Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses.

Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered. Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53fl/flLSL-KrasG12D, Ccr7-/-, Cd93-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed. Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93. Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.

Effect of the smartphone application on caesarean section in women with overweight and obesity: a randomized controlled trial in China.

BACKGROUND: The rate of caesarean section (CS) is increasing worldwide. While a CS can be life-saving when medically indicated, it can cause adverse health effects for both women and children. This trial aims to evaluate the effect of the smartphone application, which aims to control the gestational weight gain, on the rate of CS in overweight and obese women. METHODS: Overweight and obese primiparas (BMI ≥ 24 kg/m2) with age between 20 and 40 years old were recruited at Beijing Obstetrics and Gynecology Hospital, and randomly assigned into the intervention group (143 cases) and the control group (138 cases). The intervention group applied the smartphone application (App) to control gestational weight gain in addition to the usual care, and the control group received the usual care. Primary outcome was cesarean section (CS) rate. Secondary outcomes included gestational hypertension, preeclampsia and eclampsia, gestational diabetes mellitus, postpartum hemorrhage, neonatal asphyxia, and macrosomia. RESULTS: There was a significant difference in CS rate, with 53.3% in the intervention group and 65.4% in the control group (P = 0.044). The difference still exists in the overweight subgroup (32.6% vs. 55.6%, P = 0.04), but disappears in the obesity subgroup (63.0% vs. 69.1%, P = 0.381). The median of gestational weight gain (GWG) of the intervention group is 8.5 kg (IQR 5.5, 11.0), which is significantly less than that of the control group (median 10.0 kg, IQR [6.0, 14.0], P = 0.008). The intervention group has significantly lower rate of postpartum hemorrhage (5.19%) than the control group (12%) (P = 0.045). There were no significant differences between the groups in gestational hypertension, gestational diabetes mellitus, neonatal asphyxia, and macrosomia. CONCLUSION: The smartphone assisted weight control may help reduce CS rate. The effects of the smartphone application might be via the management of gestational weight gain. TRAIL REGISTRATION: This trial was registered at Chinese Clinical Trial Registry. Registration number is ChiCTR2300068845 (retrospectively registered, 01/03/2023).

Evaluating the application of the 2009 Institute of Medicine gestational weight gain guidelines on pregnant Chinese women.

BACKGROUND: The 2009 Institute of Medicine (IOM) gestational weight gain (GWG) guidelines were initially developed for pregnant women in the United States. OBJECTIVE: This study aimed to investigate whether the IOM guidelines were suitable for pregnant Chinese women. METHODS: A retrospective cohort study comprising 20,593 singleton pregnant women was conducted at the Beijing Obstetrics and Gynaecology Hospital (1 January 2018 to 31 December 2019). Applicability was evaluated by comparing the GWG corresponding to the lowest point of the predicted composite risk curve with the 2009 IOM GWG Guidelines. The IOM Guidelines serve as the standard for the GWG categories and the pre-pregnancy body mass index. An exponential function model was used to fit the weight gain during pregnancy and the probability of caesarean section, preterm birth, small for gestational age, and large for gestational age. A quadratic function model was used to fit the combined probability of the above-mentioned adverse pregnancy outcomes. The applicability of the IOM guidelines was evaluated by comparing the weights corresponding to the lowest predicted probability with the GWG range recommended by the IOM guidelines. RESULTS: According to the 2009 IOM GWG Guidelines, 43% of the women achieved adequate weight, almost 32% gained excessive weight, and 25% gained inadequate weight. The GWG range proposed by the IOM included the lowest predicted probability value for underweight women and exceeded the lowest predicted probability for normal weight, overweight, and obese women. CONCLUSIONS: The 2009 IOM guidelines were suitable for Chinese women whose pre-pregnancy body mass index was classified as underweight. The guidelines were not suitable for normal, overweight, or obese pre-pregnancy body mass index classifications. Therefore, based on the above evidence, the 2009 IOM guidelines are not suitable for all Chinese women.

Comprehensive analysis to identify the influences of SARS-CoV-2 infections to inflammatory bowel disease.

Background: Coronavirus disease 2019 (COVID-19) and inflammatory bowel disease (IBD) are both caused by a disordered immune response and have direct and profound impacts on health care services. In this study, we implemented transcriptomic and single-cell analysis to detect common molecular and cellular intersections between COVID-19 and IBD that help understand the linkage of COVID-19 to the IBD patients. Methods: Four RNA-sequencing datasets (GSE147507, GSE126124, GSE9686 and GSE36807) from Gene Expression Omnibus (GEO) database are extracted to detect mutual differentially expressed genes (DEGs) for IBD patients with the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to find shared pathways, candidate drugs, hub genes and regulatory networks. Two single-cell RNA sequencing (scRNA-eq) datasets (GSE150728, PRJCA003980) are used to analyze the immune characteristics of hub genes and the proportion of immune cell types, so as to find common immune responses between COVID-19 and IBD. Results: A total of 121 common DEGs were identified among four RNA-seq datasets, and were all involved in the functional enrichment analysis related to inflammation and immune response. Transcription factors-DEGs interactions, miRNAs-DEGs coregulatory networks, and protein-drug interactions were identified based on these datasets. Protein-protein interactions (PPIs) was built and 59 hub genes were identified. Moreover, scRNA-seq of peripheral blood monocyte cells (PBMCs) from COVID-19 patients revealed a significant increase in the proportion of CD14+ monocytes, in which 38 of 59 hub genes were highly enriched. These genes, encoding inflammatory cytokines, were also highly expressed in inflammatory macrophages (IMacrophage) of intestinal tissues of IBD patients. Conclusions: We conclude that COVID-19 may promote the progression of IBD through cytokine storms. The candidate drugs and DEGs-regulated networks may suggest effective therapeutic methods for both COVID-19 and IBD.

Hierarchical 2D-1D micelles self-assembled from the heterogeneous seeded-growth of rod-coil block copolymers.

Precise control of size and dimension is the key to constructing complex hierarchical nanostructures, particularly multi-dimensional hybrid nanoassemblies. Herein, we conducted Brownian dynamics simulations to examine the seeded-growth of rod-coil block copolymer assemblies and discovered that 2D-1D (disk-cylinder) hybrid micelles could be formed via liquid-crystallization-driven self-assembly (LCDSA). 2D nanodisk micelles with smectic-like LC cores served as seeds. After adding rod-coil block copolymers into the seed solution, the copolymers incorporated onto the 2D seed edges to generate junction points. Several cylindrical arms were formed from the elongation of junction points, resulting in 2D-1D multi-dimensional hybrid micelles. The structural transition of the micelle core from smectic-like (disk) to cholesteric-like (cylindrical arms) LC packing manners benefit from the fluidity of LC. Such a seeded-growth behavior simultaneously exhibits the features of heterogeneous nucleation and homogenous epitaxy growth. Intriguingly, the arms generate in sequence, and its junction position is in the para-position first, followed by ortho-position or meta-position, resembling the difference in the substituent activities on the benzene ring. These theoretical findings are consistent with experimental results, and provide explanations to some unaddressed issues in experiments. The obtained results also reveal that the hybrid micelles are a good stabilizer due to their high surface area and distinctive suspension behaviors.

Labor induction in term gravidas with prelabor rupture of membranes and unfavorable cervixes: Oxytocin versus vaginal misoprostol.

OBJECTIVE: To compare maternal and neonatal outcomes between oxytocin and vaginal misoprostol induction in women with term prelabor rupture of membranes (PROM) and unfavorable cervixes. METHODS: In this retrospective study, 589 pregnant women with term singleton fetuses in cephalic presentation, reactive nonstress tests, PROM of 2-24 h duration, Bishop score <6, and no previous uterine surgery were reviewed and divided into oxytocin (n = 301) and misoprostol (n = 288) groups. The primary outcomes were the rate of vaginal delivery and delivery within 24 h. RESULTS: After 24 h of induction, the misoprostol group showed a significantly higher proportion of vaginal delivery (64.6% vs. 49.5%, P < 0.001) and a lower cesarean section delivery rate (11.5% vs. 25.2%, P < 0.001) than the oxytocin group. More primiparas in the misoprostol group achieved vaginal delivery within 24 h than in the oxytocin group (60.5% vs. 45.4%, P = 0.001). Among primiparas, the misoprostol group had a significantly lower cesarean delivery rate (12.6% vs. 27.5%, P < 0.001). CONCLUSION: Vaginal misoprostol induction in term PROM gravidas with unfavorable cervixes was associated with lower cesarean section and higher vaginal delivery rates within 24 h than oxytocin infusion. Vaginal misoprostol and oxytocin infusion had similar maternal and neonatal outcomes.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1+ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.

Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-ß degradation.

TGF-ß is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-ß can greatly enhance antitumor immunity. However, there are still no effective TGF-ß inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-ß, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-ß at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-ß to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-ß at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-ß. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-ß regulation and implicate UDCA as a potential TGF-ß inhibitor to enhance antitumor immunity.

2D Liquid-Crystallization-Driven Self-Assembly of Rod-Coil Block Copolymers: Living Growth and Self-Similarity.

Liquid-crystallization-driven self-assembly (LCDSA) is an emerging methodology, which has been employed to construct controllable 1D nanostructures. However, 2D nanostructures via living LCDSA are rarely reported, and the complicated growth kinetics are not well-known. Herein, we perform Brownian dynamics (BD) simulations to investigate the 2D living growth of disklike micelles via LCDSA of rod-coil block copolymers. The 2D seeded-growth behavior is achieved by incorporating the unimers onto the edges of disklike seeds with smectic-like liquid-crystalline (LC) cores. The fluidity of such LC-like micellar cores is conducive to the chain adjustments of rod blocks during the 2D living growth process. The apparent growth rate and unique self-similarity kinetics are governed by the interplay between the variations in the growth rate coefficient and the reactive sites at the micelle edges. This work provides an in-depth understanding of the 2D living growth of micelles and guidance to construct well-defined 2D hierarchical nanostructures.

The Effects of Urban Neighborhood Environmental Evaluation and Health Service Facilities on Residents' Self-Rated Physical and Mental Health: A Comparative and Empirical Survey.

(1) Background: The neighborhood environment has been shown to be an essential factor affecting residents' quality of life and health, but the relationship between the characteristics of health service facilities and health levels is rarely known. (2) Methods: This study used a representative sample (n = 591, 303 women; 288 men, age 18-85 years, lived in Chengdu for an extensive time) of residents living in Chengdu City, China, and took spatial point data and empirical research data to construct an ordered logistic regression model. We contrastively analyzed the influence of different variables in the neighborhood environment and health service facilities on self-rated physical health (SRPH) and self-rated mental health (SRMH). (3) Results: The frequency of use and accessibility of multiple facilities in the health service facilities were significantly associated with self-rated health (SRH). Significant differences occurred between residents' perceived accessibility and actual accessibility of facilities in SRH. Comparing the results of SRPH and SRMH revealed that the influencing factors that affect the two vary. The factors that significantly affect SRMH include neighborhood physical environment evaluation; social environmental evaluation; the frequency of use of the parks and squares, and sports zones; and the accessibility of parks and squares, specialized hospitals, community hospitals, and pharmacies. However, the factors that significantly affect SRPH include the frequency of use of sports venues, general hospitals, and pharmacies and the accessibility of general hospitals. The social environment of the neighborhood is also a non-negligible part, and its interaction with the physical environment of the neighborhood affects the outcome of SRH. (4) Conclusions: Neighborhood environmental characteristics and the layout of health service facilities have significant differential effects on people's physical and psychological health, and this information is of great value in promoting healthy city development and improving the quality of life of urban populations around the world.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastasis from breast cancer: a preliminary report of 4 cases.

BACKGROUND: Breast cancer (BC) has the highest morbidity and the fifth-highest mortality rate among women in China. Peritoneal metastases from BC are rare, and presently, there are no guidelines or international consensus on its treatment. Patients with a prognosis of peritoneal carcinomatosis (PC) have poorer survival rates than patients with other regional metastases from BC. METHODS: Four BC PC patients, who had undergone cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), participated in this study. Clinicopathologic characteristics and overall survival (OS) data were collected and analyzed. RESULTS: Patients' average age when they underwent CRS + HIPEC was 59.8 years. The average time of CRS + HIPEC was 8.8 h. The median number of resected organ areas was 7. Following CRS + HIPEC, each of the 4 patients survived for 31, 28, 16 and 52 months, respectively. There were no serious adverse events during the perioperative period. CONCLUSIONS: The study examined the detailed process of CRS + HIPEC and found that patients with BC PC may benefit from this treatment. The 4 cases provided evidence that the integrated therapy of CRS + HIPEC is a promising strategy that could improve outcomes for BC PC patients. Further, no serious adverse events (SAEs) occurred during the CRS + HIPEC perioperative period.

Placenta percreta after Strassman metroplasty of complete bicornuate uterus: a case report.

BACKGROUND: A bicornuate uterus often results in infertility. While reconstructive procedures may facilitate pregnancy, spontaneous abortion or serious pregnancy complications may occur. We present a case of a bicornuate uterus with spontaneous conception after Strassman metroplasty; however, life-threatening complications during pregnancy occurred. CASE PRESENTATION: A 38-year-old woman with a history of infertility presented for prenatal care at 6 weeks of gestation. She had conceived spontaneously after four failed in vitro fertilization and embryo transfer (IVF-ET) procedures, Strassman metroplasty for a complete bicornuate uterus, and two postoperative IVF-ET pregnancies that ended in embryo arrest. This pregnancy was uneventful until the patient presented with massive vaginal bleeding at 28 weeks of gestation and was diagnosed with placenta previa and placenta percreta. Bleeding was controlled after emergency Caesarean section and delivery of a healthy neonate. However, severe adhesions were noted as well as a rupture along the metroplasty scar. Two days later, on removal of the intrauterine gauze packing, severe hemorrhage resumed, and the uterus did not respond to oxytocin, hemabate, or carbetocin. Emergency hysterectomy was required. CONCLUSIONS: Reconstructive surgical procedures for complete bicornuate uterus may allow patients to achieve spontaneous pregnancies. However, potential intrapartum complications include placenta implantation and postpartum hemorrhage, and the latter may be exacerbated as the uterus does not contract or respond to oxytocin or prostaglandin drugs. Patients should be counseled on the risks associated with pregnancy after Strassman metroplasty, and clinicians must be aware of potential severe complications.

Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have brought impressive clinical benefits in a variety of malignancies over the past years, which dramatically revolutionized the cancer treatment paradigm. Monotherapy or in combination with chemotherapy of ICIs targeting programmed death 1/programmed death ligand 1 (PD-L1) has emerged as an alternative treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, constrained by primary or acquired resistance, most patients obtain limited benefits from ICIs and occasionally suffer from severe immune-related adverse events. Moreover, owing to the complexity of the tumor microenvironment and the technical limitations, clinical application of PD-L1 and tumor mutation burden as biomarkers shows many deficiencies. Thus, additional predictive biomarkers are required to further advance the precision of proper patient selection, avoiding the exposure of potential non-responders to unnecessary immunotoxicity. Nowadays, an increasing number of investigations are focusing on peripheral blood as a noninvasive alternative to tissue biopsy in predicting and monitoring treatment outcomes. Herein, we summarize the emerging blood-based biomarkers that could predict the clinical response to checkpoint immunotherapy, specifically in patients with NSCLC.

LncRNA DLX6-AS1 aggravates the development of ovarian cancer via modulating FHL2 by sponging miR-195-5p.

BACKGROUND: Ovarian cancer (OC) is a huge burden on women's lives. Recently, the implication of long non-coding RNAs (lncRNAs) in cancers, including OC, has aroused much attention. The objective of this study was to explore the role and functional mechanism of lncRNA distal-less homeobox 6 antisense 1 (DLX6-AS1) in OC. METHODS: The expression of DLX6-AS1, miR-195-5p, and four and a half LIM domains protein 2 (FHL2) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The cell proliferation, apoptosis, migration, and invasion were assessed by cell count kit 8 (CCK-8), flow cytometry and transwell assays, respectively. The protein levels of proliferating cell nuclear antigen (PCNA), cleaved-caspase-3 (C-caspase 3), N-cadherin, Vimentin, E-cadherin and FHL2 were quantified by western blot. The relationship between miR-195-5p and DLX6-AS1 or FHL2 was predicted by bioinformatics tool starBase and verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft tumor model was established to observe the role of DLX6-AS1 in vivo. RESULTS: DLX6-AS1 and FHL2 were up-regulated in OC tissues and cells, while miR-195-5p was down-regulated. DLX6-AS1 knockdown inhibited proliferation, migration, and invasion but induced apoptosis of OC cells. However, miR-195-5p inhibition reversed these effects. Overexpression of miR-195-5p also depleted proliferation, migration, and invasion but promoted apoptosis of OC cells, while FHL2 overexpression overturned these influences. DLX6-AS1 knockdown blocked tumor growth in vivo. CONCLUSION: DLX6-AS1, as an oncogene in OC, accelerated tumor progression by up-regulating FHL2 via mediating miR-195-5p, suggesting that DLX6-AS1 was a hopeful target for the lncRNA-targeted therapy in OC.

3D Culture System for Liver Tissue Mimicking Hepatic Plates for Improvement of Human Hepatocyte (C3A) Function and Polarity.

In vitro 3D hepatocyte culture constitutes a core aspect of liver tissue engineering. However, conventional 3D cultures are unable to maintain hepatocyte polarity, functional phenotype, or viability. Here, we employed microfluidic chip technology combined with natural alginate hydrogels to construct 3D liver tissues mimicking hepatic plates. We comprehensively evaluated cultured hepatocyte viability, function, and polarity. Transcriptome sequencing was used to analyze changes in hepatocyte polarity pathways. The data indicate that, as culture duration increases, the viability, function, polarity, mRNA expression, and ultrastructure of the hepatic plate mimetic 3D hepatocytes are enhanced. Furthermore, hepatic plate mimetic 3D cultures can promote changes in the bile secretion pathway via effector mechanisms associated with nuclear receptors, bile uptake, and efflux transporters. This study provides a scientific basis and strong evidence for the physiological structures of bionic livers prepared using 3D cultures. The systems and cultured liver tissues described here may serve as a better in vitro 3D culture platform and basic unit for varied applications, including drug development, hepatocyte polarity research, bioartificial liver bioreactor design, and tissue and organ construction for liver tissue engineering or cholestatic liver injury.

Clinical efficacy and safety of apatinib combined with S-1 in advanced esophageal squamous cell carcinoma.

Background Esophageal cancer is a very common malignant tumor in China, especially esophageal squamous cell carcinoma (ESCC), but there is currently no effective treatment for patients after first-line chemotherapy failure. Apatinib has shown promising outcomes in treatment with various solid tumors. Objectives To evaluate the clinical efficacy and safety of apatinib combined with S-1 in the treatment of advanced ESCC patients after first-line chemotherapy failure. Methods In this prospective study, fifteen patients with advanced ESCC who failed first-line chemotherapy were enrolled from Nov 2016 to Apr 2019. Patients received the combination therapy with apatinib (250-500 mg, once daily) plus S-1 (40-60 mg based on body surface area, twice daily). Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR) and objective response rate (ORR). Adverse events (AEs) were recorded to evaluate the safety. Results A total of 12 patients were included in the efficacy analysis. The median PFS was 6.23 months, and the median OS was 8.83 months. Two (16.67%) patients achieved partial remission, 9 patients (75.00%) achieved stable disease and 1 (8.33%) patient achieved progressive disease. DCR and ORR was 91.67%and 16.67%, respectively. Most frequent AEs were hypertension, myelosuppression, weakness, hemorrhage, hand-foot syndrome, total bilirubin elevation, sick, proteinuria, oral ulcer, loss of appetite, and transaminase elevation. The most AEs were in grade I~II. Conclusion The combination therapy of apatinib plus S-1 was effective and well tolerated in the treatment of advanced ESCC patients after first-line chemotherapy failure. The combination therapy has the potential to be a potent therapeutic option for advanced ESCC patients after first-line chemotherapy failure.

Highly flexible reduced graphene oxide@polypyrrole-polyethylene glycol foam for supercapacitors.

A flexible and free-standing 3D reduced graphene oxide@polypyrrole-polyethylene glycol (RGO@PPy-PEG) foam was developed for wearable supercapacitors. The device was fabricated sequentially, beginning with the electrodeposition of PPy in the presence of a PEG-borate on a sacrificial Ni foam template, followed by a subsequent GO wrapping and chemical reduction process. The 3D RGO@PPy-PEG foam electrode showed excellent electrochemical properties with a large specific capacitance of 415 F g-1 and excellent long-term stability (96% capacitance retention after 8000 charge-discharge cycles) in a three electrode configuration. An assembled (two-electrode configuration) symmetric supercapacitor using RGO@PPy-PEG electrodes exhibited a remarkable specific capacitance of 1019 mF cm-2 at 2 mV s-1 and 95% capacitance retention over 4000 cycles. The device exhibits extraordinary mechanical flexibility and showed negligable capacitance loss during or after 1000 bending cycles, highlighting its great potential in wearable energy devices.

Preoperative Risk Assessment of Lymph Node Metastasis in cT1 Lung Cancer: A Retrospective Study from Eastern China.

BACKGROUND: Lymph node status of clinical T1 (diameter ≤ 3 cm) lung cancer largely affects the treatment strategies in the clinic. In order to assess lymph node status before operation, we aim to develop a noninvasive predictive model using preoperative clinical information. METHODS: We retrospectively reviewed 924 patients (development group) and 380 patients (validation group) of clinical T1 lung cancer. Univariate analysis followed by polytomous logistic regression was performed to estimate different risk factors of lymph node metastasis between N1 and N2 diseases. A predictive model of N2 metastasis was established with dichotomous logistic regression, externally validated and compared with previous models. RESULTS: Consolidation size and clinical N stage based on CT were two common independent risk factors for both N1 and N2 metastases, with different odds ratios. For N2 metastasis, we identified five independent predictors by dichotomous logistic regression: peripheral location, larger consolidation size, lymph node enlargement on CT, no smoking history, and higher levels of serum CEA. The model showed good calibration and discrimination ability in the development data, with the reasonable Hosmer-Lemeshow test (p = 0.839) and the area under the ROC being 0.931 (95% CI: 0.906-0.955). When externally validated, the model showed a great negative predictive value of 97.6% and the AUC of our model was better than other models. CONCLUSION: In this study, we analyzed risk factors for both N1 and N2 metastases and built a predictive model to evaluate possibilities of N2 metastasis of clinical T1 lung cancers before the surgery. Our model will help to select patients with low probability of N2 metastasis and assist in clinical decision to further management.