Anti-phospholipase A2 receptor antibody levels at diagnosis predicts outcome of TAC-based treatment for idiopathic membranous nephropathy patients.

BACKGROUND: Idiopathic membranous nephropathy (iMN) is recognized as an organ-specific autoimmune disease, mainly caused by anti-PLA2R antibody. This study aimed to study between anti-PLA2R antibody level at diagnosis and the response to tacrolimus (TAC)-based treatment in iMN patients. METHODS: This was a retrospective cohort study including 94 kidney biopsy-proven MN patients with positive anti-PLA2R antibody at diagnosis from May 2017 to September 2021 in our center. All iMN patients received the TAC regimen as the initial immunosuppressive therapy. All patients were divided into two groups according to anti-PLA2R antibody titer at diagnosis: high-level group (> 150 RU/ml; n = 42) and low-level group (≤ 150 RU/ml; n = 52). The association between anti-PLA2R antibody levels and clinical outcomes was assessed using the Kaplan-Meier method. RESULTS: The low density lipoprotein in the high-level group was significantly higher than low-level group at diagnosis, otherwise, serum albumin was significantly lower than low-level group; however, there was no significant difference in creatinine levels between two groups. The remission rates were significantly higher in the low-level group than high-level group after treatment with TAC for 12, 18, or 24 months (all P < 0.05). After 12 months of treatment with TAC, 82.7% of the patients in the low-level group achieved complete remission (CR) or partial remission (PR) (mean, 6.52 ± 0.53 months). However, 38.1% of the patients in high-level group achieved CR or PR (mean, 9.86 ± 0.51 months). Moreover, CR rate at 12 months in the high-level group was only 4.7% (mean, 11.88 ± 0.63 months). The infection frequency in the high-level group (35.6%) was higher than the low-level group (20%) during the TAC treatment, although there was no significant difference (P = 0.065). There were 19% patients who had end-stage kidney disease (ESKD), and 7.1% of patients died of ESKD in the high-level group during the follow-up period. CONCLUSION: Anti-PLA2R antibody level above 150 RU/ml at diagnosis can predict a poor treatment response and outcome of TAC treatment in iMN patients, who may not benefit from TAC or other calcineurin inhibitor regimens as the initial treatment.

Changes in the spectrum of kidney diseases: a survey of 2803 patients from 2010 to 2018 at a single center in southeastern China.

Primary glomerular disease was the leading cause of chronic kidney disease (CKD) in China; however, changes in the economy and environment introduce variations in the spectrum of kidney diseases. This study aimed to analyze renal biopsy data to inform disease prevention and public health interventions. In this retrospective cohort study, data from 2,803 consecutive renal biopsies conducted at our center between January 2010 and December 2018 were analyzed. The sample was disaggregated by age and the date of biopsy to facilitate analysis. Primary glomerulonephritis (PGN) is the most frequent (81.84%) finding, followed by secondary glomerulonephritis (SGN; 15.38%), tubulointerstitial nephritis (15.38%), and others (1.57%). IgA nephropathy (IgAN), idiopathic membranous nephropathy (iMN), and minimal change disease were the primary causes of PGN. Among PGN cases, the incidence of iMN arose, especially among those aged ≥ 60 years old, during the observation period. Contrary to the case of iMN, the proportion of IgAN in PGN trended downward, continuously, and at length. Moreover, IgAN mainly affected those aged 25-44 years old and less so those aged ≥ 60 years old. Lupus nephritis, Henoch-Schönlein purpura nephritis, and diabetic nephropathy (DN) were key causes of SGN. A ratio reversal between infectious disease and chronic disease dramatically changed SGN patterns. In the past year, the incidence of hepatitis B-related nephritis has constantly declined; however, the proportion of DN among SGN had steadily increased. The incidence of iMN significantly increased during these years. Among SGN cases, the proportion of DN has increased.

Glioma stages prediction based on machine learning algorithm combined with protein-protein interaction networks.

BACKGROUND: Glioma is the most lethal nervous system cancer. Recent studies have made great efforts to study the occurrence and development of glioma, but the molecular mechanisms are still unclear. This study was designed to reveal the molecular mechanisms of glioma based on protein-protein interaction network combined with machine learning methods. Key differentially expressed genes (DEGs) were screened and selected by using the protein-protein interaction (PPI) networks. RESULTS: As a result, 19 genes between grade I and grade II, 21 genes between grade II and grade III, and 20 genes between grade III and grade IV. Then, five machine learning methods were employed to predict the gliomas stages based on the selected key genes. After comparison, Complement Naive Bayes classifier was employed to build the prediction model for grade II-III with accuracy 72.8%. And Random forest was employed to build the prediction model for grade I-II and grade III-VI with accuracy 97.1% and 83.2%, respectively. Finally, the selected genes were analyzed by PPI networks, Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the results improve our understanding of the biological functions of select DEGs involved in glioma growth. We expect that the key genes expressed have a guiding significance for the occurrence of gliomas or, at the very least, that they are useful for tumor researchers. CONCLUSION: Machine learning combined with PPI networks, GO and KEGG analyses of selected DEGs improve our understanding of the biological functions involved in glioma growth.

Inhibition of HIF1A-AS1 promoted starvation-induced hepatocellular carcinoma cell apoptosis by reducing HIF-1α/mTOR-mediated autophagy.

BACKGROUND: Hepatocellular carcinoma (HCC) is still a major health burden in China considering its high incidence and mortality. Long non-coding RNAs (lncRNAs) were found playing vital roles in tumor progression, suggesting a new way of diagnosis and prognosis prediction, or treatment of HCC. This study was designed to investigate the role of HIF1A-AS1 during the progression of HCC and to explore its related mechanisms. METHODS: The expression of HIF1A-AS1 was detected in 50 paired carcinoma tissues and adjacent normal tissues by quantitative real-time PCR assay. HCC cell apoptosis was induced by nutrient-deficient culture medium and detected by Cell Counting Kit-8 and flow cytometer assays. HIF1A-AS1 inhibition in HCC cells was accomplished by small interfering RNA transfection. RESULTS: HIF1A-AS1 was overexpressed in HCC tissues and was associated with tumor size, TNM stage, and lymph node metastasis. Compared with the low HIF1A-AS1 group, the high HIF1A-AS1 group had a shorter overall survival and a worse disease-free survival. HIF1A-AS1 expression was significantly higher in HCC cell lines (7721 and Huh7) than that in normal hepatocyte cell line L02 under normal culture condition. However, under nutrient-deficient condition, HIF1A-AS1 expression was significantly increased in both HCC and normal hepatocyte cell lines and was increased with the prolongation of nutrient-free culture. Inhibition of HIF1A-AS1 promoted starvation-induced HCC cell apoptosis. Furthermore, inhibition of HIF1A-AS1 could also reduce starvation-induced HCC cell autophagy. The expression of HIF-1α and phosphorylated mTOR was significantly decreased in HCC cells after HIF1A-AS1 inhibition. CONCLUSIONS: HIF1A-AS1, overexpressed in HCC and associated with HCC prognosis, could regulate starvation-induced HCC cell apoptosis by reducing HIF-1α/mTOR-mediated autophagy, promoting HCC cell progression.

Fluorofenidone attenuates interleukin-1ß production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction.

AIM: We explored whether Fluorofenidone reduced interleukin-1ß (IL-1ß) production by interacting with NLRP3 inflammasome in unilateral ureteral obstruction (UUO). METHODS: Ureteral obstruction rats were treated with Fluorofenidone (500 mg/kg per day) for 3, 7 days. Morphologic analysis and leukocytes infiltration were assessed in ligated kidneys. Furthermore, plasmids of NLRP3, ASC, pro-Caspase-1, pro-IL-1ß were co-transfected into 293 T cells, and then treated with Fluorofenidone (2 mM). The expression of NLRP3, ASC, pro-caspase-1, cleavage caspase-1, pro-IL-1ß and cleavage IL-1ß were measured by Western blot or real-time PCR in vivo and in vitro. Moreover the interaction of NLRP3 inflammasome-assembly was detected by co-immunoprecipitation and confocal immunofluorescence. RESULTS: Fluorofenidone treatment significantly attenuated renal fibrosis and leukocytes infiltration in UUO model. Fluorofenidone had no effect on the expression of pro-IL-1ß. Interestingly, Fluorofenidone inhibited the activation of NLRP3 inflammasome, downregulated Caspase-1 levels and thereby decreased the cleavage of pro-IL-1ß into IL-1ß in vivo and in vitro. Fluorofenidone treatment distinctively weakened the interaction between NLRP3 and ASC, as well as ASC and pro-Caspase-1 in vivo. However, Fluorofenidone treatment only significantly weakened the interaction between ASC and pro-Caspase-1 in co-transfected 293 T cells. CONCLUSION: Fluorofenidone serves as a novel anti-inflammatory agent that attenuates IL-1ß production in UUO model by interacting with NLRP3 inflammasome.

Dendrimer-Assisted Formation of Fe3O4/Au Nanocomposite Particles for Targeted Dual Mode CT/MR Imaging of Tumors.

A unique dendrimer-assisted approach is reported to create Fe3O4/Au nanocomposite particles (NCPs) for targeted dual mode computed tomography/magnetic resonance (CT/MR) imaging of tumors. In this approach, preformed Fe3O4 nanoparticles (NPs) are assembled with multilayers of poly(γ-glutamic acid) (PGA)/poly(L-lysine)/PGA/folic acid (FA)-modified dendrimer-entrapped gold nanoparticles via a layer-by-layer self-assembly technique. The interlayers are crosslinked via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide chemistry, the assembled Au core NPs are then used as seed particles for subsequent seed-mediated growth of Au shells via iterative Au salt reduction process, and subsequent acetylation of the remaining amines of dendrimers leads to the formation of Fe3O4/Au(n.)Ac-FA NCPs with a tunable molar ratio of Au/Fe3O4. It is shown that the Fe3O4/Au(n.)Ac-FA NCPs at an optimized Au/Fe3O4 molar ratio of 2.02 display a relatively high R2 relaxivity (92.67 × 10(-3) M(-1) s(-1)) and good X-ray attenuation property, and are cytocompatible and hemocompatible in the given concentration range. Importantly, with the FA-mediated targeting, the Fe3O4/Au(n.)Ac-FA NCPs are able to be specifically uptaken by cancer cells overexpressing FA receptors, and be used as an efficient nanoprobe for targeted dual mode CT/MR imaging of a xenografted tumor model. With the versatile dendrimer chemistry, the developed Fe3O4/Au NCPs may be differently functionalized, thereby providing a unique platform for diagnosis and therapy of different biological systems.

Socio-economic factors related with the subjective well-being of the rural elderly people living independently in China.

BACKGROUND: Many Chinese elderly increasingly face the serious problem of the "empty nest" phenomenon. The elderly living independently, also called empty-nest elderly, refers to elderly people living alone whose children left home. However few studies concerned about the subjective well-being (SWB) of the elderly living independently. METHODS: This study employs The Memorial University of Newfoundland Scale of Happiness (MUNSH) to explore the SWB of the elderly living independently in rural areas of Wenzhou, a relatively developed region in China. 536 sampled are randomly selected. RESULTS: The results indicate that participants obtained low scores in positive affect, positive experience, and the total SWB score, but high scores in negative affect and negative experience. Age, low education, poor health condition and little income were found to be negatively correlated with SWB. The SWB score of the elderly living with a spouse is higher than those who divorced or lost their spouse and the score of women is lower than that of men. In addition, the survey revealed that children's support has a positive influence on the SWB of the rural elderly living independently. CONCLUSIONS: The elderly living independently in rural Wenzhou, China have unfavorable SWB. Poor socio-economic statuses are negative impact factors. But the children's support can help to improve. Special attention is needed to those with lower socio-economic status and less children's support.

Fluorofenidone attenuates renal fibrosis by inhibiting lysosomal cathepsin­mediated NLRP3 inflammasome activation.

Currently, no antifibrotic drug in clinical use can effectively treat renal fibrosis. Fluorofenidone (AKFPD), a novel pyridone agent, significantly reduces renal fibrosis by inhibiting the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome; however, the underlying mechanism of this inhibition is not fully understood. The present study aimed to reveal the molecular mechanism underlying the suppression of NLRP3 inflammasome activation by AKFPD. It investigated the effect of AKFPD on NLRP3 activation and lysosomal cathepsins in a unilateral ureteral obstruction (UUO) rat model, and hypoxia/reoxygenation (H/R)-treated HK-2 cells and murine peritoneal-derived macrophages (PDMs) stimulated with lipopolysaccharide (LPS) and ATP. The results confirmed that AKFPD suppressed renal interstitial fibrosis and inflammation by inhibiting NLRP3 inflammasome activation in UUO rat kidney tissues. In addition, AKFPD reduced the production of activated caspase-1 and maturation of IL-1ß by suppressing NLRP3 inflammasome activation in H/R-treated HK-2 cells and murine PDMs stimulated with LPS and ATP. AKFPD also decreased the activities of cathepsins B, L and S both in vivo and in vitro. Notably, AKFPD downregulated cathepsin B expression and NLRP3 colocalization in the cytoplasm after lysosomal disruptions. Overall, the results suggested that AKFPD attenuates renal fibrosis by inhibiting lysosomal cathepsin-mediated activation of the NLRP3 inflammasome.

HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

Targeted tumor computed tomography imaging using low-generation dendrimer-stabilized gold nanoparticles.

We report a facile approach to fabricating low-generation poly(amidoamine) (PAMAM) dendrimer-stabilized gold nanoparticles (Au DSNPs) functionalized with folic acid (FA) for in vitro and in vivo targeted computed tomography (CT) imaging of cancer cells. In this study, amine-terminated generation 2 PAMAM dendrimers were employed as stabilizers to form Au DSNPs without additional reducing agents. The formed Au DSNPs with an Au core size of 5.5 nm were covalently modified with the targeting ligand FA, followed by acetylation of the remaining dendrimer terminal amines to endow the particles with targeting specificity and improved biocompatibility. Our characterization data show that the formed FA-modified Au DSNPs are stable at different pH values (5-8) and temperatures (4-50 °C), as well as in different aqueous media. MTT assay data along with cell morphology observations reveal that the FA-modified Au DSNPs are noncytotoxic in the particle concentration range of 0-3000 nM. X-ray attenuation coefficient measurements show that the CT value of FA-modified Au DSNPs is much higher than that of Omnipaque (a clinically used CT contrast agent) at the same concentration of the radiodense elements (Au or iodine). Importantly, the FA-modified Au DSNPs are able to specifically target a model cancer cell line (KB cells, a human epithelial carcinoma cell line) over-expressing FA receptors and they enable targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo after intravenous administration of the particles. With the simple synthesis approach, easy modification, good cytocompatibility, and high X-ray attenuation coefficient, the FA-modified low-generation Au DSNPs could be used as promising contrast agents for targeted CT imaging of different tumors over-expressing FA receptors.

Dendrimer-stabilized bismuth sulfide nanoparticles: synthesis, characterization, and potential computed tomography imaging applications.

We report here a general approach to synthesizing dendrimer-stabilized bismuth sulfide nanoparticles (Bi2S3 DSNPs) for potential computed tomography (CT) imaging applications. In this study, ethylenediamine core glycidol hydroxyl-terminated generation 4 poly(amidoamine) dendrimers (G4.NGlyOH) were used as stabilizers to first complex the Bi(III) ions, followed by reaction with hydrogen sulfide to generate Bi2S3 DSNPs. By varying the molar ratio of Bi atom to dendrimer, stable Bi2S3 DSNPs with an average size range of 5.2-5.7 nm were formed. The formed Bi2S3 DSNPs were characterized via different techniques. X-ray absorption coefficient measurements show that the attenuation of Bi2S3 DSNPs is much higher than that of iodine-based CT contrast agent at the same molar concentration of the active element (Bi versus iodine). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay and hemolysis assay reveal that the formed Bi2S3 DSNPs are noncytotoxic and have a negligible hemolysis effect in the studied concentration range. Furthermore, we show that cells incubated with the Bi2S3 DSNPs are able to be imaged using CT, a prominent enhancement at the point of rabbit injected subcutaneously with the Bi2S3 DSNPs is able to be visualized via CT scanning, and the mouse's pulmonary vein can be visualized via CT after intravenous injection of the Bi2S3 DSNPs. With the good biocompatibility, enhanced X-ray attenuation property, and tunable dendrimer chemistry, the designed Bi2S3 DSNPs should be able to be further functionalized, allowing them to be used as a highly efficient contrast agent for CT imaging of different biological systems.

Sand Erosion Resistance and Failure Mechanism of Polyurethane Film on Helicopter Rotor Blades.

Polyurethane is widely used on the surface of composite materials for rotor blades as sand erosion protection materials. The failure mechanism investigation of polyurethane film under service conditions is useful for developing the optimal polyurethane film for rotor blades. In this article, the sand erosion test parameters were ascertained according to the service environment of the polyurethane film. The sand erosion resistance and failure mechanism of polyurethane film at different impact angles were analyzed by an infrared thermometer, a Fourier transform infrared spectrometer (FTIR), a differential scanning calorimeter (DSC), a field emission scanning electron microscope (FESEM), and a laser confocal microscope (CLSM). The results show that the direct measurement method of volume loss can better characterize the sand erosion resistance of the polyurethane film compared to traditional mass loss methods, which avoids the influence of sand particles embedded in the polyurethane film. The sand erosion resistance of polyurethane film at low-angle impact is much lower than that at high-angle impact. At an impact rate of 220 m/s, the volume loss after sand erosion for 15 min at the impact angle of 30° is 57.8 mm3, while that at the impact angle of 90° is only 2.6 mm3. The volume loss prediction equation was established according to the experimental data. During low-angle erosion, the polyurethane film damage is mainly caused by sand cutting, which leads to wrinkling and accumulation of surface materials, a rapid increase in roughness, and the generation of long cracks. The linking of developing cracks would lead to large-scale shedding of polyurethane film. During high-angle erosion, the polyurethane film damage is mainly caused by impact. The connection of small cracks caused by impact leads to the shedding of small pieces of polyurethane, while the change in the roughness of the film is not as significant as that during low-angle erosion. The disordered arrangement of the soft and hard blocks becomes locally ordered under the action of impact and cutting loads. Then, the disordered state is restored after the erosion test finishes. The erosion of sand particles leads to an increase in the temperature of the erosion zone of the polyurethane film, and the maximum temperature rise is 6 °C, which does not result in a significant change in the molecular structure of the polyurethane film. The erosion failure mechanism is cracking caused by sand cutting and impact.

A tumor microenvironment-responsive core-shell tecto dendrimer nanoplatform for magnetic resonance imaging-guided and cuproptosis-promoted chemo-chemodynamic therapy.

Theranostic nanoplatforms for combination tumor therapy have gained lots of attention recently due to the optimized therapeutic efficiency and simultaneous diagnosis performance. Herein, a novel tumor microenvironment (TME)-responsive core-shell tecto dendrimer (CSTD) was assembled by phenylboronic acid- and mannose-modified poly(amidoamine) dendrimers via the phenylboronic ester bonds that are responsive to low pH and reactive oxygen species (ROS), and efficiently loaded with copper ions and chemotherapeutic drug disulfiram (DSF) for tumor-targeted magnetic resonance (MR) imaging and cuproptosis-promoted chemo-chemodynamic therapy. The formed CSTD-Cu(II)@DSF could be specifically taken up by MCF-7 breast cancer cells, accumulated to the tumor model after circulation, and released drugs in response to the weakly acidic TME with overexpressed ROS. The enriched intracellular Cu(II) ions could induce the oligomerization of lipoylated proteins and proteotoxic stress for cuproptosis, and lipid peroxidation for chemodynamic therapy as well. Moreover, the CSTD-Cu(II)@DSF could cause the dysfunction of mitochondria and arrest the cell cycle at the G2/M phase, leading to enhanced DSF-mediated cell apoptosis. As a result, CSTD-Cu(II)@DSF could effectively inhibit the growth of MCF-7 tumors by a combination therapy strategy integrating chemotherapy with cuproptosis and chemodynamic therapy. Lastly, the CSTD-Cu(II)@DSF also displays Cu(II)-associated r1 relaxivity, allowing for T1-weighted real-time MR imaging of tumors in vivo. The developed tumor-targeted and TME-responsive CSTD-based nanomedicine formulation may be developed for accurate diagnosis and synergistic treatment of other cancer types. STATEMENT OF SIGNIFICANCE: Constructing an effective nanoplatform for the combination of therapeutic effects and real-time tumor imaging remains a challenge. In this study, we reported for the first time an all-in-one tumor-targeted and tumor microenvironment (TME) responsive nanoplatform based on core-shell tecto dendrimer (CSTD) for the cuproptosis-promoted chemo-chemodynamic therapy and enhanced MR imaging. The efficient loading, selective tumor-targeting, and TME-responsive release of Cu(II) and disulfiram could enhance the intracellular accumulation of drugs, induce cuproptosis of cancer cells, and amplify the synergistic chemo-chemodynamic therapeutic effect, resulting in enhanced MR imaging and accelerated tumor eradication. This study sheds new light on the development of theranostic nanoplatforms for early accurate diagnosis and effective treatment of cancers.

Facile one-pot preparation, surface functionalization, and toxicity assay of APTS-coated iron oxide nanoparticles.

We report a facile approach to synthesizing 3-aminopropyltrimethoxysilane (APTS)-coated magnetic iron oxide (Fe(3)O(4)@APTS) nanoparticles (NPs) with tunable surface functional groups for potential biomedical applications. The Fe(3)O(4) NPs with a mean diameter of 6.5 nm were synthesized by a hydrothermal route in the presence of APTS. The formed amine-surfaced Fe(3)O(4)@APTS NPs were further chemically modified with acetic anhydride and succinic anhydride to generate neutral (Fe(3)O(4)@APTS⋅Ac) and negatively charged (Fe(3)O(4)@APTS⋅SAH) NPs. These differently functionalized NPs were extensively characterized by x-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetry analysis, zeta potential measurements, and T(2) relaxometry. The cytotoxicity of the particles was evaluated by in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric viability assay of cells along with microscopic observation of cell morphology. The hemocompatibility of the particles was assessed by in vitro hemolysis assay. We show that the hydrothermal approach enables an efficient modification of APTS onto the Fe(3)O(4) NP surfaces and the formed NPs with different surface charge polarities are water-dispersible and colloidally stable. The acetylated Fe(3)O(4)@APTS⋅Ac NPs displayed good biocompatibility and hemocompatibility in the concentration range of 0-100 µg ml(-1), while the pristine Fe(3)O(4)@APTS and Fe(3)O(4)@APTS⋅SAH particles started to display slight cytotoxicity at a concentration of 10 µg ml(-1). The findings from this study suggest that the Fe(3)O(4)@APTS NPs synthesized by the one-pot hydrothermal route can be surface modified for various potential biomedical applications.

Microbial diversity response to geochemical gradient characteristics on AMD from abandoned Dashu pyrite mine in Southwest China.

The formation and release of acid mine drainage (AMD) have caused extremely serious pollution in the environment around many mining areas. The biological oxidation of metal sulfide minerals causes the production and release of AMD. To understand the interaction mechanism between microbial and AMD, the study uses Southwest Dashu pyrite as an example to investigate the geochemical gradient characteristics and microbial diversity response on AMD from abandoned mine. Through collecting and testing the water samples, the geochemical parameters such as physical and chemical indexes, main ion composition and microbial community composition of seven mine drainage points were obtained. The results showed that the geochemical and microbial community structure the decrease of AMD pollution in the study area with the decrease of altitude has obvious gradient characteristics. Although AMD has the distribution of acid-resistant iron and sulfur bacteria oxidizing bacteria, the microbial community diversity has obvious gradient characteristics. The categories with a relative abundance of > 5% include Proteobacteria, Actinobacteriota, Firmicutes, WPS-2, Chloroflexi, Bacteroidota, and Acidobacteriota. Actinobacteriota, which was common in the AMD, was distributed throughout the samples. The correlation analysis between water quality parameters and microbial community showed that the microbial community structure was affected by environmental factors. With the increase of acidity and metal ion content, the diversity of microbial community decreased, and the content of acid-resistant iron and sulfur oxidizing bacteria increased. The results showed that pH, dissolved oxygen (Do), the total iron (Fe) content (TFe), SO42-, and Al3+ were the five parameters that most affected microbiological diversity and interaction. Hydrogeochemistry and major ions analysis revealed that AMD in the study area mainly comes from the biological oxidation of metal sulfides and the dissolution and cation exchange of other minerals around the deposit. The degree of AMD pollution is related to the hydrogeochemical conditions in the mine. The higher the mine's water level, the lower the pollutants, and the less AMD is produced and released. The findings confirmed that geochemical gradients significantly changed the biota of the mine water and enriched the related microbial diversity adapted to different environmental factors. Therefore, the findings provide strong support for mine containment to inhibit oxidation and lay the foundation for prevention and control strategies of AMD pollution sources.

Programmed death-ligand 1 and mammalian target of rapamycin signaling pathway in locally advanced rectal cancer.

PURPOSE: To evaluate the role of programmed death-ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) signaling pathway in locally advanced rectal cancer (LARC). METHODS: Between February 2012 and February 2018, 103 patients with LARC treated by neoadjuvant chemoradiotherapy (neoCRT) and total mesorectal excision (TME) were included. PD-L1, mTOR and p-mTOR of pair-matched pre-neoCRT biopsies and post-neoCRT surgical tissue were evaluated by immunohistochemistry. RESULTS: The mean combined positive score (CPS), tumor proportion score (TPS) and immune cell score (IC) of pre-neoCRT were 2.24 (0-70), 1.87 (0-70) and 0.67 (0-10), respectively. The mean CPS, TPS and IC of post-neoCRT were 2.19 (0-80), 1.38 (0-80) and 1.60 (0-20), respectively. Significant difference was observed in terms of IC between pre-neoCRT and post-neoCRT (p = 0.010). The 5-year disease-free survival (DFS) rate of the whole group was 62.4%. Multivariate analysis by Cox model indicated that pre-neoCRT TPS [hazard ratio (HR) 1.052, 95% confidence interval (CI) 1.020-1.086, p = 0.001] and post-neoCRT CPS (HR 0.733, 95% CI 0.555-0.967, p = 0.028) were associated with DFS. In the 89 patients without pathological complete response, p-mTOR and IC were upregulated after neoCRT. CONCLUSIONS: For patients with LARC treated by neoCRT and TME, p-mTOR and IC were upregulated after neoCRT. Pre-neoCRT TPS and post-neoCRT CPS were independent prognostic predictors of DFS.

Glasgow prognostic score and combined positive score for locally advanced rectal cancer.

Purpose: This study was performed to investigate the association of Glasgow prognostic score (GPS), combined positive score (CPS), and clinicopathological characteristics of locally advanced rectal cancer. Methods: Between February 2012 and February 2018, 103 patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy and total mesorectal excision (TME) were retrospectively evaluated. Results: According to the classification of the GPS, 85 (82.5%), 13 (12.6%), and 5 patients (4.9%) were classified as a score of 0, 1, and 2, respectively. Patients were classified into the GPS-low group (GPS of 0, n = 85) and GPS-high group (GPS of 1 or 2, n = 18) with an area under the curve of 0.582 for overall survival (OS). The mean programmed death-ligand 1 (PD-L1) CPS of the whole group was 2.24 (range, 0-70). The PD-L1 CPS of the GPS-high group was higher than the GPS-low group (P < 0.001). Multivariate analysis by Cox proportional hazards model indicated that GPS was associated with OS and disease-free survival (DFS). Furthermore, PD-L1 CPS was associated with DFS (hazard ratio, 1.050; 95% confidence interval, 1.017-1.083; P = 0.003). Conclusion: Elevated GPS was related to the PD-L1 CPS. GPS and PD-L1 CPS were associated with the prognosis of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by TME.

The lncRNA NEAT1 Inhibits miRNA-216b and Promotes Colorectal Cancer Progression by Indirectly Activating YY1.

Background: Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) is commonly considered an oncogene in various cancers. The long noncoding RNA NEAT1 has been reported to be overexpressed in colorectal cancer (CRC). However, the exact role of NEAT1 in CRC remains unknown. Our research aimed to explore the function of NEAT1 in the tumorigenesis and the development of CRC. Methods: Real-time quantitative PCR (qRT-PCR) was used to detect the NEAT1, miR-216b, and YIN-YANG-1 (YY1) mRNA levels in CRC tissues and cells, then immunohistochemistry (IHC) was used to detect the expression of YY1 in CRC tissues. Luciferase reporter, qPCR, western blot, and DNA pulldown assays were conducted to study the relationships between NEAT1, miR-216b, and YY1. Flow cytometry analysis was performed for cell cycle and apoptosis analyses, and a colony formation assay was performed to test cell proliferation. Transwell assays were performed to detect cell invasion and migration. Results: The NEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues, and downregulation of NEAT1 suppressed the proliferation, migration, and invasion of CRC cells. Moreover, we found NEAT1 decreased the miR-216b level directly, and the suppression of miR-216b could inhibit the function of downstream YY1. However, overexpression of YY1 accelerated CRC cell proliferation, migration, and invasion. Conclusion: Our results indicated that NEAT1 acted as an oncogene in CRC and promoted the progression of CRC by directly sponging miR-216 b expression to activate the expression of YY1. The NEAT1/miR-216b/YY1 axis may be a novel therapeutic target for CRC.

Combined expression of the BRAFV600E mutation and PD-L1 in early papillary thyroid carcinoma and its relationship with clinicopathological features and recurrence-a retrospective cohort study.

Background: Identifying the high recurrence group of patients with early-stage papillary thyroid cancer (PTC) is the greatest challenge in the management of this disease. It has been noted that B-type Rafkinase (BRAF) V600E mutation and programmed death ligand 1 (PD-L1) are associated in PTC and highly expressed in PTC, correlating in PTC as potential prognostic biomarkers. However, whether they can be used to predict the aggressiveness and recurrence of early PTC remains unclear. Methods: Clinicopathological data of 137 patients with early PTC [tumor-node-metastasis (TNM) stage I-II] who underwent surgery in Zhejiang Cancer Hospital between 2008 and 2010 were retrospectively analyzed. BRAFV600E mutation and PD-L1 was detected by immunohistochemistry. The median follow-up time was 136 months (interquartile range 5.8). The presence of tumor confirmed by imaging or pathology or lymph node metastasis was considered as tumor recurrence. The association of both alone and in combination with clinicopathological features and recurrence was statistically analyzed respectively. The risk of recurrence was assessed using Cox regression models. Results: Most of the 137 early PTC were female (78.1%). The mean age was 43.2±12.1 years. The median tumor size was 1.4 cm; 14 patients developed recurrence during follow-up period; 56 patients (40.9%) were detected positive for BRAFV600E mutation; 76 patients (55.5%) were detected positive for PD-L1. Patients with both BRAFV600E mutation and PD-L1 expression had larger tumors (P=0.038), were more likely to have extrathyroidal invasion (P=0.045), and had a lower rate of cervical lymph node metastasis (P=0.046). The recurrence rate was 17.5% (7/40) in patients with BRAFV600E mutation and PD-L1 double expression compared to 8.9% (4/45) in patients with BRAFV600E mutation and PD-L1 double negative [hazard ratio (HR) =1.267; 95% CI: 0.841-1.909; P=0.257]. Survival curves showed flatter recurrence-free survival (RFS) curves in positive BRAFV600E mutation only and PD-L1 expression only, whereas decreased sharply in positive expression of both BRAFV600E mutation and PD-L1; however, the differences were not significant (P>0.05). Conclusions: The combination of BRAFV600E mutation and PD-L1 to identify group at higher risk of recurrence in early PTC has insufficient clinical evidence and should be used with caution in the clinical management of PTC.