Small-molecule inhibitor HI-TOPK-032 improves NK-92MI cell infiltration into ovarian tumours.

The effectiveness of natural killer (NK) cells transferred adoptively in combating solid tumours is limited by challenges such as their difficulty in penetrating tumours from the bloodstream and maintaining viability without the support of interleukin-2 (IL-2). Genetically modified NK-92MI cells, which can release IL-2 to sustain their viability, have been identified as a promising alternative. This adaptation addresses the negative consequences of systemic IL-2 administration. The role of PSD-95/discs large/ZO-1 (PDZ)-binding kinase (PBK) in cancer development is recognized, but its effects on immunity are not fully understood. This study explores how PBK expression influences the ability of NK-92MI cells to infiltrate ovarian tumours. Elevated levels of PBK expression have been found in various cancers, including ovarian cancer (OV), with analyses showing higher PBK mRNA levels in tumour tissues compared to normal ones. Immunohistochemistry has confirmed increased PBK expression in OV tissues. Investigations into PBK's role in immune regulation reveal its association with immune cell infiltration, indicating a potentially compromised immune environment in OV with high PBK expression. The small-molecule inhibitor HI-TOPK-032, which inhibits PBK, enhances the cytotoxicity of NK-92MI cells toward OV cells. It increases the production of interferon-γ and tumour necrosis factor-α, reduces apoptosis and encourages cell proliferation. Mechanistic studies showed that contact with OV cells treated with HI-TOPK-032 upregulates CD107a on NK-92 cells. In vivo studies demonstrated that HI-TOPK-032 improves the antitumour effects of NK-92MI cells in OVCAR3Luc xenografts, extending survival without significant side effects. Safety assessments in mice confirm HI-TOPK-032's favourable safety profile, highlighting its potential as a viable antitumour therapy. These results suggest that combining NK-92MI cells with HI-TOPK-032 enhances antitumour effectiveness against OV, indicating a promising, safe and effective treatment strategy that warrants further clinical investigation.

Cyanuric Acid-Assisted Synthesis of Hierarchical Amorphous Carbon Nitride Assembled by Ultrathin Oxygen-Doped Nanosheets for Excellent Photocatalytic Hydrogen Generation.

Amorphous carbon nitride with typical short-range order arrangement as an effective photocatalyst is worth exploring but remains a great challenge because its disordered structure induces severe recombination of photogenerated charge carriers. Herein, for the first time, we demonstrate that a hierarchical amorphous carbon nitride (HACN) with structural oxygen incorporation can be synthesized via a cyanuric acid-assisted melem hydrothermal process, accompanied by freeze-drying and pyrolysis. The complex composed of melem and cyanuric acid exhibiting a unique 3D self-supporting skeleton and significant phase transformation is responsible for the formation of an interconnected hierarchical framework and amorphous structure for HACN. These features are beneficial to enhance its visible light harvesting by the multiple-reflection effect within the architecture consisting of more exposed porous nanosheets and introducing a long band tail absorption. The well-designed morphology, band tail state, and oxygen doping effectively inhibit rapid band-to-band recombination of the photogenerated electrons and holes and facilitate subsequent separation. Accordingly, the HACN catalyst exhibits exceptional visible light (λ > 420 nm)-driven photoreduction for hydrogen production with a rate of 82.4 µmol h-1, which is 21.7 and 9.5 times higher than those of melem-derived carbon nitride and crystalline nanotube carbon nitride counterparts, respectively, and significantly surpasses those of most reported amorphous carbon nitrides. Our controlling of rearrangement of the in situ supramolecular self-assembly of melem oligomer using cyanuric acid directly instructs the development of highly efficient amorphous photocatalysts for converting solar energy into hydrogen fuel.

Unraveling the microbial puzzle: exploring the intricate role of gut microbiota in endometriosis pathogenesis.

Endometriosis (EMs) is a prevalent gynecological disorder characterized by the growth of uterine tissue outside the uterine cavity, causing debilitating symptoms and infertility. Despite its prevalence, the exact mechanisms behind EMs development remain incompletely understood. This article presents a comprehensive overview of the relationship between gut microbiota imbalance and EMs pathogenesis. Recent research indicates that gut microbiota plays a pivotal role in various aspects of EMs, including immune regulation, generation of inflammatory factors, angiopoietin release, hormonal regulation, and endotoxin production. Dysbiosis of gut microbiota can disrupt immune responses, leading to inflammation and impaired immune clearance of endometrial fragments, resulting in the development of endometriotic lesions. The dysregulated microbiota can contribute to the release of lipopolysaccharide (LPS), triggering chronic inflammation and promoting ectopic endometrial adhesion, invasion, and angiogenesis. Furthermore, gut microbiota involvement in estrogen metabolism affects estrogen levels, which are directly related to EMs development. The review also highlights the potential of gut microbiota as a diagnostic tool and therapeutic target for EMs. Interventions such as fecal microbiota transplantation (FMT) and the use of gut microbiota preparations have demonstrated promising effects in reducing EMs symptoms. Despite the progress made, further research is needed to unravel the intricate interactions between gut microbiota and EMs, paving the way for more effective prevention and treatment strategies for this challenging condition.

Immunotherapy for Ovarian Cancer: Disappointing or Promising?

Ovarian cancer, one of the deadliest malignancies, lacks effective treatment, despite advancements in surgical techniques and chemotherapy. Thus, new therapeutic approaches are imperative to improving treatment outcomes. Immunotherapy, which has demonstrated considerable success in managing various cancers, has already found its place in clinical practice. This review aims to provide an overview of ovarian tumor immunotherapy, including its basics, key strategies, and clinical research data supporting its potential. In particular, this discussion highlights promising strategies such as checkpoint inhibitors, vaccines, and pericyte transfer, both individually and in combination. However, the advancement of new immunotherapies necessitates large controlled randomized trials, which will undoubtedly shape the future of ovarian cancer treatment.

Oxygen vacancies induced by lanthanum-doped indium oxide nanofibers for promoted temperature-dependent triethylamine and formaldehyde sensing.

A novel TEA and HCHO dual-function temperature-dependent sensing material (3La-In2O3) with ultra-high sensitivity was developed via a facile electrospinning process. Though rare earth doped in In2O3-based sensors have been widely reported, the low sensitivity, poor selectivity and high operating temperature remain restrict their application. Herein, the In2O3 nanofibers with different contents of La3+ ions are firstly obtained by a facile electrospinning process. The sensing performance investigation confirms that the 3% La/In molar ratio of La3+ doped in In2O3 nanofibers are more appropriate as the sensing material for TEA and HCHO detection. The 3La-In2O3 exhibits greatest response value of 3721.60-10 ppm TEA and 1469.65-10 ppm HCHO at their best working temperature (100 â„ƒ and 160 â„ƒ), approximately 23.85-fold and 10.85-fold higher than that of pristine In2O3 nanofibers. In addition, the excellent selectivity, repeatability, and long-term stability ensure the further application of the 3La-In2O3-based sensor in actual environment. The promoted sensing performance is mainly ascribed to the more oxygen vacancies, the increasing specific surface area, the smaller grain size of In2O3 nanofibers induced by La3+ doping. The DFT results demonstrate the beneficial effect of La and oxygen vacancies on the improved target gas adsorption energy.

Ferroptosis: Mechanism and potential applications in cervical cancer.

Ferroptosis is a distinct form of cell death mechanism different from the traditional ones. Ferroptosis is characterized biochemically by lipid peroxidation, iron accumulation, and glutathione deficiency. It has already demonstrated significant promise in antitumor therapy. Cervical cancer (CC) progression is closely linked to iron regulation and oxidative stress. Existing research has investigated the role of ferroptosis in CC. Ferroptosis could open up a new avenue of research for treating CC. This review will describe the factors and pathways and the research basis of ferroptosis, which is closely related to CC. Furthermore, the review may provide potential future directions for CC research, and we believe that more studies concerning the therapeutic implications of ferroptosis in CC will come to notice.

Prevalence of human papillomavirus DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Human papillomavirus (HPV) DNA and p16INK4a positivity have crucial roles in the pathogenesis of vulvar cancer and vulvar intraepithelial neoplasia. We aimed to examine the pooled prevalence of HPV DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia worldwide. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Library databases for studies published between Jan 1, 1986, and May 6, 2022, that reported the prevalence of HPV DNA, or p16INK4a positivity, or both, in histologically verified vulvar cancer or vulvar intraepithelial neoplasia. Studies on a minimum of five cases were included. Study-level data were extracted from the published studies. Random effect models were used to examine the pooled prevalence of HPV DNA and p16INK4a positivity in both vulvar cancer and vulvar intraepithelial neoplasia, which were further investigated using stratified analyses by histological subtype, geographical region, HPV DNA or p16INK4a detection method, tissue sample type, HPV genotype, publication year, and age at diagnosis. Additionally, meta-regression was applied to explore sources of heterogeneity. FINDINGS: We retrieved 6393 search results, of which 6233 were excluded for being duplicates or after application of our inclusion and exclusion criteria. We also identified two studies from manual searches of references lists. 162 studies were eligible for inclusion in the systematic review and meta-analysis. The prevalence of HPV in vulvar cancer (91 studies; n=8200) was 39·1% (95% CI 35·3-42·9) and in vulvar intraepithelial neoplasia (60 studies; n=3140) was 76·1% (70·7-81·1). The most predominant HPV genotype in vulvar cancer was HPV16 (78·1% [95% CI 73·5-82·3]), followed by HPV33 (7·5% [4·9-10·7]). Similarly, HPV16 (80·8% [95% CI 75·9-85·2]) and HPV33 (6·3% [3·9-9·2]) were also the most two predominant HPV genotypes in vulvar intraepithelial neoplasia. The distribution of type-specific HPV genotypes in vulvar cancer among geographical regions was different, with HPV16 varying between regions, showing a high prevalence in Oceania (89·0% [95% CI 67·6-99·5]) and a low prevalence in South America (54·3% [30·2-77·4]). The prevalence of p16INK4a positivity in patients with vulvar cancer was 34·1% (95% CI 30·9-37·4; 52 studies; n=6352), and it was 65·7% (52·5-77·7; 23 studies; n=896) in patients with vulvar intraepithelial neoplasia. Furthermore, among patients with HPV-positive vulvar cancer, p16INK4a positivity prevalence was 73·3% (95% CI 64·7-81·2), compared with 13·8% (10·0-18·1) in HPV-negative vulvar cancer. The prevalence of double positivity for HPV and p16INK4a was 19·6% (95% CI 16·3-23·0) in vulvar cancer and 44·2% (26·3-62·8) in vulvar intraepithelial neoplasia. Most analyses had large heterogeneity (I2>75%). INTERPRETATION: The high prevalence of HPV16 and HPV33 in vulvar cancer and vulvar intraepithelial neoplasia emphasised the importance of nine-valent HPV vaccination in preventing vulvar neoplasm. Additionally, this study highlighted the potential clinical significance of double positivity for HPV DNA and p16INK4a in vulvar neoplasm. FUNDING: Taishan Scholar Youth Project of Shandong Province, China.

Association between dietary inflammatory index and risk of endometriosis: A population-based analysis.

Background and aims: Chronic inflammation plays a significant role in the etiology of endometriosis, which might be affected by dietary intake. This study aimed to investigate the association between dietary inflammatory index (DII) and the risk of endometriosis. Methods: A cross-sectional analysis using data from the National Health and Nutrition Examination Survey (1999-2006) was conducted on 3,410 American participants, among whom 265 reported a diagnosis of endometriosis. DII scores were calculated based on the dietary questionnaire. The association of DII scores with endometriosis was evaluated by adjusted multivariate logistic regression analyzes, which were further investigated in the subgroups. Results: In the fully adjusted models, the odds ratio (OR) for endometriosis participants in the highest and middle tertiles of DII scores were 1.57 [95% confidence interval (CI): 1.14-2.17] and 1.18 (95% CI: 0.84-1.65), compared to the lowest tertile (P trend = 0.007). In subgroup analyzes, the significant positive association between DII scores and the endometriosis risk was also observed in non-obese women (ORtertile3vs1: 1.69, 95% CI: 1.12-2.55; P trend = 0.012), women without diabetes (ORtertile3vs1: 1.62, 95% CI: 1.16-2.27; P trend = 0.005), women with hypertension (ORtertile3vs1: 2.25, 95% CI: 1.31-3.87; P trend = 0.003), parous women (ORtertile3vs1: 1.55, 95% CI: 1.11-2.17; P trend = 0.011), and women using oral contraceptives (ORtertile3vs1: 1.63, 95% CI: 1.15-2.30; P trend = 0.006). Conclusion: This nationally representative study found that increased intake of the pro-inflammatory diet, as a higher DII score, was positively associated with endometriosis risk among American adults. Our results suggested anti-inflammatory dietary interventions may be promising in the prevention of endometriosis. Further prospective studies are necessary to confirm these findings.

Risk stratification and molecular heterogeneity of endometrial cancer and expression profile of TIM-3: A retrospective cohort study.

OBJECTIVE: The present study aimed to implement ProMisE classification and risk grouping on a retrospective cohort of 628 patients with endometrial cancer (EC) and determine the molecular heterogeneity across subtypes and subgroups, as well as to investigate the potential beneficiary for TIM-3 checkpoint inhibition in ECs. METHODS: Protein expressions of p53, MMR, TIM-3 and CD8 were measured by immunohistochemistry, and massively parallel sequencing was conducted for 128 cancer-related genes. Patients were categorized into four ProMisE subtypes: MMR-deficient (MMRd), POLE-ultramutated (POLEmut), p53-wild type (p53wt), and p53-abnormal (p53abn), and were subjected to risk classification. RESULTS: 43 (6.9%) patients belonged to POLEmut, 118 (18.8%) to MMRd, 69 (11%) to p53abn, and 398 (63.3%) to p53wt. Compared to the 2016 stratification system, the 2021 ESGO/ESTRO/ESP risk stratification integrated with molecular classification revealed that 11 patients (11/628, 1.8%) were upgraded due to the p53abn signature, whereas 23 patients (23/628, 3.7%) were downgraded due to the POLEmut signature. JAK1 and RAD50 mutations showed higher frequencies in patients with aggressive phenotypes. RAD51B mutation was significantly related to poor RFS of the p53wt subtype but not of the other three molecular subgroups. TIM-3 expression was detected in 30.9% immune cells (ICs) and 29.0% tumor cells (TCs) in ECs, respectively. It was frequently expressed in POLEmut and MMRd ECs as compared to that in the other two molecular subtypes in TCs and ICs. CONCLUSIONS: Our study revealed the molecular heterogeneity across subtypes and subgroups. The new risk stratification system changed the risk grouping of some patients due to the integration of molecular features. RAD51B mutation can further stratify the recurrence risk in the p53wt subtype. Patients with MMRd or POLEmut may benefit most from immunotherapy against TIM-3.

A targetable MYBL2-ATAD2 axis governs cell proliferation in ovarian cancer.

The chromatin-modifying enzyme ATAD2 confers oncogenic competence and proliferative advantage in malignances. We previously identified ATAD2 as a marker and driver of cell proliferation in ovarian cancer (OC); however, the mechanisms whereby ATAD2 is regulated and involved in cell proliferation are still unclear. Here, we disclose that ATAD2 displays a classical G2/M gene signature, functioning to facilitate mitotic progression. ATAD2 ablation caused mitotic arrest and decreased the ability of OC cells to pass through nocodazole-arrested mitosis. ChIP-seq data analyses demonstrated that DREAM and MYBL2-MuvB (MMB), two switchable MuvB-based complexes, bind the CHR elements in the ATAD2 promoter, representing a typical feature and principle mechanism of the periodic regulation of G2/M genes. As a downstream target of MYBL2, ATAD2 deletion significantly impaired MYBL2-driven cell proliferation. Intriguingly, ATAD2 silencing also fed back to destabilize the MYBL2 protein. The significant coexpression of MYBL2 and ATAD2 at both the bulk tissue and single-cell levels highlights the existence of the MYBL2-ATAD2 signaling in OC patients. This signaling is activated during tumorigenesis and correlated with TP53 mutation, and its hyperactivation was found especially in high-grade serous and drug-resistant OCs. Disrupting this signaling by CRISPR/Cas9-mediated ATAD2 ablation inhibited the in vivo growth of OC in a subcutaneous tumor xenograft mouse model, while pharmacologically targeting this signaling with an ATAD2 inhibitor demonstrated high therapeutic efficacy in both drug-sensitive and drug-resistant OC cells. Collectively, we identified a novel MYBL2-ATAD2 proliferative signaling axis and highlighted its potential application in developing new therapeutic strategies, especially for high-grade serous and drug-resistant OCs.

Ferroptosis induced by iron overload promotes fibrosis in ovarian endometriosis and is related to subpopulations of endometrial stromal cells.

Endometriosis (EMs) is defined as the presence of tissue somewhat resembling endometrial glands and stroma outside the uterus; the retrograded endometrium grows in the peritoneal cavity and elicits fibrosis. Ferroptosis is a recently discovered form of programmed cell death, which is iron-dependent. The induction of ferroptosis has been found to participate in fibrosis. However, the relationship between EMs fibrosis and ferroptosis remains unknown. In this study, we confirmed that the iron content in ectopic stromal tissue in ovarian EMs is significantly increased. We explored the role of iron-induced ferroptosis in the pathogenesis of ovarian EMs fibrosis for the first time. We found that ferroptosis in ectopic tissues was significantly enhanced than that in eutopic tissues. Furthermore, we performed in vivo drug screening and found that ferroptosis induced by ferric ammonium citrate (FAC) could aggravate fibrosis. To clarify the mechanism of this process, the stromal composition of human uterine endometrium and endometrial tissue was characterized. Fibroblast-specific protein-1 was used for fibroblasts, smooth muscle actin alpha for myofibroblasts, and platelet-derived growth factor receptor beta (CD140b) for mesenchymal stromal cells (MSCs). The results demonstrated that the percentage of myofibroblasts was higher and the portion of MSCs was lower in ectopic endometrial stroma than those in eutopic endometrium. Moreover, the proportion of MSCs decreased significantly and the percentage of myofibroblasts increased considerably after FAC treatment in vitro. However, disruption of intracellular iron levels or ferroptosis via chelation of intracellular iron deferoxamine mesylate or ferroptosis inhibitor ferrostatin-1 could reverse this process, indicating that iron-induced ferroptosis plays a vital role in ovarian EMs fibrosis. Considering that iron accumulation can feed the Fenton reaction to generate unquenchable amounts of free radicals, causing ferroptosis and tissue damage and thereby contributing to fibrosis, we validated the underlying mechanism that excess iron can facilitate fibrotic responses. Collectively, these data provide evidence that supernumerary iron is a key regulator in promoting MSCs ferroptosis and inducing ovarian EMs fibrosis.

Analysis of the immune checkpoint lymphocyte activation gene-3 (LAG-3) in endometrial cancer: An emerging target for immunotherapy.

BACKGROUND: Lymphocyte activation gene-3 (LAG-3) is a novel molecule that participates in the immune escape of tumor cells and is a target for immunotherapy. However, the expression of LAG-3 in patients with endometrial cancer (EC) has not been comprehensively characterized. OBJECTIVES: We elucidated the expression of LAG-3 and investigated its correlation with clinicopathological parameters, ProMisE subtypes, CD8+ T-cell infiltration and relapse-free survival (RFS) in a retrospective cohort of 421 patients with endometrial cancer. METHODS: Next-generation sequencing of the polymerase epsilon (POLE) and immunohistochemistry of mismatch repair (MMR)-related protein (MLH1, PMS2, MSH2, and MSH6), p53, CD8 and LAG-3 protein in whole sections were performed. RESULTS: Positive LAG-3 was detected in tumor cells (TCs) and immune cells (ICs) in 31.6% (133/421) and 24.0% (101/421) of the patients, respectively. LAG-3 positivity in ICs was more common in high-grade, high-intermediate risk, high-risk, and advanced/metastatic subgroups and was relevant to lymphovascular space invasion, while that in TCs was more common in older individuals (≥54 years). LAG-3 expression was more prevalent in POLE ultramutated (POLEmut) and MMR-deficient (MMRd) EC than in p53-abnormal (p53abn) and p53-wild (p53wt) EC in TCs (34.4 % and 66.3% in POLEmut and MMRd versus 28.6% and 19.5% in p53abn and p53wt, P < 0.001) and ICs (78.1 % and 65.1% in POLEmut and MMRd versus 2.9% and 5.2% in p53abn and p53wt, P < 0.001). Positive expression of LAG-3 in TCs and ICs was associated with high levels of tumor-associated CD8+ T-cell immune infiltration. Additionally, LAG-3 positivity in TCs was related to improved RFS. CONCLUSIONS: This study suggests that immunotherapy targeting LAG-3 may play a role in EC patients with POLEmut or MMRd molecular markers. Positive LAG-3 expression in TCs may be a predictor of improved RFS.

The fetal outcomes after neoadjuvant platinum and paclitaxel chemotherapy during pregnancy: analysis of three cases and review of the literature.

OBJECTIVE: Data on the outcomes of fetus who are exposed to neoadjuvant platinum and paclitaxel chemotherapy during pregnancy are lacking. METHODS: Relevant data were abstracted from patients in our institution, PubMed, Embase and Cochrane Library databases. The primary assessment was the frequency of fetal death and congenital abnormalities. The secondary assessment was other negative fetal/infant outcomes including FGR, RDS, secondary malignant diseases and other recorded adverse events. RESULTS: Of the three infants in our center who exposed to platinum and paclitaxel chemotherapy during pregnancy, the physical evaluation and qualified Denver Developmental Screening Test showed normal findings at the last follow-up (19-24 months). Hearing evaluation among three children also showed normal findings. Another 34 infants (including a twins) of 21 studies in previous studies who exposed to platinum and paclitaxel chemotherapy during pregnancy were included in the final analysis. Of the 37 infants identified, 24 were exposed to cisplatin plus paclitaxel, and 13 were exposed to carboplatin plus paclitaxel. None of the 37 fetuses was abortion or dead during the pregnancy. 97.3% (36/37) infants were delivered by cesareans and the median gestational ages of delivery were 34.76 weeks (95% CI, 34.08-35.44). 1 fetus showed intrauterine growth restriction and one was found with left-sided ventriculomegaly and hydramnios before chemotherapy. Adverse events occurred in 18.9% (7/37) infants at birth, including two RDS, one hearing loss, one pathological jaundice, one first-degree intraventricular hemorrhage, one erythema, one corresponding to -0.5 standard deviation from average body weight of the same gestational weeks. No reports of neonatal cardiologic abnormalities are reported in these infants after the initiating of chemotherapy. The infant with congenital anomaly died 5 days after birth. During the follow-up, 5.4% (2/37) of the infants were diagnosed with malignant diseases. One retroperitoneal embryonal rhabdomyosarcoma at 5 years old and one acute myeloid leukemia at 22 months of age. 32/37 (86.5%) children were healthy at the end of follow-ups (median 33 months, IQR 15.75-54.25 months). CONCLUSIONS: Our results showed that neoadjuvant platinum and paclitaxel combined chemotherapy was a feasible and safe choice for the management of patients with cervical and ovarian cancer during the second and third trimesters of gestation.

Design and Simulation of Flexible Underwater Acoustic Sensor Based on 3D Buckling Structure.

The exploration of marine resources has become an essential part of the development of marine strategies of various countries. MEMS vector hydrophone has great application value in the exploration of marine resources. However, existing MEMS vector hydrophones have a narrow frequency bandwidth and are based on rigid substrates, which are not easy to be bent in the array of underwater robots. This paper introduces a new type of flexible buckling crossbeam-cilium flexible MEMS vector hydrophone, arranged on a curved surface by a flexible substrate. A hydrophone model in the fluid domain was established by COMSOL Multiphysics software. A flexible hydrophone with a bandwidth of 20~4992 Hz, a sensitivity of -193.7 dB, excellent "8" character directivity, and a depth of concave point of 41.5 dB was obtained through structured data optimization. This study plays a guiding role in the manufacture and application of flexible hydrophones and sheds light on a new way of marine exploration.

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.

Batch Transfer Printing of Small-Size Silicon Nano-Films with Flat Stamp.

Silicon nano-film is essential for the rapidly developing fields of nanoscience and flexible electronics, due to its compatibility with the CMOS process. Viscoelastic PDMS material can adhere to Si, SiO2, and other materials via intermolecular force and play a key role in flexible electronic devices. Researchers have studied many methods of transfer printing silicon nano-films based on PDMS stamps with pyramid microstructures. However, only large-scale transfer printing processes of silicon nano-films with line widths above 20 µm have been reported, mainly because the distribution of pyramid microstructures proposes a request on the size of silicon nano-films. In this paper, The PDMS base to the curing agent ratio affects the adhesion to silicon and enables the transfer, without the need for secondary alignment photolithography, and a flat stamp has been used during the transfer printing, with no requirement for the attaching pressure and detaching speed. Transfer printing of 20 µm wide structures has been realized, while the success rate is 99.3%. The progress is promising in the development of miniature flexible sensors, especially flexible hydrophone.

Real-World Study of Cisplatin, Etoposide, and Bleomycin Chemotherapy Regimen in Gestational Trophoblastic Neoplasia.

OBJECTIVE: Little observational data exist regarding the use of cisplatin, etoposide, and bleomycin (BEP) chemotherapy regimen in patients with gestational trophoblastic neoplasia (GTN). METHODS: This is a retrospective study of 95 patients with GTN in our center from June/2010 to June/2018. All patients received at least 2 cycles of BEP chemotherapy. The primary outcomes were the rate of complete remission (CR) and overall survival (OS). The secondary outcomes were disease-free survival (DFS), pregnancy rates after BEP exposure, drug resistance rate, and other adverse events. RESULTS: Of the 95 patients included, 66 (69.5%) patients received BEP as primary treatment and 29 (30.5%) were Salvage chemotherapy. The median age at diagnosis was 37 years (range 29.75-46) and 34 years (range 27-40) in two groups, respectively. The median WHO prognostic scores were 6 (range 3.5-8), and 77.32% of patients were FIGO stage III-IV in the primary treatment group. The median WHO prognostic scores were 5 (range 3-9), and 66.55% of patients were FIGO stage III-IV in the salvage treatment group. Median cycles of BEP treatment were 4 (3, 5) and 3 (2, 4) in two groups, respectively. In the primary chemotherapy group, 18.2% received additional hysterectomy, 4.5% received UAE for vaginal bleeding, and 1.52% received whole-brain radiotherapy. In the salvage chemotherapy group, 20.7% received hysterectomy, 6.9% received lobectomy, 3.4% received hysteroscopic lesion resection, and 3.4% received whole-brain radiotherapy. CR rates to initial chemotherapy were 86.4%, including 87.9% in the primary chemotherapy group and 82.8% in the salvage chemotherapy group. No predictive factor of chemotherapy resistance was identified. The rate of 5 year-DFS was 96.52% (95% CI 86.78-99.12) in the primary chemotherapy group and 92.44% (95% CI 73.02-98.06) in the salvage chemotherapy group. The rate of 5 year-OS was 98.31% (95% CI 88.57-99.76) and 95.65% (95% CI 79.93-99.38) in the two groups, respectively. During the treatment, neutropenia, thrombocytopenia, anemia, and liver dysfunction occurred in 80.3%, 6.1%, 25.8%, and 50% primary chemotherapy patients and 82.8%, 31%, 10.3%, and 86.2% salvage chemotherapy patients. In patients with fertility requirements, live birth rates were 100% (10/10) in primary chemotherapy patients and 80% (4/5) in salvage chemotherapy patients. CONCLUSIONS: BEP regimen was effective in the treatment of GTINs. The treatment was well tolerated, with no safety concerns on patients' fertility.

MiR-29c downregulates tumor-expressed B7-H3 to mediate the antitumor NK-cell functions in ovarian cancer.

OBJECTIVE: B7-H3 is a member of the B7 family of immune checkpoint molecule. Although B7-H3 has been shown to regulate T cell-mediated peripheral immune response, whether it also correlated with NK cell exhaustion in ovarian cancer remains unclear. The purpose of this study was to explore the mechanism of B7-H3 regulating NK-cell proliferation and function. MATERIAL AND METHODS: To investigate the relationship between B7-H3 expression and the NK-cell function in ovarian cancer, human ovarian tumor tissues and cell lines were first examined the protein and mRNA expression of B7-H3 by quantitative real-time PCR (qRT-PCR), Immunohistochemistry and Western-blot assays. Then we established B7-H3 knockout cell lines and measured the cytotoxicity of NK cells on these cells by LDH release assay and Flow Cytometry. In addition, we analyzed B7-H3 in the regulation of glycolysis and glycolysis-related proteins by Glycolysis Stress Test, Glucose Consumption Assay and Western-blot. Moreover, luciferase reporter assay was used to confirm the directly regulation of miR-29c to B7-H3. Finally, we carried out in vivo experiments. RESULTS: We observed that tumor-expressed B7-H3 inhibits NK-cell function in vitro and in vivo, and is associated with glycolysis of ovarian cancer cell. Therapeutically, B7-H3 blockade prolonged the survival of SKOV3 tumor-bearing mice. In addition, miR-29c improved the anti-tumor efficacy of NK-cell by directly targeting B7-H3 in vitro were observed, but not in vivo. CONCLUSION: Our results demonstrate that miR-29c downregulates B7-H3 to inhibit NK-cell exhaustion and associated with glycolysis, which suggest that NK cells may be a new target of anti-B7-H3 therapy in ovarian cancer patients.

Down-regulation of Exosomal miR-214-3p Targeting CCN2 Contributes to Endometriosis Fibrosis and the Role of Exosomes in the Horizontal Transfer of miR-214-3p.

Endometriosis (EMs) is defined as the presence of tissue which somewhat resembles endometrial glands and stroma outside the uterus, and elicits fibrosis. Fibrosis is the main factor resulting in pain and infertility, while the aetiology of endometrial fibrosis is unknown. There is strong evidence from numerous experiments showing that connective tissue growth factor (CCN2) plays a central role in fibrogenesis. Exosomal miR-214-3p can regulate the expression of CCN2 through binding to complementary sites in the 3' untranslated region. This study aimed to explore the role of exosomal miR-214-3p in endometriosis fibrosis and the relationship between CCN2 and miR-214-3p in endometriosis fibrosis. Our results demonstrated that miR-214-3p was significantly down-regulated and CCN2 was up-regulated in EMs ectopic lesion and stromal cells compared with EMs eutopic and endometrium of patients without endometriosis. Exosomal miR-214-3p can inhibit fibrosis in EMs through targeting CCN2. The results were explored and verified in vitro and in vivo, respectively. Cell co-culture was used to explore the contributions of exosomes to intercellular information transmission of miR-214-3p. The results showed that exosomes play a pivotal role in the transportation of miR-214-3p between cells. Furthermore, level of exosomal miR-214-3p in endometriosis patients' serum was lower than that in patients without endometriosis. In conclusion, exosomal miR-214-3p can inhibit fibrosis in EMs by targeting CCN2. MiR-214-3p may be considered as a bio-marker and has a potential therapeutic effect in EMs.