TME-Triggered Degradable Phototheranostic Nanoplatform for NIR-II Fluorescence Bioimaging-Guided Phototherapies and Immune Activation.

The low therapeutic efficacy and potential long-term toxicity of antitumor treatments seriously limit the clinical application of phototherapies. Herein, we develop a degradable phototheranostic nanoplatform for NIR-II fluorescence bioimaging-guided synergistic photothermal (PTT) and photodynamic therapies (PDT) and immune activation to inhibit tumor growth. The phototheranostic nanoplatform (CX@PSS) consists of multidisulfide-containing polyurethane loaded with a photosensitizer CX, which can be specifically degraded in the GSH overexpressed tumor microenvironment (TME) and exhibits good NIR-II fluorescence, photodynamic, and photothermal properties. Under 808 nm light irradiation, CX@PSS exhibits efficient photothermal conversion and ROS generation, which further induces immunogenic cell death (ICD), releasing tumor-associated antigens and activating the immune response. In vitro and in vivo studies confirm the potential of CX@PSS in NIR II FL imaging-guided tumor treatments by synergistic PTT, PDT, and immune activation. This work is expected to provide a new pathway for clinical applications of imaging-guided tumor diagnosis and treatments.

LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

Infiltrative Vessel Co-optive Growth Pattern Induced by IQGAP3 Overexpression Promotes Microvascular Invasion in Hepatocellular Carcinoma.

PURPOSE: Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. EXPERIMENTAL DESIGN: The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms. RESULTS: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. CONCLUSIONS: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.

CircMMP2(6,7) Cooperates with ß-Catenin and PRMT5 to Disrupt Bone Homeostasis and Promote Breast Cancer Bone Metastasis.

The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer-bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with ß-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/ß-catenin/PRMT5 complex-induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis. SIGNIFICANCE: Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/ß-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis.

A supramolecular nanoplatform for imaging-guided phototherapies via hypoxia tumour microenvironment remodeling.

Photodynamic therapy (PDT) has emerged as an invasive and promising antitumour treatment, however, the hypoxia in deep tumour tissues and the poor water-solubility of photosensitizers as bottlenecks greatly hinder PDT efficiency. Herein, a tumour microenvironment (TME) activated supramolecular nanoplatform consisting of the pillar[5]arene-based amphiphilic polymer POPD, the phototherapeutic agent Cy7-CN, respiratory medication atovaquone (ATO) and chemotherapeutic drug pyridinyl camptothecin (CPT-Py) was constructed for imaging-guided hypoxia-ameliorated phototherapies. Owing to host-guest interaction, the photochemical and photophysical properties of cyanine were improved exceedingly due to the suppression of π-π stacking. Triggered by the acidic microenvironment in tumour sites, the supramolecular nanoplatform would dissociate and release CPT-Py and ATO which inhibits mitochondria-associated oxidative phosphorylation (OXPHOS) and encourages more oxygen to be used in enhanced PDT. In vitro and in vivo studies verified that the rational combination of ATO-enhanced PDT and PTT overcame the disadvantages of single phototherapy and formed mutual promotion, and simultaneously sensitized chemotherapeutic drugs, which resulted in high tumour inhibition. It is hoped that the supramolecular nanoplatform could shed light on the development of phototherapeutic agents.

[Effect of diosgenin on mTOR/FASN/HIF-1α/VEGFA expression in rats with non-alcoholic fatty liver disease].

The present study aimed to investigate the effect of diosgenin on mammalian target of rapamycin(mTOR), fatty acid synthase(FASN), hypoxia inducible factor-1α(HIF-1α), and vascular endothelial growth factor A(VEGFA) expression in liver tissues of rats with non-alcoholic fatty liver disease(NAFLD) and explore the mechanism of diosgenin on lipogenesis and inflammation in NAFLD. Forty male SD rats were divided into a normal group(n=8) fed on the normal diet and an experimental group(n=32) fed on the high-fat diet(HFD) for the induction of the NAFLD model. After modeling, the rats in the experimental group were randomly divided into an HFD group, a low-dose diosgenin group(150 mg·kg~(-1)·d~(-1)), a high-dose diosgenin group(300 mg·kg~(-1)·d~(-1)), and a simvastatin group(4 mg·kg~(-1)·d~(-1)), with eight rats in each group. The drugs were continuously given by gavage for eight weeks. The levels of triglyceride(TG), total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), alanine transaminase(ALT), and aspartate transaminase(AST) in the serum were detected by the biochemical method. The content of TG and TC in the liver was detected by the enzyme method. Enzyme-linked immunosorbent assay(ELISA) was used to measure interleukin 1ß(IL-1ß) and tumor necrosis factor α(TNF-α) in the serum. Lipid accumulation in the liver was detected by oil red O staining. Pathological changes of liver tissues were detected by hematoxylin-eosin(HE) staining. The mRNA and protein expression levels of mTOR, FASN, HIF-1α, and VEGFA in the liver of rats were detected by real-time fluorescence-based quantitative polymerase chain reaction(PCR) and Western blot, respectively. Compared with the normal group, the HFD group showed elevated body weight and levels of TG, TC, LDL-C, ALT, AST, IL-1ß, and TNF-α(P<0.01), increased lipid accumulation in the liver(P<0.01), obvious liver steatosis, up-regulated mRNA expression levels of mTOR, FASN, HIF-1α, and VEGFA(P<0.01), and increased protein expression levels of p-mTOR, FASN, HIF-1α, and VEGFA(P<0.01). Compared with the HFD group, the groups with drug treatment showed lowered body weight and levels of TG, TC, LDL-C, ALT, AST, IL-1ß, and TNF-α(P<0.05, P<0.01), reduced lipid accumulation in the liver(P<0.01), improved liver steatosis, decreased mRNA expression levels of mTOR, FASN, HIF-1α, and VEGFA(P<0.05, P<0.01), and declining protein expression levels of p-mTOR, FASN, HIF-1α, and VEGFA(P<0.01). The therapeutic effect of the high-dose diosgenin group was superior to that of the low-dose diosgenin group and the simvastatin group. Diosgenin may reduce liver lipid synthesis and inflammation and potentiate by down-regulating the mTOR, FASN, HIF-1α, and VEGFA expression, playing an active role in preventing and treating NAFLD.

Downregulation of BASP1 Promotes Temozolomide Resistance in Gliomas via Epigenetic Activation of the FBXO32/NF-κB/MGMT Axis.

The chemoresistance of temozolomide-based therapy is a serious limitation for lasting effective treatment of gliomas, while the underlying mechanisms remain unclear. In this study, we showed that downregulation of BASP1 correlated negatively with the response to temozolomide therapy and disease-free survival (DFS) of patients with gliomas. Silencing BASP1 significantly enhanced the temozolomide resistance of glioma cells both in vitro and in vivo through repair of temozolomide-induced DNA damage via activation of the FBXO32/NF-κB/MGMT axis in both MGMT-methylated and -unmethylated gliomas. We demonstrated that loss of BASP1 resulted in removal of TRIM37/EZH2 complex-induced repressive histone modifications, including H2A-ub and H3K27me3, but addition of WDR5/MLL complex-mediated active histone modifications, including H3K4me3 and H3K9ac, on the FBXO32 promoter, which elicited in FBXO32 upregulation and further activated NF-κB/MGMT signaling via ubiquitin-dependent degradation of IκBα. Importantly, treatment with OICR-9429, an antagonist of the WDR5-MLL interaction, impaired the FBXO32/NF-κB/MGMT axis-mediated repair of temozolomide-induced DNA damage, leading to significant apoptosis of BASP1-downregulated glioma cells. These findings shed light on the molecular mechanism underlying BASP1-mediated epigenetic transcriptional repression and may represent a potential strategy in the fight against temozolomide-resistant gliomas. IMPLICATIONS: BASP1 downregulation promotes temozolomide resistance in gliomas through WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis, providing new target for improving outcomes in patients with temozolomide-resistant gliomas.

SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma.

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.

Effects of Acupuncture-Related Therapies in the Rehabilitation of Patients with Post-Stroke Aphasia-A Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this study was to evaluate the rehabilitation effects of four common interventions (BA: body acupuncture, SA: scalp acupuncture, TA: tongue acupuncture, SLT: speech and language training) used singly or in combination with language function in patients with post-stroke aphasia (PSA). DESIGN: We systematically searched PubMed, EMBASE, Cochrane Library, Ovid, Web of Science, CNKI, VIP, and Wanfang from inception to 4 April 2022. Only randomized controlled trials that met the eligibility criteria were included. The risk of bias of studies included was assessed using the RoB-2 tool. The effects of different interventions for PSA patients were analyzed and ranked according to the surface under the cumulative ranking (SUCRA) analysis. RESULTS: A total of 69 RCTs were included, including 5097 total participants. According to the results of the SUCRA curves, TA ranked highest in improving overall efficacy (SUCRA = 86%) and oral expression score (SUCRA = 86%). BA + TA ranked highest in increasing the comprehension score (SUCRA = 74.9%). BA + SA ranked highest in improving aphasia patients' repetition (SUCRA = 89.2%) and denomination scores (SUCRA = 93%). CONCLUSIONS: Results of our network meta-analysis and SUCRA ranking showed that tongue acupuncture, body acupuncture + tongue acupuncture, and body acupuncture + scalp acupuncture seem to offer better advantages than other interventions for improving the language function in PSA patients. Moreover, it is noteworthy that our results are limited to the Chinese population, since all eligible studies are from China. Future well-designed studies with larger sample sizes and more ethnic groups are required to further verify these findings.

Large Oncosome-Loaded VAPA Promotes Bone-Tropic Metastasis of Hepatocellular Carcinoma Via Formation of Osteoclastic Pre-Metastatic Niche.

Tumor-derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre-metastatic niche that facilitates organotropic metastasis. Identifying the organ-specific molecular determinants of EVs can develop potential anti-metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer-derived EVs, are found to play a crucial role in facilitating bone-tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre-metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP-associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV-integrin. VAPA-enriched LOs-induced pre-metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs-delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott-Aldrich syndrome protein (N-WASP) via dual mechanisms, consequently resulting in ARP2/3 complex-mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N-WASP inhibitor 187-1-packaged LOs (LOs/187-1) dramatically abolishes the inductive effect of VAPA-enriched LOs on pre-metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone-tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.

LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms.

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies.

Brown Adipose Tissue and Novel Management Strategies for Polycystic Ovary Syndrome Therapy.

Brown adipose tissue (BAT), a unique tissue, plays a key role in metabolism and energy expenditure through adaptive nonshivering thermogenesis. It has recently become a therapeutic target in the treatment of obesity and metabolic diseases. The thermogenic effect of BAT occurs through uncoupling protein-1 by uncoupling adenosine triphosphate (ATP) synthesis from energy substrate oxidation. The review discusses the recent developments and progress associated with the biology, function, and activation of BAT, with a focus on its therapeutic potential for the treatment of polycystic ovary syndrome (PCOS). The endocrine activity of brown adipocytes affects the energy balance and homeostasis of glucose and lipids, thereby affecting the association of BAT activity and the metabolic profile. PCOS is a complex reproductive and metabolic disorder of reproductive-age women. Functional abnormalities of adipose tissue (AT) have been reported in patients with PCOS. Numerous studies have shown that BAT could regulate the features of PCOS and that increases in BAT mass or activity were effective in the treatment of PCOS through approaches including cold stimulation, BAT transplantation and compound activation in various animal models. Therefore, BAT may be used as a novel management strategy for the patients with PCOS to improve women's health clinically. It is highly important to identify key brown adipokines for the discovery and development of novel candidates to establish an efficacious therapeutic strategy for patients with PCOS in the future.

NKX2-8/PTHrP Axis-Mediated Osteoclastogenesis and Bone Metastasis in Breast Cancer.

Bone metastasis is one of the most common distant metastasis of breast cancer, which could cause serious skeletal disease and increased cancer-related death. Therefore, identification of novel target(s) to develop therapeutics would improve patient outcomes. The role of NKX2-8 in modulation of bone remodeling was determined using osteoclastogenesis and micro-CT assays. The expression of NKX2-8 was examined via immunohistochemistry analysis in 344 breast cancer tissues. The mechanism underlying NKX2-8-mediated PTHrP downregulation was investigated using biotinylated deactivated Cas9 capture analysis, chromatin immunoprecipitation, co-immunoprecipitation assays. A bone-metastatic mouse model was used to examine the effect of NKX2-8 dysregulation on breast cancer bone metastasis and the impact of three PTHrP inhibitor on prevention of breast cancer bone metastasis. The downregulated expression of NKX2-8 was significantly correlated with breast cancer bone metastasis. In vivo bone-metastatic mouse model indicated that silencing NKX2-8 promoted, but overexpressing NKX2-8 inhibited, breast cancer osteolytic bone metastasis and osteoclastogenesis. Mechanistically, NKX2-8 directly interacted with HDAC1 on the PTHrP promoter, which resulted in a reduction of histone H3K27 acetylation, consequently transcriptionally downregulated PTHrP expression in breast cancer cells. Furthermore, targeting PTHrP effectively inhibited NKX2-8-downregulation-mediated breast cancer bone metastasis. Taken together, our results uncover a novel mechanism underlying NKX2-8 downregulation-mediated breast cancer bone metastasis and represent that the targeting PTHrP might be a tailored treatment for NKX2-8 silencing-induced breast cancer bone metastasis.

Integrated Analysis of Glutathione Metabolic Pathway in Pancreatic Cancer.

Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 (GPX2), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2. The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy.

Inactivation of EGLN3 hydroxylase facilitates Erk3 degradation via autophagy and impedes lung cancer growth.

EGLN3 is critically important for growth of various cancers including lung cancer. However, virtually nothing is known about the role and mechanism for EGLN3 hydroxylase activity in cancers. EGLN3 catalyzes the hydroxylation of extracellular signal-regulated kinase 3 (Erk3), a potent driver of cancers. The role and mechanism for EGLN3-induced stabilization of Erk3 remain to be defined. Here, we show that Erk3 interacts with heat shock cognate protein of 70 kDa (HSC70) and lysosome-associated membrane protein type 2 A (LAMP2A), two core components of chaperone-mediated autophagy (CMA). As a consequence, Erk3 is degraded by the CMA-lysosome pathway. EGLN3-catalyzed hydroxylation antagonizes CMA-dependent destruction of Erk3. Mechanistically, hydroxylation blunts the interaction of Erk3 with LAMP2A, thereby blocking lysosomal decay of Erk3. EGLN3 inactivation inhibits macrophage migration, efferocytosis, and M2 polarization. Studies using EGLN3 catalytically inactive knock-in mice indicate that inactivation of EGLN3 hydroxylase in host cells ameliorates LLC cancer growth through reprogramming the tumor microenvironment (TME). Adoptive transfer of macrophages with inactivated EGLN3 restrains tumor growth by mounting anti-tumor immunity and restricting angiogenesis. Administration of EGLN3 hydroxylase pharmacologic inhibitor to mice bearing LLC carcinoma impedes cancer growth by targeting the TME. LLC cells harboring inactivated EGLN3 exhibit reduced tumor burden via mitigating immunosuppressive milieu and inducing cancer senescence. This study provides novel insights into the role of CMA in regulating Erk3 stability and the mechanism behind EGLN3-enhanced stability of Erk3. This work demonstrates that inactivation of EGLN3 in malignant and stromal cells suppresses tumor by orchestrating reciprocal interplays between cancer cells and the TME. This work sheds new light on the role and mechanism for EGLN3 catalytic activity in regulating cancer growth. Manipulating EGLN3 activity holds promise for cancer treatment.

Single-cell RNA-seq highlights a specific carcinoembryonic cluster in ovarian cancer.

Expounding the heterogeneity for ovarian cancer (OC) with the cognition in developmental biology might be helpful to search for robust prognostic markers and effective treatments. In the present study, we employed single-cell RNA-seq with ovarian cancers, normal ovary, and embryo tissue to explore their heterogeneity. Then the differentiation process of clusters was explored; the pivotal cluster and markers were identified. Furthermore, the consensus clustering algorithm was used to explore the different clinical phenotypes in OC. At last, a prognostic model was construct and used to assess the prognosis for OCs. As a result, eight diverse clusters were identified, and the similarity existed in some clusters between embryo and tumours based on their gene expression. Meaningfully, a subtype of malignant epithelial cluster, PEG10+ EME, was associated with poor survival and was an intermediate stage of embryo to tumour. PEG10 was a CSC marker and might influence CSC self-renewal and promote cisplatin resistance via NOTCH pathway. Utilising specific gene profiles of PEG10+ EME based on public data sets, four phenotypes with different survival and clinical response to anti-PD-1/PD-L1 immunotherapy were identified. These insights allowed for the investigation of single-cell transcriptome of OCs and embryo, which advanced our current understanding of OC pathogenesis and resulted in promising therapeutic strategies.

Clinical analysis of second-trimester pregnancy termination after previous caesarean delivery in 51 patients with placenta previa and placenta accreta spectrum: a retrospective study.

BACKGROUNDS: Pregnancy termination during the second trimester in patients with placenta previa and placenta accreta spectrum (PAS) is a complex and challenging clinical problem. Based on our literature review, there has been a relative increase in the number of such cases being treated by hysterotomy and/or local uterine lesion resection and repair. In the present study, a retrospective analysis was conducted to compare the clinical outcomes when different management strategies were used to terminate pregnancy in the patients with placenta previa and PAS. METHODS: A total of 51 patients who underwent pregnancy termination in the second trimester in Beijing Obstetrics and Gynecology Hospital between June 2013 and December 2018 were retrospectively analyzed in this study. All patients having previous caesarean delivery (CD) were diagnosed with placenta previa status and PAS. RESULTS: ① Among the 51 patients, 16 cases received mifepristone and misoprostol medical termination, 15 cases received mifepristone and Rivanol medical termination, but 1 of them was transferred to hysterotomy due to failed labor induction, another 20 cases were performed planned hysterotomy. There was no placenta percreta cases and uterine artery embolization (UAE) was all performed before surgery.② There were 31 cases who underwent medical termination and 30 cases were vaginal delivery. Dilation and evacuation (D&E) were used in 20 cases of medical abortion failure and in all 30 cases of difficult manual removal of placental tissue. ③ A statistically significant difference was found among the three different strategies in terms of gestational weeks, the type of placenta previa status, main operative success rate and ß-HCG regression time (P < 0.05). ④ There were 4(7.8%) cases who were taken up for hysterectomy because of life-threatening bleeding or severe bacteremia during or after delivery and hysterotomy. The uterus was preserved with the implanted placenta partly or completely left in situ in 47(92.2%) cases. Combined medical and/or surgical management were used for the residual placenta and the time of menstrual recovery was 52(range: 33 to 86) days after pregnancy termination. CONCLUSIONS: Terminating a pregnancy by vaginal delivery through medical induction of labor may be feasible if clinicians have an overall understanding of gestational age, the type of placenta previa status, the type of placenta accreta, and patients concerns about preserving fertility. A collaborative team effort in tertiary medical centers with a very experience MDT and combined application of multiple methods is required to optimize patient outcomes.

Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling.

BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKß-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

Novel Role for Tranilast in Regulating NLRP3 Ubiquitination, Vascular Inflammation, and Atherosclerosis.

Background Aberrant activation of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3) inflammasome is thought to play a causative role in atherosclerosis. NLRP3 is kept in an inactive ubiquitinated state to avoid unwanted NLRP3 inflammasome activation. This study aimed to test the hypothesis that pharmacologic manipulating of NLRP3 ubiquitination blunts the assembly and activation of the NLRP3 inflammasome and protects against vascular inflammation and atherosclerosis. Since genetic studies yielded mixed results about the role for this inflammasome in atherosclerosis in low-density lipoprotein receptor- or apolipoprotein E-deficient mice, this study attempted to clarify the discrepancy with the pharmacologic approach using both models. Methods and Results We provided the first evidence demonstrating that tranilast facilitates NLRP3 ubiquitination. We showed that tranilast restricted NLRP3 oligomerization and inhibited NLRP3 inflammasome assembly. Tranilast markedly suppressed NLRP3 inflammasome activation in low-density lipoprotein receptor- and apolipoprotein E-deficient macrophages. Through reconstitution of the NLRP3 inflammasome in human embryonic kidney 293T cells, we found that tranilast directly limited NLRP3 inflammasome activation. By adopting different regimens for tranilast treatment of low-density lipoprotein receptor- and apolipoprotein E-deficient mice, we demonstrated that tranilast blunted the initiation and progression of atherosclerosis. Mice receiving tranilast displayed a significant reduction in atherosclerotic lesion size, concomitant with a pronounced decline in macrophage content and expression of inflammatory molecules in the plaques compared with the control group. Moreover, tranilast treatment of mice substantially hindered the expression and activation of the NLRP3 inflammasome in the atherosclerotic lesions. Conclusions Tranilast potently enhances NLRP3 ubiquitination, blunts the assembly and activation of the NLRP3 inflammasome, and ameliorates vascular inflammation and atherosclerosis in both low-density lipoprotein receptor- and apolipoprotein E-deficient mice.