PARP inhibition synergizes with CD47 blockade to promote phagocytosis by tumor-associated macrophages in homologous recombination-proficient tumors.

AIMS: PARP inhibitors (PARPi) are known to exert anti-tumor effects in patients with BRCA-mutated (BRCAmut) or homologous recombination (HR)-deficient cancer, but recent clinical investigations have suggested that this treatment may also be beneficial in patients with HR-proficient tumors. In this study, we aimed to investigate how PARPi exerts anti-tumor effects in non-BRCAmut tumors. MAIN METHODS: BRCA wild-type, HR-deficient-negative ID8 and E0771 murine tumor cells were treated in vitro and in vivo with olaparib, a clinically approved PARPi. The effects on tumor growth in vivo were determined in immune-proficient and -deficient mice and alterations of immune cell infiltrations were analyzed with flow cytometry. Tumor-associated macrophages (TAMs) were further investigated with RNA-seq and flow cytometry. In addition, we confirmed olaparib's effect on human TAMs. KEY FINDINGS: Olaparib did not affect HR-proficient tumor cell proliferation and survival in vitro. However, olaparib significantly decreased tumor growth in C57BL/6 and SCID-beige mice (defective in lymphoid development and NK cell activity). Olaparib increased macrophage numbers in the tumor microenvironment, and their depletion diminished the anti-tumor effects of olaparib in vivo. Further analysis revealed that olaparib improved TAM-associated phagocytosis of cancer cells. Notably, this enhancement was not solely reliant on the "Don't Eat Me" CD47/SIRPα signal. In addition, compared to monotherapy, the concomitant administration of αCD47 antibodies with olaparib improved tumor control. SIGNIFICANCE: Our work provides evidence for broadening the application of PARPi in HR-proficient cancer patients and paves the way for developing novel combined immunotherapy to upgrade the anti-tumor effects of macrophages.

A New Strategy to Improve the Toughness of Epoxy Thermosets-By Introducing Poly(ether nitrile ketone)s Containing Phthalazinone Structures.

As high brittleness limits the application of all epoxy resins (EP), here, it can be modified by high-performance thermoplastic poly(ether nitrile ketone) containing phthalazinone structures (PPENK). Therefore, the influence of different PPENK contents on the mechanical, thermal, and low-temperature properties of EP was comprehensively investigated in this paper. The binary blend of PPENK/EP exhibited excellent properties due to homogeneous mixing and good interaction. The presence of PPENK significantly improved the mechanical properties of EP, showing 131.0%, 14.2%, and 10.0% increases in impact, tensile, and flexural strength, respectively. Morphological studies revealed that the crack deflection and bridging in PPENK were the main toughening mechanism in the blend systems. In addition, the PPENK/EP blends showed excellent thermal and low-temperature properties (-183 °C). The glass transition temperatures of the PPENK/EP blends were enhanced by approximately 50 °C. The 15 phr of the PPENK/EP blends had a low-temperature flexural strength of up to 230 MPa, which was 46.5% higher than EP. Furthermore, all blends exhibited better thermal stability.

Bibliometric analysis and mini-review of global research on pyroptosis in the field of cancer.

Pyroptosis is one of the mechanisms of programmed cell death (PCD) activated by inflammasomes and involved by the caspase family and the gasdermin family. During the oncogenesis and progression of tumors, pyroptosis is crucial, and complex withal. Currently, pyroptosis is the focus topic in the research field of oncology, but there is no single bibliometric analysis systematically studying 'pyroptosis and cancer'. Our study aimed to visualize the research status of pyroptosis in oncology and excavate the hotspots and prospects in this field. Furthermore, in consideration of the professional direction of researchers, we particularly emphasized articles on pyroptosis in gynecology and formed a mini systematic review. This bibliometric work integrated and analyzed all articles from ISI Web of Science: Science Citation Index Expanded (SCI-Expanded) (dated April 25th, 2022), based on quantitative and visual mapping approaches. Systematically reviewing articles on pyroptosis in gynecology helped us complement our analysis of research advancements in this field. Including 634 articles, our study found that the number of articles on pyroptosis in cancer increased exponentially in recent years. These publications came from 45 countries and regions headed by China and the US mainly aiming at the mechanism of pyroptosis in cell biology and biochemistry molecular biology, as well as the role of pyroptosis in the development and therapeutic application of various cancers. The top 20 most cited studies on this topic mostly came from the US, followed by China and England, and half of the articles cited more than 100 times in total were published in Nature. Moreover, as for gynecologic cancer, in vitro and bioinformatics analysis were the main methodology conducting to explore roles of pyroptosis-related genes (PRGs) and formation of inflammasomes in cancer progression and prognosis. Pyroptosis has evolved into a burgeoning research field in oncology. The cellular and molecular pathway mechanism of pyroptosis, as well as the effect of pyroptosis in oncogenesis, progression, and treatment have been the hot topic of the current study and provided us the future direction as the potential opportunities and challenges. We advocate more active cooperation to improve therapeutic strategies for cancer.

Construction of Metastasis-Specific Regulation Network in Ovarian Cancer Based on Prognostic Stemness-Related Signatures.

WE aimed to reveal the correlation between ovarian cancer (OV) metastasis and cancer stemness in OV. RNA-seq data and clinical information of 591 OV samples (551 without metastasis and 40 with metastasis) were obtained from TCGA. The edgeR method was used to determine differentially expressed genes (DEGs) and transcription factors (DETFs). Then, mRNA expression-based stemness index was calculated using one-class logistic regression (OCLR). Weighted gene co-expression network analysis (WGCNA) was used to define stemness-related genes (SRGs). Univariate and multivariate Cox proportional hazard regression were conducted to identify the prognostic SRGs (PSRGs). PSRGs, DETFs, and 50 hallmark pathways quantified by gene set variation analysis (GSVA) were integrated into Pearson co-expression analysis. Significant co-expression interactions were utilized to construct an OV metastasis-specific regulation network. Cell communication analysis was carried out based on single cell RNA sequencing data to explore the molecular regulation mechanism of OV. Eventually, assay for targeting accessible-chromatin with high throughout sequencing (ATAC), chromatin immunoprecipitation sequencing (ChIP-seq) validation, and multiple data sets were used to validate the expression levels and prognostic values of key stemness-related signatures. Moreover, connectivity map (CMap) was used to identify potential inhibitors of stemness-related signatures. Based on edgeR, WGCNA, and Cox proportional hazard regression, 22 PSRGs were defined to construct a prognostic prediction model for metastatic OV. In the metastasis-specific regulation network, key TF-PSRS interaction pair was NR4A1-EGR3 (correlation coefficient = 0.81, p < 0.05, positive), and key PSRG-hallmark pathway interaction pair was EGR3-TNFα signaling via NFκB (correlation coefficient = 0.44, p < 0.05, positive), which were validated in multi-omics databases. Thioridazine was postulated to be the most significant compound in treatment of OV metastasis. PSRGs played critical roles in OV metastasis. Specifically, EGR3 was the most significant PSRG, which was positively regulated by DETF NR4A1, inducing metastasis via TNFα signaling.

Ral GEF with the PH Domain and SH3 Binding Motif 1 Regulated by Splicing Factor Junction Plakoglobin and Pyrimidine Metabolism Are Prognostic in Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a highly invasive malignant tumor that originated from the uterine epithelium. Many studies suggested that the abnormal changes of alternative splicing (AS) of pre-mRNA are related to the occurrence and metastasis of the tumor. This study investigates the mechanism of alternative splicing events (ASEs) in the tumorigenesis and metastasis of UCS. RNA-seq of UCS samples and alternative splicing event (ASE) data of UCS samples were downloaded from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases, several times. Firstly, we performed the Cox regression analysis to identify the overall survival-related alternative splicing events (OSRASEs). Secondly, a multivariate model was applied to approach the prognostic values of the risk score. Afterwards, a coexpressed network between splicing factors (SFs) and OSRASEs was constructed. In order to explore the relationship between the potential prognostic signaling pathways and OSRASEs, we fabricated a network between these pathways and OSRASEs. Finally, validations from multidimension platforms were used to explain the results unambiguously. 1,040 OSRASEs were identified by Cox regression. Then, 6 OSRASEs were incorporated in a multivariable model by Lasso regression. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was 0.957. The risk score rendered from the multivariate model was corroborated to be an independent prognostic factor (P < 0.001). In the network of SFs and ASEs, junction plakoglobin (JUP) noteworthily regulated RALGPS1-87608-AT (P < 0.001, R = 0.455). Additionally, RALGPS1-87608-AT (P = 0.006) showed a prominent relationship with distant metastasis. KEGG pathways related to prognosis of UCS were selected by gene set variation analysis (GSVA). The pyrimidine metabolism (P < 0.001, R = -0.470) was the key pathway coexpressed with RALGPS1. We considered that aberrant JUP significantly regulated RALGPS1-87608-AT and the pyrimidine metabolism pathway might play a significant part in the metastasis and prognosis of UCS.

Correlations between Clinical Characteristics and Prognosis in Patients with Grade II Glioma.

OBJECTIVE: Grade II gliomas are mostly astrocytomas and oligodendrocytomas. The treatment method is mainly surgery, combined with chemotherapy and radiotherapy. According to statistics, young patients under the age of 40 years with grade II gliomas have a 50% chance of more than 5-year survival through reasonable treatment and normal eating habits. The survival time of middle-aged and elderly patients over 40 years old is about 2-3 years under the same conditions. The study aimed at analyzing the clinical characteristics and prognostic factors of 60 patients with glioma. METHODS: A total of 60 patients diagnosed pathologically with grade II glioma according to the World Health Organization (WHO) classification in 2007 admitted into our hospital from January 2016 to December 2016 were retrospectively analyzed. The Kaplan-Meier curve was plotted to reflect 5-year survival according to patients' clinical characteristics. The Cox regression model was used to analyze prognostic factors of grade II glioma. RESULTS: Preoperative KPS scores <60, 60-80, and >80 accounted for 25.00% (15/60), 40.00% (24/60), and 35.00% (21/60), respectively. The largest tumor diameter LTD was less than 5 cm revealed in 60.00% patients, of which astrocytoma accounted for 65.00%. Subventricular zone (SVZ) expansion occurred in 23.33% of the patients and peritumoral edema occurred in 16.67% of the patients. The median follow-up time was 54 months. 5-year overall survival and progression-free survival rates of all patients were 70.0% and 56.7%, respectively. The Cox regression model indicated SVZ expansion, surgical resections, and recurrence were the independent prognostic factors of grade II glioma. CONCLUSION: These data suggested that SVZ expansion, surgical resections, and recurrence were independent factors affecting the prognosis of grade II glioma. According to the above clinical indexes of patients, individualized therapies can be established to prolong the survival time of patients.

CircLNPEP promotes the progression of ovarian cancer through regulating miR-876-3p/ WNT5A axis.

CircRNA LNPEP has been shown to promote the development of hepatocellular carcinoma, but its function in ovarian cancer (OC) remains unclear. The Kaplan-Meier method was used to analyze the clinical significance of circLNPEP expression in OC patients. The stability of circLNPEP was detected by actinomycin D and RNase R treatment. The correlations between miR-876-3p and two genes (circLNPEP and WNT5A) were predicted by bioinformatics analysis and confirmed by dual-luciferase reporter assay. Expressions of circLNPEP, miR-876-3p, and WNT5A were determined by qRT-PCR and western blot. The effect of circLNPEP/miR-876-3p/WNT5A axis on viability, proliferation, migration, and invasion, and angiogenesis of cells was determined by cell function experiment and rescue experiment. Xenograft tumor mice were constructed for in vivo verification. Expressions of apoptosis, epithelial mesenchymal transition (EMT)-related genes, and CD34 were determined by qRT-PCR, western blot and immunohistochemistry. High level of circLNPEP was related to poor prognosis in OC. CircLNPEP was highly expressed in OC tissues and cell lines, mainly distributed in the cytoplasm, while miR-876-3p was the opposite. MiR-876-3p targeted and negatively correlated with circLNPEP and WNT5A. Sh-circLNPEP repressed cell viability, proliferation, migration, invasion, angiogenesis, and EMT but promoted apoptosis, which were related to its regulation of expression of EMT- and apoptosis-related genes, WNT5A, and CD34. The regulatory effect of sh-circLNPEP can be reversed by miR-876-3p inhibitor, and that of miR-876-3p inhibitor can be reversed by sh-WNT5A. CircLNPEP promoted cancer cell proliferation, EMT and angiogenesis, and inhibited apoptosis by regulating miR-876-3p/WNT5A axis.

Identification of Stemness-Related Genes for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma by Integrated Bioinformatics Analysis.

BACKGROUND: Invasion and metastasis of cervical cancer are the main factors affecting the prognosis of patients with cervical squamous cell carcinoma (CESC). Therefore, it is of vital importance to find novel biomarkers that are associated with CESC invasion and metastasis, which will aid in the amelioration of individualized therapeutic methods for advanced patients. METHODS: The gene expression profiles of 10 metastatic and 116 non-metastatic samples were downloaded from The Cancer Genome Atlas (TCGA), where differentially expressed genes (DEGs) were defined. Weighted gene correlation network analysis (WGCNA) was employed to identify the stemness-related genes (SRGs). Univariate and multivariate regression analyses were used to identify the most significant prognostic key genes. Differential expression analysis of transcription factor (TF) and Gene Set Variation Analysis (GSVA) were utilized to explore the potential upstream regulation of TFs and downstream signaling pathways, respectively. Co-expression analysis was performed among significantly enriched TFs, key SRGs, and signaling pathways to construct a metastasis-specific regulation network in CESC. Connectivity Map (CMap) analysis was performed to identify bioactive small molecules which might be potential inhibitors for the network. Additionally, direct regulatory patterns of key genes were validated by ChIP-seq and ATAC-seq data. RESULTS: DEGs in yellow module acquired via WGCNA were defined as key genes which were most significantly related to mRNAsi. A multivariate Cox regression model was constructed and then utilized to explore the prognostic value of key SRGs by risk score. Area under curve (AUC) of the receiver operating characteristic (ROC) curve was 0.842. There was an obvious co expression pattern between the TF NR5A2 and the key gene VIM (R = 0.843, p < 0.001), while VIM was also significantly co-expressed with hallmark epithelial mesenchymal transition (EMT) signaling pathway (R = 0.318, p < 0.001). Naringenin was selected as the potential bioactive small molecule inhibitor for metastatic CESC based on CMap analysis. CONCLUSIONS: VIM positively regulated by NR5A2 affected EMT signaling pathways in metastatic CESC, and naringenin was the inhibitor for the treatment of metastatic CESC via suppressing cancer stemness. This hypothetical signaling axis and potential inhibitors provide biomarkers and novel therapeutic targets for metastatic CESC.

Polymer Vector Loading Vesicular Stomatitis Virus Matrix Protein Gene for Colon Cancer Therapy.

Gene therapy has been widely studied in colon cancer treatment. However, effective delivery of genes is a limitation for clinical applications. In the research, DOATP/mPEG-PLA-mPEG (DPLP) nanoparticles carrying the vesicular stomatitis virus matrix protein plasmid (pVSVMP) was used for colon cancer therapy, resulting in high transfection efficiency and expression efficiency in CT26 cells. Moreover, the DPLP-pVSVMP complex was provide with apoptosis induction and proliferation suppression of CT26 cells in vitro and can efficiently inhibit tumor growth in murine colon cancer model by inducing apoptosis, suppressing proliferation and angiogenesis. These results suggest that DPLP nanoparticles delivering pVSVMP might be a latent therapeutic avenue for colon cancer.

LAMC2 regulated by microRNA-125a-5p accelerates the progression of ovarian cancer via activating p38 MAPK signalling.

AIMS: Laminin γ2 (LAMC2) is over-expressed in ovarian cancer, and its high expression facilitates cell invasion. Nevertheless, the effects of LAMC2 on other ovarian cancer cell functions and its underlying mechanism remain largely unclear. Bioinformatics analysis shows that LAMC2 is a predicted target of miR-125a-5p and miR-193a-3p. Therefore, the present study aimed to investigate the effects of LAMC2 in ovarian cancer progression and determine whether LAMC2 expression is under the regulation of miR-125a-5p or miR-193a-3p in ovarian cancer. MATERIALS AND METHODS: Immunohistochemistry staining, western blot and qPCR were used to detect LAMC2 expression profiles. CCK-8, flow cytometry and tumour formation assays were used to assess cell proliferation, apoptosis and tumorigenesis. The interaction between miR-125a-5p/miR-193a-3p and LAMC2 were determined by the luciferase gene reporter assay. KEY FINDINGS: The results showed that LAMC2 was over-expressed in ovarian cancer tissues and cell lines. Over-expression of LAMC2 significantly promoted cell proliferation and repressed cell apoptosis, as well as increased the expression levels of p38, p-p38, c-myc and CREB, and translocated p38 protein to the nucleus. In addition, the promotion of cell proliferation and repression of cell apoptosis mediated by LAMC2 over-expression were all weakened when p38 was downregulated. Moreover, LAMC2 expression was negatively regulated by miR-125a-5p, which inhibited the nuclear accumulation of p38 protein. Upregulation of LAMC2 significantly abolished the effects of miR-125a-5p on cell proliferation inhibition and cell apoptosis promotion, as well as tumourigenesis repression. SIGNIFICANCE: The present study clarified that LAMC2 functioned as an oncogene in ovarian cancer through upregulating p38 under the regulation of miR-125a-5p.

P54/nrb prompts rheumatoid arthritis progression mainly by transcriptionally activating NF-κB signaling.

In various tumors, aberrant expression of P54/nrb has been identified. However, the expression pattern and specific role of P54/nrb in rheumatoid arthritis (RA) has never been explored. Here, we first demonstrated that the expression of P54/nrb was markedly enhanced in the synovial tissues of RA patients. Functional study showed that P54/nrb could enhance the levels of inflammatory factors, including IL-1, IL-2, IL-6, IL-8 and TNFα. More importantly, we first found that overexpression of P54/nrb can induce the protein levels of P65, an important subunit of NF-κB. In contrast, knockdown of P54/nrb by RNAi significantly decreased the expression of NF-κB. Luciferase reporter assay and CHIP assay showed that P54/nrb could transcriptionally activate the expression of NF-κB, thereby enhancing pro-inflammatory responses. In summary, the expression of p54 was markedly increased in the synovial tissues of RA patients. Further study demonstrated that p54 could transcriptionally activate the expression of p65, an important NF-κB subunit, thereby enhancing the pro-inflammatory response.

An application research on a novel internal grasper platform and magnetic anchoring guide system (MAGS) in laparoscopic surgery.

BACKGROUND: Laparoendoscopic single-site surgery and natural orifice transluminal endoscopic surgery attempt to reduce transabdominal port sites. These require all instruments to pass through a single access point, leading to instruments collide or work at unfamiliar angles. Thus, we designed an internal grasper under magnetic anchoring guide system (MAGS) platform and investigated its utility and operability. METHODS: We measured the configuration for magnetic force decay over distance using a standardized, ex vivo laboratory testing apparatus. An electronic balance was used to measure the force of the gallbladder pull in ten patients with gallbladder stones. One pig (11 mm abdominal wall thickness) underwent a compressed trial of MAGS platform. The device was left in place for 20 min before tissue sections were harvested, and histologic assessment was performed. The utility and operability were investigated in four pigs (38-280 kg weight). RESULTS: The magnetic attraction force decayed exponentially over distance; the force of pulling gallbladder was 7.46 ± 0.54 N. This pairing of components allowed for coupling to a theoretical distance of 10 mm. No gross tissue damage was observed. H-E stain showed no necrosis in all specimens. One failed due to wall thickness of 45 mm. Others showed the critical view, triangulation of instruments was obtained, and instrument collision or "sword fighting" was reduced. CONCLUSIONS: The MAGS platform overcomes limitations such as collisions and lack of triangulation, reduces transabdominal port sites, and is easy to operate. However, our internal grasper requires the abdominal wall thickness below 10 mm.

Inhibition of Cervical Cancer by Promoting IGFBP7 Expression Using Ellagic Acid from Pomegranate Peel.

BACKGROUND The aim of this study was to explore the mechanism by which cervical cancer is inhibited by promoting IGFBP7 expression using ellagic acid from pomegranate peel extract. MATERIAL AND METHODS HeLa cells were divided into 6 groups: control group (NC), blank control group (BL), and IGFBP7 overexpression group (IGFBP7), and 2.5 uM, 5. 0 uM, and 10.0 uM ellagic acid-treated groups. The cell proliferation ability was detected and the degree of invasion in the 6 groups was measured by Transwell assay. The expression levels of IGFBP7 and AKT/mTOR in the 6 groups of cells were detected by RT-PCR technique. RESULTS Compared with NC and BL groups, The IGFBP7 gene expressions of the IGFPB7 and ellagic acid-treated groups were significantly increased (P<0.05). There was a dose-effect dependence in the ellagic acid-treated groups. The invasion ability of the IGFBP7 group and ellagic acid-treated groups was significantly lower than that of NC and BL groups in HeLa cells (P<0.05). The apoptosis rate of the IGFBP7 group and ellagic acid-treated groups was significantly higher than that of the NC and BL groups in HeLa cells (P<0.05). AKT and mTOR mRNA and protein expressions of the IGFBP7 group and ellagic acid-treated groups were significantly lower than that of the NC and BL groups (P<0.05). There was a dose-effect dependence in the ellagic acid-treated groups. CONCLUSIONS The ellagic acid in pomegranate peel extract can inhibit the AKT/mTOR signaling pathway by enhancing the expression level of IGFBP7, which can inhibit the HeLa cells in cervical cancer.

Metformin combined with p38 MAPK inhibitor improves cisplatin sensitivity in cisplatin­resistant ovarian cancer.

The aim of the present study was to determine the effects of metformin, combined with a p38 mitogen­activated protein kinase (MAPK) inhibitor, on the sensitivity of cisplatin­resistant ovarian cancer to cisplatin. The expression and distribution of phosphorylated p38 MAPK (P­p38 MAPK) was confirmed in drug­resistant and primary ovarian cancer tissues by immunohistochemistry and western blotting. A bromodeoxyuridine ELISA kit was used to analyze the effects of metformin, SB203580, a p38 MAPK inhibitor, and metformin combined with SB203580, on the cell proliferation of SKOV3/DDP cisplatin­resistant ovarian cancer cells. The protein expression of P­p38 MAPK was significantly higher in cisplatin­resistant ovarian cancer, as compared with the primary ovarian cancer tissues. Metformin combined with SB203580 significantly enhanced the sensitivity of SKOV3/DDP cells to cisplatin. In conclusion, the p38 MAPK signaling pathway may be associated with cisplatin­resistant ovarian cancer. Metformin, combined with the p38 MAPK inhibitor, significantly increased the sensitivity of SKOV3/DDP cells to cisplatin treatment.