Risk prediction for preeclampsia in CKD patients: development of a model in a retrospective cohort.

BACKGROUND: Chronic kidney disease (CKD) may affect women of childbearing age and may lead to substantial maternal and foetal morbidity and mortality in pregnancy. There is a lack of prediction models for  preeclampsia and adverse pregnancy outcomes in pregnant women with CKD. This study aimed to create a prediction nomogram for these issues. METHODS: This retrospective cohort study included clinical data from 627 women with CKD and their 627 pregnancies at Peking University First Hospital between January 1, 2009, and December 31, 2022. Multivariate logistic regression analysis was conducted to identify independent prognostic factors and develop a nomogram for predicting the occurrence of preeclampsia. The identified risk factors were utilised to construct the nomogram, which was subsequently internally validated using receiver operating characteristic (ROC) analysis and calibration curve assessment. RESULTS: According to our multivariate analysis, age, blood urea nitrogen (BUN), serum creatinine (Scr), mean arterial pressure (MAP), 24-h proteinuria, and CKD stage were identified as predictors of preeclampsia. Additionally, Scr, MAP, BUN, and 24-h proteinuria were found to be predictors of adverse pregnancy outcomes. The nomogram for predicting preeclampsia had an area under the ROC curve of 0.910, while the nomogram for predicting adverse pregnancy outcomes had an area under the ROC curve of 0.906. Both models demonstrated excellent discriminatory ability. CONCLUSIONS: A nomogram based on 24-h proteinuria, serum creatinine, serum urea and age, and MAP allows predicting the occurrence of preeclampsia and other adverse pregnancy-related outcomes in CKD patients.

Genome-wide analysis of wheat xyloglucan endotransglucosylase/hydrolase (XTH) gene family revealed TaXTH17 involved in abiotic stress responses.

BACKGROUND: Environmental stresses, including high salinity and drought, severely diminish wheat yield and quality globally. The xyloglucan endotransglucosylase/hydrolase (XTH) family represents a class of cell wall-modifying enzymes and plays important roles in plants growth, development and stress adaptation. However, systematic analyses of XTH family genes and their functions under salt and drought stresses have not been undertaken in wheat. RESULTS: In this study, we identified a total of 135 XTH genes in wheat, which were clustered into three evolutionary groups. These TaXTHs were unevenly distributed on 21 chromosomes of wheat with a majority of TaXTHs located on homelogous groups 2, 3 and 7. Gene duplication analysis revealed that segmental and tandem duplication were the main reasons for the expansion of XTH family in wheat. Interaction network predictions indicated that TaXTHs could interact with multiple proteins, including three kinases, one methyltransferase and one gibberellin-regulated protein. The promoters of the TaXTH genes harbored various cis-acting elements related to stress and hormone responses. RNA-seq data analyses showed that some TaXTH genes were induced by salt and drought stresses. Furthermore, we verified that TaXTH17 was induced by abiotic stresses and phytohormone treatments, and demonstrated that TaXTH17 was localized in the secretory pathway and cell wall. Functional analyses conducted in heterologous expression systems and in wheat established that TaXTH17 plays a negative role in plant resistance to salt and drought. CONCLUSIONS: We identified 135 XTH genes in wheat and conducted comprehensive analyses of their phylogenetic relationships, gene structures, conserved motifs, gene duplication events, chromosome locations, interaction networks, cis-acting elements and gene expression patterns. Furthermore, we provided solid evidence supporting the notion that TaXTH17 plays a negative role in plant resistance to salt and drought stresses. Collectively, our results provide valuable insights into understanding wheat XTHs, particularly their involvement in plant stress responses, and establish a foundation for further functional and mechanistic studies of TaXTHs.

Transportation engineering for enhanced production of plant natural products in microbial cell factories.

Plant natural products (PNPs) exhibit a wide range of biological activities and have essential applications in various fields such as medicine, agriculture, and flavors. Given their natural limitations, the production of high-value PNPs using microbial cell factories has become an effective alternative in recent years. However, host metabolic burden caused by its massive accumulation has become one of the main challenges for efficient PNP production. Therefore, it is necessary to strengthen the transmembrane transport process of PNPs. This review introduces the discovery and mining of PNP transporters to directly mediate PNP transmembrane transportation both intracellularly and extracellularly. In addition to transporter engineering, this review also summarizes several auxiliary strategies (such as small molecules, environmental changes, and vesicles assisted transport) for strengthening PNP transportation. Finally, this review is concluded with the applications and future perspectives of transportation engineering in the construction and optimization of PNP microbial cell factories.

FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator FTY720 in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying hematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary hemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analyzed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary hemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferators-activated receptors (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1A (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

Genetic Analysis and Fine Mapping of QTL for the Erect Leaf in Mutant mths29 Induced through Fast Neutron in Wheat.

The erect leaf plays a crucial role in determining plant architecture, with its growth and development regulated by genetic factors. However, there has been a lack of comprehensive studies on the regulatory mechanisms governing wheat lamina joint development, thus failing to meet current breeding demands. In this study, a wheat erect leaf mutant, mths29, induced via fast neutron mutagenesis, was utilized for QTL fine mapping and investigation of lamina joint development. Genetic analysis of segregating populations derived from mths29 and Jimai22 revealed that the erect leaf trait was controlled by a dominant single gene. Using BSR sequencing and map-based cloning techniques, the QTL responsible for the erect leaf trait was mapped to a 1.03 Mb physical region on chromosome 5A. Transcriptome analysis highlighted differential expression of genes associated with cell division and proliferation, as well as several crucial transcription factors and kinases implicated in lamina joint development, particularly in the boundary cells of the preligule zone in mths29. These findings establish a solid foundation for understanding lamina joint development and hold promise for potential improvements in wheat plant architecture.

Malignancy is increased in patients with antineutrophil cytoplasmic antibody-associated vasculitis in China.

OBJECTIVE: It has been reported that in western countries malignancy risk was higher in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with that in the general population. In the current study, we investigated the incidence, spectrum and risk factors of malignancy in Chinese AAV patients. METHODS: AAV patients diagnosed from 1995 to 2021 in Peking University First Hospital with a follow-up more than 12 months were recruited. Standardized incidence ratios (SIR) were calculated to describe the risk of malignancy, adjusted for sex, age and follow-up time. RESULTS: A total of 552 AAV patients were recruited, among which 23 patients had malignancies either preceding or concurrent with AAV diagnosis, and 43 of the remaining 529 patients developed malignancies within 4.3 ± 4.2 years post AAV diagnosis (SIR: 2.24; 95% CI: 1.68-2.99; p < 0.001). Among these 66 patients, twenty different sites of malignancy were observed, lung cancer being most frequent. To get exactly expected malignancies for the calculation of SIR, 529 patients without preceding or concurrent malignancies were included in the following analysis. Lung cancer was still the leading malignancy diagnosis (SIR: 5.01; 95% CI: 3.29-7.62), followed by malignancies in the kidney, bladder, ureter and prostate. Male gender (HR:2.84; 95%CI:1.36-5.96; p = 0.006) and older age (per year, HR:1.04; 95%CI:1.00-1.07; p = 0.038) were significantly associated with increased risk of malignancy. For patients with malignancy developed beyond 5 years after the diagnosis of AAV, a significantly higher malignancy risk was observed in those with a cumulative cyclophosphamide dose over 20.0 g (SIR: 11.54; 95% CI: 4.77-27.93; p < 0.001). Within the first 2 years after the diagnosis of AAV, the risk of malignancy was still significantly higher than that in the general population, but the cumulative cyclophosphamide dose was not significantly associated with malignancy occurrence in this subgroup of patients. CONCLUSIONS: Malignancy risk is higher in Chinese AAV patients than that in the general population, with a different malignancy spectrum from western countries. Both the use of cyclophosphamide and AAV per se might be associated with higher incidence of malignancy occurrence.

Macrocarpal B blocks the binding between the phospholipase A2 receptor and its antibodies.

The pathogenic role of anti-phospholipase A2 receptor (PLA2R) antibodies in primary membranous nephropathy (MN) has been well-established. This study aimed to identify potential small-molecule inhibitors against the PLA2R-antibody interaction, offering potential therapeutic benefits. A comprehensive screening of over 4000 small-molecule compounds was conducted by ELISA to assess their inhibitory effects on the binding between the immobilized full-length extracellular PLA2R and its antibodies. The affinity of anti-PLA2R IgG from MN patients and the inhibitory efficacy of each compound were evaluated via surface plasmon resonance (SPR). Human podocyte injuries were analyzed using CCK-8 assay, wound healing assay, western blot analysis, and immunofluorescence, after exposure to MN plasma +/- blocking compound. Fifteen compounds were identified as potential inhibitors, demonstrating inhibition rates >20 % for the PLA2R-antibody interaction. Anti-PLA2R IgG exhibited a consistent affinity among patients (KD = 10-8 M). Macrocarpal B emerged as the most potent inhibitor, reducing the antigen-antibody interaction by nearly 30 % in a dose-dependent manner, comparable to the performance of the 31-mer peptide from the CysR domain. Macrocarpal B bound to the immobilized PLA2R with an affinity of 1.47 × 10-6 M, while showing no binding to anti-PLA2R IgG. Human podocytes exposed to MN plasma showed decreased podocin expression, impaired migration function, and reduced cell viability. Macrocarpal B inhibited the binding of anti-PLA2R IgG to podocytes and reduced the cellular injuries.

OsAlR3 regulates aluminum tolerance through promoting the secretion of organic acids and the expression of antioxidant genes in rice.

In acidic soils, aluminum (Al) toxicity inhibits the growth and development of plant roots and affects nutrient and water absorption, leading to reduced yield and quality. Therefore, it is crucial to investigate and identify candidate genes for Al tolerance and elucidate their physiological and molecular mechanisms under Al stress. In this study, we identified a new gene OsAlR3 regulating Al tolerance, and analyzed its mechanism from physiological, transcriptional and metabolic levels. Compared with the WT, malondialdehyde (MDA) and hydrogen peroxide (H2O2) content were significantly increased, superoxide dismutase (SOD) activity and citric acid (CA) content were significantly decreased in the osalr3 mutant lines when exposed to Al stress. Under Al stress, the osalr3 exhibited decreased expression of antioxidant-related genes and lower organic acid content compared with WT. Integrated transcriptome and metabolome analysis showed the phenylpropanoid biosynthetic pathway plays an important role in OsAlR3-mediated Al tolerance. Exogenous CA and oxalic acid (OA) could increase total root length and enhance the antioxidant capacity in the mutant lines under Al stress. Conclusively, we found a new gene OsAlR3 that positively regulates Al tolerance by promoting the chelation of Al ions through the secretion of organic acids, and increasing the expression of antioxidant genes.

Association of podocyte ultrastructural changes with proteinuria and pathological classification in type 2 diabetic nephropathy.

AIMS: Podocyte injury plays an essential role in the progression of diabetic nephropathy (DN). The associations between the ultrastructural changes of podocyte with proteinuria and the pathological classification of DN proposed by Renal Pathology Society (RPS) have not been clarified in patients with type 2 diabetic nephropathy (T2DN). METHODS: We collected 110 patients with kidney biopsy-confirmed T2DN at Peking University First Hospital from 2017 to 2022. The morphometric analysis on the podocyte foot process width (FPW) and podocyte detachment (PD) as markers of podocyte injury was performed, and the correlations between the ultrastructural changes of podocytes with severity of proteinuria and the RPS pathological classification of DN were analyzed. RESULTS: Mean FPW was significantly broader in the group of T2DN patients with nephrotic proteinuria (565.1 nm) than those with microalbuminuria (437.4 nm) or overt proteinuria (494.6 nm). The cut-off value of FPW (> 506 nm) could differentiate nephrotic proteinuria from non-nephrotic proteinuria with a sensitivity of 75.3% and a specificity of 75.8%. Percentage of PD was significantly higher in group of nephrotic proteinuria (3.2%) than that in microalbuminuria (0%) or overt proteinuria (0.2%). FPW and PD significantly correlated with proteinuria in T2DN (r = 0.473, p < 0.001 and r = 0.656, P < 0.001). FPW and PD correlated with RPS pathological classification of T2DN (r = 0.179, P = 0.014 and r = 0.250, P = 0.001). FPW value was increased significantly with more severe DN classification (P for trend =0.007). The percentage of PD tended to increase with more severe DN classification (P for trend = 0.017). CONCLUSIONS: Podocyte injury, characterized by FPW broadening and PD, was associated with the severity of proteinuria and the pathological classification of DN.

Intein-mediated temperature control for complete biosynthesis of sanguinarine and its halogenated derivatives in yeast.

While sanguinarine has gained recognition for antimicrobial and antineoplastic activities, its complex conjugated structure and low abundance in plants impede broad applications. Here, we demonstrate the complete biosynthesis of sanguinarine and halogenated derivatives using highly engineered yeast strains. To overcome sanguinarine cytotoxicity, we establish a splicing intein-mediated temperature-responsive gene expression system (SIMTeGES), a simple strategy that decouples cell growth from product synthesis without sacrificing protein activity. To debottleneck sanguinarine biosynthesis, we identify two reticuline oxidases and facilitated functional expression of flavoproteins and cytochrome P450 enzymes via protein molecular engineering. After comprehensive metabolic engineering, we report the production of sanguinarine at a titer of 448.64 mg L-1. Additionally, our engineered strain enables the biosynthesis of fluorinated sanguinarine, showcasing the biotransformation of halogenated derivatives through more than 15 biocatalytic steps. This work serves as a blueprint for utilizing yeast as a scalable platform for biomanufacturing diverse benzylisoquinoline alkaloids and derivatives.

A Chinese Multi-Specialty Delphi Consensus to Optimize RAASi Usage and Hyperkalaemia Management in Patients with Chronic Kidney Disease and Heart Failure.

Objective Variations are present in common clinical practices regarding best practice in managing hyperkalaemia (HK), there is therefore a need to establish a multi-specialty approach to optimal renin-angiotension-aldosterone system inhibitors (RAASi) usage and HK management in patients with chronic kidney disease (CKD) & heart failure (HF).This study aimed to establish a multi-speciality approach to the optimal use of RAASi and the management of HK in patients with CKD and HF. Methods A steering expert group of cardiology and nephrology experts across China were convened to discuss challenges to HK management through a nominal group technique. The group then created a list of 41 statements for a consensus questionnaire, which was distributed for a further survey in extended panel group of cardiologists and nephrologists across China. Consensus was assessed using a modified Delphi technique, with agreement defined as "strong" (≥75% and <90%) and "very strong" (≥90%). The steering group, data collection, and analysis were aided by an independent facilitator. Results A total of 150 responses from 21 provinces across China were recruited in the survey. Respondents were comprised of an even split (n=75, 50%) between cardiologists and nephrologists. All 41 statements achieved the 75% consensus agreement threshold, of which 27 statements attained very strong consensus (≥90% agreement) and 14 attained strong consensus (agreement between 75% and 90%). Conclusion Based on the agreement levels from respondents, the steering group agreed a set of recommendations intended to improve patient outcomes in the use of RAASi therapy and HK management in China.

Genetic diversity of Flaviviridae and Rhabdoviridae EVEs in Aedes aegypti and Aedes albopictus on Hainan Island and the Leizhou Peninsula, China.

BACKGROUND: Hainan Island and the Leizhou Peninsula, the southernmost part of mainland China, are areas where Aedes aegypti and Ae. albopictus are sympatric and are also high-incidence areas of dengue outbreaks in China. Many studies have suggested that Aedes endogenous viral components (EVEs) are enriched in piRNA clusters which can silence incoming viral genomes. Investigation the EVEs present in the piRNA clusters associated with viral infection of Aedes mosquitoes in these regions may provide a theoretical basis for novel transmission-blocking vector control strategies. METHODS: In this study, specific primers for endogenous Flaviviridae elements (EFVEs) and endogenous Rhabdoviridae elements (ERVEs) were used to detect the distribution of Zika virus infection associated EVEs in the genomes of individuals of the two Aedes mosquitoes. Genetic diversity of EVEs with a high detection rate was also analyzed. RESULTS: The results showed that many EVEs associated with Zika virus infection were detected in both Aedes species, with the detection rates were 47.68% to 100% in Ae. aegypti and 36.15% to 92.31% in sympatric Ae. albopictus populations. EVEs detection rates in another 17 Ae. albopictus populations ranged from 29.39% to 89.85%. Genetic diversity analyses of the four EVEs (AaFlavi53, AaRha61, AaRha91 and AaRha100) of Ae. aegypti showed that each had high haplotype diversity and low nucleotide diversity. The number of haplotypes in AaFlavi53 was 8, with the dominant haplotype being Hap_1 and the other 7 haplotypes being further mutated from Hap_1 in a lineage direction. In contrast, the haplotype diversity of the other three ERVEs (AaRha61, AaRha91 and AaRha100) was more diverse and richer, with the haplotype numbers were 9, 15 and 19 respectively. In addition, these EVEs all showed inconsistent patterns of both population differentiation and dispersal compared to neutral evolutionary genes such as the Mitochondrial COI gene. CONCLUSION: The EFVEs and ERVEs tested were present at high frequencies in the field Aedes mosquito populations. The haplotype diversity of the EFVE AaFlavi53 was relatively lower and the three ERVEs (AaRha61, AaRha91, AaRha100) were higher. None of the four EVEs could be indicative of the genetic diversity of the Ae. aegypti population. This study provided theoretical support for the use of EVEs to block arbovirus transmission, but further research is needed into the mechanisms by which these EVEs are antiviral to Aedes mosquitoes.

Association between blood methylmalonic acid and chronic kidney disease in the general US population: insights from multi-cycle National Health and Nutrition Examination Survey (NHANES).

Background: Chronic kidney disease (CKD) is significantly influenced by mitochondrial dysfunction (MD). Previous research suggests that methylmalonic acid (MMA) is involved in MD. Consequently, we aimed to investigate associations between blood MMA level and the prevalence of CKD as well as mortality in patients with CKD. Methods: The study included 23,587 individuals from National Health and Nutrition Examination Survey (NHANES). The NHANES datasets from 1999-2004 and 2011-2014 were utilized as separate primary and validation subsets. There were 3,554 patients with CKD. The association of blood MMA level with the prevalence of CKD was investigated using weighted logistic regression. Meanwhile, we employed weighted Cox regression models to evaluate the association between blood MMA level and all-cause mortality in patients with CKD. Results: Blood MMA levels had a significant positive association with urinary albumin-to-creatinine ratio (ß=45.29, P=0.01) and negative association with estimated glomerular filtration rate (ß=-15.27, P<0.001) in CKD patients. Blood MMA level exhibited a significant increase in participants with CKD compared with those without CKD (7.60±0.86 vs. 7.03±0.62, P<0.001). The level of blood MMA was significantly associated with the prevalence of CKD [odds ratio (OR): 1.32, 95% confidence interval (CI): 1.05-1.64, P=0.01]. In addition, blood MMA level was significantly associated with all-cause mortality in CKD participants [hazard ratio (HR): 1.26, 95% CI: 1.11-1.43, P<0.001] after adjusting for other potential predictors. Conclusions: Increased blood MMA levels were associated with more severe kidney impairment and increased risk of both the prevalence of CKD and mortality in participants with CKD.

External Validation of the Kidney Failure Risk Equation Among Urban Community-Based Chinese Patients With CKD.

Rationale & Objective: The Kidney Failure Risk Equations have been proven to perform well in multinational databases, whereas validation in Asian populations is lacking. This study sought to externally validate the equations in a community-based chronic kidney disease cohort in China. Study Design: A retrospective cohort study. Setting & Participants: Patients with and estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 dwelling in an industrialized coastal city of China. Exposure: Age, sex, eGFR, and albuminuria were included in the 4-variable model, whereas serum calcium, phosphate, bicarbonate, and albumin levels were added to the previously noted variables in the 8-variable model. Outcome: Initiation of long-term dialysis treatment. Analytical Approach: Model discrimination, calibration, and clinical utility were evaluated by Harrell's C statistic, calibration plots, and decision curve analysis, respectively. Results: A total of 4,587 participants were enrolled for validation of the 4-variable model, whereas 1,414 were enrolled for the 8-variable model. The median times of follow-up were 4.0 (interquartile range: 2.6-6.3) years for the 4-variable model and 3.4 (2.2-5.6) years for the 8-variable model. For the 4-variable model, the C statistics were 0.750 (95% CI: 0.615-0.885) for the 2-year model and 0.766 (0.625-0.907) for the 5-year model, whereas the values were 0.756 (0.629-0.883) and 0.774 (0.641-0.907), respectively, for the 8-variable model. Calibration was acceptable for both the 4-variable and 8-variable models. Decision curve analysis for the models at the 5-year scale performed better throughout different net benefit thresholds than the eGFR-based (<30 mL/min/1.73 m2) strategy. Limitations: A large proportion of patients lack albuminuria measurements, and only a subset of population could provide complete data for the 8-variable equation. Conclusions: The kidney failure risk equations showed acceptable discrimination and calibration and better clinical utility than the eGFR-based strategy for incidence of kidney failure among community-based urban Chinese patients with chronic kidney disease.

Accurate and reliable risk evaluation of chronic kidney disease (CKD) prognosis can be helpful for physicians to make decisions concerning treatment opportunity and therapeutic strategy. The kidney failure risk equation is an outstanding model for predicting risk of kidney failure among patients with CKD. However, the equation is lacking validation among Chinese populations. In the current study, we demonstrated that the equation had good discrimination among an urban community-based cohort of patients with CKD in China. The calibration was also acceptable. Decision curve analysis also showed that the equation performed better than a traditional kidney function-based strategy. The results provide the basis for using predictions derived from the kidney failure risk equation to improve the management of patients with CKD in community settings in China.

Disease-modifying therapies in systemic lupus erythematosus for extrarenal manifestations.

Our 2022 published working definition of disease modification in systemic lupus erythematosus (SLE) was 'minimising disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression'. The objective of this review was to classify current SLE treatments according to the proposed non-renal disease modification criteria excluding toxicities. Based on a review of select clinical trial (n=32) and observational study (n=54) publications for 14 SLE medications across different therapeutic classes, and the authors' clinical experience, we evaluated disease modification potential as per the proposed framework at three time points. Specific criteria used to determine disease modification potential included a drug's capacity to reduce: (1) non-renal disease activity, (2) severe flares, (3) use of steroids/immunosuppressants and (4) organ damage accrual. Criteria 1-3 were assessed at 1 year and 2-5 years and, when positive, were considered evidence for disease modification potential; criterion 4 was used to confirm disease modification at >5 years. Each treatment received one of four mutually exclusive designations at each time point: (a) criterion met, (b) indications of criterion met despite insufficient evidence in the literature, (c) inconclusive and (d) no available supportive data. This review excludes an assessment of potential toxicities. Eight of the 14 SLE treatments met ≥1 disease modification criteria up to year 5. Hydroxychloroquine improved overall survival at >5 years, suggesting long-term disease modification, but no data on specific organ systems were reported. Belimumab was the only treatment to meet all criteria. Belimumab and hydroxychloroquine met disease modification definitions across three time points. Evidence for other SLE therapies was incomplete, particularly at >5 years. Future studies are warranted for other treatments to meet the disease modification criteria. We discuss challenges to classification and possible updates to our published criteria.

Immunoglobulin repertoire sequencing and de novo sequencing - Powerful tools for identifying free light chains from patients with light chain cast nephropathy.

In patients with light chain cast nephropathy (LCCN), abundantly produced monoclonal immunoglobulin free light chains (FLCs) play a vital role in pathogenesis. Determining the precise sequences of patient-derived FLCs is therefore highly desirable. Although immunoglobulin repertoire sequencing (5' RACE-seq) has been proven to be sensitive enough to provide full-length V(D)J region (variable, diversity and joining genes) of FLCs using bone marrow samples, an invasive and bone marrow independent method is still in demand. Here a de novo sequencing workflow based on the bottom-up proteomics for patient-derived FLCs was established. PEAKS software was used for the de novo sequencing of peptides that were further assembled into full-length FLC sequences. This de novo protein sequencing method can obtain the full-length amino acid sequences of FLCs, and had been shown to be as reliable as 5' RACE-seq. The two LCCN sequences derived from above the two methods were identical, and they possessed more hydrophobic or nonpolar amino acids compared with the corresponding germline, which may be associated with the pathogenesis.

DDX39B protects against sorafenib-induced ferroptosis by facilitating the splicing and cytoplasmic export of GPX4 pre-mRNA in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the main histological subtype of primary liver cancer and remains one of the most common solid malignancies globally. Ferroptosis was recently defined as an iron-catalyzed form of regulated necrosis. Because cancer cells exhibit higher iron requirements than noncancer cells, treatment with ferroptosis-inducing compounds may be a feasible strategy for cancer therapy. However, cancer cells develop acquired resistance to evade ferroptosis, and the mechanisms responsible for ferroptosis resistance are not fully clarified. In the current study, we reported that DDX39B was downregulated during sorafenib-induced ferroptosis in a dose- and time-dependent manner. Exogenous introduction of DDX39B ensured the survival of HCC cells upon exposure to sorafenib, while the opposite phenomenon was observed in DDX39B-silenced HCC cells. Mechanistically, we demonstrated that DDX39B increased GPX4 levels by promoting the splicing and cytoplasmic translocation of GPX4 pre-mRNA, which was sufficient to detoxify sorafenib-triggered excess lipid ROS production, lipid peroxidation accumulation, ferrous iron levels, and mitochondrial damage. Inhibition of DDX39B ATPase activity by CCT018159 repressed the splicing and cytoplasmic export of GPX4 pre-mRNA and synergistically assisted sorafenib-induced ferroptotic cell death in HCC cells. Taken together, our data uncover a novel role for DDX39B in ferroptosis resistance by modulating the maturation of GPX4 mRNA via a posttranscriptional approach and suggest that DDX39B inhibition may be a promising therapeutic strategy to enhance the sensitivity and vulnerability of HCC cells to sorafenib.

Hypoxia inhibits ferritinophagy-mediated ferroptosis in esophageal squamous cell carcinoma via the USP2-NCOA4 axis.

Esophageal squamous cell carcinoma (ESCC) is a prevalent malignancy of the digestive system. Hypoxia is a crucial player in tumor ferroptosis resistance. However, the molecular mechanism of hypoxia-mediated ferroptosis resistance in ESCC remains unclear. Here, USP2 expression was decreased in ESCC cell lines subjected to hypoxia treatment and was lowly expressed in clinical ESCC specimens. Ubiquitin-specific protease 2 (USP2) depletion facilitated cell growth, which was blocked in USP2-overexpressing cells. Moreover, USP2 silencing enhanced the iron ion concentration and lipid peroxidation accumulation as well as suppressed ferroptosis, while upregulating USP2 promoted ferroptotic cell death in ESCC cells. Furthermore, knockout of USP2 in ESCC models discloses the essential role of USP2 in promoting ESCC tumorigenesis and inhibiting ferroptosis. In contrast, overexpression of USP2 contributes to antitumor effect and ferroptosis events in vivo. Specifically, USP2 stably bound to and suppressed the degradation of nuclear receptor coactivator 4 (NCOA4) by eliminating the Lys48-linked chain, which in turn triggered ferritinophagy and ferroptosis in ESCC cells. Our findings suggest that USP2 plays a crucial role in iron metabolism and ferroptosis and that the USP2/NCOA4 axis is a promising therapeutic target for the management of ESCC.

Proteinase­3­antineutrophil cytoplasmic antibody­associated vasculitis secondary to subacute infective endocarditis: A case report.

A 58-year-old male patient was admitted to Peking University First Hospital (Beijing, China) due to recurrent hematuria, proteinuria and kidney dysfunction. The patient was positive for proteinase-3 (PR3)-antineutrophil cytoplasmic antibody (ANCA). Pathology of the kidney showed focal proliferative necrotizing glomerulonephritis with crescent formation and immune complex-mediated glomerulonephritis. The patient was diagnosed with PR3-ANCA-associated vasculitis (AAV), received intensive immunosuppressive therapy and experienced two relapses within 1 year. After admission, aortic valve vegetation was observed via echocardiography. The patient subsequently received antibiotic treatment and valve replacement, and achieved complete remission of kidney and cardiac function. The present case emphasized the importance of identifying secondary reasons for ANCA formation, especially infective endocarditis in patients with PR3-AAV.