Expression of concern: A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma.

Expression of concern for 'A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma' by Yandong Xie, et al., Biomater. Sci., 2022, 10, 6791-6803, https://doi.org/10.1039/D2BM01145J.

TBX15 facilitates malignant progression of glioma by transcriptional activation of TXDNC5.

T-box transcription factor 15 (TBX15) plays important role in various cancers; however, its expression and role in glioma is still unclear. In this study, our findings indicated that TBX15 was increased in gliomas compared to normal brain tissues, and high levels of TBX15 were related to poor survival. Furthermore, TBX15 silencing in glioma cells not only inhibited their proliferation, migration, and invasion in vitro, but also weakened their ability to recruit macrophages and polarize the latter to the M2 subtype. Mechanism study indicated that thioredoxin domain containing 5 (TXNDC5) lies downstream of TBX15. Furthermore, rescue assays verified that the role of TBX15 in glioma cells is dependent on TXNDC5. Moreover, sh-TBX15 loaded into DNA origami nanocarrier suppressed the malignant phenotype of glioma in vitro and in vivo. Taken together, the TBX15/TXNDC5 axis is involved in the genesis and progression of glioma, and is a potential therapeutic target.

Biomimetic hypoxia-triggered RNAi nanomedicine for synergistically mediating chemo/radiotherapy of glioblastoma.

Although RNA interference (RNAi) therapy has emerged as a potential tool in cancer therapeutics, the application of RNAi to glioblastoma (GBM) remains a hurdle. Herein, to improve the therapeutic effect of RNAi on GBM, a cancer cell membrane (CCM)-disguised hypoxia-triggered RNAi nanomedicine was developed for short interfering RNA (siRNA) delivery to sensitize cells to chemotherapy and radiotherapy. Our synthesized CCM-disguised RNAi nanomedicine showed prolonged blood circulation, high BBB transcytosis and specific accumulation in GBM sites via homotypic recognition. Disruption and effective anti-GBM agents were triggered in the hypoxic region, leading to efficient tumor suppression by using phosphoglycerate kinase 1 (PGK1) silencing to enhance paclitaxel-induced chemotherapy and sensitize hypoxic GBM cells to ionizing radiation. In summary, a biomimetic intelligent RNAi nanomedicine has been developed for siRNA delivery to synergistically mediate a combined chemo/radiotherapy that presents immune-free and hypoxia-triggered properties with high survival rates for orthotopic GBM treatment.

TCFL5 knockdown sensitizes DLBCL to doxorubicin treatment via regulation of GPX4.

BACKGROUND: Resistance to chemo-drug is a major cause of bad outcome in diffuse large B-cell lymphoma (DLBCL). It was reported that TCFL5 may be related to chemoresistance in childhood acute lymphoblastic leukemia. However, it is still unclear whether TCFL5 is involved in DLBCL drug-resistance. METHODS: To explore the underlying mechanism of doxorubicin resistance, recombinant lentivirus was applied to control expression of TCFL5 in DLBCL cells. CCK-8 assay was perfomed to investigate the influence of doxorubicin on proliferation of TCFL5-overexpressed or sh-TCFL5 DLBCL cells. Correlation between TCFL5 and GPX4 was analyzed with bioinformatic methods, which was further confirmed by qPCR and western blot. TCFL5 overexpression conferred doxorubicin resistance via regulating GPX4 and was verified by TUNEL assay and western blot in vitro and mice model in vivo. RESULTS: TCFL5 was enriched in DLBCL cells and conferred doxorubicin resistance through binding to GPX4. Inhibition of TCFL5 enhanced the sensitivity of DLBCL cells to doxorubicin. GPX4 knockdown reversed doxorubicin resistance in TCFL5-overexpressed DLBCL cells. CONCLUSION: DLBCL cells overexpress TCFL5 that promotes chemoresistance by regulating GPX4. Targeting TCFL5 may provide a prospective therapeutic strategy for doxorubicin-resistant DLBCL.

Primary renal mucinous adenocarcinoma masquerading as a giant renal cyst: a case report.

Mucinous adenocarcinoma of the kidney is rarely reported in the literature. We present a previously unreported mucinous adenocarcinoma arising from the renal parenchyma. A 55-year-old male patient with no complaints showed a large cystic hypodense lesion in the upper left kidney on contrast-enhanced computed tomography (CT) scan. A left renal cyst was initially considered, and a partial nephrectomy (PN) was performed. During the operation, a large amount of jelly-like mucus and bean-curd-like necrotic tissue was found in the focus. The pathological diagnosis was mucinous adenocarcinoma, and further systemic examination revealed no clinical evidence of primary disease elsewhere. Then the patient underwent left radical nephrectomy (RN), and the cystic lesion was found in the renal parenchyma, while neither the collecting system nor the ureters were involved. Postoperative sequential chemotherapy and radiotherapy were administered, and no signs of disease recurrence were observed over 30 months of follow-up. Based on a literature review, we summarize the lesion with rarity and the associated dilemma in preoperative diagnosis and treatment. Given the high degree of malignancy, a careful history analysis accompanied by dynamic observation of imaging and tumor markers is recommended for the diagnosis of the disease. Comprehensive treatment based on surgery may improve its clinical outcomes.

Safety and efficacy associated with single-fraction high-dose-rate brachytherapy in localized prostate cancer: a systematic review and meta-analysis.

OBJECTIVE: Although single-fraction high-dose-rate brachytherapy (SFHDR) for localized prostate cancer has been tried in clinical trials, relevant medical evidence is currently lacking. It is necessary to systematically analyze the safety and efficacy of SFHDR. METHODS: Comprehensive and systematic searches for eligible studies were performed in PubMed, Embase, and the Cochrane Library databases. The primary endpoints included safety and efficacy, represented by toxic effects and biochemical recurrence-free survival (bRFS), respectively. The proportion rates were used as the effect measure for each study and were presented with corresponding 95% confidence intervals (CI) and related 95% prediction interval (PI). Restricted maximum-likelihood estimator (REML) and the Hartung-Knapp method were used in the meta-analysis. RESULTS: Twenty-five studies met the inclusion criteria for quantitative analysis, including 1440 patients. The median age of patients was 66.9 years old (62-73 years old) and the median follow-up was 47.5 months (12-75 months). The estimates of cumulative occurrence for severe gastrointestinal (GI) and genitourinary (GU) toxic effects were 0.1% (95% CI 0-0.2%) and 0.4% (95% CI 0-1.2%), and for grade 2 toxic effects were 1.6% (95% CI 0.1-4.7%) and 17.1% (95% CI 5.4-33.5%), respectively. The estimate of 3­year bRFS was 87.5% (95% CI 84.4-90.3%) and 71.0% (95% CI 63.0-78.3%) for 5­year bRFS. The pooled bRFS rates for low-risk patients were 99.0% (95% CI 85.2-100.0%) at 3 years and 80.9% (95% CI 75.4-85.9%) at 5 years, and the risk group was found to be statistically correlated with bRFS (3-year bRFS, P < 0.01; 5­year bRFS, P = 0.04). CONCLUSION: SFHDR is associated with favorable tolerability and suboptimal clinical benefit in patients with localized prostate cancer. Ongoing and planned high-quality prospective studies are necessary to verify its safety and efficacy.

Recent progress of hydrogel-based local drug delivery systems for postoperative radiotherapy.

Surgical resection and postoperative radiotherapy remained the most common therapeutic modalities for malignant tumors. However, tumor recurrence after receiving such combination is difficult to be avoided because of high invasiveness and radiation resistance of cancer cells during long-term therapy. Hydrogels, as novel local drug delivery systems, presented excellent biocompatibility, high drug loading capacity and sustained drug release property. Compared with conventional drug formulations, hydrogels are able to be administered intraoperatively and directly release the entrapped therapeutic agents to the unresectable tumor sites. Therefore, hydrogel-based local drug delivery systems have their unique advantages especially in sensitizing postoperative radiotherapy. In this context, classification and biological properties of hydrogels were firstly introduced. Then, recent progress and application of hydrogels for postoperative radiotherapy were summarized. Finally, the prospects and challenges of hydrogels in postoperative radiotherapy were discussed.

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma.

Radiotherapy-resistant glioblastoma (rrGBM) remains a significant clinical challenge because of high infiltrative growth characterized by activation of antiapoptotic signal transduction. Herein, we describe an efficiently biodegradable selenium-engineered mesoporous silica nanocapsule, initiated by high-energy X-ray irradiation and employed for at-site RNA interference (RNAi) to inhibit rrGBM invasion and achieve maximum therapeutic benefit. Our radiation-triggered RNAi nanocapsule showed high physiological stability, good blood-brain barrier transcytosis, and potent rrGBM accumulation. An intratumoral RNAi nanocapsule permitted low-dose X-ray radiation-triggered dissociation for cofilin-1 knockdown, inhibiting rrGBM infiltration. More importantly, tumor suppression was further amplified by electron-affinity aminoimidazole products converted from metronidazole polymers under X-ray radiation-exacerbated hypoxia, which sensitized cell apoptosis to ionizing radiation by fixing reactive oxygen species-induced DNA lesions. In vivo experiments confirmed that our RNAi nanocapsule reduced tumor growth and invasion, prolonging survival in an orthotopic rrGBM model. Generally, we present a promising radiosensitizer that would effectively improve rrGBM-patient outcomes with low-dose X-ray irradiation.

Single-Cell Sequencing Analysis Identified ASTN2 as a Migration Biomarker in Adult Glioblastoma.

Glioblastoma is the most common and aggressive primary central nervous system malignant tumors. With the development of targeted sequencing and proteomic profiling technology, some new tumor types have been established and a series of novel molecular markers have also been identified. The 2021 updated World Health Organization classification of central nervous system tumors first mentioned the classification of adult glioma and pediatric glioma based on the molecular diagnosis. Thus, we used single-cell RNA sequencing analysis to explore the diversity and similarities in the occurrence and development of adult and pediatric types. ASTN2, which primarily encodes astrotactin, has been reported to be dysregulated in various neurodevelopmental disorders. Although some studies have demonstrated that ASTN2 plays an important role in glial-guided neuronal migration, there are no studies about its impact on glioblastoma cell migration. Subsequent single-cell RNA sequencing revealed ASTN2 to be a hub gene of a cell cluster which had a poor effect on clinical prognosis. Eventually, a western blot assay and a wound-healing assay first confirmed that ASTN2 expression in glioblastoma cell lines is higher than that in normal human astrocytes and affects the migration ability of glioblastoma cells, making it a potential therapeutic target.

A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma.

Glioblastoma (GBM), as the most aggressive adult brain tumor, seriously threatened people's lives with a low survival time. Standard postoperative treatment, chemotherapy combined with radiotherapy (RT), was the major therapeutic strategy for GBM. However, this therapeutic efficacy was hindered by chemoradiotherapy resistance of GBM. Herein, to sensitize temozolomide (TMZ)-based chemotherapy and RT, a hypoxia-radiosensitive nanoparticle for co-delivering TMZ and siMGMT (RDPP(Met)/TMZ/siMGMT) was synthesized in this study. Our nanoparticle could effectively release the encapsulated alkylating agent (TMZ) and small interfering O6-methylguanine-DNA-methyltransferase RNA (siMGMT) in the hypoxic GBM. DNA-damage repair was effectively inhibited by down-regulating MGMT expression and activating cell apoptosis, which obviously enhanced the sensitivity of TMZ as well as RT. In vitro and in vivo experiments showed that RDPP(Met)/TMZ/siMGMT could efficiently penetrate the blood-brain barrier (BBB), accurately target GBM cells and effectively inhibit GBM proliferation. Compared with traditional TMZ combined with RT, RDPP(Met)/TMZ/siMGMT remarkably improved the survival time of orthotopic GBM-bearing mice, which demonstrated that our nanoplatform was an efficient combinatorial GBM therapy.

Intelligent Nanoparticles With pH-Sensitive Co-Delivery of Temozolomide and siEGFR to Ameliorate Glioma Therapy.

Glioblastoma (GBM) is one of the most lethal forms of human cancer, with very few long-term survivors. In addition to surgery, chemotherapy is still an important strategy. Unfortunately, GBM chemotherapy faces two main challenges: first, in GBM, epidermal growth factor receptor (EGFR) overexpression results in chemoresistance; second, temozolomide (TMZ) lacks target specificity, which can lead to a reduction in the concentration and side effects in GBM. Nowadays, with the development of nanomedicine systems for applications in tumor therapies, increasing anticancer efficacy and reducing side effects with multi-drug delivery are huge advantages. In this study, pH-sensitive and GBM-targeting nanovesicle (Tf-PEG-PAE(SS)) was fabricated. The chemotherapy drug (TMZ) and EGFR inhibitor (EGFR-siRNA) were co-encapsulated in the nanocarrier, and their anticancer outcomes were investigated in detail. In vitro experiments have shown that the nanocarrier transports TMZ and EGFR-siRNA efficiently into U87 cells, causing a vigorous apoptotic response by silencing the proliferative EGFR gene and increasing the drug concentration of TMZ simultaneously. An experimental study in mice bearing orthotropic glioma revealed that the accumulated nanocarriers in the tumor site could inhibit the tumor growth and prolong the mice survival remarkably through the intracranial injection of Tf-PEG-PAE(SS)/TMZ@siEGFR. The drug co-delivery system could extend the blood circulation time and offer a new strategy to treat glioblastoma.

Construction of a novel radiosensitivity- and ferroptosis-associated gene signature for prognosis prediction in gliomas.

Background: Gliomas are the most refractory intracranial disease characterized by high incidence and mortality rates. Therefore, radiotherapy plays a crucial role in the treatment of gliomas. However, recent evidence reveals that ferroptosis is highly associated with radiosensitivity in tumor cells. Therefore, this study aimed to investigate radiosensitivity- and ferroptosis-associated biomarkers. Moreover, the study aimed to provide new strategies for the treatment and evaluation of prognosis in gliomas. Methods: The mRNA sequencing and relevant clinical data were obtained from The Cancer Genome Atlas (TCGA). Secondly, differential analysis was conducted to reveal the radiosensitivity- and ferroptosis-associated differentially expressed genes (DEGs). Further, a predictive model based on the seven genes was constructed, and LASSO regression analysis was carried out. After that, the Chinese Glioma Genome Atlas (CGGA) was used for validation of the results. Results: A total of 36 radiosensitivity- and 19 ferroptosis-associated DEGs with a prognostic value were identified. Moreover, seven intersecting genes (HSPB1, STAT3, CA9, MAP1LC3A, MAPK1, ZEB1, and TNFAIP3) were identified as the risk signature genes. The ROC curves and K-M analysis revealed that the signature genes showed a good survival prediction. Furthermore, the functional analysis revealed that the differentially expressed genes between the high-risk and the low-risk groups were enriched in glioma-related biological processes. In addition, differences were reported in immune function status between the two groups. Conclusion: This study revealed that the seven biomarkers could help predict the prognosis in glioma patients. In addition, this study provides a basis for understanding the molecular mechanisms of radiosensitivity and ferroptosis in the treatment of gliomas.

Comprehensive exploration of long-wave emission carbon dots for brain tumor visualization.

Carbon dot (CD)-based tumor imaging has been proven to be a reliable nanodiagnostic technique. Although abundant types of CDs have been developed, it is still a major challenge to synthesize long-wavelength CDs with high quality and superior repetition due to the complicated synthetic process. Here, stable long-wavelength red-light emission carbon dots (R-CDs) have been synthesized using appropriate carbon sources via a solvothermal method, which enables effective visualization of deep brain glioblastoma (GBM) by a liposome-formulated delivery system. The luminescence phenomenon and structural growth characteristics of R-CDs have been fully investigated and it has been found that R-CDs exhibit different optical behaviors in different pH and solvent environments. In vitro and in vivo models have proved their excellent cell targeting capacity, bioluminescence imaging potential, and biosafety for GBM visualization. Considering their stability and biocompatibility, the in-depth tissue imagining and other extensive applications of R-CDs are strongly recommended.

Development and validation of a discrimination model between primary PLA2R-negative membranous nephropathy and minimal change disease confirmed by renal biopsy.

Membranous nephropathy (MN) and minimal change disease (MCD) are two common causes leading to nephrotic syndrome (NS). They have similar clinical features but different treatment strategies and prognoses. M-type phospholipase A2 receptor (PLA2R) is considered as a specific marker of membranous nephropathy. However, its sensitivity is only about 70%. Therefore, there is a lack of effective and noninvasive tools to distinguish PLA2R-negative MN and MCD patients without renal biopsy. A total 949 patients who were pathologically diagnosed as idiopathic MN or MCD were enrolled in this study, including 805 idiopathic MN and 144 MCD. Based on the basic information and laboratory examination of 200 PLA2R-negative MN and 144 MCD, we used a univariate and multivariate logistic regression to select the relevant variables and develop a discrimination model. A novel model including age, albumin, urea, high density lipoprotein, C3 levels and red blood cell count was established for PLA2R-negative MN and MCD. The discrimination model has great differential capability (with an AUC of 0.904 in training group and an AUC of 0.886 in test group) and calibration capability. When testing in all 949 patients, our model also showed good discrimination ability for all idiopathic MN and MCD.

Application of New Radiosensitizer Based on Nano-Biotechnology in the Treatment of Glioma.

Glioma is the most common intracranial malignant tumor, and its specific pathogenesis has been unclear, which has always been an unresolved clinical problem due to the limited therapeutic window of glioma. As we all know, surgical resection, chemotherapy, and radiotherapy are the main treatment methods for glioma. With the development of clinical trials and traditional treatment techniques, radiotherapy for glioma has increasingly exposed defects in the treatment effect. In order to improve the bottleneck of radiotherapy for glioma, people have done a lot of work; among this, nano-radiosensitizers have offered a novel and potential treatment method. Compared with conventional radiotherapy, nanotechnology can overcome the blood-brain barrier and improve the sensitivity of glioma to radiotherapy. This paper focuses on the research progress of nano-radiosensitizers in radiotherapy for glioma.

Effects of karanjin on dimethylhydrazine induced colon carcinoma and aberrant crypt foci are facilitated by alteration of the p53/Bcl2/BAX pathway for apoptosis.

We investigated the effects of karanjin on dimethylhydrazine (DMH) induced colon cancer in rats. Male Wistar rats were injected with DMH followed by dextran sodium sulfate in drinking water for 7 days. Karanjin at doses of 50,100 and 200 mg/kg was administered orally for 18 weeks. Colon tissues were investigated using TUNEL analysis of apoptosis; histopathological assessment including number of aberrant crypt foci (ACF); immunohistochemical staining for Bcl-2-associated X protein (BAX), B-cell lymphoma 2 (Bcl2), p53 and proliferating cell nuclear antigen (PCNA); and antioxidant assay in vivo. We found that treatment with karanjin inhibited formation of ACF in the colon mucosa and reduced colon lesions. Karanjin treatment also increased the antioxidants, catalase, glutathione and superoxide dismutase. Immunostaining showed that karanjin treatment reduced BAX, p53 and PCNA levels and increased Bcl2 expression. The TUNEL assay revealed that karanjin induced apoptosis in the colon mucosa. Our findings suggest that karanjin can ameliorate colon carcinogenesis in rats by regulating BAX, Bcl2 and p53 pathways.

Application and Analysis of 6-Mercaptopurine Nanomedicine in the Treatment of Leukemia.

As a first-line drug widely used in the treatment of leukemia, 6-MP has obvious effects on leukemia. However, 6-MP disadvantages such as poor solubility in water, easy binding with serum proteins, short circulation time, and large toxic and side effects greatly limit the application of 6-MP. For this reason, various 6-MP nano drug-loading systems have been designed to increase the water solubility of 6-MP, extend the circulation time, and increase the bioavailability of 6-MP to a certain extent, reducing its toxic and side effects. However, its therapeutic effect in vivo and in vitro is still far from expectations, and there is a lot of room for improvement. In order to solve the above problems encountered in the clinical application of 6-MP, we have tried two ways of polymer prodrugs and drug-loaded vesicles to achieve efficient targeted delivery and treatment of 6-MP. We designed hyaluronic acid (HA)-based gluteal-skin-responsive 6-MP polymer prodrug (HA-GS-MP) for highly effective targeted therapy of acute myeloid leukemia. Hyaluronic acid is a natural polysaccharide, which has excellent biocompatibility and biodegradability, and has a good ability to actively target malignant tumor cells overexpressing the CD44 receptor. 6-MP is connected to the HA chain through a vinyl sulfide bond, which is stable under physiological conditions (no drug release), and under intracellular reducing conditions, the connection bond is broken and 6-MP is quickly released. HA-GS-MP has a simple preparation process, good water solubility, long cycle time, and strong targeting ability. This GSH-responsive CD44 targeted 6-MP polymer prodrug is expected to improve the therapeutic effect on acute myeloid leukemia cells.

Resveratrol ameliorates thymus senescence changes in D-galactose induced mice.

The thymic microenvironment plays an important role in the development of T cells. A decrease of thymic epithelial cells is the main cause of age-related thymic atrophy or degeneration. Resveratrol (RSV), a phytoalexin produced from plants, has been shown to inhibit the adverse effects of dietary obesity on the structure and function of the thymus. D-Galactose (D-gal) can induce accelerated aging in mice. In the present study, young mice (2 months old) were injected with D-gal (120 mg/kg/day) for 8 consecutive weeks to construct an accelerated aging model. Compared with normal control mice, the thymus epithelium of the D-gal treated mice had structural changes, the number of senescent cells increased, the number of CD4+ T cells decreased, and CD8+ T cells increased. After RSV administration by gavage for 6 weeks, it was found that RSV improved the surface phenotypes of D-gal treated mice, and recovered thymus function by maintaining the ratio of CD4+ to CD8+ cells. It also indicated that RSV enhanced the cell proliferation and inhibited cell senescence. Increased autoimmune regulator (Aire) expression was present in the RSV treated mice. The lymphotoxin-beta receptor (LTßR) expression also increased. These findings suggested that RSV intake could restore the alterations caused by D-gal treatment in the thymus via stimulation of Aire expression.

Design of Tumor Microenvironment-Responsive Drug-Drug Micelle for Cancer Radiochemotherapy.

Concomitant radiochemotherapy is a major therapeutic strategy for treating malignant tumors. However, the greatest challenge is how to improve the therapeutic effect of radiochemotherapy to achieve the proper synergetic chemo-/radiotherapy for the tumor. In this study, ferrocenium (antitumor effect) and nitroimidazole (hypoxic cell radiosensitization) conjugates were synthesized to form amphiphilic ferrocenium-hexane-nitroimidazole (Fe-NI), which can self-assemble in aqueous solution. The Fe-NI micelles successfully encapsulate the hydrophobic chemotherapy drug doxorubicin (DOX) and are modified with hyaluronic acid (HA) by electrostatic interactions to form HA-Fe-NIs-DOX micelles. HA-Fe-NIs-DOX micelles rapidly release DOX under tumor hypoxia and a high glutathione (GSH) environment and achieve a synergetic chemo-/radiotherapy for the tumor based on the properties of nitroimidazoles and ferrocenes. The biodistribution results obtained in vivo reveal an effective accumulation in the tumor. The HA-Fe-NIs-DOX micelles show a significant radiosensitizing effect on the tumors, and the combination of chemotherapy and radiotherapy is realized for the treatment of tumor in vitro and in vivo. These findings illustrate that HA-Fe-NIs micelles are a promising candidate, which enhances the antitumor effects as a DOX delivery system, owing to the synergistic mechanisms of antitumor agents and chemo-/radiotherapy.