Feasibility of sludge deep dewaterability improvement for incineration disposal by combined conditioning of freeze-thaw and sawdust.

Sludge incineration is the main strategy for sludge reduction in China. The combined conditioning of lime and chemical agents has been proven to achieve sludge dewatering by disrupting the extracellular polymeric substances (EPS) of sludge and reducing its compressibility. However, when incineration is the intended disposal purpose, this method poses challenges such as incomplete combustion, equipment corrosion, secondary pollution, and decreased calorific value of sludge cake. In contrast, freeze-thaw conditioning, coupled with sawdust as a high-calorific-value bio-waste, emerges as an efficient and clean alternative. The research investigates the synergistic effects of freeze-thaw and sawdust co-conditioning on various sludge properties, including dewaterability, compressibility, consolidation, permeability, microscopicity, and calorific value. The study reveals that the combined conditioning significantly reduces water content and compressibility while increasing void ratio, consolidation, permeability, and enhancing the calorific value of the sludge cake. Specifically, sludge cake conditioned with 60% dried solids (DS) sawdust and freeze-thaw achieved a water content (Wc) of 49.07% and a calorific value of 1422.3 kcal/kg, meeting standards for self-sustained incineration. With heat recovery, the combined conditioning generates an economic revenue of 25.1 $/t DS after deducting costs, thereby reducing the overall cost of sludge reduction treatment. This research offers a clean and practical solution for sludge incineration and reduction, demonstrating great economic value and application potential.

Elevated histone H3 citrullination is associated with increased Beclin1 expression in HBV-related hepatocellular carcinoma.

Citrullinated histone H3 (H3Cit) is the product of the conversion of peptidylarginine to citrulline in histone H3. We evaluated the H3Cit level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) tissues and assessed its association with Beclin1 messenger RNA (mRNA) (a key autophagic regulator). The level of H3Cit was detected by a capture enzyme-linked immunosorbent assay, while Beclin1 mRNA was determined by real-time polymerase chain reaction in 80 HBV-related patients with HCC. We found that the mean level of H3Cit was 72.25 ng/mg in HCC and 44.02 ng/mg in nontumor tissues. The mean HCC/nontumor ratio of Beclin1 mRNA was higher (0.096) in tumor samples than in nontumor specimens (0.056). Specifically, Beclin1 mRNA was elevated in 51 HCC cases (63.75%) and decreased in 29 cases (36.25%). Moreover, the levels of H3Cit and Beclin1 mRNA were significantly associated with vascular invasion and serum AFP levels. A shorter survival (19 months) was associated with a high H3Cit level. We also found increased levels of Beclin1 mRNA in the H3Cit (high) group compared with the H3Cit (low) group. The results implied that elevated histone H3 citrullination is associated with increased Beclin1 expression during the development of HBV-related HCC.

Prognostic prediction and diagnostic role of Rspondin 1 expression in esophageal squamous cell carcinoma.

CONTEXT: Rspondin 1 (Rspo1), a protein family member featuring secreted furin-like domains, plays a pivotal role in cancer development and exhibits a positive correlation with tumor progression. However, its expression in esophageal squamous cell carcinoma (ESCC) is still unknown. AIMS: Here, we assessed the correlation between Rspo1 and clinicopathological features of ESCC patients, and further investigated the potential role of Rspo1 in ESCC development and clinical outcomes. SETTINGS AND DESIGN: This was a pilot study. MATERIALS AND METHODS: A total of 112 paraffin-embedded tumor samples from patients with ESCC, including 68 matched adjacent normal tissues, were collected post-surgery. Subsequently, tissue microarray (TMA) and immunohistochemistry (IHC) techniques were employed to assess the protein levels of Rspo1. STATISTICAL ANALYSIS: All statistical analyses were performed with SPSS 20.0 (SPSS, Inc., Chicago, IL). RESULTS: We found that Rspo1 expression was significantly higher in ESCC than in adjacent normal tissues (P < 0.0001). Moreover, Rspo1 was highly expressed in ESCC tumor specimens and showed a significant correlation with the T classification of ESCC (P < 0.05). Additionally, our findings indicate a positive relationship between Rspo1 and survival time in ESCC. Patients exhibiting moderate to high levels of Rspo1 expression demonstrated superior survival outcomes compared to those with low expression (P = 0.0002). CONCLUSIONS: Our investigation has demonstrated that Rspo1 is upregulated in ESCC and exhibits a positive correlation with disease progression. Furthermore, we have observed a significant association between Rspo1 overexpression and improved patient survival rates, indicating its potential as a prognostic marker and therapeutic target for ESCC treatment.

YAP promotes the early development of temporomandibular joint bony ankylosis by regulating mesenchymal stem cell function.

To explore the role of YAP, a key effector of the Hippo pathway, in temporomandibular joint (TMJ) ankylosis. The temporal and spatial expression of YAP was detected via immunohistochemistry and multiplex immunohistochemistry on postoperative Days 1, 4, 7, 9, 11, 14 and 28 in a sheep model. Isolated mesenchymal stem cells (MSCs) from samples of the Day 14. The relative mRNA expression of YAP was examined before and after the osteogenic induction of MSCs. A YAP-silenced MSC model was constructed, and the effect of YAP knockdown on MSC function was examined. YAP is expressed in the nucleus of the key sites that determine the ankylosis formation, indicating that YAP is activated in a physiological state. The expression of YAP increased gradually over time. Moreover, the number of cells coexpressing of RUNX2 and YAP-with the osteogenic active zone labelled by RUNX2-tended to increase after Day 9. After the osteogenic induction of MSCs, the expression of YAP increased. After silencing YAP, the osteogenic, proliferative and migratory abilities of the MSCs were inhibited. YAP is involved in the early development of TMJ bony ankylosis. Inhibition of YAP using shRNA might be a promising way to prevent or treat TMJ ankylosis.

The silence of MUC2 mRNA induced by promoter hypermethylation associated with HBV in Hepatocellular Carcinoma.

BACKGROUND: To evaluate the promoter methylation status of MUC2 gene and mRNA expression in patients with hepatocellular carcinoma. METHODS: We analyzed MUC2 methylation by MSP, and MUC2 mRNA by real-time PCR in 74 HCC. RESULTS: MUC2 mRNA were lower in HCC tissues (Mean -ΔCt = -4.70) than that in Non-HCC tissues (Mean -ΔCt = -2.98). Expression of MUC2 was elevated in only 23 (31.08%) of the 74 HCC patients. MUC2 promoter was hypermethylated in 62.2% (46/74) of HCCs, and in only 18.9% (14/74) of non-tumor samples. MUC2 mRNA were lower in HCC patients with hypermethylation (Mean -ΔΔCt = -2.25) than those with demethylation (Mean -ΔΔCt = -0.22), and there is a decreased tendency for MUC2 mRNA in HCC patients with promoter hypermethylation (p = 0.011). There was a significantly correlation found between MUC2 mRNA and HBV and AFP in HCC. The loss of MUC2 mRNA and hypermethylation could be poor prognostic factors. After treated by 5-Aza-CdR and TSA, we found that MUC2 mRNA induced significantly in 7721, Huh7 and HepG2 cells. CONCLUSION: The results suggested that MUC2 mRNA silenced by promoter hypermethylation is associated with high levels HBV in HCC.

Altered genome­wide hydroxymethylation analysis for neoadjuvant chemoradiotherapy followed by surgery in esophageal cancer.

Esophageal cancer has high incidence rate in China. Neoadjuvant chemoradiotherapy (nCRT) has become the standard treatment for esophageal squamous cell carcinoma (ESCC). However, there are few reliable epigenetic parameters for patients with ESCC undergoing neoadjuvant therapy. Genomic extract from tumor tissue was amplified and sequenced using the Illumina HiSeq4000 to quantify genes associated methylation or hydromethylation in 12 patients with ESCC undergoing nCRT. The genome-wide hydroxymethylation were analyzed by methylated and hydroxymethylated DNA immunoprecipitation sequencing by MACS2 software and UCSC RefSeq database. Abnormal DNA methylation was statistically different between nCRT-well (showed a pathological complete response to nCRT) and nCRT-poor (showed incomplete pathological response to nCRT) patients. Levels of ten-eleven translocation 1, 2 and 3 mRNA and protein were higher in tumor tissue in nCRT-well group patients than in nCRT-poor group patients. Illumina HiSeq 4000 sequencing identified 2925 hypo-differentially hydroxymethylated region (DhMRs) and 292 hyper-DhMRs in promoter between nCRT-well and nCRT-poor patients. Biological processes associated with hyper-DhMRs included 'snRNA processing', 'hormone-mediated signaling pathway' and 'cellular response'. Metabolic processes were associated with hypo-DhMRs. These data may explain the functional response to nCRT in patients with abnormal promoter of methylation gene-associated mRNA expression. The present results implied that hyper-DhMRs and hypo-DhMRs affect molecular pathways, such as hippo and Notch signaling pathways, highlighting epigenetic modifications associated with clinical response to nCRT in patients with esophageal cancer.

Efficient Simultaneous Detection of Metabolites Based on Electroenzymatic Assembly Strategy.

Objective and Impact Statement: We describe an electroenzymatic mediator (EM) sensor based on an electroenzymatic assembly peak separation strategy, which can efficiently realize the simultaneous detection of 3 typical cardiovascular disease (CVD) metabolites in 5 µl of plasma under one test. This work has substantial implications toward improving the efficiency of chronic CVD assessment. Introduction: Monitoring CVD of metabolites is strongly associated with disease risk. Independent and time-consuming detection in hospitals is unfavorable for chronic CVD management. Methods: The EM was flexibly designed by the cross-linking of electron mediators and enzymes, and 3 EM layers with different characteristics were assembled on one electrode. Electrons were transferred under tunable potential; 3 metabolites were quantitatively detected by 3 peak currents that correlated with metabolite concentrations. Results: In this study, the EM sensor showed high sensitivity for the simultaneous detection of 3 metabolites with a lower limit of 0.01 mM. The linear correlation between the sensor and clinical was greater than 0.980 for 242 patients, and the consistency of risk assessment was 94.6%. Conclusion: Metabolites could be expanded by the EM, and the sensor could be a promising candidate as a home healthcare tool for CVD risk assessment.

A Novel Risk Model Identified Based on Pyroptosis-Related lncRNA Predicts Overall Survival and Associates With the Immune Landscape of GC Patients.

Gastric cancer (GC) is one of the most common malignant gastrointestinal tumors worldwide. Pyroptosis was widely reported to exert a crucial function in tumor development. In addition, pyroptosis was also proved to be associated with the immune landscape. However, whether pyroptosis-related lncRNAs are associated with the prognosis and the immune landscape of GC remains unclear. In the present study, we first constructed a novel risk model by using pyroptosis-related lncRNAs. We identified 11 pyroptosis-related lncRNAs for the establishment of the risk model. The risk model could be used to predict the survival outcome and immune landscape of GC patients. The results of survival analysis and AUC value of a time-related ROC curve proved that our risk model has an elevated efficiency and accuracy in predicting the survival outcome of patients. We also found that the risk model was also associated with the immune landscape, drug sensitivity, and tumor mutation burden of GC patients. In conclusion, our risk model plays a crucial role in the tumor immune microenvironment and could be used to predict survival outcomes of GC patients.

The heparinase-linked differential time method allows detection of heparin potency in whole blood with high sensitivity and dynamic range.

Anticoagulation therapy with heparin is an effective treatment against thrombosis. Heparin tends to cause spontaneous bleeding and requires regular monitoring during therapy. Most high-sensitivity heparin sensors have focused on the concentration detection in clarified buffer solution. However, the pharmacodynamics of heparin vary depending on individual patient or disease, while potency detection with high sensitivity and dynamic range outperforms concentration detection in clinical diagnosis. In this study, a novel heparinase-linked differential time (HLDT) method was established with a two-zone of Graphene modified Carbon (GR-C) sensor, which was utilized to evaluate heparin potency in whole blood. It was based on electrochemical measurement of clotting time shifting associated with presence or absence of heparinase. Heparinase inhibits the anticoagulant ability of heparin by forming a heparin-antithrombin-thrombin complex during coagulation. And the intensity and peak time of electrochemical current were associated with thrombin activity and clotting on the electrode. The results demonstrated that the sensor had high selectivity for heparin potency in 10 µL of whole blood with a detection limit of 0.1 U/mL, and the linear detection range was 0.1-5 U/mL. The coefficient of variation (CV) of the peak time was less than 5%, and linear correlation between the GR-C sensor and the TEG-5000 instrument was 0.987. Thus, the HLDT method has better clinical application due to its good repeatability, high sensitivity and wide range in heparin potency evaluation.

Integrated microdevice with a windmill-like hole array for the clog-free, efficient, and self-mixing enrichment of circulating tumor cells.

Circulating tumor cells (CTCs) have tremendous potential to indicate disease progression and monitor therapeutic response using minimally invasive approaches. Considering the limitations of affinity strategies based on their cost, effectiveness, and simplicity, size-based enrichment methods that involve low-cost, label-free, and relatively simple protocols have been further promoted. Nevertheless, the key challenges of these methods are clogging issues and cell aggregation, which reduce the recovery rates and purity. Inspired by the natural phenomenon that the airflow around a windmill is disturbed, in this study, a windmill-like hole array on the SU-8 membrane was designed to perturb the fluid such that cells in a fluid would be able to self-mix and that the pressure acting on cells or the membrane would be dispersed to allow a greater velocity. In addition, based on the advantages of fluid coatings, a lipid coating was used to modify the membrane surface to prevent cell aggregation and clogging of the holes. Under the optimal conditions, recovery rates of 93% and 90% were found for A549 and HeLa cells in a clinical simulation test of our platform with a CTC concentration of 20-100 cells per milliliter of blood. The white blood cell (WBC) depletion rate was 98.7% (n = 15), and the CTC detection limit was less than 10 cells per milliliter of blood (n = 6). Moreover, compared with conventional membrane filtration, the advantages of the proposed device for the rapid (2 mL/min) and efficient enrichment of CTCs without clogging were shown both experimentally and theoretically. Due to its advantages in the efficient, rapid, uniform, and clog-free enrichment of CTCs, our platform offers great potential for metastatic detection and therapy analyses.

Elevated expression of the stem cell marker CD133 associated with Line-1 demethylation in hepatocellular carcinoma.

BACKGROUND: The relationship of Line-1 demethylation and the CD133 expression of cancer stem cells were discussed in hepatocellular carcinoma (HCC). METHODS: In 95 HCC and matched nontumor tissues, we analyzed the methylation level of Line-1 by quantitative real-time methylation-specific polymerase chain reaction, and the expression of CD133 by real-time reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: Unmethylation of Line-1 increased from nontumor tissues (1.23 × 10(7) copies/µg DNA) toward HCC tissues (2.99 × 10(7) copies/µg DNA), but methylation of Line-1 kept 2 × 10(8) copies/µg DNA around in HCC and nontumor tissues. The methylation index (MI) of Line-1 decreased from 0.919 in nontumor samples to 0.755 in HCC. Results showed that cumulative survival was significantly shorter in HCC patients with MI < 0.76 than that in patients with MI ≥ 0.76. CD133 mRNA expression were higher in HCC tissues (mean -∆(Ct) = -5.751) than that in nontumor tissues (mean -∆(Ct) = -6.742). A total of 73 (76.8%) patients had demethylation of Line-1 (∆MI < 0), and 22 (23.2%) patients had hypermethylation of Line-1 (∆MI ≥ 0). HCC with demethylation of Line-1 had elevated CD133 expression in tumor rather than matched nontumor tissues (mean -∆(∆Ct) = 1.101), but HCC with hypermethylation of Line-1 was considered to be lower with CD133 expression in tumor (mean -∆(∆Ct) = -0.409). CONCLUSIONS: Line-1 hypomethylation is the most common molecular abnormality during the carcinogenic process. Elevated expression of CD133 was associated with demethylation of Line-1 in HCC.

Facile and Scalable Synthesis of 3D Structures of V10O24·12H2O Nanosheets Coated with Carbon toward Ultrafast and Ultrastable Zinc Storage.

Three-dimensional (3D) structures of V10O24·12H2O nanosheets coated with carbon (denoted as V10O24@C) are facially and cost-effectively fabricated by reducing the V2O5-based aqueous solution with ethanol under hydrothermal conditions. By using the 3D V10O24@C as the cathode of zinc-ion batteries, the as-obtained 3D V10O24@C sample delivers excellent charge-discharge cycling capability, superior rate performance, and reasonable specific capacity, and a specific capacity of ca. 133.3 mA h g-1 and a 94.1% capacity retention are achieved even after 10000 cycles at a high current density of 10 A g-1 (∼80 C). Furthermore, it provides a facile and scalable approach to synthesize the 3D structures of pure-phased vanadium oxide nanosheets or other nanoscale metal oxides coated with carbon.

Mucin 1 and interleukin-11 protein expression and inflammatory reactions in the intestinal mucosa of necrotizing enterocolitis children after surgery.

BACKGROUND: Necrotizing enterocolitis (NEC) of the newborn is a frequently occurring clinical disease in infants. The mortality rate of NEC in premature infants is as high as 50%, and the morbidity rate is on the rise. NEC has already caused serious impacts on newborn survival and poses serious threats to both children and families. AIM: To investigate the expression and significance of mucin 1 (MUC1) and interleukin-11 (IL-11) in the intestinal mucosa of infants with neonatal NEC after surgery. METHODS: Forty-eight postoperative intestinal mucosal specimens from children with NEC (NEC group) and twenty-two intestinal mucosal specimens from children with congenital intestinal atresia (control group) were collected in our hospital. Immunohistochemical staining and Western blot analysis were used to examine the protein expression of MUC-1 and IL-11 in the two groups. The serum levels of tumor necrosis factor-α (TNF-α) and IL-1ß in the two groups were measured by enzyme-linked immunosorbent assay, and the relationship between MUC-1 and IL-11 protein expression and serum TNF-α and IL-1ß levels was analyzed by the linear correlation method. RESULTS: The protein expression of MUC-1 and IL-11 in the NEC group was significantly lower than that in the control group, and the difference was statistically significant (P < 0.05). The levels of serum TNF-α and IL-1ß in the NEC group were significantly higher than those in the control group (P < 0.05). The protein expression of MUC-1 and IL-11 in the NEC group negatively correlated with serum TNF-α and IL-1ß levels (P < 0.05). There was a significant negative correlation between the protein expression of MUC-1 and IL-11 and the levels of serum TNF-α and IL-1ß in the NEC group. CONCLUSION: The protein expression of MUC1 and IL-11 in the intestinal mucosa of children with NEC is significantly downregulated after surgery. This downregulation may be involved in the pathogenesis of this disease and has a certain correlation with inflammatory response factors in children with NEC.

Effect of tryptophan hydroxylase-2 rs7305115 SNP on suicide attempts risk in major depression.

BACKGROUND: Suicide and major depressive disorders (MDD) are strongly associated, and genetic factors are responsible for at least part of the variability in suicide risk. We investigated whether variation at the tryptophan hydroxylase-2 (TPH2) gene rs7305115 SNP may predispose to suicide attempts in MDD. METHODS: We genotyped TPH2 gene rs7305115 SNP in 215 MDD patients with suicide and matched MDD patients without suicide. Differences in behavioral and personality traits according to genotypic variation were investigated by logistic regression analysis. RESULTS: There were no significant differences between MDD patients with suicide and controls in genotypic (AG and GG) frequencies for rs7305115 SNP, but the distribution of AA genotype differed significantly (14.4% vs. 29.3%, p < 0.001). The G-allele frequency was significantly higher in cases than control group (58.1% vs.45.6%, p < 0.001), but the A-allele carrier indicated a decreased trend in MDD with suicide behaviors than control group (41.9% vs.54.4%, p < 0.001). The multivariate logistic regression analysis indicated that TPH2 rs7305115 AA (OR 0.33, 95% CI 0.22-0.99), family history of suicide (OR 2.98, 95% CI 1.17-5.04), negative life events half year ago (OR 6.64, 95% CI 2.48-11.04) and hopelessness (OR 7.68, 95% CI 5.79-13.74) were significantly associated with the suicide behaviors in MDD patients. CONCLUSIONS: The study suggested that hopelessness, negative life events and family history of suicide were risk factors of attempted suicide in MDD while the TPH2 rs7305115A remained a significant protective predictor of suicide attempts.

Correlation of CpG island methylator phenotype with poor prognosis in hepatocellular carcinoma.

CpG island methylator phenotype (CIMP), in which multiple genes are concurrently methylated, is an important mechanism in hepatocellular carcinoma development. We determined a hypermethylation profile in hepatocellular carcinoma (HCC). We examined the promoter methylation status of 10 genes in 60 cases of hepatocellular carcinoma (HCC), 60 cases of paired non-tumor tissues, and 6 cases of normal tissues by methylation-specific PCR. The average methylated gene numbers were significantly different between HCC and nontumor tissues (p<0.001). We found metastasis, gamma-glutamyl transpeptidase (GGT) and tumor node metastasis (TNM) stage were significantly different among patients with different CIMP status. Patients with high frequency CIMP tumors had significantly worse survival than patients with intermediate frequency or no CIMP tumors (p<0.01 and p<0.05, respectively). Our results suggested that CIMP could serve as a molecular marker of late stage and poorly prognostic HCC development.

A Dendrite-free Na-Na2S-Carbon Hybrid toward a Highly Stable and Superior Sodium Metal Anode.

An effective method to fabricate a dendrite-free Na-Na2S-carbon hybrid anode is developed by immersing sulfur-doped carbon paper into molten sodium with common tissue paper as the starting material. The as-obtained hybrid anode displays much decreased nucleation and mass-transfer-controlled overpotentials for sodium plating, and a low and stable voltage hysteresis of ∼150 mV is obtained under a current density of 4 mA cm-2. It provides a dendrite-free sodium-based anode with superior rate performance and long-term stability. Furthermore, it provides an effective avenue to alleviate the growth of dendrites and lower the overpotentials for other kinds of metal-based electrodes.

High throughput synthesis of defect-rich MoS2 nanosheets via facile electrochemical exfoliation for fast high-performance lithium storage.

A facile and cost-effective method to prepare defect-rich MoS2 nanosheets is developed via an electrochemical exfoliation process. By using bucket-like metallic titanium mesh both as inert anode and container for MoS2 powders, defect-rich thin MoS2 nanosheets can be fast exfoliated from the bulk powders in aqueous sodium sulfate electrolyte under positive potentials. The as-obtained MoS2 nanosheets exhibit excellent cycling capability, high specific capacity, and superior rate performance for lithium storage. Furthermore, it provides a novel and effective method to exfoliate insulative or semiconductive layer-structured bulk powders into defect-rich 2D nanosheets.

IL-10 promoter hypomethylation is associated with increased IL-10 expression and poor survival in hepatocellular carcinoma.

BACKGROUND: Epigenetic alterations of tumor-associated genes contribute to the pathogenesis of virtually all cancer types. We evaluated the methylation status of the interleukin-10 (IL-10) gene promoter and assessed its association with IL-10 mRNA expression and clinical prognosis in hepatocellular carcinoma (HCC) patients. METHODS: Methylation-specific polymerase chain reaction (MSP) and real-time polymerase chain reaction (PCR) were used to define the methylation index (MI) of the IL-10 gene and quantify IL-10 mRNA expression in 120 HCC samples and paired non-tumor tissues. RESULTS: Mean MI was 0.47 in HCC specimens and 0.59 in non-tumor controls, and was associated with metastasis classification and serum α-fetoprotein (AFP) levels. IL-10 mRNA levels [mean -∆∆Ct of 1.678 in HCC cases with hypomethylation (∆MI ≤0) and -0.18 in HCC cases with hypermethylation (∆MI >0)] also correlated with metastasis classification and serum AFP. An association was detected between IL-10 mRNA and its gene's MI in HCC. Also, an association was found between IL-10 hypomethylation, but not IL-10 mRNA expression and reduced postoperative HCC survival. CONCLUSIONS: These results indicate that IL-10 promoter hypomethylation is associated with increased IL-10 mRNA levels and indicative of poor survival in HCC.

A retrospective study of low-dose apatinib combined with S-1 in patients with advanced non-small cell lung cancer.

BACKGROUND: The current regimens for advanced non-small cell lung cancer (NSCLC) patients are deficient due to failings in standard treatments. This retrospective study aimed to assess the efficacy and safety of low-dose apatinib in combination with S-1 therapy in a NSCLC setting. METHODS: In this retrospective study, advanced NSCLC patients who failed standard treatment in Changzhou Cancer Hospital of Soochow University were screened for eligibility. Progression-free survival (PFS) was set as the primary endpoint. Overall response rate (ORR), disease control rate (DCR), overall survival (OS), and the safety profile were considered to be the secondary endpoints. RESULTS: A total of 31 eligible patients were included. The median PFS (mPFS) was 102 days (95% CI: 57-147 days). ORR was achieved in 7 patients (22.6%; 95% CI: 11.1-38.2%) and DCR was maintained in 23 patients (74.2%; 95% CI: 58.2-86.5%). The median OS (mOS) was 422 days (95% CI: 148-696 days). Patients with a history of smoking tended to have a shorter OS without significant differences (HR =4.105, 95% CI: 0.874-19.288, P=0.074). Treatment-related grade III toxicity was observed in 5 patients (16%) and common grade I or II adverse events (AEs) were fatigue (42%), hypertension (32%), and hand-foot-skin reaction (23%). CONCLUSIONS: Combination of low-dose apatinib and S-1 could be an effective and tolerable choice for advanced NSCLC patients who are unable to benefit from standard treatment; however, further exploration in larger clinical trials is needed.

DENN domain-containing protein FAM45A regulates the homeostasis of late/multivesicular endosomes.

DENN (differentially expressed in normal cells and neoplasia) domain-containing proteins are a family of guanine nucleotide exchange factors (GEFs) for Rab small GTPases and coordinate a plethora of intracellular membrane trafficking events. FAM45A is a non-classical DENN domain protein, whose function was unknown. In this study, we characterized cellular roles of FAM45A. We found that FAM45A localized mainly in late/multivesicular endosomes. Depletion of FAM45A resulted in clustering of endosomes to the perinuclear region. The endocytosis of EGF receptor was impaired in FAM45A knockdown cells due to a delay in the early-to-late endosome transition. Furthermore, the secretion of selected exosome subpopulations was also attenuated in FAM45A knockdown cells. Consistent with these results, Rab27a and Rab27b, two Rabs involved in endosome motility and exosome biogenesis, were found to act downstream of FAM45A pathway. FAM45A colocalized with Rab27a/b and formed complex with them in a nucleotide-dependent manner. Taken together, FAM45A defines a novel regulatory step in the homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion, possibly through activating Rab proteins such as Rab27a/b.