Parastomal Hernia Following Ileal Conduit: Incidence, Risk Factors, and Health-Related Quality of Life.

PURPOSE: The purpose of this study was to measure the incidence of parastomal hernia (PH) after radical cystectomy and ileal conduit. Secondary aims were the identification of risk factors for PH and to compare the health-related quality of life (QOL) between patients with and without PH. DESIGN: Retrospective review of medical records combined with cross-sectional administration of the QOL instrument and telephone follow-up. SUBJECTS AND SETTING: The study sample comprised 219 patients who underwent radical cystectomy and ileal conduit for urothelial cancer between February 2014 and December 2018. The study setting was Peking University First Hospital (Beijing, China). METHODS: Demographic and pertinent clinical data, including development of PH, were gathered via the retrospective review of medical records. Participants were also asked to complete the traditional Chinese language version of the City of Hope Quality of Life-Ostomy Questionnaire (C-COH). Multiple linear regression analysis was used to identify the effect of PH on C-COH scores. Logistic regression analysis was used to identify risk factors for PH development. RESULTS: At a median follow-up of 34 months (IQR = 21-48), 43 of 219 (19.63%) patients had developed a PH. A body mass index (BMI) indicating overweight (OR = 3.548; 95% CI, 1.562-8.061; P = .002), a prior history of hernia (OR = 5.147; 95% CI, 1.195-22.159; P = .028), and chronic high abdominal pressure postdischarge (CHAP-pd) (OR = 3.197; 95% CI, 1.445-7.075; P = .004) were predictors of PH after operation. There was no significant difference between C-COH scores of patients with or without PH. No significant differences were found when participants with PH were compared to those without PH on 4 factors of the C-COH: physical scores (ß= .347, P = .110), psychological scores (ß= .316, P = .070), spiritual scores (ß=-.125, P = .714), and social scores (ß= .054, P = .833). CONCLUSION: Parastomal hernia is prevalent in patients undergoing radical cystectomy and ileal conduit urinary diversion. Overweight, hernia history, and CHAP-pd were predictors of PH development. No significant differences in QOL were found when patients with PH were compared to those without PH.

[Inhibitory Effects and Mechanisms of Three Benzodiazepines on Helicobacter pylori].

Objective To explore the inhibitory effects and mechanisms of benzodiazepines on Helicobacter pylori (Hp).Methods The Hp international standard strain ATCC43504 was treated with benzodiazepines diazepam,midazolam,and remimazolam,respectively.The treatments with amoxicillin and clarithromycin were taken as the positive controls,and that with water for injection as the negative control.The inhibition zone of each drug was measured by the disk diffusion method.The minimum inhibitory concentration(MIC)and minimum bactericidal concentration(MBC)of each drug against Hp were determined.Hp suspension was configured and treated with diazepam and midazolam,respectively.The bacterial suspension without drug added was used as the control group.The concentration of K+ in each bacterial suspension was measured by an automatic biochemical analyzer before drug intervention(T0)and 1(T1),2(T2),3(T3),4(T4),5(T5),6(T6),and 7 h(T7)after intervention.Hp urease was extracted and treated with 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,2 MIC midazolam,1 mg/ml acetohydroxamic acid,and water for injection,respectively.The time required for the rise from pH 6.8 to pH 7.7 in each group was determined by the phenol red coloring method.Results The inhibition zones of diazepam,midazolam,remimazolam,amoxicillin,clarithromycin,and water for injection against Hp were 52.3,42.7,6.0,72.3,60.8,and 6.0 mm,respectively.Diazepam and midazolam showed the MIC of 12.5 µg/ml and 25.0 µg/ml and the MBC of 25 µg/ml and 50 µg/ml,respectively,to Hp.The concentrations of K+ in the diazepam,midazolam,and control groups increased during T1-T7 compared with those at T0(all P<0.01).The concentration of K+ in diazepam and midazolam groups during T1-T4 was higher than that in the control group(all P<0.01).The time of inhibiting urease activity in the 1/2 MIC diazepam,1 MIC diazepam,2 MIC diazepam,1/2 MIC midazolam,1 MIC midazolam,and 2 MIC midazolam groups was(39.86±5.11),(36.52±6.65),(38.58±4.83),(39.25±6.19),(36.36±4.61),and(35.81±6.18)min,respectively,which were shorter than that in the acetohydroxamic acid group(all P<0.01)and had no significance differences from that in the water for injection group(all P>0.05).Conclusion Diazepam and midazolam exerted inhibitory effects on Hp,which may be related to the cleavage of Hp cells rather than inhibiting urease.

pH-gated nanoparticles selectively regulate lysosomal function of tumour-associated macrophages for cancer immunotherapy.

Tumour-associated macrophages (TAMs), as one of the most abundant tumour-infiltrating immune cells, play a pivotal role in tumour antigen clearance and immune suppression. M2-like TAMs present a heightened lysosomal acidity and protease activity, limiting an effective antigen cross-presentation. How to selectively reprogram M2-like TAMs to reinvigorate anti-tumour immune responses is challenging. Here, we report a pH-gated nanoadjuvant (PGN) that selectively targets the lysosomes of M2-like TAMs in tumours rather than the corresponding organelles from macrophages in healthy tissues. Enabled by the PGN nanotechnology, M2-like TAMs are specifically switched to a M1-like phenotype with attenuated lysosomal acidity and cathepsin activity for improved antigen cross-presentation, thus eliciting adaptive immune response and sustained tumour regression in tumour-bearing female mice. Our findings provide insights into how to specifically regulate lysosomal function of TAMs for efficient cancer immunotherapy.

ortho-Methoxycarbonylethynylphenyl Thioglycosides (MCEPTs): Versatile Glycosyl Donors Enabled by Electron-Withdrawing Substituents and Catalyzed by Gold(I) or Cu(II) Complexes.

With easily accessible and operator-friendly reagents, shelf-stable ortho-methoxycarbonylethynylphenyl thioglycosides were efficiently prepared. Based on these MCEPT glycoside donors, a novel glycosylation protocol featuring mild and catalytic promotion conditions with Au(I) or Cu(II) complexes, expanded substrate scope encompassing challenging donors and acceptors and clinically used pharmaceuticals, and versatility in various strategies for highly efficient synthesis of glycosides has been established. The practicality of the MCEPT glycosylation protocol was fully exhibited by highly efficient and scalable synthesis of surface polysaccharide subunits of Acinetobacter baumannii via latent-active, reagent-controlled divergent orthogonal one-pot and orthogonal one-pot strategies. The underlying reaction mechanism was investigated systematically through control reactions, leading to the isolation and characterization of the vital catalyst species in MCEPT glycosylation, the benzothiophen-3-yl-gold(I) complex. Based on the results obtained both from control reactions and from studies leading to the glycosylation protocol establishment, an operative mechanism was proposed and the effect of the vital catalyst species reactivity on the results of metal-catalyzed alkyne-containing donor-involved glycosylation was disclosed. Moreover, the mechanism for C-glycosylation side product formation from ortho-(substituted)ethynylphenyl thioglycoside donors with electron-donating substituents was also illuminated.

The deubiquitinating enzyme complex BRISC regulates Aurora B activation via lysine-63-linked ubiquitination in mitosis.

Faithful chromosome segregation requires bi-oriented kinetochore-microtubule attachment on the metaphase spindle. Aurora B kinase, the catalytic core of the chromosome passage complex (CPC), plays a crucial role in this process. Aurora B activation has widely been investigated in the context of protein phosphorylation. Here, we report that Aurora B is ubiquitinated in mitosis through lysine-63 ubiquitin chains (K63-Ub), which is required for its activation. Mutation of Aurora B at its primary K63 ubiquitin site inhibits its activation, reduces its kinase activity, and disrupts the association of Aurora B with other components of CPC, leading to severe mitotic defects and cell apoptosis. Moreover, we identify that BRCC36 isopeptidase complex (BRISC) is the K63-specific deubiquitinating enzyme for Aurora B. BRISC deficiency augments the accumulation of Aurora B K63-Ubs, leading to Aurora B hyperactivation and erroneous chromosome-microtubule attachments. These findings define the role of K63-linked ubiquitination in regulating Aurora B activation and provide a potential site for Aurora B-targeting drug design.

Applications of liquid chromatography-mass spectrometry based metabolomics in predictive and personalized medicine.

Metabolomics is a fast-developing technique used in biomedical researches focusing on pathological mechanism illustration or novel biomarker development for diseases. The ability of simultaneously quantifying thousands of metabolites in samples makes metabolomics a promising technique in predictive or personalized medicine-oriented researches and applications. Liquid chromatography-mass spectrometry is the most widely employed analytical strategy for metabolomics. In this current mini-review, we provide a brief update on the recent developments and novel applications of LC-MS based metabolomics in the predictive and personalized medicine sector, such as early diagnosis, molecular phenotyping or prognostic evaluation. COVID-19 related metabolomic studies are also summarized. We also discuss the prospects of metabolomics in precision medicine-oriented researches, as well as critical issues that need to be addressed when employing metabolomic strategy in clinical applications.

Predictive value of proteomic markers for advanced rectal cancer with neoadjuvant chemoradiotherapy.

BACKGROUND: Preoperative neoadjuvant chemoradiation (nCRT) has been the standard treatment for locally advanced rectal cancer. Serum biomarkers to stratify patients with respect to prognosis and response to nCRT are needed due to the diverse response to the therapy. METHODS: Thirteen paired pre- and post-nCRT sera from rectal cancer patients were analyzed by isobaric tags for relative and absolute quantitation (iTRAQ) method. Twenty-five proteins were selected for validation by parallel reaction monitoring (PRM) in ninety-one patients. RESULTS: Totally, 310 proteins were identified and quantified in sera samples. Reactome pathway analysis showed that the immune activation-related pathways were enriched in response to nCRT. Twenty-five proteins were selected for further validation. PRM result showed that the level of PZP was higher in pathological complete response (pCR) patients than non-pCR patients. The Random Forest algorithm identified a prediction model composed of 10 protein markers, which allowed discrimination between pCR patients and non-pCR patients (area under the curve (AUC) = 0.886 on testing set). Higher HEP2 and GELS or lower S10A8 in baseline sera were associated with better prognosis. Higher APOA1 in post nCRT sera was associated with better disease-free survival (DFS). CONCLUSIONS: We identified and confirmed a 10-protein panel for nCRT response prediction and four potential biomarkers HEP2, GELS, S10A8 and APOA1 for prognosis of rectal cancer based on iTRAQ-based comparative proteomics screening and PRM-based targeted proteomic validation.

Angiopoietin-like 3 (ANGPTL3) drives cell proliferation, migration and angiogenesis in cervical cancer via binding to integrin alpha v beta 3.

Angiopoietin-like 3 (ANGPTL3) has been uncovered to play an oncogenic role in several kinds of human malignancies. Nevertheless, whether ANGPTL3 functions in cervical cancer (CC) has not yet been reported. This paper is intended to explore the impact of ANGPTL3 on CC cells and elucidate the potential mechanism. In this study, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were performed to analyze the ANGPTL3 expression. Western blot was also performed to examine integrin αvß3 protein level. Cell proliferation was evaluated by MTT assay, EdU staining and Western blot analysis. In addition, the migratory and invasive abilities of cells were, respectively, estimated by wound healing and transwell assays. Tube formation assay was performed to determine endothelial cell angiogenesis. Levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) were measured by ELISA. As a result, ANGPTL3 expression was significantly higher in CC cells relative to that in normal cervical cells. Silencing of ANGPTL3 suppressed cell proliferation, migration and invasion. Besides, downregulation of ANGPTL3 inhibited human umbilical vein endothelial cell (HUVEC) angiogenesis and repressed protein level of integrin alpha v beta 3 (αvß3). Upregulation of αvß3 offsets the inhibitory effect of ANGPTL3 on proliferation, migration and invasion in CC cells. Upregulated expression of αvß3 promoted blood vessel formation and secretions of VEGF and VEGFR2. In conclusion, ANGPTL3 silencing may serve as a tumor suppressor in CC through integrin αvß3, which provides a potentially novel therapeutic target for patients with CC.

Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway.

Senescence in mesenchymal stem cells (MSCs) not only hinders the application of MSCs in regenerative medicine but is also closely correlated with biological aging and the development of degenerative diseases. In this study, we investigated the anti-aging effects of curcumin (Cur) on canine bone marrow-derived MSCs (cBMSCs), and further elucidated the potential mechanism of action based on the modulation of autophagy. cBMSCs were expanded in vitro with standard procedures to construct a cell model of premature senescence. Our evidence indicates that compared with the third passage of cBMSCs, many typical senescence-associated phenotypes were observed in the sixth passage of cBMSCs. Cur treatment can improve cBMSC survival and retard cBMSC senescence according to observations that Cur (1 µM) treatment can improve the colony-forming unit-fibroblasts (CFU-Fs) efficiency and upregulated the mRNA expression of pluripotent transcription factors (SOX-2 and Nanog), as well as inhibiting the senescence-associated beta-galactosidase (SA-ß-gal) activities and mRNA expression of the senescence-related markers (p16 and p21) and pro-inflammatory molecules (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Furthermore, Cur (0.1 µM~10 µM) was observed to increase autophagic activity, as identified by upregulation of microtubule-associated protein 1 light chain 3 (LC3), unc51-like autophagy-activating kinase-1 (ULK1), autophagy-related gene (Atg) 7 and Atg12, and the generation of type II of light chain 3 (LC3-II), thereby increasing autophagic vacuoles and acidic vesicular organelles, as well as causing a significant decrease in the p62 protein level. Moreover, the autophagy activator rapamycin (RAP) and Cur were found to partially ameliorate the senescent features of cBMSCs, while the autophagy inhibitor 3-methyladenine (3-MA) was shown to aggravate cBMSCs senescence and Cur treatment was able to restore the suppressed autophagy and counteract 3-MA-induced cBMSC senescence. Hence, our study highlights the important role of Cur-induced autophagy and its effects for ameliorating cBMSC senescence and provides new insight for delaying senescence and improving the therapeutic potential of MSCs.

Protective effect of MitoQ on oxidative stress-mediated senescence of canine bone marrow mesenchymal stem cells via activation of the Nrf2/ARE pathway.

The destruction of biological activity such as senescence and apoptosis caused by oxidative stress could play a pivotal role in the poor therapeutic efficiency of bone marrow mesenchymal stem cells (BMSCs) transplantation. Mitoquinone (MitoQ) has a highly effective mitochondrial antioxidant effect, and has been widely used in many oxidative damage models. This study aimed to investigate the protective effect of MitoQ on the oxidative stress-mediated senescence of canine BMSCs and the underlying mechanism. The senescence of BMSCs was determined by senescence-associated ß-galactosidase staining and quantitative real-time PCR. The expression of p-Nrf2 protein was detected by Western blotting. The results demonstrated that, as BMSCs were expanded in vitro, the senescent phenotype appeared. And the senescence of BMSCs may be caused by oxidative stress, manifested by increasing the level of ROS and decreasing the activity of antioxidant enzymes. Treatment of MitoQ down-regulated the mRNA levels of senescence-related and apoptosis-related genes, but up-regulated the mRNA levels of proliferation-related genes. Meanwhile, ROS generation and senescent activity were reduced in MitoQ-treated BMSCs. Further mechanism studies showed that MitoQ obviously promoted Nrf2 phosphorylation, and also facilitated the translocation of Nrf2 into the nucleus. Moreover, treatment of MitoQ increased the mRNA levels of downstream antioxidant genes and enhanced the activities of superoxide dismutase, catalase, and glutathione peroxidase. Thus, our study revealed that MitoQ, via the Nrf2/ARE signaling pathway, exerts an antioxidant effect as well as potentially delays OS-mediated senescence during BMSCs that were expanded in vitro, which may serve as a novel strategy to optimize the clinical application of BMSCs.

Comprehensive plasma metabolomic and lipidomic analyses reveal potential biomarkers for heart failure.

Heart failure is a syndrome with symptoms or signs caused by cardiac dysfunction. In clinic, four stages (A, B, C, and D) were used to describe heart failure progression. This study was aimed to explore plasma metabolomic and lipidomic profiles in different HF stages to identify potential biomarkers. Metabolomics and lipidomics were performed using plasma of heart failure patients at stages A (n = 49), B (n = 61), and C+D (n = 26). Analysis of Variance (ANOVA) was used for screening dysregulated molecules. Bioinformatics was used to retrieve perturbed metabolic pathways. Univariate and multivariate receiver operating characteristic curve (ROC) analyses were used for potential biomarker screening. Stage A showed significant difference to other stages, and 142 dysregulated lipids and 134 dysregulated metabolites were found belonging to several metabolic pathways. Several marker panels were proposed for the diagnosis of heart failure stage A versus stage B-D. Several molecules, including lysophosphatidylcholine 18:2, cholesteryl ester 18:1, alanine, choline, and Fructose, were found correlated with B-type natriuretic peptide or left ventricular ejection fractions. In summary, using untargeted metabolomic and lipidomic profiling, several dysregulated small molecules were successfully identified between HF stages A and B-D. These molecules would provide valuable information for further pathological researches and biomarker development.

Proteomic Analyses Identify Differentially Expressed Proteins and Pathways Between Low-Risk and High-Risk Subtypes of Early-Stage Lung Adenocarcinoma and Their Prognostic Impacts.

The histopathological subtype of lung adenocarcinoma (LUAD) is closely associated with prognosis. Micropapillary or solid predominant LUAD tends to relapse after surgery at an early stage, whereas lepidic pattern shows a favorable outcome. However, the molecular mechanism underlying this phenomenon remains unknown. Here, we recruited 31 lepidic predominant LUADs (LR: low-risk subtype group) and 28 micropapillary or solid predominant LUADs (HR: high-risk subtype group). Tissues of these cases were obtained and label-free quantitative proteomic and bioinformatic analyses were performed. Additionally, prognostic impact of targeted proteins was validated using The Cancer Genome Atlas databases (n = 492) and tissue microarrays composed of early-stage LUADs (n = 228). A total of 192 differentially expressed proteins were identified between tumor tissues of LR and HR and three clusters were identified via hierarchical clustering excluding eight proteins. Cluster 1 (65 proteins) showed a sequential decrease in expression from normal tissues to tumor tissues of LR and then to HR and was predominantly enriched in pathways such as tyrosine metabolism and ECM-receptor interaction, and increased matched mRNA expression of 18 proteins from this cluster predicted favorable prognosis. Cluster 2 (70 proteins) demonstrated a sequential increase in expression from normal tissues to tumor tissues of LR and then to HR and was mainly enriched in pathways such as extracellular organization, DNA replication and cell cycle, and high matched mRNA expression of 25 proteins indicated poor prognosis. Cluster 3 (49 proteins) showed high expression only in LR, with high matched mRNA expression of 20 proteins in this cluster indicating favorable prognosis. Furthermore, high expression of ERO1A and FEN1 at protein level predicted poor prognosis in early-stage LUAD, supporting the mRNA results. In conclusion, we discovered key differentially expressed proteins and pathways between low-risk and high-risk subtypes of early-stage LUAD. Some of these proteins could serve as potential biomarkers in prognostic evaluation.

Identification and quantification analysis of the chemical constituents from Mahonia fortune using Q­Exactive HF Mass Spectrometer and UPLC-ESI-MS/MS.

In this research, a comprehensive and innovative method was established for the qualitative and quantitative analysis of the main components in Mahonia fortune (MF). On the one hand, comprehensive insight of the constituents in MF extracts was achieved with a Q­Exactive HF Mass Spectrometer using data-independent acquisition method. The identification of 17 compounds was based on comparison with authentic reference standards and the deduction of 119 additional compounds both in positive and negative modes was using the MS-dial strategy and comparison with literature data. The proportion of alkaloids and phenols were the most in MF. On the other hand, an ultra-performance liquid chromatographic-electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS) method for the quantification of 25 components in MF extract were developed and validated. The method established provided satisfactory precision and accuracy; acceptable recovery and stability; a good linearity and a reasonable limit of detection. The MF samples from 11 different sources were detected, and relative principal component analysis were applied to discriminate these samples. The variations of Columbamine, Jatrorrhizine, Palmatine and Berberine were suggested as important indicators of MF quality. This study supplies a novel and comprehensive method for the quality evaluation of MF. This research presents a MS based analytical strategy which shows an application potential in the analysis of the chemical constituents in Traditional Chinese Medicine (TCM).

An Accurate Linear Method for 3D Line Reconstruction for Binocular or Multiple View Stereo Vision.

For the problem of 3D line reconstruction in binocular or multiple view stereo vision, when there are no corresponding points on the line, the method called Direction-then-Point (DtP) can be used, and if there are two pairs of corresponding points on the line, the method called Two Points 3D coordinates (TPS) can be used. However, when there is only one pair of corresponding points on the line, can we get the better accuracy than DtP for 3D line reconstruction? In this paper, a linear and more accurate method called Point-then-Direction (PtD) is proposed. First, we used the intersection method to obtain the 3D point's coordinate from its corresponding image points. Then, we used this point as a position on the line to calculate the direction of the line by minimizing the image angle residual. PtD is also suitable for multiple camera systems. The simulation results demonstrate that PtD increases the accuracy of both the direction and the position of the 3D line compared to DtP. At the same time, PtD achieves a better result in direction of the 3D line than TPS, but has a lower accuracy in the position of 3D lines than TPS.

Controlling the thermally activated delayed fluorescence of axially chiral organic emitters and their racemate for information encryption.

A pair of axially chiral organic enantiomers were facilely prepared through a one-pot sequential synthesis. They exhibit circularly polarized luminescence activities and have thermally activated delayed fluorescence (TADF) and aggregation-induced emission enhancement properties. Meanwhile, these two enantiomers present remarkable and reversible thermochromism in the crystalline state, enabling dual-colour TADF switching between orange and red. However, when they form cocrystals, the resulting racemate shows opposite thermochromic behaviors. These intriguing results probably emanate from their different optical activities, leading to distinct molecular packing modes and molecular conformation variations. Moreover, information encryption based on thermochromism of organic enantiomers and their racemate has been presented for the first time. This work may expand the application scope of chiral organic luminogens and pave a new way to construct intelligent luminescent systems.

Proteomic analysis reveals distinctive protein expression patterns of thrombus in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a type of malignant tumor of the urinary system. The renal vein or vena cava thrombus can be found in a subset of ccRCC patients in whom it leads to worse prognosis. However, the protein expression profile and molecular features of ccRCC thrombus remain largely unclear. Here, a comparative proteomic analysis was performed using the 2D-LC-MS strategy for the thrombus-tumor-normal tissue triples of 15 ccRCC patients. Statistical analysis, GO enrichment analysis, protein-protein interaction network construction, and mRNA-based survival analysis were used to interpret the proteomic data. Three dysregulated proteins, GGT5 (gamma-glutamyl transferase 5), KRT7 (keratin 7) and CFHR1 (complement factor H related 1), were analyzed using western blot (WB) and immunohistochemistry (IHC) to validate the reliability of the proteomic analysis. The result of this analysis revealed 251 dysregulated proteins, which could be divided into 11 clusters depending on the changing trends, among the thrombus, tumor, and normal tissues. Several pathways and regulation networks were found to be associated with the thrombus, and some dysregulated proteins showed potential values for prognosis prediction. WB and IHC results were in accordance with the proteomic results, further validating the reliability of this study. In conclusion, our findings provide an overview of the thrombus at the molecular level as well as valuable information for further pathological studies or research on biomarkers and therapeutic targets.

Circulating lead modifies hexavalent chromium-induced genetic damage in a chromate-exposed population: An epidemiological study.

Chromium (Cr) can coexist with other heavy metals in the blood of chronically chromate-exposed individuals. However, few studies have explored the health impacts of other hazardous metals after exposure to hexavalent chromium [Cr(VI)]. This study aimed to assess the modification effects of blood lead (Pb) on the genetic damage induced by Cr(VI). During 2010-2019, 1000 blood samples were collected from 455 workers exposed to chromate and 545 workers not exposed to chromate from the same factory with similar labor intensity. The levels of Cr and Pb were measured in whole blood samples. Micronucleus frequency (MNF) and urinary 8-hydroxydeoxyguanosine (8-OHdG) were measured to reflect different types of genetic damage. Multivariate linear regression analyses were performed to evaluate the associations between hazardous metals and the modification effects of Pb on genetic damage. The geometric mean levels of Cr and Pb in the exposure group were significantly higher than those in the control group [Cr: 6.42 (6.08- 6.79) vs. 1.29 (1.22- 1.36) µg/L; Pb: 38.82 (37.22- 40.50) vs. 34.47 (33.15- 35.85) µg/L]. The geometric means of urinary 8-OHdG and MNF in exposure group were 4.00 (3.64- 4.40) µg/g and 5.40 (4.89- 5.97) ‰, respectively, significantly higher than the 3.20 (2.94- 3.48) µg/g and 4.57 (4.15- 5.03) ‰, respectively, in control group. log2Cr was independently and positively associated with urinary 8-OHdG (ß-adjusted = 0.143, 95% CI: 0.082- 0.204) and MNF (ß-adjusted = 0.303, 95%CI: 0.020- 0.587). With the change in circulating Pb levels, the types of genetic damage induced by Cr(VI) were different. At low levels of circulating Pb (<30.80 µg/L), chromate mainly caused changes in 8-OHdG, while at high circulating Pb levels (≥44.88 µg/L), chromate induced alterations in MNF. The findings suggested that chromate exposure could cause multiple types of genetic damage, and circulating Pb might modify the association between circulating Cr and the form of genetic damage.

Integrated proteomics and phosphoproteomics reveal perturbed regulative pathways in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to its inefficient diagnosis, rapid progress, and tenacious drug resistance. Here, we aimed to analyze the expressive patterns of proteins and phosphorylation in PDAC tissue samples and compare them to normal pancreatic tissue to investigate the underlying mechanisms and to reveal potential protein targets for diagnosis and drug development. Liquid chromatography coupled to mass spectrometry (LC-MS) based proteomics and phosphoproteomics analyses were performed using 20 pairs of patient-derived PDAC tissue and normal pancreatic tissue samples. Protein identification and quantification were conducted using MaxQuant software. Bioinformatics analysis was used to retrieve PDAC-relevant pathways and gene ontology (GO) terms. 4985 proteins and 3643 phosphoproteins were identified with high confidence; of these, 322 proteins and 235 phosphoproteins were dysregulated in PDAC. Several pathways, including several extracellular matrix-related pathways, were found to be strongly associated with PDAC. Further, the expression levels of filamin A (FLNA), integrin alpha-V (ITGAV), thymidine phosphorylase (TYMP), medium-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADM), short-chain specific acyl-CoA dehydrogenase, mitochondrial (ACADS), and acetyl-CoA acetyltransferase, mitochondrial (ACAT1) were examined through western blot and immunohistochemistry analysis, and the results confirmed the validity of the proteomics analysis results. These findings provide comprehensive insight into the dysregulated regulative networks in PDAC tissue samples at the protein and phosphorylation levels, and they provide clues for further pathological studies and drug-target development.

Autophagy: a promising therapeutic target for improving mesenchymal stem cell biological functions.

Mesenchymal stem cells (MSCs) are considered to be a promising therapeutic material due to their capacities for self-renewal, multilineage differentiation, and immunomodulation and have attracted great attention in regenerative medicine. However, MSCs may lose their biological functions because of donor age or disease and environmental pressure before and after transplantation, which hinders the application of MSC-based therapy. As a major intracellular lysosome-dependent degradative process, autophagy plays a pivotal role in maintaining cellular homeostasis and withstanding environmental pressure and may become a potential therapeutic target for improving MSC functions. Recent studies have demonstrated that the regulation of autophagy is a promising approach for improving the biological properties of MSCs. More in-depth investigations about the role of autophagy in MSC biology are required to contribute to the clinical application of MSCs. In this review, we focus on the role of autophagy regulation by various physical and chemical factors on the biological functions of MSCs in vitro and in vivo, and provide some strategies for enhancing the therapeutic efficacy of MSCs.

Metabolomic and Lipidomic Profiling of Preoperative CSF in Elderly Hip Fracture Patients With Postoperative Delirium.

OBJECTIVE: To investigate dysregulated molecules in preoperative cerebrospinal fluid (CSF) of elderly hip fracture patients with postoperative delirium (POD), in order to identify potential pathological mechanisms and biomarkers for pre-stage POD. MATERIALS AND METHODS: This nested case control study used untargeted metabolomic and lipidomic analysis to profile the preoperative CSF of patients (n = 40) who developed POD undergone hip fracture surgery (n = 10) and those who did not (n = 30). Thirty Non-POD patients were matched to 10 POD patients by age (± 2 years) and Mini Mental State Examination score (± 2 points). CSF was collected after successful spinal anesthesia and banked for subsequent analysis. On the first two postoperative days, patients were assessed twice daily using the Confusion Assessment Method-Chinese Revision. CSF samples from the two groups were analyzed to investigate possible relevant pathological mechanisms and identify candidate biomarkers. RESULTS: Demographic characteristics of the groups were matched. Eighteen metabolites and thirty-three lipids were dysregulated in the preoperative CSF of POD patients. Pathway enrichment analysis revealed perturbations in D-glutamine and D-glutamate metabolism; glycerophospholipid metabolism; alanine, aspartate and glutamate metabolism; sphingolipid metabolism; histidine metabolism; and arginine biosynthesis at the pre-delirium stage. Receiver operating characteristic curve analysis indicated that phosphatidylethanolamine (PE, 40:7e), with an area under the curve value of 0.92, is a potential biomarker for POD. CONCLUSION: Multiple pathological mechanisms in the POD group were involved before surgery, including neuroinflammation, oxidative stress, and energy metabolism disorders induced by hypoxia, as well as neurotransmitter imbalances such as increased dopamine and glutamate, and decreased glutamine. These metabolic abnormalities potentially increase the fragility of the brain, thus contributing to POD. PE (40:7e) might be a potential biomarker for POD. Not only do our results provide potential biomarkers for POD, but also provide information for deep pathological research. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier ChiCTR1900021533.