GPNMB+ Gal-3+ hepatic parenchymal cells promote immunosuppression and hepatocellular carcinogenesis.

Hepatocellular carcinoma (HCC) formation is a multi-step pathological process that involves evolution of a heterogeneous immunosuppressive tumor microenvironment. However, the specific cell populations involved and their origins and contribution to HCC development remain largely unknown. Here, comprehensive single-cell transcriptome sequencing was applied to profile rat models of toxin-induced liver tumorigenesis and HCC patients. Specifically, we identified three populations of hepatic parenchymal cells emerging during HCC progression, termed metabolic hepatocytes (HCMeta ), Epcam+ population with differentiation potential (EP+Diff ) and immunosuppressive malignant transformation subset (MTImmu ). These distinct subpopulations form an oncogenic trajectory depicting a dynamic landscape of hepatocarcinogenesis, with signature genes reflecting the transition from EP+Diff to MTImmu . Importantly, GPNMB+ Gal-3+ MTImmu cells exhibit both malignant and immunosuppressive properties. Moreover, SOX18 is required for the generation and malignant transformation of GPNMB+ Gal-3+ MTImmu cells. Enrichment of the GPNMB+ Gal-3+ MTImmu subset was found to be associated with poor prognosis and a higher rate of recurrence in patients. Collectively, we unraveled the single-cell HCC progression atlas and uncovered GPNMB+ Gal-3+ parenchymal cells as a major subset contributing to the immunosuppressive microenvironment thus malignance in HCC.

Proteomic Analysis of Idiopathic Nephrotic Syndrome Triggered by Primary Podocytopathies in Adults: Regulatory Mechanisms and Diagnostic Implications.

Idiopathic nephrotic syndrome (NS) is a heterogeneous group of glomerular disorders which includes two major phenotypes: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). MCD and FSGS are classic types of primary podocytopathies. We aimed to explore the molecular mechanisms in NS triggered by primary podocytopathies and evaluate diagnostic value of the selected proteomic signatures by analyzing blood proteome profiling. Totally, we recruited 90 participants in two cohorts. The first cohort was analyzed using label-free quantitative (LFQ) proteomics to discover differential expressed proteins and identify enriched biological process in NS which were further studied in relation to clinical markers of kidney injury. The second cohort was analyzed using parallel reaction monitoring-based quantitative proteomics to verify the data of LFQ proteomics and assess the diagnostic performance of the selected proteins using receiver-operating characteristic curve analysis. Several biological processes (such as immune response, cell adhesion, and response to hypoxia) were found to be associated with kidney injury during MCD and FSGS. Moreover, three proteins (CSF1, APOC3, and LDLR) had over 90% sensitivity and specificity in detecting adult NS triggered by primary podocytopathies. The identified biological processes may play a crucial role in MCD and FSGS pathogenesis. The three blood protein markers are promising for diagnosing adult NS triggered by primary podocytopathies.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

AIF1 + CSF1R + MSCs, induced by TNF-α, act to generate an inflammatory microenvironment and promote hepatocarcinogenesis.

BACKGROUND AND AIMS: Increasing evidence suggests that mesenchymal stem cells (MSCs) home to injured local tissues and the tumor microenvironment in the liver. Chronic inflammation is regarded as the major trait of primary liver cancer. However, the characteristics of endogenous MSCs in the inflammatory environment and their role in the occurrence of liver cancer remain obscure. APPROACH AND RESULTS: Using single-cell RNA sequencing, we identified a distinct inflammation-associated subset of MSCs, namely AIF1 + CSF1R + MSCs, which existed in the microenvironment before the occurrence of liver cancer. Furthermore, we found that this MSC subgroup is likely to be induced by TNF-α stimulation through the TNFR1/SIRT1 (sirtuin 1) pathway. In a rat primary liver cancer model, we showed that MSCs with high SIRT1 expression (Ad-Sirt1-MSCs) promoted macrophage recruitment and synergistically facilitated liver cancer occurrence by secreting C-C motif chemokine ligand (CCL) 5. Interestingly, depletion of macrophages or knockdown of CCL5 expression in Ad-Sirt1-MSCs attenuated the promotive effect of Ad-Sirt1-MSCs on liver inflammation and hepatocarcinogenesis (HCG). Finally, we demonstrated that SIRT1 up-regulated CCL5 expression through activation of the AKT/HIF1α signaling axis in MSCs. CONCLUSIONS: Together, our results show that MSCs, which are mobilized to the injured site, can be educated by macrophages. In turn, the educated MSCs are involved in generating a chronic inflammatory microenvironment and promoting HCG.

Effects of the Carbon Support on Heterogeneous Molecular Catalysts for Carbon Dioxide Reduction.

Molecular catalysts stabilized on a support material, also called heterogeneous molecular catalysts, exhibit excellent performance in carbon dioxide reduction reaction (CO2 RR). Different support in these electrocatalysts can have a substantial influence on the activity, making support control one tool to enhance the CO2 RR performance. However, a systematic understanding of the support effects is lacking. Taking cobalt phthalocyanine (CoPc) immobilized onto different carbon materials as examples, we demonstrate that the surface area, pore structure and the morphology of the as-prepared heterogeneous molecular catalysts can influence the CO2 transfer and adsorption, and then change the CO2 RR activity. In contrast to the other four materials, CoPc/mesoporous carbon (MC) can efficiently convert carbon dioxide to carbon monoxide at minimal overpotential (-0.8 V vs. RHE) due to its special nanostructure and pore distribution. The results of this study suggest that the performance of electrocatalytic reduction of carbon dioxide can be improved by changing different substrates.

Evaluating effects of tetrabromobisphenol A and microplastics on anaerobic granular sludge: Physicochemical properties, microbial metabolism, and underlying mechanisms.

Tetrabromobisphenol A (TBBPA) and microplastics are emerging contaminants of widespread concern. However, little is known about the effects of combined exposure to TBBPA and microplastics on the physicochemical properties and microbial metabolism of anaerobic granular sludge. This study investigated the effects of TBBPA, polystyrene microplastics (PS MP) and polybutylene succinate microplastics (PBS MP) on the physicochemical properties, microbial communities and microbial metabolic levels of anaerobic granular sludge. The results showed that chemical oxygen demand (COD) removal of sludge was lowest in the presence of TBBPA alone and PS MP alone with 33.21% and 30.06%, respectively. The microorganisms promoted the secretion of humic substances under the influence of TBBPA, PS MP and PBS MP. The lowest proportion of genes controlling glycolytic metabolism in sludge was 1.52% when both TBBPA and PS MP were added. Microbial reactive oxygen species were increased in anaerobic granular sludge exposed to MPS. In addition, TBBPA treatment decreased electron transfer of the anaerobic granular sludge and disrupted the pathway of anaerobic microorganisms in acquiring adenosine triphosphate, and MPs attenuated the negative effects of TBBPA on the acetate methanogenesis process of the anaerobic granular sludge. This study provides a reference for evaluating the impact of multiple pollutants on anaerobic granular sludge.

Can The Pitch Dimension Influence the Physical Fitness Adaptations Induced by Small-Sided Training Programs Added to Regular In-Field Training? A Randomized Controlled Study in Youth Soccer Players.

Small-sided games (SSGs) are frequently utilized in training settings to elicit specific stimuli that can promote physical fitness adaptations over time. However, various task constraints, such as pitch dimensions, can significantly influence both the acute external and internal load responses. Thus, understanding the impact of different pitch dimensions on physical fitness adaptations is crucial. This study sought to compare the physical adaptations induced by an SSG-based program utilizing more elongated pitches (SSGlw2; length-to-width ratio: 2.0) versus less elongated pitches (SSGwl1; length-to-width ratio: 1.0) on the Yo-Yo intermittent recovery test level 1 (YYIRT), and 30-meter sprint. This study employed a randomized controlled design. Forty-eight male soccer players (16.4 ± 0.6 years) participated. These players were randomly allocated to two experimental groups (N = 16, SSGlw1; N = 16, SSGlw2) and underwent two weekly additional training sessions over an 8-week period, while a group of 16 players continued with their regular in-field sessions as a control group. Evaluations were conducted before and after the intervention period. Significant interactions time u group were observed in regards YYIRT (F = 15.857; p < 0.001; = 0.413) and 30-m sprint test (p < 0.001). Between-group differences on YYIRT were found in post-intervention (p < 0.001), on which SSGlw2 (p < 0.001) and SSGlw1 (p < 0.001) were significantly greater in comparison to control group. Additionally, between-group differences on 30-m sprint were found in post-intervention (p < 0.001), on which SSGlw2 was significantly better than SSGlw1 (p < 0.001) and control group (p < 0.001). Coaches are advised to prioritize the use of more elongated pitch sizes to promote adaptations in sprint performance, while still acknowledging that aerobic capacity improvements remain significant compared to other pitch shapes.

Immunosuppressive CD10+ALPL+ neutrophils promote resistance to anti-PD-1 therapy in HCC by mediating irreversible exhaustion of T cells.

BACKGROUND & AIMS: Remodeling the tumor microenvironment is a critical strategy for treating advanced hepatocellular carcinoma (HCC). Yet, how distinct cell populations in the microenvironment mediate tumor resistance to immunotherapies, such as anti-PD-1, remains poorly understood. METHODS: We analyzed the transcriptomic profile, at a single-cell resolution, of tumor tissues from patients with HCC scheduled to receive anti-PD-1-based immunotherapy. Our comparative analysis and experimental validation using flow cytometry and histopathological analysis uncovered a discrete subpopulation of cells associated with resistance to anti-PD-1 treatment in patients and a rat model. A TurboID-based proximity labeling approach was deployed to gain mechanistic insights into the reprogramming of the HCC microenvironment. RESULTS: We identified CD10+ALPL+ neutrophils as being associated with resistance to anti-PD-1 treatment. These neutrophils exhibited a strong immunosuppressive activity by inducing an apparent "irreversible" exhaustion of T cells in terms of cell number, frequency, and gene profile. Mechanistically, CD10+ALPL+ neutrophils were induced by tumor cells, i.e., tumor-secreted NAMPT reprogrammed CD10+ALPL+ neutrophils through NTRK1, maintaining them in an immature state and inhibiting their maturation and activation. CONCLUSIONS: Collectively, our results reveal a fundamental mechanism by which CD10+ALPL+ neutrophils contribute to tumor immune escape from durable anti-PD-1 treatment. These data also provide further insights into novel immunotherapy targets and possible synergistic treatment regimens. IMPACT AND IMPLICATIONS: Herein, we discovered that tumor cells reprogrammed CD10+ALPL+ neutrophils to induce the "irreversible" exhaustion of T cells and hence allow tumors to escape from the intended effects of anti-PD-1 treatment. Our data provided a new theoretical basis for the elucidation of special cell populations and revealed a molecular mechanism underpinning resistance to immunotherapy. Targeting these cells alongside existing immunotherapy could be looked at as a potentially more effective therapeutic approach.

GDF11 Improves Ischemia-Reperfusion-Induced Acute Kidney Injury via Regulating Macrophage M1/M2 Polarization.

INTRODUCTION: Acute kidney injury (AKI) is a clinical emergency caused by the rapid decline of renal function caused by various etiologies. Growth differentiation factor 11 (GDF11) can promote renal tubular regeneration and improve kidney function in AKI, but the specific mechanism remains unclear. Herein, we investigated the effect and mechanisms of GDF11 in ameliorating AKI induced by ischemia-reperfusion (I/R). METHODS: An animal model of AKI was established by I/R method, and the changes of serum urea nitrogen and creatinine were measured to evaluate the AKI. Enzyme-linked immunosorbent assay (ELISA) was used to measure cytokines, malondialdehyde, superoxide dismutase, nitric oxide synthase, and arginase 1 levels. Flow cytometry was used to count the M1/M2 macrophages. IHC, WB, and q-PCR experiments were used to evaluate the expression of GDF11. RESULTS: The changes in serum levels of urea nitrogen and creatinine after I/R suggest that an animal model of AKI induced by I/R was successfully established. AKI caused by I/R significantly changed the M1/M2 macrophage polarization balance, with an increase in M2 being significantly higher than M1 as well as increased oxidative stress. Treatment with GDF11 after I/R significantly increased the differentiation of M2 cells and inhibited the differentiation of M1 macrophages, as well as decreased oxidative stress. CONCLUSION: GDF11 can promote the repair of AKI caused by I/R by regulating the balance of M1/M2 polarization in macrophages and oxidative stress.

COL28 promotes proliferation, migration, and EMT of renal tubular epithelial cells.

Type XXVIII collagen (COL28) is involved in cancer and lung fibrosis. COL28 polymorphisms and mutations might be involved in kidney fibrosis, but the exact role of COL28 in renal fibrosis is unknown. This study explored the function of COL28 in renal tubular cells by examining the expression of COL28 mRNA and the effects of COL28 overexpression in human tubular cells. COL28 mRNA expression and localization were observed in normal and fibrotic kidney tissues from humans and mice using real-time PCR, western blot, immunofluorescence, and immunohistochemistry. The consequences of COL28 overexpression on cell proliferation, migration, cell polarity, and epithelial-to-mesenchymal transition (EMT) induced by TGF-ß1 were examined in human tubular HK-2 cells. COL28 expression was low in human normal renal tissues, mainly observed in the renal tubular epithelial cells and especially in proximal renal tubules. COL28 protein expression in human and mouse obstructive kidney disease was higher than in normal tissues (p < 0.05) and more significant in the UUO2-Week than the UUO1-Week group. The overexpression of COL28 promoted HK-2 cell proliferation and enhanced their migration ability (all p < 0.05). TGF-ß1 (10 ng/ml) induced COL28 mRNA expression in HK-2 cells, decreased E-cadherin and increased α-SMA in the COL28-overexpression group compared with controls (p < 0.05). ZO-1 expression decreased while COL6 increased in the COL28-overexpression group compared with controls (p < 0.05). In conclusion, COL28 overexpression promotes the migration and proliferation of renal tubular epithelial cells. The EMT could also be involved. COL28 could be a therapeutic target against renal- fibrotic diseases.

Targeted blocking of CCR2 and CXCR2 improves the efficacy of transarterial chemoembolization of hepatocarcinoma.

BACKGROUND: Transarterial chemoembolization (TACE) has been shown to prolong survival in patients with unresectable hepatocellular carcinoma (HCC); however, the long-term survival remains dismal. Targeting macrophage and neutrophil infiltration is a promising strategy. The CCL2/CCR2 and CXCLs/CXCR2 axes are required for recruitment of macrophages and neutrophils, respectively, in HCC. We investigated the feasibility of CCL2/CCR2 and CXCLs/CXCR2 as therapeutic targets in combination with TACE for treating HCC. METHODS: Expression of CCL2/CCR2 and CXCLs/CXCR2 was analyzed in the primary rat HCC model and one HCC cohort. The relationship between expression levels, neutrophil and macrophage infiltration, hepatocarcinogenesis progression in the rat model, and survival of HCC patients was assessed. The anti-tumor effects of blocking the CCL2/CCR2 and CXCLs/CXCR2 axes by CCR2 and CXCR2 antagonists in combination with TACE were evaluated in HCC rats. The numbers of macrophages, neutrophils, and hepatic progenitor cells were further determined to explore the underlying mechanisms. RESULTS: High macrophage and neutrophil infiltration and CXCL8 expression were associated with poor prognosis in the TCGA liver cancer dataset. High expression of CCL2/CCR2 and CXCL8/CXCR2 in clinical HCC specimens was associated with reduced survival. Expression of CCL2/CCR2 and CXCL1/CXCR2 was correlated with hepatocarcinogenesis progression in the primary rat HCC model. Blockade of CCL2/CCR2 and CXCLs/CXCR2 enhanced the anti-tumor effect of TACE treatment in this model. Blocking the CCL2/CCR2 and CXCLs/CXCR2 axes with CCR2 and CXCR2 antagonists in TACE-treated rats reduced macrophage and neutrophil infiltration and hepatic progenitor cell activation and thus overcame TACE resistance in HCC. CONCLUSIONS: The results demonstrate the translational potential of immunotherapy targeting the CCL2/CCR2 and CXCLs/CXCR2 axes in combination with TACE therapy for the treatment of HCC.

Extracellular microparticles derived from hepatic progenitor cells deliver a death signal to hepatoma-initiating cells.

The malignant transformation of normal resident hepatic stem/progenitor cells has a critical role in hepatocarcinogenesis and the recurrence of hepatocellular carcinoma (HCC). We defined such hepatic progenitor cells as hepatoma-initiating cells. An efficient strategy is required to target and kill the hepatoma-initiating cells. We isolated extracellular microparticles (MPs) derived from apoptotic hepatic progenitor cells (HPCs) and tested their ability to inhibit hepatocarcinogenesis. Extracellular MPs were isolated from HPCs, hepatocytes and liver tumor cells. Their effects on tumor growth were investigated in rat primary HCC models, in which hepatocarcinogenesis is induced by diethylnitrosamine (DEN). The extracellular MPs derived from apoptotic HPCs, apoptotic hepatocytes and apoptotic liver tumor cells were similar in morphology, diameter and zeta potential. However, they had different antitumor effects. In DEN-exposed rats, only the MPs derived from apoptotic HPCs effectively inhibit hepatocarcinogenesis. In vitro and in vivo analyses confirmed that HPCs preferentially take up MPs derived from apoptotic HPCs compared to MPs from other liver cell types. Proteomic analysis of MPs from apoptotic HPCs showed enrichment of proteins involved in cell death pathways. Thus, HPC-derived MPs contain a death signal to induce the killing of hepatoma-initiating cells. Our findings provide evidence that a death signal encapsulated in HPC-derived extracellular microparticles can efficiently clear hepatoma-initiating cells and prevent hepatocarcinogenesis.

Effects of PFOA on the physicochemical properties of anaerobic granular sludge: Performance evaluation, microbial community and metagenomic analysis.

The impact of perfluorooctanoic acid (PFOA) on the anaerobic granular sludge was evaluated through a sequential batch experiment. Results showed that PFOA inhibited the chemical oxygen demand (COD) removal rate of the sludge and the dosage of 100 mg/L PFOA was more obvious. However, this negative effect would gradually weaken with the adaptation of microorganisms. For the 50 mg/L PFOA experimental group, the proteins content in the extracellular polymeric substances (EPS) of the anaerobic granular sludge increased from 1.53 mg/g to 3.65 mg/g. Meanwhile, PFOA inhibited the 2-(p-iodophenyl)-3-(p-nitrophenyl)-5-phenyltetrazolium chloride (INT) activity of the anaerobic granular sludge. Furthermore, 100 mg/L PFOA reduced the relative abundance of Proteobacteria by 5.99% and Longilinea by 1.11%. 100 mg/L PFOA mainly restricted COD removal by affecting the glycolysis process, with the abundances of glucokinase and pyruvate kinase reduced by 8% and 28.1%, respectively. Compared with the control group, the relative abundance of the methyl-coenzyme M reductase alpha subunit increased by 84%, respectively, under 100 mg/L PFOA.

Screening and Demulsification Mechanism of Fluorinated Demulsifier Based on Molecular Dynamics Simulation.

In order to solve the problem of demulsification difficulties in Liaohe Oilfield, 24 kinds of demulsifiers were screened by using the interface generation energy (IFE) module in the molecular dynamics simulation software Materials Studio to determine the ability of demulsifier molecules to reduce the total energy of the oil-water interface after entering the oil-water interface. Neural network analysis (NNA) and genetic function approximation (GFA) were used as technical means to predict the demulsification effect of the Liaohe crude oil demulsifier. The simulation results show that the SDJ9927 demulsifier with ethylene oxide (EO) and propylene oxide (PO) values of 21 (EO) and 44 (PO) reduced the total energy and interfacial tension of the oil-water interface to the greatest extent, and the interfacial formation energy reached -640.48 Kcal/mol. NNA predicted that the water removal amount of the SDJ9927 demulsifier was 7.21 mL, with an overall error of less than 1.83. GFA predicted that the water removal amount of the SDJ9927 demulsifier was 7.41mL, with an overall error of less than 0.9. The predicted results are consistent with the experimental screening results. SDJ9927 had the highest water removal rate and the best demulsification effect. NNA and GFA had high correlation coefficients, and their R2s were 0.802 and 0.861, respectively. The higher R2 was, the more accurate the prediction accuracy was. Finally, the demulsification mechanism of the interfacial film breaking due to the collision of fluorinated polyether demulsifiers was studied. It was found that the carbon-fluorine chain had high surface activity and high stability, which could protect the carbon-carbon bond in the demulsifier molecules to ensure that there was no re-emulsion due to the stirring external force.

Sirt1-Overexpressing Mesenchymal Stem Cells Drive the Anti-tumor Effect through Their Pro-inflammatory Capacity.

The major obstacles for the efficacy of tumor immunotherapies are their immune-related systemic adverse events. Therefore, tumor tropism property and pro-inflammatory ability of mesenchymal stem cells (MSCs) could be utilized in combination to potentiate local immunity for cancer eradication. We previously observed that MSCs with the type III histone deacetylase silent information regulator 2 homologue 1 (Sirt1) overexpression displayed a pro-inflammatory capacity. However, the anti-tumor effect of Sirt1-overexpressing MSCs and the role of Sirt1 in regulating the pro-inflammatory capacity of MSCs still need to be clarified. In this study, utilizing the hepatic metastasis model of colorectal carcinoma, we demonstrated that Sirt1-overexpressing MSCs significantly exerted anti-tumor activity through increasing the number of CD8+ T cells. Furthermore, Sirt1 did not affect chemokine secretion in MSCs induced by inflammatory cytokines, but impaired the immunosuppressive ability of MSCs through suppressing inflammatory cytokine-stimulated inducible nitric oxide synthase (iNOS) production via deacetylating p65. iNOS overexpression negated the anti-tumor effect of Sirt1-overexpressing MSCs. Collectively, our data defined Sirt1 as the critical regulator for modulating the pro-inflammatory ability of MSCs, and they suggested that Sirt1-overexpressing MSCs secreting chemokines but little iNOS under the inflammatory milieu were capable of attracting immune cells to close proximity without suppressing their proliferation, thereby achieving a potent anti-tumor effect.

Neurotoxicity of ß-HgS differs from environmental mercury pollutants (MeHgCl and HgCl2) in Neuro-2a cell.

ß-HgS, differing from environmental mercury pollutants (MeHgCl and HgCl2) in chemical form, is used as traditional medicine in Asian countries for thousands of years. In this study, Neuro-2a cells were exposed to ß-HgS, MeHgCl and HgCl2 (5 µM) for 6-24 h. The cell viability of ß-HgS was higher than MeHgCl with 25.9% and 72.4% in 12 h and 24 h respectively. As the incubation time increased, MeHgCl had obvious damage to cell morphology, decreased the ratio of Bcl-2 and Bak and increased the expressions of TNF-α, IL-6 and IL-1ß significantly. Furthermore, the expressions of IL-1ß and IL-6 in HgCl2 group were increased significantly in 6 h and 24 h. The apoptotic rates in MeHgCl and HgCl2 group were respectively higher than ß-HgS with 32.2% and 7.30% in 24 h. Our findings indicate that ß-HgS is much less neurotoxicity than MeHgCl and HgCl2 in Neuro-2a cells.

A new fluorescence sensor developed with polydopamine nanospheres for the detection of anti-PLA2R antibody biomarkers of idiopathic membranous nephropathy.

Anti-PLA2R antibody is only expressed in podocytes from patients with idiopathic membranous nephropathy (IMN). The detection of anti-PLA2R antibody in serum is therefore able to obtain essential information for rapid diagnosis and evaluation of the disease activity of IMN. In the present study, a polydopamine nanosphere-based fluorescent sensor was constructed for direct detection of anti-PLA2R antibodies in human serum. In this sensing system, the double-stranded DNA was phosphorylated under the action of anti-PLA2R antibody and the single-stranded DNA was cut by exonuclease. The single-stranded DNA was then adsorbed on polydopamine microspheres. The fluorescent groups labeled on the DNA were quenched, and the concentration of anti-PLA2R antibody was detected quantitatively by measuring the fluorescence signal changes before and after the reaction. The experimental results show that the method has a good linear detection range between 0.05 and 10 µg/mL for anti-PLA2R antibody and the detection limit is 0.02 µg/mL. Graphical abstract.

Severe renal impairment as an adverse prognostic factor for survival in newly diagnosed multiple myeloma patients.

BACKGROUND: Renal impairment (RI) is associated with poor survival in newly diagnosed multiple myeloma (MM) patients. Renal function recovery has been one of the main therapeutic goals in those patients. METHODS: The records from 393 newly diagnosed MM patients in our hospital between January 2012 and December 2016 were retrospectively analyzed. RI was defined as an eGFR < 40 mL/min according to the novel IMWG criteria. RI patients were categorized based on their renal function at diagnosis: severe RI: eGFR < 30 mL/min, and mild RI: 30 mL/min ≤ eGFR <40 mL/min. We explored whether RI, and particularly severe RI, was an adverse prognostic factor for survival, and investigated the impact of renal function recovery on survival. RESULTS: Severe RI, hemoglobin <100 g/L, LDH ≥ 245 U/L, hyperuricemia, 1q21 amplification, and lack of novel agent treatment were associated with decreased overall survival (OS). Severe RI patients with renal response had a median OS of 27 months compared with 18 months for those patients without renal response (P = .030), but their median OS was still significantly lower than that for patients without severe RI, which was 51 months. In severe RI patients, the overall renal response rate in bortezomib-based regimens was significantly higher than that in nonbortezomib-based regimens. CONCLUSION: Our results suggest that severe RI is an adverse prognostic factor for survival in newly diagnosed MM patients, restoration of renal function may improve survival, and bortezomib-based regimens may be the preferred treatment in patients with severe RI.

Autophagy and Tumorigenesis.

Tumour cells are derived from normal cells that undergo numerous genetic and epigenetic mutations under various stresses. This process involves changes in many intrinsic cellular mechanisms and in the microenvironment. Understanding the process is important for preventing tumorigenesis and tumour recurrence. Numerous studies have shown that sputum autophagy not only plays an important role in tumorigenesis but also has a dual role in tumour suppression and cancer promotion. On the one hand, excessive autophagy can cause apoptosis and death, thereby inducing an autophagic death mechanism that leads to the death of drug-resistant tumour cells in malignant tumours. On the other hand, autophagy can mediate tumour escape and promote the survival of tumour cells. With the expansion of in-depth research, increasing evidence has shown that the specific role of autophagy in tumorigenesis may be related to the specific stage of tumour development and specific tumour type.

Autophagy and Tumour Stem Cells.

Autophagy is critical for the survival and stemness maintenance of cancer stem cells (CSCs) and is an enhancer of CSC tumorigenesis. At the same time, autophagy contributes to conditions optimal for facilitating the invasion and metastasis of CSCs. Moreover, autophagy induces the dormant state of CSCs to help them resist the cytotoxic effects of chemotherapy and radiotherapy, thereby improving the likelihood of their survival. The combination of autophagy inhibitors with specific drugs targeting specific CSC subpopulations is expected to act specifically on CSCs and produce fewer toxic side effects on normal tissues. This in-depth study is very timely and important for further identifying the potential role of autophagy in different states of CSCs and places a particular emphasis on exploring molecular mechanisms in the regulation of autophagy via advanced techniques based on molecular biology.