancer associations. NoncoRNA might serve as an immeasurable resource for understanding the roles of ncRNAs in cancer therapy.

Over 20% of cancer 'driver' genes encode chromatin regulators. Long noncoding RNAs (lincRNAs), which are dysregulated in various cancers, play a critical role in chromatin dynamics and gene regulation by interacting with key epigenetic regulators. It has been previously reported that the lincRNA HOTAIR mediates recruitment of polycomb repressive complex 2 (PRC2) leading to aberrant transcriptional silencing of tumor suppressor genes in glioma and breast cancer. Thus, lincRNA HOTAIR can serve as a promising therapeutic target. Herein, we identified a small-molecule compound AC1Q3QWB (AQB) as a selective and efficient disruptor of HOTAIR-EZH2 interaction, resulting in blocking of PRC2 recruitment and increasing tumor suppressors expression. Molecular docking and high-throughput screening were performed to identify the small compound, AQB. RIP and ChIRP assays were carried to assess the selective interference of AQB with the HOTAIR-EZH2 interaction. The effects of AQB on tumor malignancy were evaluated in a variety of cancer cell lines and orthotopic breast cancer models. The combination therapy of AQB and 3-Deazaneplanocin A (DZNep), an inhibitor of the histone methyltransferase EZH2 was used and in orthotopic breast cancer and glioblastoma patient-derived xenograft (PDX) models. Tumor cells highly expressing HOTAIR and EZH2 were sensitive to AQB. APC2, as one of the target genes, was significantly up-regulated by AQB and led to degradation of β-catenin resulting in suppression of Wnt/β-catenin signaling which may contribute to inhibition of tumor growth and metastasis and in orthotopic breast cancer models. Remarkably, AQB enhanced the toxicity of DZNep . In orthotopic breast cancer and glioblastoma patient-derived xenografts (PDX) models, the combination of low doses of AQB and DZNep realized much better killing than DZNep treatment alone. AQB is a HOTAIR-EZH2 inhibitor, which blocks PRC2 recruitment and has great potential as an effective agent for targeted cancer therapy.