Incidence, risk factors, and clinical outcomes of acute brain swelling associated with traumatic acute subdural hematoma: a retrospective study utilizing novel diagnostic criteria.

Background: Post-traumatic acute brain swelling (ABS) is a major cause of elevated intracranial pressure and thus mortality. The current definition of post-traumatic ABS has certain limitations, and there is limited information available regarding ABS associated with traumatic acute subdural hematoma (ASDH). Objectives: To investigate the incidence, risk factors, and clinical outcomes of ABS associated with traumatic ASDH. Design: Retrospective study. Methods: Data for 161 patients diagnosed with traumatic ASDH were retrospectively collected. Novel computed tomography-based criteria were proposed for diagnosing ABS in patients with ASDH and determining its incidence. Univariate and multivariate logistic regression analyses were performed to explore the risk factors of post-traumatic ABS. The Glasgow Outcome Scale (GOS) score, mortality, and functional prognosis of all patients at discharge and the proportion of intraoperative malignant brain bulge in surgical patients were taken as clinical outcome measures. Results: A total of 45 (28%) patients experienced post-traumatic ABS, exhibiting significantly lower Glasgow Coma Scale scores on admission (p < 0.001). The incidence of hemispheric and whole-brain swelling was 8.1% and 19.9%, respectively. Risk factors independently associated with post-traumatic ABS were: (1) age [odds ratio (OR) = 0.917, p < 0.001]; (2) platelet to white blood cell ratio (PWR) (OR = 0.887, p = 0.012); and (3) traumatic subarachnoid hemorrhage (SAH) (OR = 4.346, p = 0.005). The ABS cohort had a lower GOS score [2 (1-3) versus 4 (3-5); p < 0.001], higher mortality (46.7% versus 6.9%; p < 0.001), and higher proportion of unfavorable functional prognosis (75.6% versus 34.5%; p < 0.001) upon discharge compared to the no ABS cohort, along with higher proportion of intraoperative malignant brain bulge (43.8% versus 0%; p < 0.001). Conclusion: The incidence of ABS associated with ASDH is significantly high overall. Patients with ASDH who have young age, low PWR, and traumatic SAH are at an increased risk of developing post-traumatic ABS, and therefore of poor clinical outcomes.

Yolk-Shell Gradient-Structured SiOx Anodes Derived from Periodic Mesoporous Organosilicas Enable High-Performance Lithium-Ion Batteries.

Gradient-structured materials hold great promise in the areas of batteries and electrocatalysis. Here, yolk-shell gradient-structured SiOx -based anode (YSG-SiOx /C@C) derived from periodic mesoporous organosilica spheres (PMOs) through a selective etching method is reported. Capitalizing on the poor hydrothermal stability of inorganic silica in organic-inorganic hybrid silica spheres, the inorganic silica component in the hybrid spheres is selectively etched to obtain yolk-shell-structured PMOs. Subsequently, the yolk-shell PMOs are coated with carbon to fabricate YSG-SiOx /C@C. YSG-SiOx /C@C is comprised of a core with uniform distribution of SiOx and carbon at the atomic scale, a middle void layer, and outer layers of SiOx and amorphous carbon. This unique gradient structure and composition from inside to outside not only enhances the electrical conductivity of the SiOx anode and reduces the side reactions, but also reserves void space for the expansion of SiOx , thereby effectively mitigating the stress caused by volumetric effect. As a result, YSG-SiOx /C@C exhibits exceptional cycling stability and rate capability. Specifically, YSG-SiOx /C@C maintains a specific capacity of 627 mAh g-1 after 400 cycles at 0.5 A g-1 , and remains stable even after 550 cycles at current density of 2 A g-1 , achieving a specific capacity of 519 mAh g-1 .

Feasibility of Sentinel Lymph Node Mapping With Carbon Nanoparticles in Cervical Cancer: A Retrospective Study.

INTRODUCTION: This retrospective study aims to investigate the feasibility of using carbon nanoparticles to detect sentinel lymph nodes (SLNs) in cervical cancer. METHODS: This study involved 174 patients with cervical cancer. Cervix tissues adjacent to the cancer were injected with 1 mL of carbon nanoparticles (CNPs) at the 3 and 9 o'clock positions according to the instructions. The pelvic lymph nodes were then dissected, and the black-stained sentinel lymph nodes were sectioned for pathological examination. RESULTS: Of 174 cases, 88.5% of patients (154/174) had at least 1 sentinel lymph node, and 131 patients (75.29%) had bilateral pelvic sentinel lymph nodes. The left pelvic lymph node was the most common sentinel lymph node (34.16%). At least 1 sentinel lymph node was observed in 285 out of 348 hemipelvises, with a detection rate of a side-specific sentinel lymph node of 81.89%. In total, 47 hemipelvises had metastasis of the lymph node, and 33 involved the sentinel lymph node, with a sensitivity of 70.21% and a false-negative rate of 29.79%. There were 238 hemipelvises with no metastasis of the lymph node, as well as negative sentinel lymph nodes, with a specificity of 100% and a negative predictive value of 94.44%. The univariate analysis demonstrated that risk factors included tumor size (OR .598, 95% CI: .369-.970) and deep stromal invasion (OR .381, 95% CI: .187-.779). The deep stromal invasion was the only variable for the false-negative detection of a sentinel lymph node. CONCLUSION: Sentinel lymph node mapping with carbon nanoparticles might be applied to predict the metastasis of pelvic lymph nodes in cervical cancer. However, tumor size and deep stromal invasion might negative influence the detection rate of SLN.

Causes and risk factors of an unplanned second craniotomy in patients with traumatic brain injury.

BACKGROUND: The purpose of this retrospective study was to evaluate the causes and risk factors of an unplanned second craniotomy in patients with traumatic brain injury (TBI). METHODS: A total of 219 patients with TBI who underwent initial unilateral intracranial supratentorial surgery between January 2016 to November 2021 were included. We evaluated the causes of an unplanned second craniotomy in 40 patients, and analyzed the risk factors for a contralateral second craniotomy in 21 patients using a multivariate logistic regression analysis. RESULTS: The most common cause for an unplanned second craniotomy was delayed or enlarged hematoma in the non-operation area (26/40; 65%), followed by recurrent hematoma in the operation area (8/40; 20%), ipsilateral massive cerebral infarction (3/40; 7.5%), diffuse brain swelling (2/40; 5%) and enlarged cerebral contusion (1/40; 2.5%). Multivariate logistic regression analysis showed that a contralateral craniocerebral injury feature (CCIF) (OR = 13.175), defined on preoperative computerized tomography scanning, was independent risk factor for a contralateral second craniotomy. CONCLUSIONS: An unplanned second craniotomy in patients with TBI was mainly related to delayed or enlarged hematoma. An increased risk of a contralateral second craniotomy occurs in patients with CCIF.

Unravelling the Effect of Activators used in The Synthesis of Biomass-Derived Carbon Electrocatalysts on the Electrocatalytic Performance for CO2 Reduction.

N-doped carbon materials can be efficient and cost-effective catalysts for the electrochemical CO2 reduction reaction (CO2 RR). Activators are often used in the synthesis process to increase the specific surface area and porosity of these carbon materials. However, owing to the diversity of activators and the differences in physicochemical properties that these activators induce, the influence of activators used for the synthesis of N-doped carbon catalysts on their electrochemical performance is unclear. In this study, a series of bagasse-derived N-doped carbon catalysts is prepared with the assistance of different activators to understand the correlation between activators, physicochemical properties, and electrocatalytic performance for the CO2 RR. The properties of N-doped carbon catalysts, such as N-doping content, microstructure, and degree of graphitization, are found to be highly dependent on the type of activator applied in the synthesis procedure. Moreover, the overall CO2 RR performance of the synthesized electrocatalysts is not determined only by the N-doping level and the configuration of the N-dopant, but rather by the overall surface chemistry, where the porosity and the degree of graphitization are jointly responsible for significant differences in CO2 RR performance.

Construction of circRNA-associated ceRNA network reveals the regulation of fibroblast proliferation in cervical cancer.

BACKGROUND: Cervical cancer is one of the major cancers that threaten the health of women. CircRNA is an important factor in the regulation of cancer development and progression. The role of circRNA in cervical cancer is less well studied. The aim of this study was to explore the mechanism of circRNA effects on cervical cancer using circRNA-seq technology to study the expression profile data of 9 pairs of primary cervical cancer and paracancerous tissues. METHOD: DESeq2 was used to analyse differentially expressed circRNA and mRNA in cervical cancer and paracancerous tissues. MiRanda and TargetScan are used to predict miRNAs that interact with circRNAs and mRNAs and to construct circRNA-miRNA-mRNA regulatory networks. KEGG and GO are used for functional annotation of differentially expressed genes. TIDE, TIMER2.0 was used to assess the status of the tumour immune microenvironment in cervical cancer. GEPIA2 was used to validate the results of differential expression analysis. RESULTS: We eventually obtained 22 differentially expressed circRNAs (7 up-regulated and 15 down-regulated) and 1834 differentially expressed genes (613 up-regulated and 1221 down-regulated). The results of the KEGG analysis showed that the differentially expressed genes were mainly enriched in cell cycle and cancer-related signalling pathways. The new circRNA: circZNF208 was identified to promote fibroblast proliferation by interfering with its downstream hsa-miR-324-3p regulating four downstream genes LPHN3. The level of fibroblast infiltration is implicated in the poor prognosis of cervical cancer. CONCLUSION: We have identified a novel circRNA: circZNF208 that can interfere with fibroblast proliferation in cervical cancer through a ceRNA regulatory network, thereby promoting fibroblast proliferation in cervical cancer and affecting the prognosis of cancer patients.

The circular RNA expression profile in ovarian serous cystadenocarcinoma reveals a complex circRNA-miRNA regulatory network.

BACKGROUND: Ovarian serous cystadenocarcinoma is one of the most serious gynecological malignancies. Circular RNA (circRNA) is a type of noncoding RNA with a covalently closed continuous loop structure. Abnormal circRNA expression might be associated with tumorigenesis because of its complex biological mechanisms by, for example, functioning as a microRNA (miRNA) sponge. However, the circRNA expression profile in ovarian serous cystadenocarcinoma and their associations with other RNAs have not yet been characterized. The main purpose of this study was to reveal the circRNA expression profile in ovarian serous cystadenocarcinoma. METHODS: We collected six specimens from three patients with ovarian serous cystadenocarcinoma and adjacent normal tissues. After RNA sequencing, we analyzed the expression of circRNAs with relevant mRNAs and miRNAs to characterize potential function. RESULTS: 15,092 unique circRNAs were identified in six specimens. Approximately 46% of these circRNAs were not recorded in public databases. We then reported 353 differentially expressed circRNAs with oncogenes and tumor-suppressor genes. Furthermore, a conjoint analysis with relevant mRNAs revealed consistent changes between circRNAs and their homologous mRNAs. Overall, construction of a circRNA-miRNA network suggested that 4 special circRNAs could be used as potential biomarkers. CONCLUSIONS: Our study revealed the circRNA expression profile in the tissues of patients with ovarian serous cystadenocarcinoma. The differential expression of circRNAs was thought to be associated with ovarian serous cystadenocarcinoma in the enrichment analysis, and co-expression analysis with relevant mRNAs and miRNAs illustrated the latent regulatory network. We also constructed a complex circRNA-miRNA interaction network and then demonstrated the potential function of certain circRNAs to aid future diagnosis and treatment.

LncCCLM inhibits lymphatic metastasis of cervical cancer by promoting STAU1-mediated IGF-1 mRNA degradation.

Cervical cancer (CC) patients with lymph node (LN) metastasis often have an extremely poor prognosis. However, the precise molecular mechanisms involved in LN metastasis of CC remain largely unknown. Herein, through RNA screening, we identified a novel long noncoding RNA (lncRNA), LncCCLM, that was downregulated in cervical cancer tissues and closely associated with lymphatic metastasis in cervical cancer patients. Gain-of-function and loss-of-function studies in CC cells demonstrated that LncCCLM inhibited cervical cancer-associated lymphangiogenesis, and CC cell migration and invasion in vitro and suppressed LN metastasis in vivo, but did not affect the growth of CC cells. Mechanistically, LncCCLM localized in the cytoplasm and interacted with staufen double-stranded RNA binding protein 1 (STAU1), promoting the binding of the STAU1 protein to the 3' untranslated region (3'UTR) of insulin-like growth factor 1 (IGF-1) mRNA, which accelerated the degradation of IGF-1 mRNA and decreased the IGF-1 protein level, ultimately reducing lymphangiogenesis and lymphatic metastasis in cervical cancer. Collectively, our findings suggest that LncCCLM acts as a tumor suppressor and may be used as a prognostic biomarker and therapeutic target for clinical intervention in LN-metastatic cervical cancer.

SNX10 and PTGDS are associated with the progression and prognosis of cervical squamous cell carcinoma.

BACKGROUND: Cervical cancer (CC) is the primary cause of death in women. This study sought to investigate the potential mechanism and prognostic genes of CC. METHODS: We downloaded four gene expression profiles from GEO. The RRA method was used to integrate and screen differentially expressed genes (DEGs) between CC and normal samples. Functional analysis was performed by clusterprofiler. We built PPI network by Search Tool for the Retrieval of Interacting Genes Database (STRING) and selected hub modules via Molecular COmplex Detection (MCODE). CMap database was used to find molecules with therapeutic potential for CC. The hub genes were validated in GEO datasets, Gene Expession Profiling Interactive Analysis (GEPIA), immunohistochemistry, Cox regression analysis, TCGA methylation analysis and ONCOMINE were carried out. ROC curve analysis and GSEA were also performed to describe the prognostic significance of hub genes. RESULTS: Functional analysis revealed that 147 DEGs were significantly enriched in binding, cell proliferation, transcriptional activity and cell cycle regulation. PPI network screened 30 hub genes, with CDK1 having the strongest connectivity with CC. Cmap showed that apigenin, thioguanine and trichostatin A might be used to treat CC(P < 0.05). Eight genes (APOD, CXCL8, MMP1, MMP3, PLOD2, PTGDS, SNX10 and SPP1) were screened out through GEPIA. Of them, only PTGDS and SNX10 had not appeared in previous studies about CC. The validation in GEO showed that PTGDS showed low expression while SNX10 presented high expression in tumor tissues. Their expression profiles were consistent with the results in immunohistochemistry. ROC curve analysis indicated that the model had a good diagnostic efficiency (AUC = 0.738). GSEA analysis demonstrated that the two genes were correlated with the chemokine signaling pathway (P < 0.05). TCGA methylation analysis showed that patients with lowly-expressed and highly-methylated PTGDS had a worse prognosis than those with highly-expressed and lowly-methylated PTGDS (p = 0.037). Cox regression analysis showed that SNX10 and PTGDS were independent prognostic indicators for OS among CC patients (P = 0.007 and 0.003). CONCLUSIONS: PTGDS and SNX10 showed abnormal expression and methylation in CC. Both genes might have high prognostic value of CC patients.

LncRNA LIPE-AS1 Predicts Poor Survival of Cervical Cancer and Promotes Its Proliferation and Migration via Modulating miR-195-5p/MAPK Pathway.

Aims: A growing number of studies have unveiled that long non-coding RNA (lncRNA) is conductive to cervical cancer (CC) development. However, the effect of LIPE-AS1 is remained to be studied in CC. Main Methods: Reverse transcription-polymerase chain reaction (RT-PCR) was employed to measure LIPE-AS1 expression in CC tissues and the adjacent normal tissues. Additionally, we conducted gain- and loss-of functional experiments of LIPE-AS1 and adopted CCK8 assay, BrdU assay, and in vivo tumor formation experiment to test the proliferation of CC cells (HCC94 and HeLa). Besides, the apoptosis, invasion, and epithelial-mesenchymal transformation (EMT) of CC cells were estimated using flow cytometry, transwell assay, and western blot, respectively. Further, LIPE-AS1 downstream targets were analyzed through bioinformatics, and the binding relationships between LIPE-AS1 and miR-195-5p were verified via dual-luciferase activity experiment and RNA Protein Immunoprecipitation (RIP) assay. Moreover, rescue experiments were conducted to confirm the effects of LIPE-AS1 and miR-195-5p in regulating CC development and the expressions of MAPK signaling pathway related proteins were detected by RT-PCR, western blot, and immunofluorescence. Key Findings: LIPE-AS1 was over-expressed in CC tissues (compared to normal adjacent tissues) and was notably related to tumor volume, distant metastasis. Overexpressing LIPE-AS1 accelerated CC cell proliferation, migration and EMT, inhibited apoptosis; while LIPE-AS1 knockdown had the opposite effects. The mechanism studies confirmed that LIPE-AS1 sponges miR-195-5p as a competitive endogenous RNA (ceRNA), which targets the 3'-untranslated region (3'-UTR) of MAP3K8. LIPE-AS1 promoted the expression of MAP3K8 and enhanced ERK1/2 phosphorylation, which were reversed by miR-195-5p. Significance: LIPE-AS1 regulates CC progression through the miR-195-5p/MAPK signaling pathway, providing new hope for CC diagnosis and treatment.

Genome-Wide Analysis of the Expression of Circular RNA Full-Length Transcripts and Construction of the circRNA-miRNA-mRNA Network in Cervical Cancer.

Increasing evidence suggests that circular RNA (circRNA) plays an important role in tumorigenesis by regulating gene expression at the transcriptional and post-transcriptional levels. Alternative splicing events permit multiple transcript isoforms of circRNA to be produced; however, changes in the expression of circRNA full-length transcripts in cervical cancer remain unclear. Here, we systematically explored the dysregulation circRNA full-length transcripts and constructed an improved circRNA-miRNA-mRNA regulatory network to provide potential biomarkers and possible treatment targets in cervical cancer. We identified 9359 circular full-length transcripts from RNase R-treated RNA-seq data in cervical cancer, of which 353 circular full-length transcripts were significantly differentially expressed (DE) between the tumor and normal group. A total of 881 DE mRNA transcript isoforms were also identified from total RNA-seq data in cervical cancer, of which 421 (47.8%) transcript isoforms were up-regulated, and 460 (52.2%) transcript isoforms were down-regulated in tumor samples. Two circRNA-miRNA-mRNA competitively regulated networks, including 33 circRNA transcripts, 2 miRNAs, and 189 mRNA transcripts were constructed. Three genes (COPE, RAB3B, and TFPI) in the network were significantly associated with overall survival (P < 0.05), which indicated that these genes could act as prognostic biomarkers for patients with cervical cancer. Our study revealed genome-wide differential expression of full-length circRNA transcripts and constructed a more accurate circRNA-miRNA-mRNA network at the full-length transcript expression level in cervical cancer. CircRNA may thus be involved in the development of cervical cancer by regulating the expression of COPE, RAB3B, and TFPI. However, the specific regulatory mechanism in cervical cancer requires further study.

Identification of a metabolism-related gene expression prognostic model in endometrial carcinoma patients.

BACKGROUND: Metabolic abnormalities have recently been widely studied in various cancer types. This study aims to explore the expression profiles of metabolism-related genes (MRGs) in endometrial cancer (EC). METHODS: We analyzed the expression of MRGs using The Cancer Genome Atlas (TCGA) data to screen differentially expressed MRGs (DE-MRGs) significantly correlated with EC patient prognosis. Functional pathway enrichment analysis of the DE-MRGs was performed. LASSO and Cox regression analyses were performed to select MRGs closely related to EC patient outcomes. A prognostic signature was developed, and the efficacy was validated in part of and the entire TCGA EC cohort. Moreover, we developed a comprehensive nomogram including the risk model and clinical features to predict EC patients' survival probability. RESULTS: Forty-seven DE-MRGs were significantly correlated with EC patient prognosis. Functional enrichment analysis showed that these MRGs were highly enriched in amino acid, glycolysis, and glycerophospholipid metabolism. Nine MRGs were found to be closely related to EC patient outcomes: CYP4F3, CEL, GPAT3, LYPLA2, HNMT, PHGDH, CKM, UCK2 and ACACB. Based on these nine DE-MRGs, we developed a prognostic signature, and its efficacy in part of and the entire TCGA EC cohort was validated. The nine-MRG signature was independent of other clinical features, and could effectively distinguish high- and low-risk EC patients and predict patient OS. The nomogram showed excellent consistency between the predictions and actual survival observations. CONCLUSIONS: The MRG prognostic model and the comprehensive nomogram could guide precise outcome prediction and rational therapy selection in clinical practice.

Identification of miRNA-mRNA Regulatory Network and Construction of Prognostic Signature in Cervical Cancer.

Cervical cancer (CC) remains a most prevalent female cancer worldwide, but there are few biomarkers used in diagnosis and prognosis of CC. The aim of this study is to find reliable and effective biomarkers regarding CC development. Microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database to search potential miRNA-mRNA in CC. The gene ontology term enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were conducted to reveal the underlying functions and pathways of differently expressed genes (DEGs). Univariate Cox, multivariate Cox, and risk scoring methods were performed to identify a prognostic model. A total of 209 DEGs of CC were identified. In the protein-protein interaction network, hub module, and hub genes were recognized. Based on DEGs, three small molecules (thioguanosine, apigenin, and trichostatin A) were screened out as potential drugs. Two miRNAs (hsa-mir-101-3p and hsa-mir-6507-5p) and some transcription factors were found to be associated with prognosis of CC. A five-candidate gene signature (APOBEC3B, DSG2, CXCL8, ABCA8, and PLAGL1) was constructed to stratify risk subgroups for patients with CC. The risk score of the prognostic model was also found to be associated with immune cells infiltration, including mast cell activation, natural killer cells resting, dendritic cells resting, T cells regulatory (Tregs), and T cells follicular helper. The miRNA-mRNA regulatory network and the prognostic model are of great clinical significance in promoting prognosis prediction and treatment of CC.

Down-regulated lncRNA AGAP2-AS1 contributes to pre-eclampsia as a competing endogenous RNA for JDP2 by impairing trophoblastic phenotype.

Recently, growing evidence has shown that aberrant long non-coding RNA (lncRNA) expression in conjunction with an impaired trophoblastic phenotype could implicate the pathological process of pre-eclampsia (PE). However, only a small portion of lncRNAs has been characterized with regard to the function and molecular mechanisms involved in PE. There are still gaps in the available knowledge; as a result, there are currently only a few applicable treatments for PE in the context of lncRNA. Here, we found that lncRNA AGAP2-AS1 is abnormally down-regulated in severe PE placenta tissues. Using human trophoblasts, we established that AGAP2-AS1 knockdown could inhibit trophoblasts proliferation and invasion and promote cell apoptosis. Further, we showed that overexpression of AGAP2-AS1 substantially stimulated the development of the trophoblastic phenotype. Through high-throughput sequencing analysis, we demonstrated that silencing of AGAP2-AS1 favourably regulated various genes which are relevant to trophoblastic growth and invasion. Mechanistically, AGAP2-AS1 promoted the suppressor protein, Jun dimerization protein 2 (JDP2), by sponging miR-574-5p. Resultantly, further impairment of the trophoblastic phenotype was achieved by way of inhibiting cell growth, apoptosis and invasion. We also determined that the expression of AGAP2-AS1 could be mediated by FOXP1. Our results showed that the down-regulated expression of lncRNA AGAP2-AS1 might serve as a key suppressor in PE via inhibition of JDP2 at the post-transcriptional level by competing for miR-574; thus, this presents a novel therapeutic strategy for PE.

Role of cancer-associated fibroblasts in tumor structure, composition and the microenvironment in ovarian cancer.

Ovarian cancer (OVAC) remains the most lethal gynecological malignancy; it is ranked fifth among the most common types of cancer that affect women worldwide. Several aspects of the disease, including molecular pathogenesis, epidemiology, histological subtypes, poor prognosis at early stages due to the absence of specific signs and symptoms, and curative treatments in the advanced stages are all responsible for the poor survival rate, which is evaluated to be at 5 years once the cancer is diagnosed and treatment begins. A better understanding of the pathogenesis of ovarian cancer is therefore crucial, even though unexplored pathways, in order to improve the prognosis of patients with OVAC and to develop novel therapeutic approaches. Accordingly, the tumor microenvironment, defined as the combination of proteins produced by all tumor cells and by non-cancerous cells or the stroma, and composed of several cells, including those from the immune, inflammatory and adipose systems, as well as the mesenchymal stem, endothelial and fibroblasts cells, has recently attracted attention. Of particular interest are fibroblasts, which can be activated into cancer-associated fibroblast (CAFs) to become a potent supporter of carcinogenesis, promoting the initiation of epithelial tumor formation, tumor growth, angiogenesis and metastasis, as well as therapeutic resistance and immunosuppression. Thus, the targeting of CAFs for early diagnosis and effective therapy warrants our attention. In this review, we discuss the mechanisms through which CAFs may affect the structure, composition and microenvironment of the ovarian tumor. We also aim to highlight important aspects of OVAC pathobiology involving CAFs, in an attempt to provide insight into novel diagnostic windows and provide new therapeutic perspectives.

A fully human monoclonal antibody targeting PD-L1 with potent anti-tumor activity.

BACKGROUND: Programmed cell death ligand-1 (PD-L1) with its receptor PD-1 pathway is overactivated in many tumors. Inhibiting the interaction of PD-L1 and PD-1 is an attractive strategy to restore tumor-specific T cell immunity for tumor therapy. METHODS: A fully human anti-PD-L1 monoclonal antibody (mAb) B60-55 was identified by yeast surface display. The affinity, specificity, activity, and efficacy of mAb B60-55 were investigated in vitro or in vivo. RESULTS: mAb B60-55 (purity >99%) could bind to PD-L1 that is expressed on HEK293 cells with a dissociation constant of 0.2 nM, and specifically bind to human or cynomolgus macaque PD-L1 without a cross-reaction with murine PD-L1. Moreover, mAb B60-55 is an antagonistic antibody, which can block PD-L1 binding to its receptors, including PD-1 (PDCD1) and B7.1 (CD80). In vitro assays demonstrated the ability of mAb B60-55 to enhance T cell responses and cytokine production in the mixed lymphocyte reaction. In vivo studies showed that administration of mAb B60-55 exhibited a potent antitumor activity toward tumor cell carcinoma xenograft, with a mean half-life of 177.9h in cynomolgus monkeys. CONCLUSION: mAb B60-55 is a potential candidate for clinical development in cancer treatment.

Dehydroeffusol inhibits gastric cancer cell growth and tumorigenicity by selectively inducing tumor-suppressive endoplasmic reticulum stress and a moderate apoptosis.

Gastric cancer is ranked as the third leading cause of cancer-related death in the world. Although extensive efforts have been made in recent decades to treat gastric cancer with various anticancer drugs, effective anti-gastric cancer therapeutics to cure the disease are still lacking in the clinics. Therefore, potent novel anti-gastric cancer drugs are greatly needed. In this study, we explored a novel anti-gastric cancer agent from a medicinal herb named Juncus effusus and found that the active component dehydroeffusol (DHE), a small molecular phenanthrene, effectively inhibited gastric cancer cell proliferation and tumorigenesis by inducing tumor suppressive endoplasmic reticulum (ER) stress and by triggering moderate apoptosis. Mechanistic studies revealed that DHE selectively activated the intracellular tumor suppressive stress response by promoting the overexpression of the key ER stress marker DNA damage-inducible transcript 3 (DDIT3), through upregulation of activating transcription factor 4 (ATF4). Concurrently, DHE suppressed the expression of the cell survival and ER stress marker glucose regulated protein of molecular mass 78 (GRP78) via downregulation of the transcription factor ATF6. In addition, DHE markedly activated the stress response signaling pathway MEKK4-MKK3/6-p38-DDIT3, but significantly inhibited ERK signaling. Our data suggest that DHE inhibits gastric cancer cell growth and tumorigenicity through selectively inducing a robust tumor suppressive ER stress response and a moderate apoptosis response. Therefore, DHE may provide a novel drug candidate for further development of potential anti-gastric cancer therapeutics.

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy.

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy.

All-trans retinoic acid suppresses topoisomerase IIα through the proteasomal pathway.

Topoisomerase IIα is a nuclear enzyme that alters DNA topology. It is a well-known anticancer target and related to cell differentiation status. All-trans retinoic acid (ATRA), an important active metabolite of vitamin A, is a promising anticancer agent in numerous malignancies. However, there are little data on the effect of retinoids on topoisomerase IIα regulation. In the present study, we investigated the relationship between ATRA and topoisomerase IIα, and the potential mechanisms of ATRA on topoisomerase IIα regulation. In several human carcinoma cell lines, ATRA was shown to suppress topoisomerase IIα protein, but not mRNA expression. ATRA induced the degradation of topoisomerase IIα through the proteasome pathway, but not the lysosome pathway. Ubiquitination was involved in this degradation. Western blot and immunocytochemistry proved that ATRA-induced topoisomerase IIα repression occurred only in the cell nuclei. ATRA not only influenced the cycle procession but also reduced the expression of cyclin D1. Cyclin D1, which is involved in cell differentiation, was regulated by topoisomerase IIα. Similar to cyclin D1, knockdown of topoisomerase IIα resulted in the increased differentiation of the cells, which was in contrast to the overexpression of topoisomerase IIα in the cells. Taken together, these data suggested that ATRA could target topoisomerase IIα and exert potential beneficial effects on cell differentiation.

Preclinical humanized mouse model with ectopic ovarian tissues.

The aim of the present study was to establish human ovarian stroma within the mouse subcutaneously, in order for the resulting stroma to serve as a useful preclinical tool to study the progression of human ovarian cancer in a humanized ovarian microenvironment. Normal human ovarian tissues were subcutaneously implanted into severe combined immunodeficient (SCID) mice and then the implants were identified by immunohistochemistry. The implants became vascularized and retained their original morphology for about 4 weeks following implantation. Immunohistochemical staining for cytokeratin-7 confirmed the ovarian origin of the epithelial cells. CD34 staining demonstrated human-derived vessels. Positive estrogen receptor and partially-positive progesterone receptor staining indicated the estrogen and progesterone dependence of the implants. Only vascular pericytes expressed α-smooth muscle actin, indicating the normal ovarian origin of the xenografts. Human ovarian tissue successfully survived in SCID mice and retained its original properties. This humanized mouse model may be used as preclinical tool to investigate ovarian cancer.