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Abstract Glioblastoma (GBM), the most common primary brain malignancy in adults, is notoriously difficult to treat due to several factors: tendency to be radiation resistant, the presence of the blood brain barrier (BBB) which limits drug delivery and immune-privileged status which hampers effective immune responses. Traditionally, high-dose irradiation (8 Gy) is known to effectively enhance anti-tumor immune responses, but its application is limited by the risk of severe brain damage. Currently, conventional dose segmentation (2 Gy) is the standard radiotherapy method, which does not fully exploit the potential of high-dose irradiation for immune activation. The hypothesis of our study posits that instead of directly applying high doses of radiation, which is risky, a strategy could be developed to harness the immune-stimulating benefits of high-dose irradiation indirectly. This involves using nanoparticles to enhance antigen presentation and immune responses in a safer manner. Angiopep-2 (A2) was proved a satisfactory BBB and brain targeting and Dbait is a small molecule that hijack DNA double strand break damage (DSB) repair proteins to make cancer cells more sensitive to radiation. In view of that, the following two nanoparticles were designed to combine immunity of GBM, radiation resistance and BBB innovatively. One is cationic liposome nanoparticle interacting with Dbait (A2-CL/Dbait NPs) for radiosensitization effect; the other is PLGA-PEG-Mal nanoparticle conjugated with OX40 antibody (A2-PLGA-PEG-Mal/anti-OX40 NPs) for tumor-derived protein antigens capture and optimistic immunoregulatory effect of anti-OX40 (which is known to enhance the activation and proliferation T cells). Both types of nanoparticles showed favorable targeting and low toxicity in experimental models. Specifically, the combination of A2-CL/Dbait NPs and A2-PLGA-PEG-Mal/anti-OX40 NPs led to a significant extension in the survival time and a significant tumor shrinkage of mice with GBM. The study demonstrates that combining these innovative nanoparticles with conventional radiotherapy can effectively address key challenges in GBM treatment. It represents a significant step toward more effective and safer therapeutic options for GBM patients.

Purpose: The prognosis of isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM) with the subventricular zone (SVZ) invasion is extremely unfavorable but the underlying mechanism remains unclear. We aimed to conduct a retrospective study to mainly investigate the prognostic value of SVZ invasion and MGMT status, and developed a novel clinical prediction model based on our findings. Methods: 139 patients with IDH wild-type GBM were retrospectively studied. They were categorized into four types, taking into consideration of the spatial positional relationship between tumor, SVZ and the cerebral cortex (Ctx) on the preoperative T1-weighted contrast-enhanced images (T1WI + C). Survival analysis was conducted to identify significant variables, which were then included in a clinical model to predict patient survival outcomes. Results: Among the included patients, 41 (29.5 %) were type I, 23 (16.5 %) were type II, 59 (42.4 %) were type III, and 16 (11.5 %) were type IV. In Cox regression analysis, partial surgical resection, SVZ invasion, MGMT unmethylation, short adjuvant chemotherapy cycles, and distant recurrence were identified as independent risk factors of prognosis. A clinical prediction model based on these factors was developed to accurately predicted the survival outcome at 6, 12, and 18 months. Conclusion: Both SVZ invasion and MGMT unmethylation negatively influenced the prognosis of patients with IDH wild-type GBM. The clinical model developed in this study accurately predicts the survival outcome, providing a basis and reference for clinical practice.

Abstract Background Radioresistance and immune escape are crucial reasons for unsatisfactory therapeutic effects of glioblastoma (GBM). Although triggering receptor expressed on myeloid cells-2 (TREM2) involved in forming immunosuppressive microenvironment, but the underlying mechanism and its roles in mediating cancer radioresistance remain unclear, moreover, the efficient delivery of drugs targeting TREM2 to GBM encounters serious challenges. Hence, this study aimed to elucidate the effect and mechanisms of targeted TREM2 silencing on reversing the radioresistance and immune escape of GBM aided by a glutathione-responsive biomimetic nanoparticle (NP) platform. Methods Radioresistant GBM cell lines and TREM2 stable knockdown GBM cell lines were firstly established. RNA sequencing, colony formation assay, western blot, enzyme-linked immunosorbent assay and co-immunoprecipitation assay were used to detect the molecular mechanisms of TREM2 in regulating the radioresistance and immune escape of GBM. The glutathione-responsive biomimetic NP, angiopep-2 (A2)- cell membrane (CM)-NP/siTREM2/spam1, was then constructed to triply and targeted inhibit TREM2 for in vivo study. Orthotopic GBM-bearing mouse models were established to evaluate the anti-GBM effect of TREM2 inhibition, multiplex immunofluorescence assay was conducted to detect the infiltration of immune cells. Results TREM2 was a regulator in accelerating the radioresistance and immune escape of GBM through participating in DNA damage repair and forming a positive feedback loop with high mobility group box 1 (HMGB1) to cascade the activation of Toll-like receptor 4 (TLR4)/protein kinase B (Akt) signaling. A2-CM-NP/siTREM2/spam1 was successfully synthesized with excellent passive targeting, active targeting and homologous targeting, and the in vivo results exhibited its remarkable anti-GBM therapeutic effect through promoting the infiltration of type 1 helper T cells and CD8+T cells, reducing the infiltration of type 2 helper T cells and regulatory T cells, repolarizing macrophages to M1-type, and decreasing the secretion of pro-tumor and immunosuppressive cytokines. Conclusions Targeting TREM2 therapy is a promising avenue for optimizing radiotherapy and immunotherapy to improve the prognosis of GBM patients.

Abstract Hepatocellular carcinoma (HCC) is a highly heterogeneous and malignant cancer with poor overall survival. The application of sorafenib is a major breakthrough in the treatment of HCC. In our study, FOXQ1 was significantly overexpressed in sorafenib-resistant HCC cells and suppressed sorafenib-induced ferroptosis. We found that phosphorylation of FOXQ1 at serine 248 is critical for the suppression of sorafenib-induced ferroptosis. Furthermore, as the upstream phosphorylation kinase of FOXQ1, JNK1, which is activated by sorafenib, can directly phosphorylate the serine 248 site of FOXQ1. Then, the phosphorylated FOXQ1 got a high affinity for the promoter of ETHE1 and activates its transcription. Further flow cytometry results showed that ETHE1 reduced intracellular lipid peroxidation and iron levels. Collectively, our study implicated the JNK1-FOXQ1-ETHE1 axis in HCC ferroptosis induced by sorafenib, providing mechanistic insight into sensitivity to sorafenib therapy of HCC.

Abstract Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.

Abstract Background Yin Yang‐1 (YY1) is identified as a transcription factor with multiple functions. However, the role of YY1 in tumorigenesis remains controversial and its regulatory effects may depend upon not only cancer types, but also its interacting partners, chromatin structure, and the context in which it acts. It has been detected that YY1 was highly expressed in colorectal cancer (CRC). Intriguingly, many YY1‐repressed genes exhibit tumor suppressive potential while YY1 silencing is related to chemotherapy resistance. Therefore, it is crucial to meticulously explore YY1 protein structure and the dynamic alteration of its interactome in each cancer type. This review attempts to describe the structure of YY1, summarize the mechanism that influence the expression level of YY1 and also highlight the recent advances in our understanding of regulatory insights of YY1 functions in CRC. Methods Related studies were identified through scoping search of PubMed, Web of science, Scopus and Emhase concerning the terms of “colorectal cancer”, colorectal carcinoma” or CRC with “YY1”. The retrieval strategy included title, abstract, and keywords with no language limitations. All the included articles were categorized depending on the mechanisms they explored. Results In total, 170 articles were identified for further screening. After removing the duplication, not relevant outcomes and review articles, 34 were finally included in the review. Among them, 10 articles revealed the reasons of YY1 high expression in CRC, 13 articles explored YY1 function in CRC, and 11 articles fell into both aspects. In addition, we also summarized 10 clinical trials concerning the expression and activity of YY1 in various diseases, which offers a hint for future application. Conclusions YY1 is highly expressed in CRC and broadly recognized as an oncogenic factor during the whole course of CRC. Sporadic controversial views are raised in term of CRC treatment, reminding us that future studies should take the influence of therapeutic regimens into concern.

Purpose: The present study aimed to reveal the function and underlying molecular mechanism of circRNA NIMA related kinase 6 (circNEK6) in promoting the progression of pancreatic ductal adenocarcinoma (PDAC). Methods: The differentially expressed circRNAs in three paired PDAC tissues and adjacent tissues were identified by RNA sequencing. CircNEK6 was screened out to further explore its relationship with the prognosis of PDAC patients. The target microRNAs and mRNAs of circNEK6 were analyzed through online databases and detected by quantitative real-time polymerase chain reaction. Cell counting kit-8 assay, clone formation assay, transwell assay, flow cytometry and western blot were used to explore the function of circNEK6 on the biological behaviors of PDAC cells. The in vivo antitumor effect of circNEK6 silencing on PDAC was investigated by nude mouse xenograft models. Results: 203 differentially expressed circRNAs including circNEK6 were identified between paired PDAC tissues and adjacent tissues, and the expression level of circNEK6 was negatively correlated with the prognosis of PDAC patients. The results of in vitro experiments showed that knockdown of circNEK6 repressed the proliferation, migration and invasion, but induced the apoptosis of PDAC cells. Moreover, circNEK6 silencing inhibited tumor growth and prolonged the survival time of PDAC-bearing mice. Mechanistically, miR-503/cyclin D1 (CCND1) axis was predicted and confirmed as the target of circNEK6. Conclusions: CircNEK6 serves as a competing endogenous RNA of CCND1 by absorbing miR-503, which might be treated as a novel and potential target for PDAC treatment.

IntroductionThe gut-lung axis has long been recognized as an important mechanism affecting intestinal and lung immunity. Still, few studies have examined the correlation between the intestinal and pharyngeal microbiota in early neonates, especially when feeding patterns are one of the main drivers of microbiota development.MethodsTo explore the composition and function of intestinal and pharyngeal microbiota and to analyze the effect of limited formula feeding on the initial microbiota colonization in early full-term neonates, we characterized the stool and oropharyngeal microbiota of 20 healthy full-term newborns sampled on days 0 and 5–7 after birth using 16S rRNA gene sequencing. Based on the sequencing results, a comparison was made of the compositions and functions of the intestinal and oropharyngeal microbiota for analysis.Results and discussionAt the phylum level, Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes were the most abundant in both niches. At the genus level, the species of pioneer bacteria were rich in the intestine and oropharynx but low in abundance on day 0. On days 5–7, Bifidobacterium (25.40%) and Escherichia-Shigella (22.16%) were dominant in the intestine, while Streptococcus (38.40%) and Staphylococcus (23.13%) were dominant in the oropharynx. There were eight core bacteria genera in the intestine and oropharynx on days 5–7, which were Bifidobacterium, Escherichia-Shigella, Staphylococcus, Streptococcus, Bacteroides, Parabacteroides, Rothia, and Acinetobacter. As indicated by PICRUSt analysis, on days 5–7, the intestinal microbiota was more predictive than the oropharyngeal microbiota in transcription, metabolism, cell motility, cellular processes and signaling, and organismal system function in the KEGG pathway. Compared to exclusive breastfeeding, limited formula feeding (40–60%) had no significant effect on the neonatal intestinal and oropharyngeal microbiota composition during the initial colonization period. Our results suggest that the initial colonization of microbiota is closely related to the ecological niche environment in the intestine and oropharynx, with their core microbiota being closely correlated. We found that early limited formula feeding could not significantly affect the initial colonization of microbiota in the intestine and oropharynx.

Abstract Necroptosis, a distinctive type of programmed cell death different from apoptosis or necrosis, triggered by a series of death receptors such as tumor necrosis factor receptor 1 (TNFR1), TNFR2, and Fas. In case that apoptosis process is blocked, necroptosis pathway is initiated with the activation of three key downstream mediators which are receptor‐interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain‐like protein (MLKL). The whole process eventually leads to destruction of the cell membrane integrity, swelling of organelles, and severe inflammation. Over the past decade, necroptosis has been found widely involved in life process of human beings and animals. In this review, we attempt to explore the therapeutic prospects of necroptosis regulators by describing its molecular mechanism and the role it played in pathological condition and tissue homeostasis, and to summarize the research and clinical applications of corresponding regulators including small molecule inhibitors, chemicals, Chinese herbal extracts, and biological agents in the treatment of various diseases.

Abstract Background Transcatheter arterial chemoembolization has been widely used in patients with hepatocellular carcinoma. However, double blood supply and the existence of portal vein tumor thrombus influence the efficacy of transcatheter arterial chemoembolization. Main body Theoretically, portal vein embolization combined with transcatheter arterial chemoembolization may bring a breakthrough in the therapeutic effect of hepatocellular carcinoma. The feasibility, efficacy, long-term survival benefits, and side effects of the combined treatment have been explored in previous studies. Chemotherapeutic agents may also be added in the portal vein embolization procedure to further improve the treatment response. Conclusion In this study, we review the existing data and studies on the combined treatment in patients with hepatocellular carcinoma and provide an overall view of the strategy.

To date, immune checkpoint inhibitors have been successively approved and widely used in clinical cancer treatments, however, the overall response rates are very low and almost all cancer patients eventually progressed to drug resistance, this is mainly due to the intricate tumor microenvironment and immune escape mechanisms of cancer cells. One of the main key mechanisms leading to the evasion of immune attack is the presence of the immunosuppressive microenvironment within tumors. Recently, several studies illustrated that triggering receptor expressed on myeloid cells-2 (TREM2), a transmembrane receptor of the immunoglobulin superfamily, was a crucial pathology-induced immune signaling hub, and it played a vital negative role in antitumor immunity, such as inhibiting the proliferation of T cells. Here, we reviewed the recent advances in the study of TREM2, especially focused on its regulation of tumor-related immune signaling pathways and its role as a novel target in cancer immunotherapy.

Combining DNA damage repair inhibitors and chemotherapeutic agents is an emerging strategy in cancer treatment. In this study, we engineered the polycation nanoparticle (NP), which co-encapsulated DNA damage repair inhibitor Dbait and chemotherapeutic drug Docetaxel (Dtxl), using H1 nanopolymer (folate–-polyethylenimine600–cyclodextrin), and the size of H1/Dbait/Dtxl was about 117 nm. We demonstrated that H1/Dbait/Dtxl enhanced the efficiency of radio-chemotherapy in prostate cancer cells by CCK-8 assay and colony-forming assay. Importantly, the improvement of radio-chemotherapy of H1/Dbait/Dtxl in prostate cancer was also validated in vivo, and the NP did not have a high toxicity profile. The results of immunohistochemistry and western blot supported that the improved therapeutic efficacy was through inhibiting DNA damage repair signalling pathway. Our study supports further investigations using NP to co-deliver DNA damage repair inhibitors and chemotherapeutics to improve the therapeutic efficacy of cancer.

Background: Recently, RNA-binding proteins (RBPs) were reported to interact with target mRNA to regulate gene posttranscriptional expression, and RBP-mediated RNA modification can regulate the expression and function of proto-oncogenes and tumor suppressor genes. We systematically analyzed the expression of RBPs in pancreatic adenocarcinoma (PAAD) and constructed an RBP-associated prognostic risk model.Methods: Gene expression data of normal pancreatic samples as well as PAAD samples were downloaded from TCGA-PAAD and GTEx databases. Wilcoxon test and univariate Cox analysis were, respectively, applied to screen differential expression RBPs (DE-RBPs) and prognostic-associated RBPs (pRBPs). Functional enrichment was analyzed by GO, KEGG, and GSEA. Protein–protein interaction (PPI) network was constructed by STRING online database. Modeling RBPs were selected by multivariate Cox analysis. Kaplan–Meier survival and Cox analysis were applied to evaluate the effects of risk score on the overall survival of PAAD patients. ROC curves and validation cohort were applied to verify the accuracy of the model. Nomogram was applied for predicting 1-, 3-, and 5-year overall survival (OS) of PAAD patients. At last, modeling RBPs were further analyzed to explore their differential expression, prognostic value, as well as enrichment pathways in PAAD.Results: RBPs (453) were differentially expressed in normal and tumor samples, besides, 28 of which were prognostic associated. DE-RBPs (453) are functionally associated with ribosome, ribonuclease, spliceosome, etc. Eight RBPs (PABPC1, PRPF6, OAS1, RBM5, LSM12, IPO7, FXR1, and RBM6) were identified to construct a prognostic risk model. Higher risk score not only predicted poor prognosis but also was an independent poor prognostic indicator, which was verified by ROC curves and validation cohort. Eight modeling RBPs were confirmed to be significantly differentially expressed between normal and tumor samples from RNA and protein level. Besides, all of eight RBPs were related with overall survival of PAAD patients.Conclusions: We successfully constructed an RBP-associated prognostic risk model in PAAD, which has a potential clinical application prospect.

The treatment of metastatic renal cell carcinoma (RCC) and urothelial carcinoma (UC) remains a major challenge. Past research has implicated the immune system in tumor surveillance of both malignancies, leading to the application of immunotherapy agents for both cancers. Among them, the most promising agents are the checkpoint blockade drugs, such as antibodies targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor 1 (PD-1), and PD-1 ligand (PD-L1). In normal physiology, these immune checkpoints act as inhibitory signals to fine-tune the duration and strength of immune reactions, which is pivotal for maintaining self-tolerance. However, tumor cells also utilize immune checkpoint pathways to evade anti-tumor immune response, leading to disease progression and metastasis. Thus, there has been intense preclinical and clinical effort focused on the application of checkpoint inhibitors in metastatic RCC and UC. To date, nivolumab (anti-PD-1) and atezolizumab (anti-PD-L1) have been approved for the treatment of metastatic RCC and UC, respectively. Despite these successes, challenges remain in how to further improve response rates to immunotherapy and how to select patients that will benefit from this approach. In this report, we review existing data and research on immunotherapy in metastatic RCC and UC. Keywords: Immune checkpoint inhibitors, Nivolumab, Atezolizumab, Pembrolizumab, Renal cell carcinoma, Urothelial carcinoma

Radiotherapy has been an integral treatment modality for cancer. The field arose from and progressed through innovations in physics, engineering, and biology. The evolution of radiation oncology will rely on the continued adoption of advances from other fields. A new area of science that possesses the ability to impact radiation oncology is nanomedicine. Materials on the nanoscale provide many unique properties such as enhanced permeability and retention effect and superparamagnetism that are well suited for applications in radiation oncology. In this review, we will provide a comprehensive summary on how nanotechnology can improve cancer radiotherapy in aspects of treatment delivery and monitoring as well as diagnosis. [ABSTRACT FROM AUTHOR]