Quantitative analysis of microplastics in water environments based on Raman spectroscopy and convolutional neural network.

With the increasing interest in microplastics (MPs) pollutants, quantitative analysis of MPs in water environment is an important issue. Vibrational spectroscopy, represented by Raman spectroscopy, is widely used in MP detection because they can provide unique fingerprint characteristics of chemical components of MPs, but it is difficult to provide quantitative information. In this paper, an ingenious method for quantitative analysis of MPs in water environment by combining Raman spectroscopy and convolutional neural network (CNN) is proposed. It is innovatively proposed to collect the average mapping spectra (AMS) of the samples to improve the uniformity of Raman spectroscopy detection, and to increase the effective detection range of concentration by filtering different volumes of the same MP solutions. In order to verify the universality and effectiveness of the proposed method, 6 different sizes of Polyethylene (PE) MPs were used as detection objects and mixed into 5 different actual water environments. The R2 and RMSE of CNN for identifying the concentration of PE solutions could reach 0.9972 and 0.033, respectively. Meanwhile, by comparing machine learning models such as Random Forest (RF) and Support Vector Machine (SVM) were compared, and CNN combined with Raman spectroscopy has significant advantages in identifying the concentration of MPs.

Hepatic glycogenesis antagonizes lipogenesis by blocking S1P via UDPG.

The identification of mechanisms to store glucose carbon in the form of glycogen rather than fat in hepatocytes has important implications for the prevention of nonalcoholic fatty liver disease (NAFLD) and other chronic metabolic diseases. In this work, we show that glycogenesis uses its intermediate metabolite uridine diphosphate glucose (UDPG) to antagonize lipogenesis, thus steering both mouse and human hepatocytes toward storing glucose carbon as glycogen. The underlying mechanism involves transport of UDPG to the Golgi apparatus, where it binds to site-1 protease (S1P) and inhibits S1P-mediated cleavage of sterol regulatory element-binding proteins (SREBPs), thereby inhibiting lipogenesis in hepatocytes. Consistent with this mechanism, UDPG administration is effective at treating NAFLD in a mouse model and human organoids. These findings indicate a potential opportunity to ameliorate disordered fat metabolism in the liver.

Phosphorus forms and zinc concentrations affect the physiological ecology and sinking rate of Thalassiosira weissflogii.

The combined effects of phosphorus (P) forms and zinc (Zn) concentrations on diatom silicification remain unclear. In this study, we investigate the effects of different Zn concentrations on the growth, cellular silicon content and sinking rate of Thalassiosira weissflogii under different P forms. The results showed that under the dissolved inorganic phosphorus (DIP) treatments, the specific growth rate of T. weissflogii in Zn limitation culture was significantly lower than that in Zn-replete culture. However, T. weissflogii cellular silicon content and sinking rate increased. Moreover, the reduced specific growth rate (7 %, p < 0.05), enhanced ALP activity (63 %, p < 0.05), and sinking rate (20 %, p < 0.05) for Zn-deplete T. weissflogii implied that the bioavailability of dissolved organic phosphorus (DOP) was depressed under Zn deplete medium. This study demonstrates that the physiological ecology and sinking rate of the diatom T. weissflogii were affected by both individual and combined changes in P forms and Zn concentrations.

Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing.

Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.

From service capacity to spatial equity: Accurately and comprehensively evaluating urban park green space distribution under multi-trips mode.

The health of city inhabitants is considerably impacted by the urban park green spaces (UPGS). Existing studies lack an assessment of the UPGS equity from different perspectives and are limited to poor accuracy. This study reviews the definition and determination methods of UPGS, as well as UPGS accessibility and spatial equity related studies. Then, a spatial equity evaluation system is established from the dimensions of equity in providing UPGS services and equity in supply and demand matching. This study extrapolates from micro to macro analysis using network big data and census data to pinpoint the population down to the building level in the main urban area of Fuzhou City, China. The network analysis method, improved Gaussian floating catchment area method, Gini coefficient, and Lorenz curve measurement help to evaluate UPGS service euquity, explore the similarities and differences of UPGS fairness under different travel modes. It also helps to understand the service relationship between UPGS service and population demand under objective space, and to pinpoint the weak supply area using the locational entropy method. The results show that: (1) The overall accessibility and per capita accessibility show similar spatial distribution patterns under different travel modes, which are "high around and low in the middle" and "centered on the Minjiang River and dispersed to the north and south, respectively" in study area. (2) The supply of UPGS services in Fuzhou is relatively adequate and at a relatively equity level, while varies in the allocation of UPGS services among sub-districts. The spatial equity of different traveling modes varies widely. (3) The sub-districts on the periphery of the study area should be subject to increased UPGS and improvements to the road network and public infrastructure. Sub-district with high population density and old neighborhoods should implement micro-renewal and build community parks. Our study presents a new idea for spatial equity research.

Improving flame retardant and electromagnetic interference shielding properties of poly(lactic acid)/poly(ε-caprolactone) composites using catalytic imidazolium modified CNTs and ammonium polyphosphate.

The flame retardants and electromagnetic interference (EMI) shielding performance were enhanced by using imidazolium-functionalized polyurethane (IPU) modified multi-walled carbon nanotubes (CNTs) and ammonium polyphosphate (APP) for polylactic acid (PLA)/polycaprolactone (PCL) composites. The PLA/PCL/10APP/8CNT/1.6IPU composite containing 10 wt% APP and 8 wt% imidazolium modified CNTs reached the limiting oxygen index (LOI) value of 30.3 % and passed the V-0 rating in UL-94 tests. Moreover, the peak of the heat release rate (pHRR) and total heat release (THR) for this composite reached around 302 kW/m2 and 64 KJ/m2, which were decreased by 39.1 % and 15.8 % compared with that of PLA/PCL/10APP composite. The improved flame retardancy was attributed to the interplay of catalytic, barrier, and condensed char forming of imidazolium-modified CNTs and APP. IPU catalyzed the charring effect of the polymer matrix during combustion and regulated the migration of more CNTs to disperse at the two-phase interface. The dispersion of imidazolium-modified CNTs and co-continuous phase structure of the composites can establish continuous conductive pathways. The PLA/PCL/APP/CNT/IPU composite obtained a higher conductivity compared to the PLA/PCL/APP/CNT composite and whose EMI SE reached 33.9 dB, which is a promising candidate for next-generation sustainable and protective plastics.

Micro- and nano-plastics in the atmosphere: A review of occurrence, properties and human health risks.

The ubiquitous occurrence of micro/nano plastics (MNPs) poses potential threats to ecosystem and human health that have attracted broad concerns in recent decades. Detection of MNPs in several remote regions has implicated atmospheric transport as an important pathway for global dissemination of MNPs and hence as a global health risk. In this review, the latest research progress on (1) sampling and detection; (2) origin and characteristics; and (3) transport and fate of atmospheric MNPs was summarized. Further, the current status of exposure risks and toxicological effects from inhaled atmospheric MNPs on human health is examined. Due to limitations in sampling and identification methodologies, the study of atmospheric nanoplastics is very limited today. The large spatial variation of atmospheric MNP concentrations reported worldwide makes it difficult to compare the overall indoor and outdoor exposure risks. Several in vitro, in vivo, and epidemiological studies demonstrate adverse effects of immune response, apoptosis and oxidative stress caused by MNP inhalation that may induce cardiovascular diseases and reproductive and developmental abnormalities. Given the emerging importance of atmospheric MNPs, the establishment of standardized sampling-pretreatment-detection protocols and comprehensive toxicological studies are critical to advance environmental and health risk assessments of atmospheric MNPs.

Airborne microplastics in urban, rural and wildland environments on the Tibetan Plateau.

The concentration of airborne microplastics is largely unknown in the remote high mountain area of the Tibetan Plateau. Here we report airborne microplastic concentrations of 2.5-58.8 n/m3 in urban, rural and wildland areas across the Tibetan Plateau, with smaller (∼89% <100 µm) fragments (>80%) dominating. Polyethylene terephthalate, polyethylene, polyamide and polystyrene were the dominant polymers of airborne microplastics on the Tibetan Plateau. Distribution of airborne microplastics was positively correlated with anthropogenic activity indices, such as population density and nighttime light intensity. Although the contribution of long-range atmospheric transport is valid, dispersed villages also appear to be a source of airborne microplastics for wildland areas across the Tibetan Plateau.

Integrated pollution analysis, pollution area identification and source apportionment of heavy metal contamination in agricultural soil.

Given the global prevalence of soil heavy metal contamination, knowledge concerning of soil environmental quality assessment, pollution area identification and source apportionment is critical for implementation of soil pollution prevention and safe utilization strategies. In this study, soil static environmental capacity (QI) for heavy metals was selected to evaluate pollution risks in agricultural soils of Wenzhou, southeast China. Combined with geostatistical methods, the pollution area was identified along with uncertainty analysis. Potential sources were quantitatively apportioned using a positive matrix factorization model (PMF). Results showed that agricultural soils in this study were mainly contaminated by Cd and Pb based on both Nemerow and QI indices. The environmental capacity assessment found more than 90% areas were identified as polluted soils for Qi-Zn, Qi-Cd and Qi-Pb, with minor uncertain areas. Cu was identified as having a high proportion of uncertain pollution area status, which was similar to the results of the integrated environmental capacity for all metals. PMF results indicated that industrial discharge, agrochemicals and parent material accounted for 32.1%, 32.2% and 35.7% of heavy metal accumulation in soils, respectively. Implementation of strict policies to reduce anthropogenic source emissions and remediate soil pollution are crucial to minimize metal pollution inputs, improve agricultural soil quality and enhance food safety.

Aryl hydrocarbon receptor sulfenylation promotes glycogenolysis and rescues cancer chemoresistance.

Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells' response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.

Mismatch between infrastructure supply and demand within a 15-minute living circle evaluation in Fuzhou, China.

Rapid urbanization has gradually increased the contradiction between the demand and supply of urban resources. The quantitative optimization and adjustment of the infrastructure of the 15-min living circle is conducive to the scientific formulation of living circle planning guidelines, and also allows the evaluation of the effectiveness and practicality of policies. We investigate the spatial allocation pattern of infrastructure construction, the actual service capacity of facilities, and the spatial matching of facility service supply and residents' demand from the spatial dimension. Taking Fuzhou City as an example, this study uses multi-source network big data to accurately quantify the supply and demand, and constructs a 15-min living circle facility service supply evaluation system based on the kernel density analysis method, the network analysis method, and the supply and demand matching model. We propose infrastructure enhancement strategies in conjunction with the current status of Fuzhou's urban development. This study also further explores the factors influencing the spatial distribution of basic service facilities and the construction status of community living circles in China. The results show that (a) The distribution of infrastructure presents a different spatial distribution pattern from the actual service supply within the living circle. (b) The infrastructure service in the main area of Fuzhou can basically cope with the demand of residents, but there is still a mismatch between supply and demand. The areas with insufficient supply are mainly distributed in the periphery of the study area. (c) In order to further improve the construction of community living circle, we should first focus on the sub-districts with low service supply level and insufficient supply. According to the specific distribution of facilities, the number of public service facilities should be increased or decreased based on the demand of residents. This paper enriches the practical application of multi-source network big data in urban infrastructure construction, provides a guideline for the spatial layout and resource allocation of infrastructure in 15-min living circles in other cities.

Antitumor studies evaluation of triphenylphosphine ruthenium complexes with 5,7-dihalo-substituted-8-quinolinoline targeting mitophagy pathways.

Both ruthenium-containing complexes and 8-quinolinoline compounds have emerged as a potential novel agent for malignant tumor therapy. Here, three triphenylphosphine ruthenium complexes, [Ru(ZW1)(PPh3)2Cl2] (PPh3 = triphenylphosphine) (RuZ1), [Ru(ZW2)(PPh3)2Cl2] (RuZ2) and [Ru(ZW2)2(PPh3)Cl2]·CH2Cl2 (RuZ3) bearing 5,7-dichloro-8-quinolinol (H-ZW1) and 5,7-dichloro-8-hydroxyquinaldine (H-ZW2), have been synthesized, characterized and tested for their anticancer potential. We showed that triphenylphosphine ruthenium complexes RuZ1-RuZ3 impaired the cell viability of ovarian adenocarcinoma cisplatin-resistant SK-OV-3/DDP (SKO3CR) and SK-OV-3 (SKO3) cancer cells with greater selectivity and specificity than cisplatin. In addition, RuZ1-RuZ3 show higher excellent cytotoxicity than cisplatin towards SKO3CR cells, with IC50 values of 9.66 ± 1.08, 4.05 ± 0.67 and 7.18 ± 0.40 µM, respectively, in which the SKO3CR cells was the most sensitive to RuZ1-RuZ3. Depending on the substituent type, the antiproliferative ability of RuZ1-RuZ3 followed the trend: -CH3 > -H. However, RuZ1-RuZ3 have no obvious toxicity to normal cell HL-7702. Besides, RuZ1 and RuZ2 could induce mitophagy related-apoptosis pathways through suppression of mitochondrial membrane potential (ΔΨm), accumulation of [Ca2+] and reactive oxygen species (ROS), and regulation of LC3 II/LC3 I, Beclin-1, P62, FUNDC1, PINK1, Parkin, cleaved-caspase-3, caspase-9 and cytochrome c signaling pathway, and hindering the preparation of mitochondrial respiration complexes I and IV and ATP levels. Mechanistic study revealed that RuZ1 and RuZ2 induce apoptosis in SKO3CR cells via mitophagy related-apoptosis pathways induction and energy (ATP) generation disturbance. Taken together, the studied triphenylphosphine ruthenium complexes RuZ1-RuZ3 are promising chemotherapeutic agents with high effectiveness and low toxicity.

YAP Inactivation by Soft Mechanotransduction Relieves MAFG for Tumor Cell Dedifferentiation.

Solid tumor cells live in a highly dynamic mechanical microenvironment. How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma. Here, we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells. Mechanistically, integrin ß8 was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein (YAP). YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G (MAFG), allowing MAFG to transactivate the stemness genes NANOG, SOX2, and NESTIN. Inactivation also restored ß8 expression, thereby forming a closed mechanical loop. Importantly, MAFG expression is correlated with worse prognosis. Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation, which has therapeutic implications for exploring innovative strategies to attack malignancies.

Development and validation of a prognostic nomogram for gallbladder papillary adenocarcinoma.

Background: Gallbladder papillary adenocarcinoma (GBPA) is an uncharacteristically gallbladder cancer subtype. Although some studies have shown that the prognosis of GBPA patients is significantly better than that of gallbladder adenocarcinoma (GBA) and gallbladder mucinous adenocarcinoma (GBMA) due to its rarity, there is a lack of large sample studies necessary to confirm the clinical characteristics and survival rate of GBPA. Therefore, this study aimed to describe the clinicopathological characteristics affecting survival in GBPA. This data was then used to establish a prognostic nomogram for GBPA. Methods: The data of patients diagnosed with gallbladder cancer between 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The clinical features and survival of patients with GBPA were compared with those of GBA and GBMA after balancing the baseline characteristics using propensity score matching (PSM). Univariate and multivariate Cox analyses were used to identify the prognostic factors for GBPA. Subsequently, the overall survival (OS) and cancer-specific survival (CSS) nomograms were established to predict GBPA prognosis. The performance and discrimination of the nomogram were measured using concordance index (C-index), calibration curves, receptor operating characteristic curves(ROC), and decision curve analysis (DCA) was applied to examine the net benefit of tients with GBPA, 5798 patients with GBA, and 223 patients with GBMA. The mean 1-, 3- and 5-year OS rates for GBPA were 81.3%, 58.8%, and 49.1%, respectively, while the mean 1-, 3- and 5-year CSS rates were 85.0%, 68.1%, and 61.0%, respectively. The median OS rates was 58 months (95% CI: 43-88), while the median CSS was not reached. The PSM analysis showed a differ statistically significantly in the OS between GBPA and GBA. However, there has no statistically difference in CSS. Conversely, the OS and CSS between GBPA and GBMA have statistically significant differences. Age, marital, T stage, and M stage were strongly linked to the prognosis for OS, while T-stage, M-stage, and surgery were significantly associated with the prognosis for CSS in GBPA patients. The AUC for the 1-, 3-, and 5-year OS were 0.722 (95%CI: 0.630-0.813), 0.728 (95%CI: 0.665-0.790), and 0.706 (95%CI: 0.641-0.771), respectively. The AUC for the 1-, 3-, and 5-year CSS were 0.749 (95%CI: 0.659-0.840), 0.698 (95%CI: 0.627-0.770), and 0.665 (95%CI: 0.594-0.735), respectively. The C-indices for the OS and CSS nomograms were 0.701 (95% CI: 0.634-0.744) and 0.651 (95% CI: 0.598-0.703), respectively. The calibration curves showed that the nomograms were well consistency. The DCA showed that compared with the TNM system, the nomogram models had a significant positive net benefit in survival prediction. Conclusion: GBPA has distinct clinicopathological characteristics and survival compared to other gallbladder carcinomas. The established nomogram provided a better prediction of survival for GBPA patients than the traditional TNM models.

Component identification for the SERS spectra of microplastics mixture with convolutional neural network.

With the increasing interest in microplastics (MPs) pollutants, relevant detection technologies are also developing. In MPs analysis, vibrational spectroscopy represented by surface-enhanced Raman spectroscopy (SERS) is widely used because they can provide unique fingerprint characteristics of chemical components. However, it is still a challenge to separate various chemical components from the SERS spectra of MPs mixture. In this study, it is innovatively proposed to combine the convolutional neural networks (CNN) model to simultaneously identify and analyze each component in the SERS spectra of six common MPs mixture. Different from the traditional method, which requires a series of spectral preprocessing such as baseline correction, smoothing and filtering, the average identification accuracy of MP components is as high as 99.54 % after the unpreprocessed spectral data is trained by CNN, which is better than other classical algorithms such as support vector machine (SVM), principal component analysis linear discriminant analysis (PCA-LDA), partial least squares discriminant analysis (PLS-DA), Random Forest (RF), and K Near Neighbor (KNN), with or without spectral preprocessing. The high accuracy shows that CNN can be used to quickly identify MPs mixture with unpreprocessed SERS spectra data.

Fabricating super tough polylactic acid based composites by interfacial compatibilization of imidazolium polyurethane modified carbon nanotubes.

The interfacial compatibilization and dispersion of carbon nanotubes (CNTs) in incompatible poly(lactic acid)/poly(butylene terephthalate adipate) (PLA/PBAT) composites are key points for evaluating the performance of the composites. To address this, a novel compatibilizer, sulfonate imidazolium polyurethane (IPU) containing PLA and poly(1,4-butylene adipate) segments modified CNTs, employed in conjunction with multi-component epoxy chain extender (ADR) to toughen synergistically PLA/PBAT composites. The thermal stability, rheological behavior, morphology, and mechanical properties of PLA/PBAT composites were performed by TGA, DSC, dynamic rheometer, SEM, tensile, and notched Izod impact measure. Moreover, the elongation at break and notched Izod impact strength of PLA5/PBAT5/4C/0.4I composites achieved 341 % and 61.8 kJ/m2 respectively, whose tensile strength was 33.7 MPa. The interfacial compatibilization and adhesion were enhanced because of the interface reaction catalyzed by IPU and the refined co-continuous phase structure. The CNTs non-covalently modified by IPU that bridged at the PBAT phase and interface transferred the stress into the matrix, prevented the development of microcracks, and absorbed impact fracture energy in the form of pull-out of the matrix, inducing shear yielding and plastic deformation. This new type of compatibilizer with modified CNTs is of great significance for realizing the high performance of PLA/PBAT composites.

Eradication of the nidus in arteriovenous malformations with a dominant outflow vein in the lower extremities using coils and absolute ethanol.

OBJECTIVE: In the present study, we summarize our experience in locating the nidus of arteriovenous malformations (AVMs) with a dominant outflow vein (DOV) in the lower extremities and eradicating the nidus with ethanol and coils. METHODS: Twelve patients with lower extremity AVMs who underwent ethanol embolization combined with DOV occlusion from January 2017 to May 2018 were enrolled in the present study. Selective angiography was used to locate the nidus of the AVMs, which was eradicated using ethanol and coils via the direct puncture pathway. All treated patients underwent postoperative follow-up (mean, 25.5 months; range, 14-37 months). RESULTS: The 12 patients underwent a total of 29 procedures (mean, 2.4; range, 1-4) with 27 detachable coils and 169 Nester coils (Cook Medical Inc, Bloomington, IN). Of the 12 patients, 7 (58.3%) had a complete response and 5 (41.7%) a partial response. Three patients (25%) had minor complications such as blister and superficial skin ulcers during follow-up. However, they recovered spontaneously and completely. No major complications were recorded. CONCLUSIONS: Ethanol embolization combined with coil-assisted DOV occlusion has the potential to eradicate the nidus of lower extremity AVMs with acceptable complication rates.

Efficacy and safety of apatinib combined with liposomal doxorubicin or paclitaxel versus liposomal doxorubicin or paclitaxel monotherapy in patients with recurrent platinum-resistant ovarian cancer.

AIM: Apatinib is an effective treatment for patients with gynecological cancers. This study aimed to further explore the efficacy and safety of apatinib plus chemotherapy in patients with recurrent platinum-resistant ovarian cancer (PROC). METHODS: Totally, 105 patients with recurrent PROC receiving apatinib plus chemotherapy (N = 51) and chemotherapy alone (N = 54) were retrospectively enrolled in this cohort study. RESULTS: Objective response rate (37.3% vs. 14.8%) (p = 0.009) and disease control rate (80.4% vs. 61.1%) (p = 0.030) were increased in the apatinib plus chemotherapy group versus the chemotherapy group. The median (95% confidence interval [CI]) progression-free survival (PFS) and overall survival (OS) were 5.5 (3.4-7.6) and 21.4 (16.2-26.6) months in the apatinib plus chemotherapy group, and they were 3.8 (3.0-4.6) and 14.8 (11.9-17.7) months in the chemotherapy group. Meanwhile, the Kaplan-Meier curves revealed that PFS (p = 0.008) and OS (p = 0.012) were prolonged in the apatinib plus chemotherapy group versus the chemotherapy group. This finding was confirmed by multivariate Cox's proportional regression analyses: enter method (hazard ratio [HR] = 0.515, p = 0.007 for PFS; HR = 0.222, p < 0.001 for OS) and step-forward method (HR = 0.608, p = 0.019 for PFS; HR = 0.346, p = 0.001 for OS). Additionally, the incidence of hypertension was increased in the apatinib plus chemotherapy group versus the chemotherapy group (p = 0.038), while others were not different between the two groups (all p > 0.05). Grades 3 and 4 adverse events were neutropenia, hypertension, leukopenia, hand-foot syndrome, nausea and vomiting, fatigue, thrombocytopenia, and anemia in the apatinib plus chemotherapy group. CONCLUSION: Apatinib combined with chemotherapy is a superior choice over chemotherapy alone for recurrent PROC management.

Comprehensive analysis of exosomal circRNA, lncRNA, and mRNA profiles to identify the potential RNAs involved in the pathogenesis of venous malformation.

BACKGROUND: Venous malformation (VM) is a kind of congenital vascular anomaly with a high incidence of recurrence, detailed pathogenesis and standard treatment of VM still lack now. Increasing evidence showed exosomal RNA plays a pivotal role in various diseases. However, the underlying mechanism of VM based on the potential differentially exosomal RNAs remains unclear. METHODS: Comparative high-throughput sequencing with serum exosomes from three VM patients and three healthy donors was used to explore differentially expressed (DE) circRNAs, DE lncRNAs, and DE mRNAs involving the formation of VM. We identified and verified DE circRNAs, DE lncRNAs, and DE mRNAs via qRT-PCR assay. We explored the potential functions of these exosomal DE non-coding RNAs via performing further Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Besides, circRNA/lncRNA-miRNA-mRNA linkages were also constructed to find their potential relationships in VM. RESULTS: A total of 121 circRNAs, 53 lncRNAs, and 42 mRNAs (|log2 FC| ≥ 2.0, FDR <0.05, n = 3) were determined to be differentially expressed. QRT-PCR validated that these top-changed DE circRNAs, lncRNAs, and mRNAs had significant expression changes. Functional studies demonstrated that DE circRNAs play a pivotal role in thyroid hormone signaling pathway, DE lncRNAs function as a key regulator in MAPK signaling pathway and DE miRNAs participate in the process of hepatocellular carcinoma mostly. CONCLUSION: Our study comprehensively depicted exosomal DE non-coding RNAs networks related to the pathogenesis of VM which can provide new insight into, a novel target for treating VM.

Epigenetic modification of CSDE1 locus dictates immune recognition of nascent tumorigenic cells.

Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immunotherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocompetent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain-containing protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phosphatase (TCPTP). A methyltransferase SET and MYN domain-containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of CSDE1 locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effectiveness that requires further investigation.