Ferroptosis-related genes, a novel therapeutic target for focal segmental glomerulosclerosis.

Recent studies have suggested that ferroptosis participates in various renal diseases. However, its effect on focal segmental glomerulosclerosis remains unclear. This study analyzed the GSE125779 and GSE121211 datasets to identify the differentially expressed genes (DEGs) in renal tubular samples with and without FSGS. The Cytoscape was used to construct the protein-protein interaction network. Moreover, the ferroptosis-related genes (FRGs) were obtained from the ferroptosis database, while ferroptosis-related DEGs were obtained by intersection with DEGs. The target genes were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The GSE108112 dataset was used to verify the expression of target FRGs. Besides, we built the mRNA-miRNA network regarding FRGs using the NetworkAnalyst database, and circRNAs corresponding to key miRNAs were predicted in the ENCORI database. In this study, 16 ferroptosis-related DEGs were identified between FSGS and healthy subjects, while five co-expressed genes were obtained by three topological algorithms in Cytoscape. These included the most concerned Hub genes JUN, HIF1A, ALB, DUSP1 and ATF3. The KEGG enrichment analysis indicated that FRGs were associated with mitophagy, renal cell carcinoma, and metabolic pathways. Simultaneously, the co-expressed hub genes were analyzed to construct the mRNA-miRNA interaction network and important miRNAs such as hsa-mir-155-5p, hsa-mir-1-3p, and hsa-mir-124-3p were obtained. Finally, 75 drugs targeting 54 important circRNAs and FRGs were predicted. This study identified the Hub FRGs and transcriptomic molecules from FSGS in renal tubules, thus providing novel diagnostic and therapeutic targets for FSGS.

Common Key Genes in Differentiating Parathyroid Adenoma From Thyroid Adenoma.

Recent studies have demonstrated the close relationship between parathyroid adenoma (PA) and thyroid follicular adenoma (FTA). However, the underlying pathogenesis remains unknown. This study focused on exploring common pathogenic genes, as well as the pathogenesis of these two diseases, through bioinformatics methods. This work obtained PA and FTA datasets from the Integrated Gene Expression Database to identify the common differentially expressed genes (DEGs) of two diseases. The functions of the genes were investigated by GO and KEGG enrichment. The program CytoHubba was used to select the hub genes, while receiver operating characteristic curves were plotted to evaluate the predictive significance of the hub genes. The DGIbd database was used to identify gene-targeted drugs. This work detected a total of 77 DEGs. Enrichment analysis demonstrated that DEGs had activities of 3',5'-cyclic AMP, and nucleotide phosphodiesterases and were associated with cell proliferation. NOS1, VWF, TGFBR2, CAV1, and MAPK1 were identified as hub genes after verification. The area under the curve of PA and FTA was>0.7, and the hub genes participated in the Relaxin Signaling Pathway, focal adhesion, and other pathways. The construction of the mRNA-miRNA interaction network yielded 11 important miRNAs, while gene-targeting drug prediction identified four targeted drugs with possible effects. This bioinformatics study demonstrated that cell proliferation and tumor suppression and the hub genes co-occurring in PA and FTA, have important effects on the occurrence and progression of two diseases, which make them potential diagnostic biomarkers and therapeutic targets.

Identification of monocyte-associated biomarkers in systemic lupus erythematosus and their pan-cancer analysis.

Immune dysregulation is not only a pathogenic mechanism in systemic lupus erythematosus (SLE) but also a potential cause of the link between SLE and cancer. The current understanding of SLE monocyte-associated biomarkers is limited, and the precise mechanism behind the link between SLE and cancer is uncertain. By using WGCNA and immune infiltration to analyze the GSE72326 dataset, we determined the most pertinent modules for monocytes and discovered eight candidate hub genes from them. The limma software was used to find genes that were differently expressed in SLE. The genes that overlapped between the two were chosen using a Venn diagram as the essential genes related to monocytes in SLE, and the essential genes were verified by several datasets. Correlation analysis and GSEA analysis were used to examine the probable immunological pathways connected to key genes. We examined the expression of hub genes in cancer and their interaction with monocytes using the GEPIA and TIMER databases to understand the significance of essential genes in tumorigenesis. In addition, we performed transcription factor identification. We discovered three biomarkers (IFI30, BLVRA, and RIN2) that are mostly involved in interferon-related signaling pathways and are associated with monocyte-mediated immune responses in SLE. The three important genes are also strongly expressed in a number of malignancies and have a relationship with monocytes. As a result, IFI30, BLVRA, and RIN2 may act as SLE-associated biomarkers of monocytes and as a bridge between SLE and tumors. We proposed that interferon-related signaling pathways might function as possible mediators of cancer risk in SLE.

Acute Kidney Injury During Extracorporeal Membrane Oxygenation: VA ECMO Versus VV ECMO.

PURPOSE: Acute kidney injury (AKI) has been reported to be one of the most common complications in patients receiving extracorporeal membrane oxygenation (ECMO), yet variations in AKI between different types of ECMO remain unclear. This meta-analysis systematically compares AKI/severe AKI in adult patients requiring different types of ECMO. METHODS: Two authors independently performed a literature search using PubMed, Web of Science, and Embase, encompassing publications up until April 20, 2020 (inclusive). The number of AKI patients, including patients who required/did not require renal replacement therapy (RRT), and deceased patients with AKI/severe AKI, who received different types of ECMO were collated and analyzed using STATA. RESULTS: The results indicated that there were no significant differences in the risk of AKI/severe AKI among different types of ECMO. However, the presence of AKI and severe AKI during veno-arterial (VA) ECMO was more strongly associated with mortality. CONCLUSIONS: Although mortality rates related to AKI/severe AKI during VV ECMO are high, the occurrence of AKI/severe AKI during VA ECMO should be given greater attention, as these instances are considered strong indicators of patient deterioration and even death. Additional studies are needed to corroborate these findings.

Polymeric RNAi Constructs Tailored with Appreciable Transcellular Trafficking Functions for Potential Suppression of Parathyroid Hormone Production.

Polymeric small interfering RNA (siRNA) conjugate was elaborated to sequentially circumvent the predefined biological barriers encountered in the journey of transcellular delivery of siRNA into cytosol. Herein, classic ring-opening polymerization was employed for synthesis of well-defined poly(amino acid) derivatives possessing an array of carboxyl groups in an attempt to resemble the structural characteristics of hyaluronan. Furthermore, the hyaluronan-like synthetic was conjugated with a multiple of siRNA through a glutathione (GSH)-responsive disulfide linkage. The siRNA conjugate appeared to utilize the hyaluronan-specific receptors of CD44 for cell internalization, indicating similar functionalities to our hyaluronan-mimicking synthetic. Furthermore, the carboxyl groups of hyaluronan-like synthetics were designed to be selectively detached in subcellular acidic endosomes/lysosomes and transform into the cytomembrane-disruptive flanking ethylenediamine moieties, which appeared to be crucial in facilitating translocation of siRNA payloads from entrapment and degradation in lysosomes toward the cytosol. Eventually, active siRNA could be smoothly released from the synthetic due to the GSH cleavage disulfide linkage (disulfide), consequently accounting for potent RNA knockdown activities (>90%) toward cancerous cells. In addition, appreciable knockdown of parathyroid hormone was also achieved from our proposed siRNA conjugates in parathyroid cells. Hence, the elaborated siRNA conjugate showed tremendous potential in treatment of hyperparathyroidism, and could be developed further for systemic RNA interference (RNAi) therapeutics. Moreover, this study could also be the first example of a synthetic mimic to hyaluronan acquiring its functionalities, which could have important implications for further development of biomimic materials in pursuit of biomedical applications.

Intensified treatment of hyperphosphatemia associated with reduction in parathyroid hormone in patients on maintenance hemodialysis.

BACKGROUND: This study investigated the therapeutic effect of intensive phosphorus-lowering therapy on intact-parathyroid hormone (iPTH) levels in hemodialysis patients. METHODS: Ninety-five hemodialysis patients with serum phosphorus ≥1.78 mmol/L and iPTH ≥300 pg/dL were apportioned to either the treatment or control group (n = 43 and 52, respectively) based on patient commitment to treatment. The treatment group was given phosphorus-lowering therapies with phosphate binders (lanthanum, sevelamer or/and calcium reagent) combined with dietary phosphate restriction and intensified hemodialysis. The control individuals were given low doses of calcium agents, if serum calcium was <2.54 mmol/L. Percent changes in serum phosphorus and iPTH levels were compared between the two groups. In addition, based on the time required to achieve >20% decrease in serum phosphorus, the patients in the treatment group were further stratified as rapid responders (≤2 months; 27 patients) or slow responders (>2 months; 16 patients) and percent changes in iPTH were compared. RESULTS: Serum phosphorus and iPTH levels decreased from baseline in the treatment group (-24.08 ± 1.93% and -9.92 ± 3.70%, respectively) but increased in the control group (22.00 ± 3.63% and 104.21 ± 23.89%; both p < .001). In the rapid responders subgroup, the iPTH decreased (-16.93 ± 3.49%), but in the slow responders subgroup the iPTH increased slightly (0.68 ± 7.37%, p < .05). CONCLUSIONS: For these patients on maintenance hemodialysis, intensive treatment of hyperphosphatemia was associated with a decrease in iPTH levels, especially for those who had achieved substantial reduction in serum phosphorus within 2 months.

Investigation of optimum N-terminal probrain natriuretic peptide level in patients on maintained hemodialysis.

BACKGROUND: Serum N-terminal probrain natriuretic peptide (NT-proBNP) level is known to be strongly associated with fluid overload, and serves as a guide for fluid management in patients on hemodialysis (HD). This study aimed at investigating the relationship between NT-proBNP level and blood pressure (BP), ultrafiltration/dry weight ratio as well as hemoglobin, and to explore the optimal cutoff point of NT-proBNP level in Chinese patients on HD. METHODS: A total of 306 patients on maintained HD for stage 5 chronic kidney disease (CKD) were included in this prospective study [corrected]. Their average ultrafiltration/dry weight ratio and BP before dialysis were recorded. The serum NT-proBNP, hemoglobin, serum calcium, and phosphorus were detected. The cutoff value for NT-proBNP level was calculated using receiver operating characteristic (ROC) analysis. RESULTS: The high NT-proBNP level was associated with high BP and ultrafiltration/dry weight ratio, and low hemoglobin level. The optimal cutoff point of NT-proBNP level for patients on maintained HD was 5666 pg/mL, with a sensitivity of 78.5%, specificity of 43.9%, and area under the curve (AUC) of 0.703 (<0.001). CONCLUSIONS: NT-proBNP level ≤5666 pg/mL was recommended to achieve the target BP, hemoglobin level, and ultrafiltration/dry weight ratio in patients on maintained HD with an ejection fraction (EF) >50%.

Characterization of Mechanical Heterogeneity in Dissimilar Metal Welded Joints.

Dissimilar metal welded joints (DMWJs) possess significant localized mechanical heterogeneity. Using finite element software ABAQUS with the User-defined Material (UMAT) subroutine, this study proposed a constitutive equation that may be used to express the heterogeneous mechanical properties of the heat-affected and fusion zones at the interfaces in DMWJs. By eliminating sudden stress changes at the material interfaces, the proposed approach provides a more realistic and accurate characterization of the mechanical heterogeneity in the local regions of DMWJs than existing methods. As such, the proposed approach enables the structural integrity of DMWJs to be analyzed in greater detail.

Thermal Decomposition Kinetics and Compatibility of 3,5-difluoro-2,4,6-trinitroanisole (DFTNAN).

In this paper, the thermal decomposition behavior of 3,5-difluoro-2,4,6-trinitroanisole (DFTNAN) was studied by differential scanning calorimetry (DSC) and thermogravimetry (TG) by using different heating rates (2, 5, 10, 15 °C·min-1). Subsequently, the kinetic and thermodynamic parameters of non-isothermal thermal decomposition of DFTNAN were calculated. The critical temperature of thermal explosion (Tb) and self-accelerating decomposition temperature (TASDT) were determined to be 249.03 °C and 226.33 °C, respectively. The compatibility of DFTNAN with a number of high explosives (cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX), 1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaaza-tetracyclo-[5.5.0.05,9.03,11]-dodecane (CL-20) and dihydroxylammonium 5,5'-bistetrazole-1,1'-diolate (TKX-50)) was studied at different mass ratios using DSC. The criteria to judge the compatibility between the materials were based on a standardization agreement (STANAG 4147). The thermodynamic study results revealed that DFTNAN possessed superior thermal safety and stability. The experimental of compatibility results indicated that the mass ratios of the high explosives in the DFTNAN/RDX, DFTNAN/HMX and DFTNAN/CL-20 compositions more than 40%, 60% and 70% exhibited good compatibility, whereas DFTNAN/TKX-50 demonstrated poor compatibility.

A facile fabrication of porous fluoro-polymer with excellent mechanical properties based on high internal phase emulsion templating using PLA as co-stabilizer.

The stability of fluoro-high internal phase emulsion (fluoro-HIPE) systems and fluoro-polyHIPEs' mechanical strength require further improvement to meet the requirements of future applications. In this study, we used polylactic acid (PLA) as a co-stabilizer to improve the stability of the fluoro-polyHIPE. The effects of concentration and molecular weight of PLA on the pores of the fluoro-polyHIPEs were investigated. The addition of PLA produced a porous material with narrower void size distributions, higher specific surface areas and enhanced mechanical properties compared to the fluoro-polyHIPE material without the additive. The resulting fluoro-polyHIPE showed smaller pore sizes (void diameters ranged from 1-3 µm) and an improved hydrophobic nature (contact angle can reach to 148.6°). The crush strength and Young's modulus values can reach 4.42 and 74.07 MPa, respectively, at a PLA addition of 25 wt% (oil phase composition), representing increases of 246% and 650% over fluoro-polyHIPE without PLA addition. The fluoro-poly-HIPE demonstrated excellent mechanical properties compared to many engineering foams, such as melamine, polystyrene, and even graphite foams. Improvements in the performance of porous fluoropolymer materials will be beneficial for many applications, such as chemical adsorption and separation, etc.

High Dose ESAs Are Associated with High iPTH Levels in Hemodialysis Patients with End-Stage Kidney Disease: A Retrospective Analysis.

OBJECTIVE: Anemia and secondary hyperparathyroidism are the two most common complications associated with chronic kidney disease. Erythropoiesis-stimulating agents (ESAs) are widely used in the management of anemia in hemodialysis patients. A reverse correlation has been established between hyperparathyroidism and hemoglobin levels. The aim of this retrospective study is to evaluate the relationship of high-dose ESAs and hyperparathyroidism in hemodialysis patients with anemia. METHODS: A total of 240 uremic patients maintained on regular hemodialysis were enrolled in this study. Among them, 142 patients were treated with Epiao(®) (epoetin-alfa) and 98 patients were treated with Recormon(®) (epoetin-beta). The target hemoglobin concentration was 110-130 g/L. Laboratory measurements including hemoglobin, calcium, phosphorus, albumin, intact-parathyroid hormone (iPTH), serum ferritin, and transferrin saturation were collected. RESULTS: Hemoglobin concentration increased as iPTH level decreased by stratification. However, no significant association between anemia and calcium or phosphorus level was found. Patients with iPTH levels within 150-300 pg/mL had the highest levels of hemoglobin, serum ferritin, and transferrin saturation. Patients treated with Recormon and Epiao had similar hemoglobin concentrations. However, the dose of Recormon for anemia treatment was significantly less than that the dose of Epiao (P < 0.05). The level of iPTH in the Recormon group was significantly lower than in the Epiao group. In patients with hemoglobin levels between 110 and 130 g/L (P < 0.05), iPTH level was found to be significantly lower in patients treated with lower doses of ESAs than in patients treated with higher doses of ESAs, no matter which ESA was used (Recormon or Epiao, P < 0.05). CONCLUSION: The dose of ESAs might be positively associated with iPTH level, suggesting that a reasonable hemoglobin target can be achieved by using the lowest possible ESA dose.