Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function.

Sustained energy starvation leads to activation of AMP-activated protein kinase (AMPK), which coordinates energy status with numerous cellular processes including metabolism, protein synthesis, and autophagy. Here, we report that AMPK phosphorylates the histone methyltransferase EZH2 at T311 to disrupt the interaction between EZH2 and SUZ12, another core component of the polycomb repressive complex 2 (PRC2), leading to attenuated PRC2-dependent methylation of histone H3 at Lys27. As such, PRC2 target genes, many of which are known tumor suppressors, were upregulated upon T311-EZH2 phosphorylation, which suppressed tumor cell growth both in cell culture and mouse xenografts. Pathologically, immunohistochemical analyses uncovered a positive correlation between AMPK activity and pT311-EZH2, and higher pT311-EZH2 correlates with better survival in both ovarian and breast cancer patients. Our finding suggests that AMPK agonists might be promising sensitizers for EZH2-targeting cancer therapies.

Convolutional Neural Networks Facilitate Process Understanding of Megacity Ozone Temporal Variability.

Ozone pollution is profoundly modulated by meteorological features such as temperature, air pressure, wind, and humidity. While many studies have developed empirical models to elucidate the effects of meteorology on ozone variability, they predominantly focus on local weather conditions, overlooking the influences from high-altitude and broader regional meteorological patterns. Here, we employ convolutional neural networks (CNNs), a technique typically applied to image recognition, to investigate the influence of three-dimensional spatial variations in meteorological fields on the daily, seasonal, and interannual dynamics of ozone in Shenzhen, a major coastal urban center in China. Our optimized CNNs model, covering a 13° × 13° spatial domain, effectively explains over 70% of daily ozone variability, outperforming alternative empirical approaches by 7 to 62%. Model interpretations reveal the crucial roles of 2-m temperature and humidity as primary drivers, contributing 16% and 15% to daily ozone fluctuations, respectively. Regional wind fields account for up to 40% of ozone changes during the episodes. CNNs successfully replicate observed ozone temporal patterns, attributing -5-6 µg·m-3 of interannual ozone variability to weather anomalies. Our interpretable CNNs framework enables quantitative attribution of historical ozone fluctuations to nonlinear meteorological effects across spatiotemporal scales, offering vital process-based insights for managing megacity air quality amidst changing climate regimes.

Effect of different treatment modalities on the prognosis of stage IV epithelial ovarian cancer: analysis of the SEER database.

BACKGROUND: The prognosis of advanced ovarian cancer is often poor. Although there are several treatment options for stage IV epithelial ovarian cancer, it is not clear which treatment will benefit the patient's prognosis.We conducted an analysis using the SEER database to compare the impact of different treatment modalities on the prognosis of advanced ovarian cancer. METHODS: The present study conducts a retrospective analysis of relevant data from the SEER database pertaining to patients diagnosed with stage IV epithelial ovarian cancer between 2011 and 2020 (n = 5345). Statistical methods including Kaplan-Meier curves, log-rank tests, and Cox regression analysis are employed to ascertain the impact of different treatment regimens on the prognosis of patients with stage IV epithelial ovarian cancer. RESULTS: Among patients with stage IV epithelial ovarian cancer, age ≥ 60 and the presence of lung metastases or multiple metastases were identified as poor prognostic factors. Conversely, being Asian or Pacific Islander, married, and testing negative for CA125 were associated with favorable prognoses. In terms of the choice of treatment for patients, surgery plus chemotherapy was the best treatment modality, and timely surgery could significantly improve the prognosis of patients, but there was no difference between chemoradiotherapy alone and the surgery group among patients with lung metastases. CONCLUSION: The prognosis of patients with stage IV epithelial ovarian cancer is influenced by many factors. In terms of the choice of treatment, patients with surgery plus chemotherapy have the best prognosis. In cases where lung metastases are inoperable, a combination of radiotherapy and chemotherapy can be used. In other cases, radiotherapy does not improve outcomes in patients with stage IV epithelial ovarian cancer. This study provides a basis for the choice of treatment for patients with stage IV epithelial ovarian cancer.

Early prediction of sepsis-induced respiratory tract infection using a biomarker-based machine-learning algorithm.

Early and differential diagnosis of sepsis is essential to avoid unnecessary antibiotic use and further reduce patient morbidity and mortality. Here, we aimed to identify predictors of sepsis and advance a machine-learning strategy to predict sepsis-induced respiratory tract infection (RTI). Patients with sepsis and RTI were selected via retrospective analysis, and essential population characteristics and laboratory parameters were recorded. To improve the performance of the primary model and avoid over-fitting, a recursive feature elimination with cross-validation (RFECV) strategy was used to screen the optimal subset of biomarkers and construct nine machine-learning models based on this subset; the average accuracy, precision, recall, and F1-score were used for evaluation of the models. We identified 430 patients with sepsis and 686 patients with RTI. A total of 39 features were collected, with 23 features identified for initial model construction. Using the RFECV algorithm, we found that the XGBoost classifier, which only needed to include seven biomarkers, demonstrated the best performance among all prediction models, with an average accuracy of 89.24 ± 2.28, while the Ridge classifier, which included 11 biomarkers, had an average accuracy of only 83.87 ± 4.69. The remaining models had prediction accuracies greater than 88%. We developed nine models for predicting sepsis using a strategy that combined RFECV with machine learning. Among these models, the XGBoost classifier, which included seven biomarkers, showed the best performance and highest accuracy for predicting sepsis and may be a promising tool for the timely identification of sepsis.

Intra- and Interimage Reliability of Inter-Rectus Distance Measurements Determined via Ultrasound Imaging by the Same or Different Testers in Women in the Early Postpartum Period.

OBJECTIVES: No consensus regarding the optimal position and location for the measurement of the inter-rectus distance (IRD) via ultrasound (US) has been reached. By investigating the intra- and interimage reliability of IRD measurements taken in different positions and at different locations within and between testers, this study provides a theoretical basis for the current situation. METHODS: The IRD was measured via US in 46 women at 42-60 days after delivery at the superior margin of the umbilicus and 3 cm above, 5 cm above and 3 cm below the umbilicus while the women were in the supine, crunch and standing positions. In the interimage test, every participant was tested 2 times by Physician X and 1 time by Physician Y; in the intraimage test, the images collected by Physician X during the first test were saved in the machines, and two measurements were performed by Physician X and one measurement was performed by Physician Y. Paired t tests and intraclass correlation coefficients (ICCs) were calculated. RESULTS: Only the first IRD measurements by tester X and tester Y at 3 cm below the umbilicus in the crunch position were significantly different (9.56 ± 6.00 versus 11.00 ± 5.55) (P < .05). All the ICCs were greater than .75, and the intratester ICCs were greater than or equal to the corresponding intertester ICCs. The ICCs at 3 cm below the umbilicus were the smallest in the supine and crunch positions and the largest in the standing position due to the increased frequency of IRD values of 0. The ICCs for the crunch position were greatest according to the intraimage test but smallest according to the interimage test. The interimage ICCs between the two testers in the supine position at the superior margin, 3 cm above, 5 cm above, and 3 cm below the umbilicus were .972, .974, .975, and .956, respectively. CONCLUSIONS: Ultrasound imaging (USI) is a reliable method for measuring the IRD in women in the early postpartum period. The dynamic measurement of the IRD at or above the umbilicus in the supine position by different testers in real time showed the highest reliability.

Track Irregularity Identification Method of High-Speed Railway Based on CNN-Bi-LSTM.

Track smoothness has become an important factor in the safe operation of high-speed trains. In order to ensure the safety of high-speed operations, studies on track smoothness detection methods are constantly improving. This paper presents a track irregularity identification method based on CNN-Bi-LSTM and predicts track irregularity through car body acceleration detection, which is easy to collect and can be obtained by passenger trains, so the model proposed in this paper provides an idea for the development of track irregularity identification method based on conventional vehicles. The first step is construction of the data set required for model training. The model input is the car body acceleration detection sequence, and the output is the irregularity sequence of the same length. The fluctuation trend of the irregularity data is extracted by the HP filtering (Hodrick Prescott Filter) algorithm as the prediction target. The second is a prediction model based on the CNN-Bi-LSTM network, extracting features from the car body acceleration data and realizing the point-by-point prediction of irregularities. Meanwhile, this paper proposes an exponential weighted mean square error with priority inner fitting (EIF-MSE) as the loss function, improving the accuracy of big value data prediction, and reducing the risk of false alarms. In conclusion, the model is verified based on the simulation data and the real data measured by the high-speed railway comprehensive inspection train.

M2pep-Modified Cyclodextrin-siRNA Nanoparticles Modulate the Immunosuppressive Tumor Microenvironment for Prostate Cancer Therapy.

Prostate cancer (PCa) is the most prevalent cause of cancer deaths in men. Conventional strategies, such as surgery, radiation, or chemotherapy, face challenges including poor prognosis and resistance. Therefore, the development of new improved strategies is vital to enhance patient outcomes. Recently, immunotherapy has shown potential in the treatment of a range of cancers, including PCa. Tumor-associated macrophages (TAMs) play an important role in the tumor microenvironment (TME) and reprogramming of TAMs is associated with remodeling the TME. The colony-stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) signaling pathway is closely related to the polarization of TAMs. The downregulation of CSF-1R, using small interfering RNA (siRNA), has been shown to achieve the reprogramming of TAMs, from the immunosuppressive M2 phenotype to the immunostimulatory M1 one. To maximize specific cellular delivery an M2 macrophage-targeting peptide, M2pep, was formulated with an amphiphilic cationic ß-Cyclodextrin (CD) incorporating CSF-1R siRNA. The resulting nanoparticles (NPs) increased M2 macrophage targeting both in vitro and in vivo, promoting the release of M1 factors and simultaneously downregulating the levels of M2 factors through TAM reprogramming. The subsequent remodeling of the TME resulted in a reduction in tumor growth in a subcutaneous PCa mouse model mainly mediated through the recruitment of cytotoxic T cells. In summary, this M2pep-targeted CD-based delivery system demonstrated significant antitumor efficacy, thus presenting an alternative immunotherapeutic strategy for PCa treatment.

Developing a machine learning prediction algorithm for early differentiation of urosepsis from urinary tract infection.

OBJECTIVES: Early recognition and timely intervention for urosepsis are key to reducing morbidity and mortality. Blood culture has low sensitivity, and a long turnaround time makes meeting the needs of clinical diagnosis difficult. This study aimed to use biomarkers to build a machine learning model for early prediction of urosepsis. METHODS: Through retrospective analysis, we screened 157 patients with urosepsis and 417 patients with urinary tract infection. Laboratory data of the study participants were collected, including data on biomarkers, such as procalcitonin, D-dimer, and C-reactive protein. We split the data into training (80%) and validation datasets (20%) and determined the average model prediction accuracy through cross-validation. RESULTS: In total, 26 variables were initially screened and 18 were statistically significant. The influence of the 18 variables was sorted using three ranking methods to further determine the best combination of variables. The Gini importance ranking method was found to be suitable for variable filtering. The accuracy rates of the six machine learning models in predicting urosepsis were all higher than 80%, and the performance of the artificial neural network (ANN) was the best among all. When the ANN included the eight biomarkers with the highest influence ranking, its model had the best prediction performance, with an accuracy rate of 92.9% and an area under the receiver operating characteristic curve of 0.946. CONCLUSIONS: Urosepsis can be predicted using only the top eight biomarkers determined by the ranking method. This data-driven predictive model will enable clinicians to make quick and accurate diagnoses.

Survival after laparoscopic radical surgery for stage IA-IIB cervical cancer: 1316 consecutive cases from a national laparoscopic training center in China.

BACKGROUND: To investigate the survival of cervical cancer patients undergoing laparoscopic radical hysterectomy (LRH) in a minimally invasive gynecology center. METHODS: A consecutive series of patients undergoing first LRH for cervical cancer from May 2008 to December 2017 at a national laparoscopic training center was retrospectively analyzed. The overall survival (OS) and progression-free survival (PFS) were compared between groups. RESULTS: In total, 1316 women with FIGO (2009) stage IA-IIB cervical cancer received LRH. Among them, 1114 (84.7%) were followed up for 3 months or longer; the median follow-up period was 48 months (range 3-144 months). In patients with stage IA, IB1 (≤ 2 cm), IB1 (> 2 cm), IB2, IIA1 and IIA2-IIB tumors, the 4-year PFS rates were 98.6, 94.5, 87.4, 65.6, 80.0 and 67.4%, respectively, and the 4-year OS rates were 98.6, 96.8, 91.1, 77.4, 85.6 and 76.2%, respectively. The 4-year PFS and OS were as high as 96.2 and 97.5%, respectively, in patients with squamous cell carcinoma of 2 cm or smaller in diameter. A stable high 4-year OS and PFS was achieved after completing 100 LRHs. In patients operated on by the same surgeon, an improvement in survival was observed after 40 LRHs. CONCLUSION: Favorable oncologic outcomes can be achieved in patients with IA-IB1 cervical cancer after LRH in a center with a high surgery volume.

Differences in the global exposure, mortality and disability of low bone mineral density between men and women: the underestimated burden in men.

Talking about osteoporosis, we tend to focus on post-menopause women who are at increased risk due to estrogen depletion, while less attention has been paid to the disease in men. Currently, there is a lack of understanding about the difference of osteoporosis incidence and burden by sex. In this study, we used data from the Global Burden of Disease Study 2019 (GBD 2019) to compare the difference in the prevalence and burden of low bone mineral density (LBMD) between men and women, by location, year, age and socio-demographic index. We found the prevalence of LBMD was higher in women than in men. However, the age standardized mortality rate was greatly higher in men than in women. Using disability-adjusted life year (DALY) to measure the burden, we also observed higher age standardized DALY rate in men. Using sociodemographic index (SDI) as the measure of social development level, we found that higher mortality and DALY rates were mainly seen in middle and high SDI countries. Falls were the leading cause for of deaths and disabilities in both men and women with LBMD, followed by transport injuries. Fall-related mortality was higher in women, while transport injuries caused more deaths and disabilities in men. Conclusively, more attention should be paid to osteoporosis in men, and related policies, clinical practices, and guidelines are in need to reduce the burden of LBMD and osteoporosis in men.

Competing risk nomogram for predicting prognosis of patients with spinal and pelvic chordoma: A SEER-based retrospective study.

PURPOSE: Recently, competing risk nomograms were widely applied to predict prognosis in numerous tumors other than chordoma. Here, we aimed to construct and validate a competing-risk-based prognostic nomogram to predict 3- and 5-year cancer-specific death (CSD) in patients with spinal and pelvic chordoma. METHODS: All chordoma patient data were abstracted from the Surveillance, Epidemiology, and End Results (SEER) resource, and a total of 485 chordoma patients were eventually included in this study. Multivariate competing risk model and multivariate Cox model were used to determine independent prognostic factors, respectively, and the results of the two models were compared. Nomogram was employed to visualize the competing risk model. The discrimination, calibration, and clinical utility of this model were evaluated by Harrell concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Ten-fold cross-validation was further utilized to validate the prognostic nomogram. RESULTS: Significant prognostic factors affecting CSD were age (P = 0.016), localized involvement (P < 0.0001), and radical resection (P < 0.001) in the multivariate competing risk model. C-indexes were 0.799 and 0.76, and AUC were 0.812 and 0.778 for 3- and 5-year CSD. Calibration plots demonstrated the nomogram was well-fitted, and DCA indicated good clinical utility. The nomogram showed good performance in the 10-fold cross-validation. CONCLUSION: We successfully built the first competing-risk-based nomogram to predict clinical outcomes in patients with spinal and pelvic chordoma. This well-established nomogram hopes to help clinicians with precise prognostic assessment and thus improve clinical outcomes.

Sacubitril/Valsartan Cannot Improve Cardiac Function Compared with Valsartan in Patients Suffering Nonvalvular Atrial Fibrillation without Systolic Heart Failure.

This study investigates the effect of sacubitril/valsartan (Sac/Val) in patients diagnosed with nonvalvular atrial fibrillation (AF) without systolic heart failure (SHF).Nonvalvular AF patients without SHF admitted to the People's Hospital of Bortala Mongol Autonomous Prefecture from December 2020 to December 2021 were enrolled and randomly divided into Sac/Val treatment group (group T) and valsartan treatment group (group C, control). For subgroup analysis, patients were divided into subgroups with and without diastolic heart failure (DHF). After 1-month adaptive phase and subsequent 3-month treatment period, patients were followed up in the cardiology clinic. Plasma levels of biochemical markers and echocardiographic parameters before and after treatment were evaluated, and DHF scores were computed to assess diastolic function.Of 61 enrolled patients, 46 patients completed follow-up. Sac/Val treatment did not increase the percentage of sinus rhythm. Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) expression tended to be reduced in both groups after 3 months of treatment, the differences compared with respective baseline levels and between groups were not significant. According to subgroup analysis, although NT-proBNP expression in the subgroup with DHF was lower at follow-up compared to baseline, the difference was not statistically significant. Similarly, no marked differences in echocardiographic parameters or tissue Doppler parameters related to DHF were detected between the groups (P > 0.05). Additionally, a subgroup analysis found no significant variations in the echocardiographic measures (P > 0.05).Sac/Val is not superior to valsartan for the short-term treatment of patients suffering with AF without SHF in improving NT-proBNP level and cardiac function.

Observation on the aerosol and ozone precursors in suburban areas of Shenzhen and analysis of potential source based on MAX-DOAS.

Long-term stereoscopic observations of aerosol, NO2, and HCHO were carried out at the Yangmeikeng (YMK) site in Shenzhen. Aerosol optical depths and NO2 vertical column concentration (NO2 VCD) derived from MAX-DOAS were found to be consistent with other datasets. The total NO2 VCD values of the site remained low, varying from 2 × 1015 to 8 × 1015 mol/cm2, while the HCHO VCD was higher than NO2 VCD, varying from 7 × 1015 to 11 × 1015 mol/cm2. HCHO VCD was higher from September to early November than that was from mid-late November to December and during February 2021, in contrast, NO2 VCD did not change much during the same period. In January, NO2 VCD and HCHO VCD were both fluctuating drastically. High temperature and HCHO level in the YMK site is not only driving the ozone production up but also may be driving up the ozone concentration as well, and the O3 production regime in the YMK site tends to be NOx-limited. At various altitudes, backward trajectory clustering analysis and Potential Source Contribution Function (PSCF) were utilized to identify possible NO2 and HCHO source locations. The results suggested that the Huizhou-Shanwei border and the Daya Bay Sea area were the key potential source locations in the lower (200 m) and middle (500 m) atmosphere (WPSCF > 0.6). The WPSCF value was high at the 1000 m altitude which was closer to the YMK site than the near ground, indicating that the pollution transport capability in the upper atmosphere was limited.

Predictive value of preoperative platelet-to-albumin ratio and apolipoprotein B-to-apolipoprotein A1 ratio for osteosarcoma in children and adolescents: a retrospective study of 118 cases.

BACKGROUND: This retrospective study investigated biomarkers that can reflect coagulation, inflammation, and lipid abnormalities: platelet-to-albumin ratio (PAR), platelet-to lymphocyte ratio (PLR), low-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (LDL-C/HDL-C), apolipoprotein B-to-apolipoprotein ratio (ApoB/ApoA1) whether may be viable prognostic predictors in children and adolescents with osteosarcoma. METHODS: The retrospective review has enrolled a total of 118 children and adolescent patients diagnosed with osteosarcoma. Analyses with a receiver operating characteristic (ROC) curve were performed to evaluate the optimal cut-off values and to compare the area under curves (AUC). Kaplan-Meier curves were used to visualize survival outcome and a Cox proportional hazards model were used to confirm independent prognostic factors. RESULTS: Osteosarcoma patients in high PAR group (> 4.41) and high ApoB/ApoA1 group (> 0.82) experienced significantly shorter overall survival compared with those in low PAR group (≤ 4.41) and low ApoB/ApoA1 group (≤ 0.82). In univariate and multivariable analyses, preoperative PAR and ApoB/ApoA1 were identified as independent prognostic factors for OS in children and adolescents with osteosarcoma. CONCLUSION: Preoperative PAR and ApoB/ApoA1 can be used as promising predictors in children and adolescents with osteosarcoma to help clinicians recognize patients with an increased risk of poor prognosis.

Nano delivery of simvastatin targets liver sinusoidal endothelial cells to remodel tumor microenvironment for hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) developed in fibrotic liver does not respond well to immunotherapy, mainly due to the stromal microenvironment and the fibrosis-related immunosuppressive factors. The characteristic of liver sinusoidal endothelial cells (LSECs) in contributing to fibrosis and orchestrating immune response is responsible for the refractory to targeted therapy or immunotherapy of HCC. We aim to seek a new strategy for HCC treatment based on an old drug simvastatin which shows protecting effect on LSEC. METHOD: The features of LSECs in mouse fibrotic HCC model and human HCC patients were identified by immunofluorescence and scanning electron microscopy. The effect of simvastatin on LSECs and hepatic stellate cells (HSCs) was examined by immunoblotting, quantitative RT-PCR and RNA-seq. LSEC-targeted delivery of simvastatin was designed using nanotechnology. The anti-HCC effect and toxicity of the nano-drug was evaluated in both intra-hepatic and hemi-splenic inoculated mouse fibrotic HCC model. RESULTS: LSEC capillarization is associated with fibrotic HCC progression and poor survival in both murine HCC model and HCC patients. We further found simvastatin restores the quiescence of activated hepatic stellate cells (aHSCs) via stimulation of KLF2-NO signaling in LSECs, and up-regulates the expression of CXCL16 in LSECs. In intrahepatic inoculated fibrotic HCC mouse model, LSEC-targeted nano-delivery of simvastatin not only alleviates LSEC capillarization to regress the stromal microenvironment, but also recruits natural killer T (NKT) cells through CXCL16 to suppress tumor progression. Together with anti-programmed death-1-ligand-1 (anti-PD-L1) antibody, targeted-delivery of simvastatin achieves an improved therapeutic effect in hemi-splenic inoculated advanced-stage HCC model. CONCLUSIONS: These findings reveal an immune-based therapeutic mechanism of simvastatin for remodeling immunosuppressive tumor microenvironment, therefore providing a novel strategy in treating HCC.

An Injectable Hydrogel Scaffold Loaded with Dual-Drug/Sustained-Release PLGA Microspheres for the Regulation of Macrophage Polarization in the Treatment of Intervertebral Disc Degeneration.

Due to the unique physical characteristics of intervertebral disc degeneration (IVDD) and the pathological microenvironment that it creates, including inflammation and oxidative stress, effective self-repair is impossible. During the process of intervertebral disc degeneration, there is an increase in the infiltration of M1 macrophages and the secretion of proinflammatory cytokines. Here, we designed a novel injectable composite hydrogel scaffold: an oligo [poly (ethylene glycol) fumarate]/sodium methacrylate (OPF/SMA) hydrogel scaffold loaded with dual-drug/sustained-release PLGA microspheres containing IL-4 (IL-4-PLGA) and kartogenin (KGN-PLGA). This scaffold exhibited good mechanical properties and low immunogenicity while also promoting the sustained release of drugs. By virtue of the PLGA microspheres loaded with IL-4 (IL-4-PLGA), the composite hydrogel scaffold induced macrophages to transition from the M1 phenotype into the M2 phenotype during the early induced phase and simultaneously exhibited a continuous anti-inflammatory effect through the PLGA microspheres loaded with kartogenin (KGN-PLGA). Furthermore, we investigated the mechanisms underlying the immunomodulatory and anti-inflammatory effects of the composite hydrogel scaffold. We found that the scaffold promoted cell proliferation and improved cell viability in vitro. While ensuring mechanical strength, this composite hydrogel scaffold regulated the local inflammatory microenvironment and continuously repaired tissue in the nucleus pulposus via the sequential release of drugs in vivo. When degenerative intervertebral discs in a rat model were injected with the scaffold, there was an increase in the proportion of M2 macrophages in the inflammatory environment and higher expression levels of type II collagen and aggrecan; this was accompanied by reduced levels of MMP13 expression, thus exhibiting long-term anti-inflammatory effects. Our research provides a new strategy for promoting intervertebral disc tissue regeneration and a range of other inflammatory diseases.

Two nanoformulations induce reactive oxygen species and immunogenetic cell death for synergistic chemo-immunotherapy eradicating colorectal cancer and hepatocellular carcinoma.

BACKGROUND: FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu. METHODS: A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies. RESULTS: Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice. CONCLUSION: This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.

Size-dependent strain-engineered nanostructures in MoS2monolayer investigated by atomic force microscopy.

The strain has been employed for controlled modification of electronical and mechanical properties of two-dimensional (2D) materials. However, the thermal strain-engineered behaviors of the CVD-grown MoS2have not been systematically explored. Here, we investigated the strain-induced structure and properties of CVD-grown triangular MoS2flakes by several advanced atomic force microscopy. Two different kinds of flakes with sharp-corner or vein-like nanostructures are experimentally discovered due to the size-dependent strain behaviors. The critical size of these two kinds of flakes can be roughly estimated at âˆ¼17µm. Within the small flakes, the sharp-corner regions show specific strain-modified properties due to the suffering of large tensile strain. While in the large MoS2flakes, the complicated vein-like nanoripple structures were formed due to the interface slipping process under the larger tensile strain. Our work not only demonstrates the size-specific strain behaviors of MoS2flakes but also sheds light on the artificial design and preparation of strain-engineered nanostructures for the devices based on the 2D materials.

HOTAIR maintains the stemness of ovarian cancer stem cells via the miR-206/TBX3 axis.

The poor prognosis of ovarian cancer is partly attributed to the frequent chemo-resistance and recurrence, which may be mediated by ovarian cancer stem cells (OCSCs). In the present study, we investigated the mechanisms contributing to the stemness of OCSCs, focusing on the long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR). Ovarian cancer cells were tested for high aldehyde dehydrogenase (ALDH) activity or high in vitro sphere-formation ability to identify OCSCs. HOTAIR was highly expressed in the OCSCs and its depletion caused a decrease in sphere-formation ability, along with reduced resistance to cisplatin and in vivo tumorigenicity. T-box transcription factor 3 (TBX3) was highly expressed in the OCSCs and was confirmed to be positively regulated by HOTAIR. Moreover, TBX3 maintained cell stemness, whereas elevating TBX3 could relieve the weakened sphere-formation ability caused by HOTAIR depletion. Subsequently, miR-206 was found to mediate the expression regulation of TBX3 by HOTAIR, and functionally involved in the regulation of stemness in OCSCs. In line with these findings, circulating HOTAIR expression was up-regulated in ovarian cancer patients. Collectively, our findings suggest that HOTAIR relieves the inhibition of TBX3 expression mediated by miR-206 in OCSCs and provide novel therapeutic targets for the treatment of ovarian cancer.

Application of the modified cytosine base-editing in the cultured cells of bama minipig.

Bama minipig is a unique miniature swine bred from China. Their favorable characteristics include delicious meat, strong adaptability, tolerance to rough feed, and high levels of stress tolerance. Unfavorable characteristics are their low lean meat percentage, high fat content, slow growth rate, and low feed conversion ratio. Genome-editing technology using CRISPR/Cas9 efficiently knocked out the myostatin gene (MSTN) that has a negative regulatory effect on muscle production, effectively promoting pig muscle growth and increasing lean meat percentage of the pigs. However, CRISPR/Cas9 genome editing technology is based on random mutations implemented by DNA double-strand breaks, which may trigger genomic off-target effects and chromosomal rearrangements. The application of CRISPR/Cas9 to improve economic traits in pigs has raised biosafety concerns. Base editor (BE) developed based on CRISPR/Cas9 such as cytosine base editor (CBE) effectively achieve targeted modification of a single base without relying on DNA double-strand breaks. Hence, the method has greater safety in the genetic improvement of pigs. The aim of the present study is to utilize a modified CBE to generate MSTN-knockout cells of Bama minipigs. Our results showed that the constructed "all-in-one"-modified CBE plasmid achieved directional conversion of a single C·G base pair to a T·A base pair of the MSTN target in Bama miniature pig fibroblast cells. We successfully constructed multiple single-cell colonies of Bama minipigs fibroblast cells carrying the MSTN premature termination and verified that there were no genomic off-target effects detected. This study provides a foundation for further application of somatic cell cloning to construct MSTN-edited Bama minipigs that carry only a single-base mutation and avoids biosafety risks to a large extent, thereby providing experience and a reference for the base editing of other genetic loci in Bama minipigs.