A Phase 3 Study of Pembrolizumab versus Placebo for Previously Treated Patients from Asia with Hepatocellular Carcinoma: Health-Related Quality of Life Analysis from KEYNOTE-394.

Introduction: KEYNOTE-394 showed pembrolizumab significantly improved overall survival, progression-free survival, and objective response rate with manageable safety versus placebo for patients from Asia with previously treated advanced hepatocellular carcinoma. We present results on health-related quality of life (HRQoL). Methods: HRQoL was evaluated using the EORTC Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EuroQol-5D-3L (EQ-5D-3L) questionnaires. Key HRQoL endpoints were least squares mean (LSM) score changes from baseline to week 12 and time to deterioration (TTD) for EORTC QLQ-C30 global health status (GHS)/QoL. p values were one-sided and nominal without adjustment for multiplicity. Results: The HRQoL population included patients randomly assigned to pembrolizumab (n = 298) and placebo (n = 152). From baseline to week 12, a greater decline in EORTC QLQ-C30 GHS/QoL score was observed with placebo (LSM, -8.4; 95% CI: -11.7 to -5.1) versus pembrolizumab (-4.0; 95% CI: -6.4 to -1.6; difference vs. placebo: 4.4; 95% CI: 0.5-8.4; nominal p = 0.0142). Similarly, a greater decline in the EQ-5D-3L visual analog scale score was observed with placebo (-6.9; 95% CI: -9.4 to -4.5) versus pembrolizumab (-2.7; 95% CI: -4.5 to -1.0; difference vs. placebo: 4.2; 95% CI: 1.2-7.2; nominal p = 0.0030). TTD in EORTC QLQ-C30 GHS/QoL score was similar between arms (hazard ratio, 0.85; 95% CI: 0.58-1.25; nominal p = 0.1993). Conclusion: Patients receiving placebo showed a greater decline in HRQoL than those receiving pembrolizumab. Combined with efficacy and safety data from KEYNOTE-394 and the global KEYNOTE-240 and KEYNOTE-224 trials, our data support the clinically meaningful benefit and manageable tolerability of pembrolizumab as second-line therapy for patients with advanced hepatocellular carcinoma.

GLP-1 receptor agonists' impact on cardio-renal outcomes and mortality in T2D with acute kidney disease.

Previous studies have explored the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in reducing cardiovascular events in type 2 diabetes. Here we show that GLP-1 RAs are associated with lower risks of mortality, major cardiovascular events (MACEs), and major adverse kidney events (MAKEs) in type 2 diabetes patients with acute kidney disease (AKD). Utilizing global data from the TriNetX database (2002/09/01-2022/12/01) and propensity score matching, we compare 7511 GLP-1 RAs users to non-users among 165,860 AKD patients. The most common causes of AKI are sepsis (55.2%) and cardiorenal syndrome (34.2%). After a median follow-up of 2.3 years, GLP-1 RAs users exhibit reduced risks of mortality (adjusted hazard ratio [aHR]: 0.57), MACEs (aHR: 0.88), and MAKEs (aHR: 0.73). External validation in a multicenter dataset of 1245 type 2 diabetes patients with AKD supports the favorable outcomes. These results emphasize the potential of GLP-1 RAs in individualized treatment for this population.

Unveiling the enigma of acute kidney disease: predicting prognosis, exploring interventions, and embracing a multidisciplinary approach.

Acute kidney disease (AKD) is a critical transitional period between acute kidney injury and chronic kidney disease. The incidence of AKD following acute kidney injury is approximately 33.6%, and it can occur without identifiable preceding acute kidney injury. The development of AKD is associated with increased risks of chronic kidney disease, dialysis, and mortality. Biomarkers and subphenotypes are promising tools to predict prognosis in AKD. The complex clinical situations in patients with AKD necessitate a comprehensive and structured approach, termed "KAMPS" (kidney function check, advocacy, medications, pressure, sick day protocols). We introduce "MAND-MASS," an acronym devised to summarize the reconciliation of medications during episodes of acute illness, as a critical component of the sick day protocols at AKD. A multidisciplinary team care, consisting of nephrologists, pharmacists, dietitians, health educators, and nurses, is an optimal model to achieve the care bundle in KAMPS. Although the evidence for patients with AKD is still lacking, several potential pharmacological agents may improve outcomes, including but not limited to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide 1 receptor agonists. In conclusion, accurate prognosis prediction and effective treatment for AKD are critical yet unmet clinical needs. Future studies are urgently needed to improve patient care in this complex and rapidly evolving field.

KLF11 promotes the proliferation of breast cancer cells by inhibiting p53-MDM2 signaling.

Abnormal Krüppel-like factor 11 (KLF11) expression is frequently found in tumor tissues and is associated with cancer prognosis, but its biological functions and corresponding mechanisms remain elusive. Here, we demonstrated that KLF11 functions as an oncoprotein to promote tumor proliferation in breast cancer cells. Mechanistically, at the transcription level, KLF11 decreased TP53 mRNA expression. Notably, KLF11 also interacted with and stabilized MDM2 through inhibiting MDM2 ubiquitination and subsequent degradation. This increase in MDM2 in turn accelerated the ubiquitin-mediated proteolysis of p53, leading to the reduced expression of p53 and its target genes, including CDKN1A, BAX, and NOXA1. Accordingly, data from animals further confirmed that KLF11 significantly upregulated the growth of breast cancer cells and was inversely correlated with p53 expression. Taken together, our findings reveal a novel mechanism for breast cancer progression in which the function of the tumor suppressor p53 is dramatically weakened.

Exploring the regulatory role of FBXL19-AS1 in triple-negative breast cancer through the miR-378a-3p/OTUB2 axis.

The regulatory potential of long noncoding RNA (lncRNA) FBXL19-AS1 has been highlighted in various cancers, but its effect on triple-negative breast cancer (TNBC) remains unclear. Here, we aimed to elucidate the role of FBXL19-AS1 in TNBC and its underlying mechanism. RT-qPCR was employed to detect the expressions of FBXL19-AS1 and miR-378a-3p in tissues and cells. Immunohistochemical staining and western blot were utilized to detect the expression levels of proteins. Cell activities were detected using flow cytometry, CCK-8, and transwell assay. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were deployed to investigate interactions of different molecules. Protein-protein interaction (PPI) network, gene ontology (GO), and Kyoto encyclopedia of genes and genomes (KEGG) pathways were used to analyze the downstream pathway. In vivo xenograft model was conducted to detect the effect of FBXL19-AS1 on tumor growth. FBXL19-AS1 was overexpressed in TNBC tissues and cell lines compared with counterparts. FBXL19-AS1 knockdown suppressed TNBC cell activities, whereas its overexpression exhibited the opposite effect. Mechanistically, FBXL19-AS1 was found to interact with miR-378a-3p. Further analysis revealed that miR-378a-3p exerted tumor-suppressive effects in TNBC cells. Additionally, miR-378a-3p targeted and downregulated the expression of ubiquitin aldehyde binding 2 (OTUB2), a deubiquitinase associated with TNBC progression. In vivo experiments substantiated the inhibitory effects of FBXL19-AS1 knockdown on TNBC tumorigenesis, and a miR-378a-3p inhibitor partially rescued these effects. The downstream pathway of the miR-378a-3p/OTUB2 axis was explored, revealing connections with proteins involved in modifying other proteins, removing ubiquitin molecules, and influencing signaling pathways, including the Hippo signaling pathway. Western blot analysis confirmed changes in YAP and TAZ expression levels, indicating a potential regulatory network. In summary, FBXL19-AS1 promotes exacerbation in TNBC by suppressing miR-378a-3p, leading to increased OTUB2 expression. The downstream mechanism may be related to the Hippo signaling pathway. These findings propose potential therapeutic targets for TNBC treatment.

Lipopolysaccharide modification enhances the inhibitory effect of clodronate liposomes on hepatic fibrosis by depletion of macrophages and hepatic stellate cells.

Hepatic fibrosis is a complex chronic liver disease in which both macrophages and hepatic stellate cells (HSCs) play important roles. Many studies have shown that clodronate liposomes (CLD-lipos) effectively deplete macrophages. However, no liposomes have been developed that target both HSCs and macrophages. This study aimed to evaluate the therapeutic efficacy of lipopolysaccharide-coupled clodronate liposomes (LPS-CLD-lipos) and the effects of liposomes size on hepatic fibrosis. Three rat models of hepatic fibrosis were established in vivo; diethylnitrosamine (DEN), bile duct ligation (BDL), and carbon tetrachloride (CCl4). Hematoxylin and eosin staining and serological liver function indices were used to analyze pathological liver damage. Masson's trichrome and Sirius red staining were used to evaluate the effect of liposomes on liver collagen fibers. The hydroxyproline content in liver tissues was determined. In vitro cell counting kit-8 (CCK-8) and immunofluorescence assays were used to further explore the effects of LPS modification and liposomes size on the killing of macrophages and HSCs. Both in vitro and in vivo experiments showed that 200 nm LPS-CLD-lipos significantly inhibited hepatic fibrosis and the abnormal deposition of collagen fibers in the liver and improved the related indicators of liver function. Further results showed that 200 nm LPS-CLD-lipos increased the clearance of macrophages and induced apoptosis of hepatic stellate cells, significantly. The present study demonstrated that 200 nm LPS-CLD-lipos could significantly inhibit hepatic fibrosis and improve liver function-related indices and this study may provide novel ideas and directions for hepatic fibrosis treatment.

Identification of non-canonical antagonistic bacteria via interspecies contact-dependent killing.

BACKGROUND: Canonical biocontrol bacteria were considered to inhibit pathogenic bacteria mainly by secreting antibiotic metabolites or enzymes. Recent studies revealed that some biocontrol bacteria can inhibit pathogenic bacteria through contact-dependent killing (CDK) mediated by contact-dependent secretion systems. The CDK was independent of antibiotic metabolites and often ignored in normal biocontrol activity assay. RESULTS: In this study, we aimed to use a pathogen enrichment strategy to isolate non-canonical bacteria with CDK ability. Rhizosphere soil samples from Chinese cabbage showing soft rot symptom were collected and Pectobacterium carotovorum subsp. carotovorum (Pcc), the pathogen of cabbage soft rot, were added into these samples to enrich bacteria which attached on Pcc cells. By co-culture with Pcc, four bacteria strains (named as PcE1, PcE8, PcE12 and PcE13) showing antibacterial activity were isolated from Chinese cabbage rhizosphere. These four bacteria strains showed CDK abilities to different pathogenic bacteria of horticultural plants. Among them, PcE1 was identified as Chryseobacterium cucumeris. Genome sequencing showed that PcE1 genome encoded a type VI secretion system (T6SS) gene cluster. By heterologous expression, four predicted T6SS effectors of PcE1 showed antibacterial activity to Escherichia coli. CONCLUSION: Overall, this study isolated four bacteria strains with CDK activity to various horticultural plant pathogens, and revealed possible involvement of T6SS of Chryseobacterium cucumeris in antibacterial activity. These results provide valuable insight for potential application of CDK activity in biocontrol bacteria. © 2024 Society of Chemical Industry.

Species-specific functional trait responses of canopy-forming and rosette-forming macrophytes to nitrogen loading: Implications for water-sediment interactions.

Globally intensified lake eutrophication, attributed to excessive anthropogenic nitrogen loading, emerges as a significant driver of submerged vegetation degradation. Consequently, the impact of nitrogen on the decline of submerged macrophytes has received increasing attention. However, a functional trait-based approach to exploring the response of submerged macrophytes to nitrogen loading and its environmental feedback mechanism was unclear. Our study utilized two different growth forms of submerged macrophytes (canopy-forming Myriophyllum spicatum, and rosette-forming Vallisneria natans) to established "submerged macrophytes-water-sediment" microcosms. We assessed the influence of nitrogen loading, across four targeted total nitrogen concentrations (original control, 2, 5, 10 mg/L), on plant traits, water parameters, sediment properties, enzyme activities, and microbial characteristics. Our findings revealed that high nitrogen (10 mg/L) adversely impacted the relative growth rate of fresh biomass and total chlorophyll content in canopy-forming M. spicatum, while the chlorophyll a/b and free amino acid content increased. On the contrary, the growth and photosynthetic traits of resource-conservative V. natans were not affected by nitrogen loading. Functional traits (growth, photosynthetic, and stoichiometric) of M. spicatum but not V. natans exhibited significant correlations with environmental variables. Nitrogen loading significantly increased the concentration of nitrogen components in overlying water and pore water. The presence of submerged macrophytes significantly reduced the ammonia nitrogen and total nitrogen both in overlying water and pore water, and decreased total organic carbon in pore water. Nitrogen loading significantly inhibited sediment extracellular enzyme activities, but the planting of submerged macrophytes mitigated their negative effects. Furthermore, rhizosphere bacterial interactions were less compact compared to bare control, while eukaryotic communities exhibited increased complexity and connectivity. Path modeling indicated that submerged macrophytes mitigated the direct effects of nitrogen loading on overlying water and amplified the indirect effects on pore water, while also attenuating the direct negative effects of pore water on extracellular enzymes. The findings indicated that the restoration of submerged vegetation can mitigate eutrophication resulting from increased nitrogen loading through species-specific changes in functional traits and direct or indirect feedback mechanisms in the water-sediment system.

Mechanistic insight into the impact of polystyrene microparticle on submerged plant during asexual propagules germination to seedling: Internalization in functional organs and alterations of physiological phenotypes.

Asexual reproduction is one of the most important propagations in aquatic plants. However, there is a lack of information about the growth-limiting mechanisms induced by microplastics on the submerged plant during asexual propagule germination to seedling. Hence, we investigated the effects of two sizes (2 µm, 0.2 µm) and three concentrations (0.5 mg/L, 5 mg/L, and 50 mg/L) of polystyrene microplastics (PSMPs) on Potamogeton crispus turion germination and seedling growth. Both PSMPs sizes were found in P. crispus seedling tissues. Metabolic profile alterations were observed in leaves, particularly affecting secondary metabolic pathways and ATP-binding cassette transporters. Metal elements are indispensable cofactors for photosynthesis; however, alterations in the metabolic profile led to varying degrees of reduced concentrations in magnesium, iron, copper, and zinc within P. crispus. Therefore, the maximum quantum yield of photosystem II significantly decreased in all concentrations with 0.2 µm-PSMPs, and at 50 mg/L with 2 µm-PSMPs. These findings reveal that internalization of microplastics, nutrient absorption inhibition, and metabolic changes contribute to the negative impact on P. crispus seedlings.

Recovery Dynamics and Prognosis After Dialysis for Acute Kidney Injury.

Importance: The interplay among baseline kidney function, severity of acute kidney disease (AKD), and post-AKD kidney function has significant associations with patient outcomes. However, a comprehensive understanding of how these factors are collectively associated with mortality, major adverse cardiac events (MACEs), and end-stage kidney disease (ESKD) in patients with dialysis-requiring acute kidney injury (AKI-D) is yet to be fully explored. Objective: To investigate the associations of baseline kidney function, AKD severity, and post-AKD kidney function with mortality, MACEs, and ESKD in patients with AKI-D. Design, Setting, and Participants: This nationwide, population-based cohort study of patients with AKI-D was conducted between January 1, 2015, and December 31, 2018, using data from various health care settings included in the Taiwan nationwide population-based cohort database. Data analysis was conducted from April 28, 2022, to June 30, 2023. Exposure: Exposure to severe AKI and baseline and post-AKD kidney function. Main Outcomes and Measures: The primary outcomes were all-cause mortality and incident MACEs, and secondary outcomes were risks of permanent dialysis and readmission. Results: A total of 6703 of 22 232 patients (mean [SD] age, 68.0 [14.7] years; 3846 [57.4%] male) with AKI-D with post-AKD kidney function follow-up and AKD stage data were enrolled. During a mean (SD) 1.2 (0.9) years of follow-up, the all-cause mortality rate was 28.3% (n = 1899), while the incidence rates of MACEs and ESKD were 11.1% (n = 746) and 16.7% (n = 1119), respectively. After adjusting for known covariates, both post-AKD kidney function and baseline kidney function, but not AKD severity, were independently associated with all-cause mortality, MACEs, ESKD, and readmission. Moreover, worse post-AKD kidney function correlated with progressive and significant increases in the risk of adverse outcomes. Conclusions and Relevance: In this cohort study of patients with AKI-D, more than one-quarter of patients died after 1.2 years of follow-up. Baseline and post-AKD kidney functions serve as important factors associated with the long-term prognosis of patients with AKI-D. Therefore, concerted efforts to understand the transition from post-AKD to chronic kidney disease are crucial.

[Retracted] MicroRNA­454­3p inhibits cervical cancer cell invasion and migration by targeting c­Met.

[This retracts the article DOI: 10.3892/etm.2018.5714.].

Synergistic anti-tumor effects of lenalidomide and gefitinib by upregulating ADRB2 and inactivating the mTOR/PI3K/AKT signaling pathway in lung adenocarcinoma.

Gefitinib is commonly used to be the first-line therapy for advanced non-small cell lung cancer (NSCLC). Therapeutic effect of gefitinib is reduced due to acquired resistance, and combined treatment is recommended. In this research, we planned to explore the impacts of combined treatment of lenalidomide and gefitinib on gefitinib-sensitive or -resistant NSCLC cells. The co-treatment results demonstrated that enhanced antitumor impact on NSCLC cell growth, migration, invasion, cell cycle process and apoptosis. The tumor-bearing mouse models were established using PC9/GR cells. In vivo assays also showed that lenalidomide and gefitinib synergistically inhibited mouse tumor growth along increased the survival of mice. ADRB2 was identified as a lowly expressed gene in PC9/GR cells and LUAD tumor tissues. LUAD patients with high ADRB2 expression were indicated with favorable survival outcomes. Moreover, ADRB2 was upregulated in lenalidomide and/or gefitinib-treated PC9/GR cells. ADRB2 deficiency partially offsets the suppressive impacts of lenalidomide and gefitinib co-treatment on the viability and proliferation of PC9/GR cells. Additionally, lenalidomide and gefitinib cotreatment significantly inactivated the mTOR/PI3K/AKT signaling pathway compared with each treatment alone. Rescue assays were performed to explore whether lenalidomide and gefitinib synergistically inhibited the growth of PC9/GR cells via the PI3K/AKT pathway. PI3K activator SC79 significantly restored reduced cell proliferation, migration and invasion along with elevated cell cycle arrest and apoptosis caused by lenalidomide and gefitinib cotreatment. In conclusion, lenalidomide and gefitinib synergistically suppressed LUAD progression and attenuated gefitinib resistance by upregulating ADRB2 and inactivating the mTOR/PI3K/AKT signaling pathway in lung adenocarcinoma.

Discriminatory fluorescence and FRET in the chiral-perovskite/RhB system.

Förster resonance energy transfer (FRET) holds a significant position in various natural and artificial systems, especially within donor-acceptor systems encompassing chiral components. Despite extensive investigations, a clear understanding of the effects of chirality and FRET on discriminatory fluorescence remains elusive. Here, chiral perovskite nanowires (CPNWs) and achiral rhodamine B (RhB) are employed to examine the FRET and discriminatory fluorescence behavior in a donor-acceptor system involving a chiral nanostructure. A notable FRET from the CPNWs to RhB is observed, along with circular dichroism (CD) and circularly polarized luminescence (CPL) activities in RhB. Although the FRET interaction remains consistent over time, a notable inversion in the polarity preference of the CD and CPL of RhB is observed. This reveals that the discriminatory fluorescence of the acceptor arises from the electromagnetic influence of the chiral donor. These findings elucidate that "chirality", as a property related to spatial orientation, cannot accompany the transfer of energy (which is a scalar) from chiral nanostructures to achiral molecules, which helps advance the understanding of the discriminatory fluorescence in the donor-acceptor system with a chiral nanostructure.

The effects of double-filtration plasmapheresis on coagulation profiles and the risk of bleeding.

BACKGROUND/PURPOSE: Double-filtration plasmapheresis (DFPP) can be used to remove circulating pathogenic molecules. By reclaiming filtered albumin, DFPP reduces the need for albumin and plasma replacement. Large proteins, such as fibrinogen, are removed. Our institution adopts a DFPP treatment protocol consisting of active surveillance of coagulation profiles and prophylactic supplementation of blood products containing fibrinogen. This study aims to investigate the effects of consecutive DFPP treatments on serial coagulation profiles and the risk of bleeding under this protocol. METHODS: Serial laboratory data and bleeding events at a single tertiary medical center were prospectively collected. Prophylactic transfusion of cryoprecipitate or fresh frozen plasma (FFP) was instituted if significant coagulopathy or a clinically evident bleeding event was observed. RESULTS: After the first treatment session, plasma fibrinogen levels decreased from 332 ± 106 mg/dL to 96 ± 44 mg/dL in the 37 study patients. In the following sessions, plasma fibrinogen levels were maintained at around 100 mg/dL under prophylactic transfusion. No major bleeding events were recorded, but five (14%) patients experienced minor bleeding. CONCLUSION: DFPP treatment might be performed safely along with active monitoring of coagulation profiles and prophylactic transfusion of cryoprecipitate or FFP.

Visceral adipose tissue and risk of diabetic nephropathy: A Mendelian randomization study.

OBJECTIVE: Previous observational studies have established a correlation between visceral adipose tissue (VAT) and diabetic nephropathy (DN). However, the causality of this association remains unclear. Therefore, the aim of this study was to investigate the causal association between VAT and DN by employing two-sample Mendelian randomization (MR) methods. METHODS: The primary MR approach employed was the random-effects inverse-variance weighted (IVW) method. Additionally, we employed alternative methods, including the weighted median (WM) approach, MR-Egger regression, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO). Sensitivity analyses were conducted to evaluate the robustness of the MR analyses. RESULTS: Genetically predicted higher VAT mass was causally associated with a higher risk of DN. The results of the MR analyses were as follows: IVW(Beta = 0.948, odds ratio (OR) = 2.581, 95 % confidence interval (CI) = 2.100-3.173, p = 1.980e-19), WM (Beta = 1.126, OR = 3.082, 95 % CI = 2.278-4.171, p = 2.997e-13), MR-Egger (Beta = 1.315, OR = 3.724, 95 % CI = 1.981-6.998, p = 6.446e-05), and MR-PRESSO (Beta = 0.914, OR = 2.493, 95 % CI = 2.292-2.695, p = 3.121e-16). No pleiotropy was detected (p = 0.230). CONCLUSIONS: This study provided genetic evidence that higher VAT mass was causally associated with a higher risk of DN.

Fetal overgrowth and weight trajectories during infancy and adiposity in early childhood.

BACKGROUND: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood. Little is known about how infancy growth trajectories affect adiposity in early childhood in LGA. METHODS: In the Shanghai Birth Cohort, we followed up 259 LGA (birth weight >90th percentile) and 1673 appropriate-for-gestational age (AGA, 10th-90th percentiles) children on body composition (by InBody 770) at age 4 years. Adiposity outcomes include body fat mass (BFM), percent body fat (PBF), body mass index (BMI), overweight/obesity, and high adiposity (PBF >85th percentile). RESULTS: Three weight growth trajectories (low, mid, and high) during infancy (0-2 years) were identified in AGA and LGA subjects separately. BFM, PBF and BMI were progressively higher from low- to mid-to high-growth trajectories in both AGA and LGA children. Compared to the mid-growth trajectory, the high-growth trajectory was associated with greater increases in BFM and the odds of overweight/obesity or high adiposity in LGA than in AGA children (tests for interactions, all P < 0.05). CONCLUSIONS: Weight trajectories during infancy affect adiposity in early childhood regardless of LGA or not. The study is the first to demonstrate that high-growth weight trajectory during infancy has a greater impact on adiposity in early childhood in LGA than in AGA subjects. IMPACT: Large-for-gestational age (LGA), a marker of fetal overgrowth, has been linked to obesity in adulthood, but little is known about how weight trajectories during infancy affect adiposity during early childhood in LGA subjects. The study is the first to demonstrate a greater impact of high-growth weight trajectory during infancy (0-2 years) on adiposity in early childhood (at age 4 years) in subjects with fetal overgrowth (LGA) than in those with normal birth size (appropriate-for-gestational age). Weight trajectory monitoring may be a valuable tool in identifying high-risk LGA children for close follow-ups and interventions to decrease the risk of obesity.

The disruptor of telomeric silencing 1-like (DOT1L) promotes peritoneal fibrosis through the upregulation and activation of protein tyrosine kinases.

The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential.

Sodium-Glucose Cotransport Protein 2 Inhibitors in Patients With Type 2 Diabetes and Acute Kidney Disease.

Importance: Sodium-glucose cotransport protein 2 inhibitors (SGLT-2is) have demonstrated associations with positive kidney-related and cardiovascular outcomes in patients with type 2 diabetes. However, the association of SGLT-2is with outcomes among patients with type 2 diabetes and acute kidney disease (AKD) remains unclear. Objective: To examine the long-term associations of SGLT-2is with mortality, major adverse kidney events (MAKEs), and major adverse cardiovascular events (MACEs) in patients with type 2 diabetes and AKD. Design, Setting, and Participants: This cohort study used global health care data (the TriNetX database) spanning from September 30, 2002, to September 30, 2022. Propensity score matching was used to select a cohort of patients, and follow-up was conducted with a maximum duration of 5 years (completed on September 30, 2022) or until the occurrence of an outcome or death. Intervention: The use of SGLT-2is. Main Outcomes and Measures: The primary outcomes measured were mortality, MAKEs, and MACEs. Adjusted hazard ratios (AHR) with 95% CIs were calculated to compare the risks between SGLT-2i users and nonusers, representing the mean treatment effect among the treated patients. Results: A total of 230 366 patients with AKD (mean [SD] age, 67.1 [16.4] years; 51.8% men and 48.2% women) were enrolled in the study, which had a median follow-up duration of 2.3 (IQR, 1.2-3.5) years. Among these, 5319 individuals (2.3%) were identified as SGLT-2i users. Among nonusers, the incidence of mortality was 18.7%, the incidence of MAKEs was 21.0%, and the incidence of MACEs was 25.8%. After propensity score matching, the absolute differences between SGLT-2i users and nonusers for incidence of mortality, MAKEs, and MACEs were 9.7%, 11.5%, and 12.3%, respectively. Based on the treated population, SGLT-2i use was associated with a significantly lower risk of mortality (AHR, 0.69 [95% CI, 0.62-0.77]), MAKEs (AHR, 0.62 [95% CI, 0.56-0.69]), and MACEs (AHR, 0.75 [95% CI, 0.65-0.88]) compared with nonuse. External validation using a multicenter cohort data set of 1233 patients with AKD patients who were SGLT-2i users confirmed the observed beneficial outcomes. Notably, the risk reduction associated with SGLT-2is remained significant even among patients without hypertension, those with advanced chronic kidney disease, and those not receiving other hypoglycemic agents. Conclusions and Relevance: In this cohort study of patients with type 2 diabetes and AKD, administration of SGLT-2is was associated with a significant reduction in all-cause mortality, MAKEs, and MACEs when compared with nonuse, underscoring the importance of SGLT-2is in care after acute kidney injury. These findings emphasize the potential benefits of SGLT-2is in managing AKD and mitigating the risks of major cardiovascular and kidney diseases.

Calcineurin inhibitors in the treatment of systemic lupus erythematosus during pregnancy: A narrative review with emphasis on efficacy and safety.

Systemic lupus erythematosus (SLE) predominantly affects child-bearing women, leading to an elevated risk of maternal and fetal complications and adverse pregnancy outcomes. Since some medications can cross the placental barrier that persist a threat to both mother and fetus, the risk-benefit ratio of SLE medications should be taken into consideration during pregnancy. Calcineurin inhibitor (CNI), mainly including cyclosporin A, tacrolimus, and voclosporin, is a category of immunosuppressive agents that inhibit calcium/calmodulin-dependent phosphatase calcineurin to block T cell activation. Based on the current clinical evidence, CNI is an alternative in pregnant SLE patients with persistent disease activity (especially lupus nephritis patients) and non-responders to azathioprine. However, there is no comprehensive review that summarizes the efficacy and safety profile of CNI for SLE management during pregnancy. This review presents a summary on the utilization of CNI for SLE management during pregnancy, including the mechanism of action, gestational amelioration of lupus flare, and the balance of maternal benefit-fetal risk, which may provide more references for the management of SLE pregnancies.