Elongation factor P modulates Acinetobacter baumannii physiology and virulence as a cyclic dimeric guanosine monophosphate effector.

Cyclic diguanosine monophosphate (c-di-GMP) is widely used by bacteria to control biological functions in response to diverse signals or cues. A previous study showed that potential c-di-GMP metabolic enzymes play a role in the regulation of biofilm formation and motility in Acinetobacter baumannii. However, it was unclear whether and how A. baumannii cells use c-di-GMP signaling to modulate biological functions. Here, we report that c-di-GMP is an important intracellular signal in the modulation of biofilm formation, motility, and virulence in A. baumannii. The intracellular level of c-di-GMP is principally controlled by the diguanylate cyclases (DGCs) A1S_1695, A1S_2506, and A1S_3296 and the phosphodiesterase (PDE) A1S_1254. Intriguingly, we revealed that A1S_2419 (an elongation factor P [EF-P]), is a novel c-di-GMP effector in A. baumannii. Response to a c-di-GMP signal boosted A1S_2419 activity to rescue ribosomes from stalling during synthesis of proteins containing consecutive prolines and thus regulate A. baumannii physiology and pathogenesis. Our study presents a unique and widely conserved effector that controls bacterial physiology and virulence by sensing the second messenger c-di-GMP.

An anthranilic acid-responsive transcriptional regulator controls the physiology and pathogenicity of Ralstonia solanacearum.

Quorum sensing (QS) is widely employed by bacterial cells to control gene expression in a cell density-dependent manner. A previous study revealed that anthranilic acid from Ralstonia solanacearum plays a vital role in regulating the physiology and pathogenicity of R. solanacearum. We reported here that anthranilic acid controls the important biological functions and virulence of R. solanacearum through the receptor protein RaaR, which contains helix-turn-helix (HTH) and LysR substrate binding (LysR_substrate) domains. RaaR regulates the same processes as anthranilic acid, and both are present in various bacterial species. In addition, anthranilic acid-deficient mutant phenotypes were rescued by in trans expression of RaaR. Intriguingly, we found that anthranilic acid binds to the LysR_substrate domain of RaaR with high affinity, induces allosteric conformational changes, and then enhances the binding of RaaR to the promoter DNA regions of target genes. These findings indicate that the components of the anthranilic acid signaling system are distinguished from those of the typical QS systems. Together, our work presents a unique and widely conserved signaling system that might be an important new type of cell-to-cell communication system in bacteria.

Pharmacological inhibition of the mixed lineage leukemia 1-menin interaction aggravates acute kidney injury induced by folic acid and ischemia-reperfusion in mice.

Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation (H3K4me3) and partially exerts its untoward functional effects by interacting with multiple subunits including menin and WD repeat-containing protein 5 (WDR5). In this study, we investigated the role and mechanisms of MLL1 in murine models of acute kidney injury induced by folic acid (FA) and ischemia-reperfusion. Injury to the kidney elevated the expression of MLL1, menin, WDR5, and H3K4Me3, which was accompanied by increased serum creatinine and blood urea nitrogen, renal tubular injury, and apoptosis. Pharmacological inhibition of MLL1 activity with MI503 to disrupt the interaction between MLL1 with menin further increased serum creatinine and blood urea nitrogen levels, enhanced expression of neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, and induced more apoptosis in the kidney following FA and ischemia-reperfusion injury. In contrast, MI503 treatment decreased the expression of vimentin and proliferating cell nuclear antigens. Similarly, treatment with MM102 to disrupt the interaction between MLL1 and WDR5 also worsened renal dysfunction, aggravated tubular cell injury, increased apoptosis, and inhibited cellular dedifferentiation and proliferation in mice following FA injection. Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase-1/2 in injured kidneys. Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the epidermal growth factor receptor signaling pathway.NEW & NOTEWORTHY Mixed lineage leukemia 1 (MLL1) is a methyltransferase that induces histone H3 lysine 4 trimethylation and exerts its functional roles by interacting with multiple subunits. In this study, we demonstrated that inhibition of MLL1 activity by MI503 or MM102 aggravated renal injury and apoptosis and suppressed renal tubular cell dedifferentiation and proliferation, suggesting that MLL1 activation during acute kidney injury acts as an intrinsic protective mechanism to mediate renal tubular cell survival and regeneration.

Ubiquitin-specific protease 11 promotes partial epithelial-to-mesenchymal transition by deubiquitinating the epidermal growth factor receptor during kidney fibrosis.

The aberrant expression of ubiquitin-specific protease 11 (USP11) is believed to be related to tumor progression. However, few studies have reported the biological function and clinical importance of USP11 in kidney fibrosis. Here, we demonstrated USP11 was highly upregulated in the kidneys from patients with chronic kidney disease and correlated positively with fibrotic lesion but negatively with kidney function. Conditional USP11 deletion or pharmacologic inhibition with Mitoxantrone attenuated pathological lesions and improved kidney function in both hyperuricemic nephropathy (HN)- and folic acid (FA)-induced mouse models of kidney fibrosis. Mechanistically, by RNA sequencing, USP11 was found to be involved in nuclear gene transcription of the epidermal growth factor receptor (EGFR). USP11 co-immunoprecipitated and co-stained with extra-nuclear EGFR and deubiquitinated and protected EGFR from proteasome-dependent degradation. Genetic or pharmacological depletion of USP11 facilitated EGFR degradation and abated augmentation of TGF-ß1 and downstream signaling. This consequently alleviated the partial epithelial-mesenchymal transition, G2/M arrest and aberrant secretome of profibrogenic and proinflammatory factors in uric acid-stimulated tubular epithelial cells. Moreover, USP11 deletion had anti-fibrotic and anti-inflammatory kidney effects in the murine HN and FA models. Thus, our study provides evidence supporting USP11 as a promising target for minimizing kidney fibrosis and that inhibition of USP11 has potential to be an effective strategy for patients with chronic kidney disease.

Centimeter-Sized Single Crystals of Tetrahedral Manganese (II) Halide Hybrids for Wide-Color Gamut Backlighting Displays.

Phosphors with narrow-band green emissions and high photoluminescent quantum efficiency (PLQY) are significantly required for backlighting displays with wider color gamut. In this work, two centimeter-sized manganese (II) halide single crystals TMG2 MnCl4 and TMG2 MnBr4 (TMG = 1,1,3,3-tetramethylguanidine) are synthesized, exhibiting bright narrow-band green emissions with high PLQYs up to 62% and 90%, respectively. The narrow-band green light emission is located at 520 nm with a full-width at half-maximum (FWHM) of only 57 nm. The photoluminescence mechanisms of two single crystals are elaborated. Two white-light-emitting diodes for backlighting displays (BD-WLEDs) based on them are fabricated, exhibiting the widest color gamut of 122% National Television Standards Committee (NTSC), and a luminous efficacy reached ≈93 lm W-1 with excellent luminescence stability at high temperatures. These properties indicate the potential applications of tetrahedral manganese (II) hybrids in wide-color gamut backlighting displays.

Membrane-enclosed Pseudomonas quinolone signal attenuates bacterial virulence by interfering with quorum sensing.

Outer membrane vesicle (OMV)-delivered Pseudomonas quinolone signal (PQS) plays a critical role in cell-cell communication in Pseudomonas aeruginosa. However, the functions and mechanisms of membrane-enclosed PQS in interspecies communication in microbial communities are not clear. Here, we demonstrate that PQS delivered by both OMVs from P. aeruginosa and liposome reduces the competitiveness of Burkholderia cenocepacia, which usually shares the same niche in the lungs of cystic fibrosis patients, by interfering with quorum sensing (QS) in B. cenocepacia through the LysR-type regulator ShvR. Intriguingly, we found that ShvR regulates the production of the QS signals cis-2-dodecenoic acid (BDSF) and N-acyl homoserine lactone (AHL) by directly binding to the promoters of signal synthase-encoding genes. Perception of PQS influences the regulatory activity of ShvR and thus ultimately reduces QS signal production and virulence in B. cenocepacia. Our findings provide insights into the interspecies communication mediated by the membrane-enclosed QS signal among bacterial species residing in the same microbial community.IMPORTANCEQuorum sensing (QS) is a ubiquitous cell-to-cell communication mechanism. Previous studies showed that Burkholderia cenocepacia mainly employs cis-2-dodecenoic acid (BDSF) and N-acyl homoserine lactone (AHL) QS systems to regulate biological functions and virulence. Here, we demonstrate that Pseudomonas quinolone signal (PQS) delivered by outer membrane vesicles from Pseudomonas aeruginosa or liposome attenuates B. cenocepacia virulence by targeting the LysR-type regulator ShvR, which regulates the production of the QS signals BDSF and AHL in B. cenocepacia. Our results not only suggest the important roles of membrane-enclosed PQS in interspecies and interkingdom communications but also provide a new perspective on the use of functional nanocarriers loaded with QS inhibitors for treating pathogen infections.

One-Dimensional Organic-Inorganic Lead Bromide Hybrids with Excitation-Dependent White-Light Emission Templated by Pyridinium Derivatives.

Organic-inorganic hybrid metal halides have attracted widespread attention due to their excellent tunability and versatility. Here, we have selected pyridinium derivatives with different substituent groups or substitution positions as the organic templating cations and obtained six 1D chain-like structures. They are divided into three types: type I (single chain), type II (double chain), and type III (triple chain), with tunable optical band gaps and emission properties. Among them, only (2,4-LD)PbBr3 (2,4-LD = 2,4-lutidine) shows an exciton-dependent emission phenomenon, ranging from strong yellow-white to weak red-white light. By comparing its photoluminescence spectrum with that of its bromate (2,4-LD)Br, it is found that the strong yellow-white emission at 534 nm mainly came from the organic component. Furthermore, through a comparison of the fluorescence spectra and lifetimes of (2,4-LD)PbBr3 and (2-MP)PbBr3 (2-MP = 2-methylpyridine) with similar structures at different temperatures, we confirm that the tunable emission of (2,4-LD)PbBr3 comes from different photoluminescent sources corresponding to organic cations and self-trapped excitons. Density functional theory calculations further reveal that (2,4-LD)PbBr3 has a stronger interaction between organic and inorganic components compared to (2-MP)PbBr3. This work highlights the importance of organic templating cations in hybrid metal halides and the new functionalities associated with them.

Inhibition of polycomb repressive complex 2 by targeting EED protects against cisplatin-induced acute kidney injury.

Polycomb repressive complex 2 (PRC2) is a multicomponent complex with methyltransferase activity that catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3). Interaction of the epigenetic reader protein EED with EZH2, a catalytic unit of PRC, allosterically stimulates PRC2 activity. In this study, we investigated the role and underlying mechanism of the PRC2 in acute kidney injury (AKI) by using EED226, a highly selective PRC2 inhibitor, to target EED. Administration of EED226 improved renal function, attenuated renal pathological changes, and reduced renal tubular cell apoptosis in a murine model of cisplatin-induced AKI. In cultured renal epithelial cells, treatment with either EED226 or EED siRNA also ameliorated cisplatin-induced apoptosis. Mechanistically, EED226 treatment inhibited cisplatin-induced phosphorylation of p53 and FOXO3a, two transcriptional factors contributing to apoptosis, and preserved expression of Sirtuin 3 and PGC1α, two proteins associated with mitochondrial protection in vivo and in vitro. EED226 was also effective in enhancing renal tubular cell proliferation, suppressing expression of multiple inflammatory cytokines, and reducing infiltration of macrophages to the injured kidney. These data suggest that inhibition of the PRC2 activity by targeting EED can protect against cisplatin-induced AKI by promoting the survival and proliferation of renal tubular cells and inhibiting inflammatory response.

Identification and quantification of immune infiltration landscape on therapy and prognosis in left- and right-sided colon cancer.

BACKGROUND: The left-sided and right-sided colon cancer (LCCs and RCCs, respectively) have unique molecular features and clinical heterogeneity. This study aimed to identify the characteristics of immune cell infiltration (ICI) subtypes for evaluating prognosis and therapeutic benefits. METHODS: The independent gene datasets, corresponding somatic mutation and clinical information were collected from The Cancer Genome Atlas and Gene Expression Omnibus. The ICI contents were evaluated by "ESTIMATE" and "CIBERSORT." We performed two computational algorithms to identify the ICI landscape related to prognosis and found the unique infiltration characteristics. Next, principal component analysis was conducted to construct ICI score based on three ICI patterns. We analyzed the correlation between ICI score and tumor mutation burden (TMB), and stratified patients into prognostic-related high- and low- ICI score groups (HSG and LSG, respectively). The role of ICI scores in the prediction of therapeutic benefits was investigated by "pRRophetic" and verified by Immunophenoscores (IPS) (TCIA database) and an independent immunotherapy cohort (IMvigor210). The key genes were preliminary screened by weighted gene co-expression network analysis based on ICI scores. And they were further identified at various levels, including single cell, protein and immunotherapy response. The predictive ability of ICI score for prognosis was also verified in IMvigor210 cohort. RESULTS: The ICI features with a better prognosis were marked by high plasma cells, dendritic cells and mast cells, low memory CD4+ T cells, M0 macrophages, M1 macrophages, as well as M2 macrophages. A high ICI score was characterized by an increased TMB and genomic instability related signaling pathways. The prognosis, sensitivities of targeted inhibitors and immunotherapy, IPS and expression of immune checkpoints were significantly different in HSG and LSG. The genes identified by ICI scores and various levels included CA2 and TSPAN1. CONCLUSION: The identification of ICI subtypes and ICI scores will help gain insights into the heterogeneity in LCC and RCC, and identify patients probably benefiting from treatments. ICI scores and the key genes could serve as an effective biomarker to predict prognosis and the sensitivity of immunotherapy.

Ion-Selective Organic Electrochemical Transistors: Recent Progress and Challenges.

The charged species inside biofluids (blood, interstitial fluid, sweat, saliva, urine, etc.) can reflect the human body's physiological conditions and thus be adopted to diagnose various diseases early. Among all personalized health management applications, ion-selective organic electrochemical transistors (IS-OECTs) have shown tremendous potential in point-of-care testing of biofluids due to low cost, ease of fabrication, high signal amplification, and low detection limit. Moreover, IS-OECTs exhibit excellent flexibility and biocompatibility that enable their application in wearable bioelectronics for continuous health monitoring. In this review, the working principle of IS-OECTs and the recent studies of IS-OECTs for performance improvement are reviewed. Specifically, contemporary studies on material design and device optimization to enhance the sensitivity of IS-OECTs are discussed. In addition, the progress toward the commercialization of IS-OECTs is highlighted, and the recently proposed solutions or alternatives are summarized. The main challenges and perspectives for fully exploiting IS-OECTs toward future preventive and personal medical devices are addressed.

Iodine-125 seed represses the growth and facilitates the apoptosis of colorectal cancer cells by suppressing the methylation of miR-615 promoter.

BACKGROUND: Colorectal cancer (CRC) represents a common malignancy in gastrointestinal tract. Iodine-125 (125I) seed implantation is an emerging treatment technology for unresectable tumors. This study investigated the mechanism of 125I seed in the function of CRC cells. METHODS: The CRC cells were irradiated with different doses of 125I seed (0.4, 0.6 and 0.8 mCi). miR-615 expression in CRC tissues and adjacent tissues was detected by RT-qPCR. miR-615 expression was intervened with miR-615 mimic or miR-615 inhibitor, and then the CRC cells were treated with 5-AZA (methylation inhibitor). The CRC cell growth, invasion and apoptosis were measured. The methylation level of miR-615 promoter region was detected. The xenograft tumor model irradiated by 125I seed was established in nude mice. The methylation of miR-615, Ki67 expression and CRC cell apoptosis were detected. RESULTS: 125I seed irradiation repressed the growth and facilitated apoptosis of CRC cells in a dose-dependent manner. Compared with adjacent tissues, miR-615 expression in CRC tissues was downregulated and miR-615 was poorly expressed in CRC cells. Overexpression of miR-615 suppressed the growth of CRC cells. 125I seed-irradiated CRC cells showed increased miR-615 expression, reduced growth rate and enhanced apoptosis. The methylation level of miR-615 promoter region in CRC cells was decreased after 125I seed treatment. In vivo experiments confirmed that 125I seed-irradiated xenograft tumors showed reduced methylation of the miR-615 promoter and increased miR-615 expression, as well as decreased Ki67 expression and enhanced apoptosis. The target genes of miR-615 and its regulatory downstream pathway were further predicted by bioinformatics analysis. CONCLUSIONS: 125I seed repressed the growth and facilitated the apoptosis of CRC cells by suppressing the methylation of the miR-615 promoter and thus activating miR-615 expression. The possible mechanism was that miR-615-5p targeted MAPK13, thus affecting the MAPK pathway and the progression of CRC.

White Light-Emitting Diodes Based on One-Dimensional Organic-Inorganic Hybrid Metal Chloride with Dual Emission.

White-light emissive organic-inorganic hybrid metal halides (MHs) have shown promising potential applications in solid-state lighting. As one-dimensional (1D) MHs for white-light emission remain rare and the key role of halogen regulation in 1D hybrid MHs for broadband emission (BE) has not been well established yet, herein, we report a family of 1D hybrid MHs TMGPbX3 (TMG = 1,1,3,3-tetramethylguanidine, X = Cl-, Br-, or I-) to systematically explore the influence of halogen on crystal structures and photoluminescence (PL) properties in 1D organic-inorganic hybrid MHs. Under ultraviolet excitation, TMGPbBr3 and TMGPbI3 exhibit BE originating from self-trapped excitons (STEs), while TMGPbCl3 manifests the special blue-white dual emission, which is contributed by STEs in inorganic frameworks and free excitons (FEs) in the organic component. Different emission mechanisms of three 1D MHs are well demonstrated and compared. With a PL quantum yield (PLQY) up to 11.67%, a white light-emitting diode (WLED) based on TMGPbCl3 was fabricated to show its valuable application in solid-state lighting.

A panel of differentially methylated regions enable prognosis prediction for colorectal cancer.

We aim to identify a panel of differentially methylated regions (DMRs) for predicting survival outcomes for patients with CRC from the TCGA (n = 393). Four DMRs (MUC12, TBX20, CHN2, and B3GNT7) were selected as candidate prognostic markers for CRC. The prediction potential of selected DMRs was validated by the targeted bisulfite sequencing method in an independent cohort with 251 Chinese CRC patients. DMR methylation scores (DMSs) were constructed to evaluate the prognosis of CRC. Results of the validation cohort confirmed that higher DMSs were associated with poor overall survival (OS) of CRC, with hazard ratio (HR) value ranged from 1.445 to 2.698 in multivariable Cox models. Patients in the high prognostic index (high-PI) group showed a markedly unfavorable prognosis compared to the low-PI group in both TCGA discovery cohort (HR = 3.508, 95%CI: 2.196-5.604, P < 0.001) and independent validation cohort (HR = 1.912, 95%CI: 1.258-2.907, P = 0.002).

Nintedanib attenuates peritoneal fibrosis by inhibiting mesothelial-to-mesenchymal transition, inflammation and angiogenesis.

Nintedanib, an Food and Drug Administration (FDA) approved multiple tyrosine kinase inhibitor, exhibits an anti-fibrotic effect in lung and kidneys. Its effect on peritoneal fibrosis remains unexplored. In this study, we found that nintedanib administration lessened chlorhexidine gluconate (CG)-induced peritoneal fibrosis and reduced collagen I and fibronectin expression. This coincided with suppressed phosphorylation of platelet-derived growth factor receptor, fibroblast growth factor receptors, vascular endothelial growth factor receptor and Src family kinase. Mechanistically, nintedanib inhibited injury-induced mesothelial-to-mesenchymal transition (MMT), as demonstrated by decreased expression of α-smooth muscle antigen and vimentin and preserved expression of E-cadherin in the CG-injured peritoneum and cultured human peritoneal mesothelial cells exposed to transforming growth factor-ß1. Nintedanib also suppressed expression of Snail and Twist, two transcription factors associated with MMT in vivo and in vitro. Moreover, nintedanib treatment inhibited expression of several cytokines/chemokines, including tumour necrosis factor-α, interleukin-1ß and interleukin-6, monocyte chemoattractant protein-1 and prevented infiltration of macrophages to the injured peritoneum. Finally, nintedanib reduced CG-induced peritoneal vascularization. These data suggest that nintedanib may attenuate peritoneal fibrosis by inhibiting MMT, inflammation, and angiogenesis and have therapeutic potential for the prevention and treatment of peritoneal fibrosis in patients on peritoneal dialysis.

Comprehensive analysis of prognostic immune-related genes and drug sensitivity in cervical cancer.

BACKGROUND: Cervical cancer (CC) is the leading cause of cancer-related death in women. A limited number of studies have investigated whether immune-prognostic features can be used to predict the prognosis of CC. This study aimed to develop an improved prognostic risk scoring model (PRSM) for CC based on immune-related genes (IRGs) to predict survival and determine the key prognostic IRGs. METHODS: We downloaded the gene expression profiles and clinical data of CC patients from the TCGA and GEO databases. The ESTIMATE algorithm was used to calculate the score for both immune and stromal cells. Differentially expressed genes (DEGs) in different subpopulations were analyzed by "Limma". A weighted gene co-expression network analysis (WGCNA) was used to establish a DEG co-expression module related to the immune score. Immune-related gene pairs (IRGPs) were constructed, and univariate- and Lasso-Cox regression analyses were used to analyze prognosis and establish a PRSM. A log-rank test was used to verify the accuracy and consistency of the scoring model. Identification of the predicted key IRG was ensured by the application of functional enrichment, DisNor, protein-protein interactions (PPIs) and heatmap. Finally, we extracted the key prognostic immune-related genes from the gene expression data, validated the key genes by immunohistochemistry and analyzed the correlation between their expression and drug sensitivity. RESULTS: A new PRSM was developed based on 22 IRGPs. The prognosis of the low-risk group in the model group (P < 0.001) and validation group (P = 0.039) was significantly better than that in the high-risk group. Furthermore, M1 and M2 macrophages were highly expressed in the low-risk group. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) and the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway were significantly enriched in the low-risk group. Three representative genes (CD80, CD28, and LCP2) were markers of CC prognosis. CD80 and CD28 may more prominent represent important indicators to improve patient prognosis. These key genes was positively correlated with drug sensitivity. Finally, we found that differences in the sensitivity to JNK inhibitors could be distinguished based on the use and risk grouping of this PRSM. CONCLUSIONS: The prognostic model based on the IRGs and key genes have potential clinical significance for predicting the prognosis of CC patients, providing a foundation for clinical prognosis judgment and individualized treatment.

Correlation analysis between expression of histone deacetylase 6 and clinical parameters in IgA nephropathy patients.

BACKGROUND: It has been demonstrated that histone deacetylase 6 (HDAC6) is involved in various kidney diseases in experimental study. However, correlation between HDAC6 and clinical parameters in IgA nephropathy (IgAN) patients is still unknown. METHODS: A total of 46 human kidney biopsy specimens with IgAN were selected as observation group, specimens of normal renal cortex tissue that was not affected by the tumor from patients with renal carcinoma (n = 7) served as control. We investigated the relationship between HDAC6 and clinical parameters in IgAN. RESULTS: HDAC6 was highly expressed in human kidney biopsy specimens with IgAN compared with control group, while the number of acetyl histone H3 positive cells were significantly decreased. There was a statistical difference in the indexes of albumin, estimated glomerular filtration rate (eGFR), serum urea, serum creatinine, serum uric acid, ß2-microglobulin, cystatin C, cholesterol, high-density lipoprotein, low-density lipoprotein, and HDAC6 positive area among the different Oxford Classification (p < 0.05). The expression of HDAC6 was different in various eGFR levels, the expression of HDAC6 increased with the decreasing of eGFR level, the expression of acetyl histone H3 decreased with the decreasing of eGFR level. In addition, the expression of HDAC6 positively correlated with Masson trichrome positive area, serum urea, serum creatinine, ß2 macroglobulin, and cystatin C, while negatively correlated with eGFR and acetyl histone H3. Multivariate linear regression analysis demonstrated that eGFR and cystatin C were independently associated with HDAC6, respectively (p < 0.05). CONCLUSIONS: These results suggested that high level of HDAC6 expression in IgAN is correlated with renal dysfunction.

Clinical outcomes, quality of life, and costs evaluation of peritoneal dialysis management models in Shanghai Songjiang District: a multi-center and prospective cohort study.

Background: The new Family-Community-Hospital (FCH) three-level comprehensive management aimed to improve the efficiency and scale of peritoneal dialysis (PD) to meet the increased population of end-stage renal disease (ESRD). Our study focused on the clinical outcomes, quality of life, and costs evaluation of this model in a multi-center and prospective cohort study.Methods: A total of 190 ESRD patients who commenced PD at Shanghai Songjiang District were enrolled. According to different PD management models, patients were divided into the Family-Community-Hospital three-level management model (n = 90) and the conventional all-course central hospital management model (n = 100). The primary outcome was clinical outcomes of PD. The secondary outcomes were health-related quality of life (HRQOL) and medical costs evaluation.Results: Compared to conventional management, community-based FCH management achieved a similar dialysis therapeutic effect, including dropout rate (p = 0.366), peritonitis rate (p = 0.965), patient survival (p = 0.441), and technique survival (p = 0.589). Follow-up data showed that similar levels of the renal and peritoneal functions, serum albumin, cholesterol and triglyceride, PTH, serum calcium, and phosphorus between the two groups (all p > 0.05). HRQOL survey showed that the FCH management model helped to improve the psychological status of PD patients, including social functioning (p = 0.006), role-emotional (p = 0.032), and mental health (p = 0.036). FCH management also reduced the hospitalization (p = 0.009) and outpatient visits (p = 0.001) and saved annual hospitalization costs (p = 0.005), outpatient costs (p = 0.026), and transport costs (p = 0.006).Conclusions: Compared with conventional management, community-based FCH management achieved similar outcomes, improved psychological health, reduced medical budgets, and thus had a good social prospect.

SCTR hypermethylation is a diagnostic biomarker in colorectal cancer.

Diagnostic markers for both colorectal cancer (CRC) and its precursor lesions are lacking. Although aberrant methylation of the secretin receptor (SCTR) gene was observed in CRC, the diagnostic performance has not been evaluated. Therefore, this study aimed to assess and verify the diagnostic value of SCTR methylation of CRC and its precursor lesions through integrating the largest methylation data. The diagnostic performance of SCTR methylation was analyzed in the discovery set from The Cancer Genome Atlas (TCGA) CRC methylation data (N = 440), and verified in a large-scale test set (N = 938) from the Gene Expression Omnibus (GEO). Targeted bisulfite sequencing analysis was developed and applied to detect the methylation status of SCTR in our independent validation set (N = 374). Our findings revealed that the SCTR gene was frequently hypermethylated at its CpG islands in CRC. In the TCGA discovery set, the diagnostic score was constructed using 4 CpG sites (cg01013590, cg20505223, cg07176264, and cg26009192) and achieved high diagnostic performance (area under the ROC curve [AUC] = 0.964). In the GEO test set, the diagnostic score had robust diagnostic ability to distinguish CRC (AUC = 0.948) and its precursor lesions (AUC = 0.954) from normal samples. Moreover, hypermethylation of the SCTR gene was also found in cell-free DNA samples collected from CRC patients, but not in those from healthy controls. In the validation set, consistent results were observed using the targeted bisulfite sequencing array. Our study highlights that hypermethylation at CpG islands of the SCTR gene is a potential diagnostic biomarker in CRCs and its precursor lesions.

Spexin/NPQ Induces FBJ Osteosarcoma Oncogene (Fos) and Produces Antinociceptive Effect against Inflammatory Pain in the Mouse Model.

Spexin/NPQ is a novel highly conserved neuropeptide. It has a widespread expression in the periphery and central nervous system. However, the effects of central spexin on acute inflammatory pain are still unknown. This study explored the mechanisms and effects of supraspinal spexin on inflammatory pain. The results from the mouse formalin test show that i.c.v. administration of spexin decreased licking/biting time during the late and early phases. The nonamidated spexin had no effect on pain response. The antinociception of spexin was blocked by galanin receptor 3 antagonist SNAP 37889. The Galr3 and Adcy4 mRNA levels in the brain were increased after injection with spexin. The antinociceptive effects of spexin were completely reversed by opioid receptor antagonist naloxone and κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride. Spexin up-regulated the dynorphin and κ-opioid receptor gene and protein expression. PCR array assay and real-time PCR analysis show that spexin up-regulated the mRNA level of the FBJ osteosarcoma oncogene (Fos). T-5224, the inhibitor of c FBJ osteosarcoma oncogene (c-Fos)/activator protein 1 (AP-1), blocked the increased mRNA level of Pdyn and Oprk1 induced by spexin. I.C.V. spexin (2.43 mg/kg) increased the number of c-Fos-positive neurons in most subsections of periaqueductal gray. In addition, in the acetic acid-induced writhing test, i.c.v. spexin produced an antinociceptive effect. Our results indicate that spexin might be a novel neuropeptide with an antinociceptive effect against acute inflammatory pain.

Colorectal cancer-derived exosomal miR-106b-3p promotes metastasis by down-regulating DLC-1 expression.

Cancer-derived exosomal miRNAs play an important role in the development of metastasis, but the effects and underlying mechanisms remain unclear. In the present study, we investigated the miRNA expression profiles of 5 paired serum exosomal samples from metastatic colorectal cancer (mCRC) and non-mCRC patients via RNA sequencing. After we evaluated the differentially expressed miRNAs in 80 CRC patients, miR-106b-3p was selected as a metastasis-associated miRNA of CRC. We showed that the expression level of serum exosomal miR-106b-3p was significantly higher in CRC patients with metastasis than those without metastasis. Additionally, high serum exosomal miR-106b-3p expression in patients was correlated with a poor prognosis. Coculture of low-metastatic CRC cells with high-metastatic CRC cell-derived exosomes promoted cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), which was caused by the transport and transduction of miR-106b-3p in vitro. Moreover, exosomal miR-106b-3p promoted lung metastasis of CRC cells in vivo. In addition, we demonstrated that miR-106b-3p regulated metastasis by targeting deleted in liver cancer-1 (DLC-1). A negative correlation was also identified between miR-106b-3p and DLC-1 expression in human CRC tumour tissues and in mouse lung metastatic lesions. Collectively, our study indicated that metastasis-associated miR-106b-3p from serum exosomes could be used as a potential prognostic biomarker and therapeutic target for CRC patients.