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Liang Yin,1,&ast; Kai-Cai Liu,2,&ast; Wei-Fu Lv,1 Shao-Bao Xu,2 Dong Lu,1 Chun-Ze Zhou,1 De-Lei Cheng,1 Zong-Gen Gao,2 Chang-Sheng Shi,2 Ming-Xue Su2 1Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, People’s Republic of China; 2Infection Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei-Fu Lv, Department of Radiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, People’s Republic of China, Email weifulv@ustc.edu.cnObjective: To validate the robust predictive values of tumor vascularity and reactive cutaneous capillary endothelial proliferation (RCCEP) in combination treatment of transarterial chemoembolization (TACE) and camrelizumab for patients with advanced hepatocellular carcinoma (HCC) and then select the potential candidates who would survive best from such treatment.Methods: The clinical data of 113 patients with advanced HCC treated with TACE and camrelizumab from January 2019 to December 2021 were analyzed retrospectively. Mann Whitney U-test was used to evaluate the correlation between vascular distribution and RCCEP and tumor response; Kaplan Meier technique was used to evaluate time to progress (TTP) and overall survival (OS), and log rank test was used for comparison; multivariate Cox regression analysis was used to evaluate the related influencing factors.Results: The TTP and OS of TACE combined with carrelizumab in patients with advanced HCC were 7.1 and 14.3 months. Hypervascularity and development of RCCEP were good predictors of TTP (HR 2.561, P < 0.001; HR 1.486, P = 0.032) and OS (HR 2.854, P < 0.001; HR 1.634, P = 0.011). The median TTP and OS of patients with hypervascularity and RCCEP were 10.6 and 19.3 months, which were better than those with only hypervascularity (6.8 months, P = 0.016; 11.6 months, P = 0.003) and only RCCEP (6.2 months, P = 0.039; 13.5 months, P = 0.042), as well as those with neither (3.8 months, P < 0.001; 7.4 months, P < 0.001).Conclusion: Tumor hypervascularity and development of RCCEP were favorable predictive factors for the combination treatment of TACE and carrelizumab, with both of which the patients survived longest and might be the potential candidates.Keywords: hepatocellular carcinoma, transarterial chemoembolization, camrelizumab, vascularity, RCCEP

Kai-Cai Liu,1,* Ying-Hong Hao,2,* Wei-Fu Lv,2 Wei-Dong Jia,3 Chu-Shu Ji,4 Chun-Ze Zhou,2 De-Lei Cheng,2 Shao-Bao Xu,1 Zong-Gen Gao,1 Ming-Xue Su,1 Chang-Sheng Shi1 1Infection Hospital, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230000, People’s Republic of China; 2Department of Radiology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230022, People’s Republic of China; 3Department of General Surgery, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230022, People’s Republic of China; 4Medical Oncology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230022, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei-Fu LvDepartment of Radiology, The First Affiliated Hospital of USTC, Anhui Provincial Hospital, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui 230022, People’s Republic of ChinaTel/ Fax +86 551 6228 3139Email weifulv@ustc.edu.cnPurpose: Transcatheter arterial chemoembolization (TACE) and targeted therapy have become common methods in the treatment of advanced hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of TACE combined with sorafenib (TACE-sorafenib) and TACE alone for the treatment of Barcelona clinical stage C HCC.Methods: The clinical data of 75 patients with BCLC stage C HCC who received TACE-sorafenib or TACE as the initial treatment were retrospectively analyzed. Tumor response, time to progression (TTP), overall survival (OS), and adverse events were compared at 1 month after surgery in the two groups.Results: One month after treatment, the disease control rate in the TACE-sorafenib group was higher than that in the TACE group alone (82.76% and 57.50%, respectively, P = 0.018). The median values of TTP and OS in the TACE-sorafenib group were longer than those in the TACE group (TTP was 7.6 and 3.4 months, respectively, P = 0.002; OS was 13.6 and 6.3 months, respectively, P = 0.041). The cumulative survival time at 3 months, 6 months, and 1 year was higher in the TACE-sorafenib group than in the TACE group (83.5%, 71.2%, 45.7% vs 57.4%, 40.6%, 21.2%). Sorafenib-related side effects such as hypertension, hand-foot syndrome, and oral ulcers were more common than those in the TACE group alone (P< 0.05).Conclusion: Compared with TACE treatment alone, TACE combined with sorafenib in BCLC-C stage HCC significantly improved disease control rate, TTP, and OS, and no significant increase in adverse reactions was observed.Keywords: hepatocellular carcinoma, TACE, sorafenib, survival

Chih-Chang Yeh,1,2 Yu-Han Su,3 Yu-Jhe Lin,3 Pin-Jyun Chen,3 Chung-Sheng Shi,1 Cheng-Nan Chen,3,* Hsin-I Chang3,* 1Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, Republic of China; 2Orthopaedic Department, Chiayi Branch, Taichung Veterans General Hospital, Chiayi, Taiwan, Republic of China; 3Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan, Republic of China *These authors contributed equally to this work Abstract: Curcumin (Cur) and bisdemethoxycurcumin (BDMC), extracted from Curcuma longa, are poorly water-soluble polyphenol compounds that have shown anti-inflammatory potential for the treatment of osteoarthritis. To increase cellular uptake of Cur and BDMC in bone tissue, soybean phosphatidylcholines were used for liposome formulation. In this study, curcuminoid (Cur and BDMC)-loaded liposomes were characterized in terms of particle size, encapsulation efficiency, liposome stability, and cellular uptake. The results show that there is about 70% entrapment efficiency of Cur and BDMC in liposomes and that particle sizes are stable after liposome formation. Both types of liposome can inhibit macrophage inflammation and osteoclast differential activities. In comparison with free drugs (Cur and BDMC), curcuminoid-loaded liposomes were less cytotoxic and expressed high cellular uptake of the drugs. Of note is that Cur-loaded liposomes can prevent liposome-dependent inhibition of osteoblast differentiation and mineralization, but BDMC-loaded liposomes could not. With interleukin (IL)-1β stimulation, curcuminoid-loaded liposomes can successfully downregulate the expression of inflammatory markers on osteoblasts, and show a high osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) ratio to prevent osteoclastogenesis. In the present study, we demonstrated that Cur and BDMC can be successfully encapsulated in liposomes and can reduce osteoclast activity and maintain osteoblast functions. Therefore, curcuminoid-loaded liposomes may slow osteoarthritis progression. Keywords: liposome, osteoarthritis, curcuminoid, OPG/RANKL ratio, bone turnover

Ferroptosis, a distinct type of cell death caused by iron and lipid peroxidation, has been associated with several diseases, including cardiovascular disorders. Ferrostatin-1 (Fer-1) is a known ferroptosis inhibitor, but its clinical application is limited by low efficacy and stability. In the present study, a series of Fer-1-based diamide derivatives was synthesized and evaluated to enhance ferroptosis inhibition and in vitro metabolic stability. The synthesized compounds were tested for their protective effects against Erastin-induced injury in human vascular endothelial cells (HUVECs). Among the derivatives, compound 36 exhibited the most potent anti-ferroptosis activity with an EC 50 value of 0.58 ± 0.02 µM. Remarkably, compound 36 also demonstrated superior stability in both microsomal (human and mouse) and mouse plasma assays. These findings indicated ferroptosis inhibitor 36 as a promising hit for further developing potential therapeutic drug candidates in cardiovascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The present study focuses on the design and synthesis of novel 1,4-diformyl-piperazine-based ferrostatin-1 (Fer-1) derivatives, and their evaluation against ferroptosis activity. The synthesized compounds demonstrated significant anti-ferroptosis activity in human umbilical vascular endothelial cells (HUVECs), with Compound 24 showing the highest potency. Mechanistic studies revealed that Compound 24 effectively reduced intracellular reactive oxygen species (ROS) levels, mitigated mitochondrial damage, and enhanced glutathione peroxidase 4 (GPX4) expression. Additionally, Compound 24 exhibited improved solubility and plasma stability compared to control compounds, Fer-1 and JHL-12. These findings suggest that 1,4-diformyl-piperazine-based Fer-1 derivatives hold promise as therapeutic agents for ferroptosis-associated cardiovascular diseases., (© 2024 John Wiley & Sons Ltd.)

Background: The light spectrum of intense pulsed light (IPL) comprises visible to near-infrared light. It has been widely employed in the field of aesthetics for approximately 30 years. However, several studies have demonstrated the appearance of various undesirable biomarkers on the skin after IPL irradiation, which remain elucidated., Methods: We reviewed the evolving concepts and explored the potentially harmful effects of IPL that may have been neglected in the past., Results: Increased levels of reactive oxidative stress, p53, p16, proliferating cell nuclear antigen, interleukin-6, C-reactive protein, and cleaved caspase 3 and decreased albumin levels in human or mouse skin have been observed after IPL treatment. Visible and infrared light can exert harmful and beneficial effects on human skin., Conclusion: If perform improperly, IPL treatment may lead to cellular senescence, photoaging, photocarcinogenesis, thermal aging, and inflammaging. Further studies are required to verify the significance of the changes in the relevant biomarkers. The selection of treatment candidates, optimal parameters, and standardized protocols for IPL therapy are necessary., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Ventilator-induced lung injury is a serious complication in mechanically ventilated patients. Neddylation, the post-translational modification of neural precursor cell-expressed developmentally down-regulated 8 (NEDD8) conjugation, regulates numerous biological functions. However, its involvement and therapeutic significance in ventilator-induced lung injury remains unknown. Therefore, this study aimed to examine the kinetics and contribution of activated neddylation and the impact of neddylation inhibition in mice subjected to high tidal volume (HTV) ventilation in vivo and human pulmonary alveolar epithelial cells stimulated through cyclic stretching (CS) in vitro. The neddylation and expression of ubiquitin conjugating enzyme 3 (UBA3), a NEDD8-activating enzyme (NAE) catalytic subunit, were time-dependently upregulated in HTV-ventilated mice. Additionally, the NAE inhibitor MLN4924 considerably attenuated acute lung injury induced by HTV ventilation, manifesting as reduced inflammation and oxidative stress. Furthermore, MLN4924 effectively reduced the secretion of inflammatory cytokines from Ly6C high monocytes and neutrophils, subsequently decreasing endothelial permeability. Moreover, our study revealed an upregulation of the neddylation pathway, oxidative stress, and apoptosis during CS of alveolar epithelial cells. However, blockade of neddylation via MLN4924 or through UBA3 knockdown suppressed this upregulation. Overall, the inhibition of neddylation may alleviate HTV-induced acute lung injury by preventing CS-induced damage to alveolar epithelial cells. This indicates that the neddylation pathway plays a critical role in the progression of ventilator-induced lung injury. These findings may provide a new therapeutic target for treating ventilator-induced lung injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Acute lung injury (ALI) is a serious respiratory disease characterized by diffuse alveolar injury, and it has emerged as a major concern in clinical practice due to limited treatments. This study aimed to explore the pharmacological effects and regulatory mechanism of sappanone A (SA) on ALI. In vivo, mice were administered with SA followed by intratracheal injection of lipopolysaccharide (LPS) to establish an animal model of ALI. We observed that SA exerted comparable anti-inflammatory effects to dexamethasone, as evidenced by effectively mitigating histopathological abnormalities and suppressing the inflammatory response in the lung tissues of mice with ALI. RNA sequencing analysis revealed that SA significantly inhibited the activation of the nuclear factor kappa B (NF-κB) signaling pathway. In vitro, we found that SA protected BEAS-2B cells against LPS-induced cellular injury and reduced inflammatory cytokine generation. Furthermore, both in vivo and in vitro experiments demonstrated that SA effectively prevented LPS-induced oxidative stress and apoptosis. Consistent with the results of the RNA sequencing analysis, SA significantly inhibited the increased protein expressions of p105, p50, c-REL, as well as the ratios of p-p65/p65 and p-IκBα/IκBα in the lung tissues of mice with ALI and LPS-stimulated BEAS-2B cells. Additionally, SA inhibited the nuclear translocation of p65 in BEAS-2B cells stimulated with LPS. Importantly, specific blockade of the NF-κB signaling pathway using BAY11-7082 was identified to alleviate LPS-induced cellular injury in BEAS-2B cells. Collectively, these findings suggest that SA can ameliorate ALI, at least in part, through the inhibition of NF-κB signaling pathway activation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer because of its aggressive clinical behaviour and lack of effective targeted agents. Krüppel-like factor 5 (KLF5) is an oncogenic transcription factor that is highly expressed in BLBC. The deubiquitinase (DUB) BRCA1-associated protein 1 (BAP1) stabilizes KLF5 and promotes BLBC growth and metastasis. Therefore, pharmacological inhibition of the BAP1‒KLF5 axis is an effective therapeutic strategy for BLBC. Here, through screening, we identified a series of tetrahydro-β-carboline derivatives that effectively reduced the protein expression of KLF5 and exhibited strong antitumour activity. Among the investigated compounds, the lead compound LN-439A presented the strongest antitumour activity and inhibitory effect on KLF5 expression. LN-439A suppressed the proliferation and migration of BLBC cells, induced G2/M arrest, and induced apoptosis. Mechanistically, LN-439A functions as a small molecule catalytic inhibitor of BAP1 by binding to the catalytic pocket of BAP1, leading to the ubiquitination and degradation of KLF5. Consistent with this finding, the overexpression of KLF5 suppressed the antitumour effects of LN-439A. In summary, LN-439A is a promising therapeutic agent for BLBC that functions by targeting the BAP1‒KLF5 axis., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Hepatic ischemia-reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end-stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra-small copper-based multienzyme-like nanoparticles with catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) catalytic activities significantly scavenge the surge-generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra-small copper SOD-like activity and manganese dioxides CAT-like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N-acetylcysteamine acid (NAC), an FDA-approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next-generation nanomedicines for scavenging ROS., (© 2024 Wiley‐VCH GmbH.)

Ferrostatin-1 (Fer-1), a first potent ferroptosis inhibitor, faces limitations in clinical use due to its low potency and metabolic instability. This study introduces a series of novel Ferrostatin-1 analogs designed to enhance plasm stability. Our design strategy focused on the modification of the 3-NH2 of Fer-1 with benzenesulfonyl groups, resulting in analogs 9-25. Biological evaluation revealed that compound 18, with an EC50 value of 0.57 µM, outperformed Fer-1 in inhibiting ferroptosis. It reduced intracellular ferrous ion accumulation, lipid peroxidation, and restored glutathione (GSH) and glutathione peroxidase 4 (GPX4) levels effectively. Moreover, compound 18 exhibited favorable solubility and remarkable metabolic stability in rat plasma. These results position compound 18 as a promising candidate for developing therapeutics against ferroptosis-related diseases., (© 2024 Wiley‐VCH GmbH.)

Objective: To evaluate the efficacy and safety of the through-and-through wire (TTW) technique for antegrade ureteral Double-J stent placement after failure of either antegrade or retrograde ureteral stent placement., Method: This retrospective study analyzed the medical records of consecutive patients who underwent Double-J stent placement with the TTW technique at Asan Medical Center and Gil Medical Center between January 2016 and February 2023. Patient histories, reasons for employing the TTW technique, TTW pathways, and complications were reviewed. Eight patients were included in the study. The reasons for using the TTW technique were failure to advance a larger-diameter catheter, balloon catheter, or Double-J stent passing over the guidewire beyond the stricture (6/8, 75.0%); failure to negotiate the stricture with a guidewire (1/8, 12.5%); and guidewire passing through a ureteropelvic junction defect (1/8, 12.5%)., Results: TTW was applied either between a percutaneous nephrostomy (PCN) and the urethral orifice (n=4), between a PCN and an ileostomy pouch (n=3), or between a left and right PCN (n = 1). Urologic assistance was required for retrograde ureteral cannulation in one male patient (12.5%). Subsequently, balloon dilation and/or Double-J stent placement were performed in all eight patients, resulting in 100% technical success. No major or minor complications occurred., Conclusions: The TTW technique was safe and effective in the undertaking of PCN and antegrade Double-J stent placement in patients for whom either antegrade or retrograde access had failed., Competing Interests: Conflict of interest: None., (Copyright: © Pakistan Journal of Medical Sciences.)

Telmisartan, an angiotensin II type 1 receptor (AT1R) blocker, exhibits broad anti-tumor activity. However, in vitro, anti-proliferative effects are shown at doses far beyond the therapeutic plasma concentration. Considering the role of tumor microenvironment in glioma progression, glioma-astrocyte co-cultures were employed to test the anti-tumor potential of low-dose telmisartan. When a high dose was required for a direct anti-proliferative effect on glioma cell lines, a low dose significantly inhibited glioma cell proliferation and migration in the co-culture system. Under co-culture conditions, upregulated IL-6 expression in astrocytes played a critical role in glioma progression. Silencing IL-6 in astrocytes or IL-6R in glioma cells reduced proliferation and migration. Telmisartan (5 μM) inhibited astrocytic IL-6 expression, and its anti-tumor effects were reversed by silencing IL-6 or IL-6R and inhibiting signal transducer and activator of transcription 3 (STAT3) activity in glioma cells. Moreover, the telmisartan-driven IL-6 downregulation was not imitated by losartan, an AT1R blocker with little capacity of peroxisome proliferator-activated receptor-gamma (PPARγ) activation, but was eliminated by a PPARγ antagonist, indicating that the anti-glioma effects of telmisartan rely on its PPARγ agonistic activity rather than AT1R blockade. This study highlights the importance of astrocytic IL-6-mediated paracrine signaling in glioma growth and the potential of telmisartan as an adjuvant therapy for patients with glioma, especially those with hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: The aim of this study is to evaluate the significance of combined detection of Septin9 and syndecan-2 (SDC2) methylation markers and serum tumor markers for the early diagnosis of colorectal cancer., Methods: A total of 116 patients diagnosed with colorectal cancer between December 2022 and February 2024 were designated as the colorectal cancer group. Additionally, 31 patients with colorectal adenoma were assigned to the adenoma group, while 44 individuals undergoing routine physical examinations were included in the control group. Concentrations of Septin9, SDC2, fecal occult blood (FOB), and four tumor markers-carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), and carbohydrate antigen 724 (CA724)-were measured. Diagnostic performance was assessed using receiver operating characteristic (ROC) curves for Septin9, SDC2, the four tumor markers, FOB, the combination of Septin9 and SDC2, and the combined use of all seven indicators (CEA, CA19-9, CA125, CA72-4, FOB, Septin9, and SDC2)., Results: The colorectal cancer group exhibited the highest positive rates for Septin9, SDC2, the four tumor markers, the combined detection of Septin9 and SDC2, and the combined detection of all seven indicators, compared to both the adenoma and control groups (P < 0.05). The adenoma group also showed higher positive rates than the control group (P < 0.05). For patients with stage I-III colorectal cancer, the positive rates for the combined detection of Septin9 and SDC2 were 81.3%, 78.9%, and 90.2%, respectively, surpassing those for the combined detection of the four tumor markers (43.8%, 55.3%, and 61.0%). Additionally, the positive rates for the two-gene combination in stage III colorectal cancer were higher than those for FOB (P < 0.05). The sensitivity and area under the curve (AUC) for SDC2 were 73.3% and 0.855, respectively, exceeding the sensitivity and AUC for the combined four tumor markers, which were 60.3% and 0.734 (P < 0.05). The combined detection of the two methylated genes demonstrated a sensitivity of 86.2% and an AUC of 0.908, outperforming both FOB and the combined detection of the four tumor markers (P < 0.05)., Conclusion: The detection of SDC2 exhibits high sensitivity for colorectal cancer, and when combined with Septin9, it significantly enhances the diagnostic accuracy for early-stage colorectal cancer, offering substantial clinical value., (© 2024. The Author(s).)

The quest for novel antibacterial agents is imperative in the face of escalating antibiotic resistance. Naturally occurring tetrahydro-β-carboline (THβC) alkaloids have been highlighted due to their significant biological derivatives. However, these structures have been little explored for antibacterial drugs development. In this study, a series of 1,2,3,4-THβC derivatives were synthesized and assessed for their antibacterial prowess against both gram-positive and gram-negative bacteria. The compounds exhibited moderate to good antibacterial activity, with some compounds showing superior efficacy against gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA), to that of Gentamicin. Among these analogs, compound 3k emerged as a hit compound, demonstrating rapid bactericidal action and a significant post-antibacterial effect, with significant cytotoxicity towards human LO2 and HepG2 cells. In addition, compound 3k (10 mg/kg) showed comparable anti-MRSA efficacy to Ciprofloxacin (2 mg/kg) in a mouse model of abdominal infection. Overall, the present findings suggested that THβC derivatives based on the title compounds hold promising applications in the development of antibacterial drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression., Methods: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression., Results: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (β - 7.5 × 10 -6 , CI - 1.2 × 10 -5 , - 3 × 10 -6 , p = 0.001) and incident cases of NS (vs. prevalent) (β - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (β 0.16, CI 0.04, 0.29, p = 0.01) over time., Conclusion: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Primary glomerular diseases are rare entities. This has hampered efforts to better understand the underlying pathobiology and to develop novel safe and effective therapies. NEPTUNE is a rare disease network that is focused on patients of all ages with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. It is a longitudinal cohort study that collects detailed demographic, clinical, histopathologic, genomic, transcriptomic, and metabolomic data. The goal is to develop a molecular classification for these disorders that supersedes the traditional pathological features-based schema. Pediatric patients are important contributors to this ongoing project. In this review, we provide a snapshot of the children and adolescents enrolled in NEPTUNE and summarize some key observations that have been made based on the data accumulated during the study. In addition, we describe the development of NEPTUNE Match, a program that aims to leverage the multi-scalar information gathered for each individual patient to provide guidance about potential clinical trial participation based on the molecular characterization and non-invasive biomarker profile. This represents the first organized effort to apply principles of precision medicine to the treatment of patients with primary glomerular disease. NEPTUNE has proven to be an invaluable asset in the study of glomerular diseases in patients of all ages including children and adolescents., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gα i proteins, which stimulates cytoskeletal reorganization and cell polarity changes. To better understand the signaling events responsible for these cellular changes, we focused on early changes in F-actin dynamics after engagement of the chemokine receptor CXCR5 in murine splenic B cells. Within 10 seconds of exposure to the CXCR5 ligand CXCL13, three-dimensional lamellar-like pseudopods and F-actin-rich ridges appeared. The transient F-actin increase depended on Gα i2/3 signaling, the PI3K/AKT pathway, ERK activation, phospholipase C activity, and Rac1/2 activation mediated by Dock2 (dedicator of cytokinesis 2). Immunoblot analyses identified the kinase WNK1 (with no lysine kinase 1) as a potential early AKT effector. Treating B cells with specific WNK inhibitors disrupted F-actin dynamics and impaired B cell polarity, motility, and chemotaxis. These changes were mimicked in a murine B cell line by CRISPR-Cas9 gene editing of Wnk1 , which also suggested that WNK1 contributed to B cell proliferation. Administration of a single dose of a WNK inhibitor transiently reduced B cell motility and polarity in the lymph nodes of live mice. These results indicate that WNK1 signaling maintains B cell responsiveness to CXCL13 and suggest that pharmacological inhibition of WNK1, which is involved in cancer progression and blood pressure regulation, may affect humoral immunity.

Low-dimension metal halide perovskites are attractive for bandgap tunable optoelectronic materials. Among them, 1-D CsPbBr 3 quantum wires (QWs) are emerging as promising deep-blue luminescent material. However, the growth dynamics of 1-D perovskite QWs are intricate, making the study and control of 1-D QWs highly challenging. In this study, a strategy for controlling both the length and width of the CsPbBr 3 QWs was realized. The temperature-dependent isotropic growth mechanism was revealed and employed as the main tool for the oriented growth of 1-D CsPbBr 3 QWs for various aspect ratios. Our results pave the way for the controlled synthesis of ultrasmall perovskite nanocrystals.

Language barriers are major obstacles that Asian American immigrants face when accessing health care in the USA. This study was conducted to explore the impact of language barriers and facilitators on the health care of Asian Americans. Qualitative, in-depth interviews and quantitative surveys were conducted with 69 Asian Americans (Chinese, Filipino, Japanese, Malaysian, Indonesian, Vietnamese, and mixed Asian backgrounds) living with HIV (AALWH) in three urban areas (New York, San Francisco, and Los Angeles) in 2013 and from 2017 to 2020. The quantitative data indicate that language ability is negatively associated with stigma. Major themes emerged related to communication, including the impact of language barriers on HIV care and the positive impact of language facilitators-family members/friends, case managers, or interpreters-who can communicate with healthcare providers in the AALWH's native language. Language barriers negatively impact access to HIV-related services and thus result in decreased adherence to antiretroviral therapy, increased unmet healthcare needs, and increased HIV-related stigma. Language facilitators enhanced the connection between AALWH and the healthcare system by facilitating their engagement with health care providers. Language barriers experienced by AALWH not only impact their healthcare decisions and treatment choices but also increase levels of external stigma which may influence the process of acculturation to the host country. Language facilitators and barriers to health services for AALWH represent a target for future interventions in this population., (© 2023. The Author(s).)

Objective: To evaluate the prognostic factors and survival outcomes of patients with surgically treated high-grade neuroendocrine carcinoma of the cervix (NECC)., Methods: This multicenter, retrospective study involved 98 cervical cancer patients with stage IA2-IIA2 and IIIC1/2p high-grade NECC. We divided the patients into two groups based on histology: the pure and mixed groups. All clinicopathologic variables were retrospectively evaluated. Cox regression and Kaplan-Meier methods were used for analysis., Results: In our study, 60 patients were in the pure group and 38 patients were in the mixed group. Cox multivariate analysis showed that mixed histology was a protective factor impacting overall survival (OS) (P = 0.026) and progression free survival (PFS) (P = 0.018) in surgically treated high-grade NECC. Conversely, survival outcomes were negatively impacted by ovarian preservation (OS: HR, 20.84; 95% CI: 5.02-86.57, P < 0.001), age >45 years (OS: HR, 4.50; 95% CI: 1.0-18.83, P = 0.039), tumor size >4 cm (OS: HR, 6.23; 95% CI: 2.34-16.61, P < 0.001), parity >3 (OS: HR, 4.50; 95% CI: 1.02-19.91, P = 0.048), and perineural invasion (OS: HR, 5.21; 95% CI: 1.20-22.53, P = 0.027). Kaplan-Meier survival curves revealed notable differences in histologic type (OS: P = 0.045; PFS: P = 0.024), chemotherapy (OS: P = 0.0056; PFS: P = 0.0041), ovarian preservation (OS: P = 0.00031; PFS: P = 0.0023), uterine invasion (OS: P < 0.0001; PFS: P < 0.0001), and depth of stromal invasion (OS: P = 0.043; PFS: P = 0.022)., Conclusion: Patients with mixed histologic types who undergo surgery for high-grade NECC have a better prognosis. Meanwhile, ovarian preservation, tumor size >4 cm, parity >3, age >45 years and perineural invasion were poor prognostic predictors. Therefore, patients with high-risk factors should be considered in clinical practice., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Introduction: Atherosclerotic cardiovascular disease is associated with a high mortality rate due to vascular calcification. The role of fetuin-A in aortic arch calcification (AAC) is less well understood., Methods: An analysis of secondary biomarkers was performed on 800 individuals from the biobank using the community database. AAC was defined by radiologists based on imaging. Multiple variables logical analysis was used for risk analysis., Results: A total of 736 individual samples were collected based on age and gender. The average age is 65 ± 10 years, and half the population comprises men. In spite of similar body weight, renal function, and hepatic function, the AAC group had higher blood pressure and fetuin-A levels independently: systolic blood pressure (SBP) index ≥130 mmHg [adjusted odds ratio (aOR) 1.85, 95% confidence interval (CI) 1.34-2.57, p  = 0.002] and fetuin-A (aOR 0.62, 95% CI 0.50-0.76, p  < 0.001). Moreover, it is evident that AAC can be predicted more accurately when combined with SBP ≥130 mmHg and a low fetuin-A level (<358 μg/ml: aOR 5.39, 95% CI 3.21-9.08) compared with the reference., Conclusion: Low fetuin-A levels are significantly correlated with AAC while there is an increased association between vascular calcification and coexisting hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Lin, Lin, Shi, Lin, Lin, Yang, Liao, Chen, Tsai and Lin.)

Background: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response., Methods: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia., Results: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time., Conclusions: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Fluorescent whitening agents (FWAs) are dyes that emit visible blue or blue-purple fluorescence upon ultraviolet-light absorption. Taking advantage of light complementarity, FWAs can compensate for the yellow color of many substances to achieve a whitening effect; thus, they are used extensively in various applications. FWAs are generally stable, but their presence in the environment can lead to pollution and accumulation in the body through the food chain. Recent studies have revealed that some types of FWAs, such as coumarin-based FWAs, may exhibit photo-induced mutagenic effects that can trigger allergic reactions in humans and even pose carcinogenic risks. Hence, the development of an accurate and highly sensitive method for detecting FWAs in food-related samples is a crucial endeavor. Owing to the high polarity and structural similarity of FWAs, the accurate determination of these substances in complex food samples requires an analytical method that offers both efficient separation and sensitive detection. Capillary electrophoresis (CE) exhibits essential features such as high separation efficiency, short analysis times, very small sample injection requirements, minimal use of organic solvents, and simple operation. Thus, it is often used as an effective alternative to liquid chromatographic techniques. Over the past few decades, electrospray ionization mass spectrometry (ESI-MS) has been utilized as a highly sensitive and accurate detection method in numerous chemical analytical fields because it enables the analysis of molecular structures. By combining the high separation efficiency of CE with the high sensitivity of ESI-MS, a powerful tool for identifying and quantifying trace amounts of FWAs in food samples may be obtained. In this study, we present a method based on sheathless CE coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS) for the simultaneous detection of six trace FWAs in flour. In the proposed method, the CE separation device is directly coupled to the mass spectrometer through a sheathless interface without the need for a sheath liquid for electric contact, thereby avoiding the dilution of the analytes and improving detection sensitivity. Various conditions that could affect extraction recovery, separation efficiency, and detection sensitivity were evaluated and optimized. The FWAs were effectively extracted from the sample matrix with reduced matrix effects by ultrasonic-assisted extraction at a temperature of 30 ℃ for 20 min using CHCl 3 -MeOH (3∶2, v/v) as the extraction solvent. The extract was centrifuged, dried under N 2 , and reconstituted in CHCl 3 -MeOH (1∶4, v/v) for subsequent analysis. During the detection process, the CE device was coupled to the ESI-MS/MS instrument via a highly sensitive porous spray needle, which served as the sheathless electrospray interface. The target FWAs were scanned in positive-ion mode (ESI + ) to ensure the stability and intensity of the obtained signals. Additionally, multiple-reaction monitoring (MRM) mode and MS/MS analysis were used to simultaneously quantify the six targets with high selectivity. The developed sheathless CE-ESI-MS/MS method detected the FWAs with high sensitivity over wide linear ranges with low method limits of detection (0.04-0.67 ng/g). The recoveries of the six target FWAs at three spiked levels were between 77.5% and 97.2%, with good interday (RSD≤11.5%) and intraday (RSD≤10.2%) precision. Analyses of the six target FWAs in eight commercial flour samples were performed using this method, and four positive samples were identified. These results demonstrate that the proposed CE-ESI-MS/MS method is a promising strategy for the determination of trace FWAs in complex food sample matrices with efficient separation and high sensitivity.

Bacterial pore-forming toxins (PFTs) that disrupt host plasma membrane integrity (PMI) significantly contribute to the virulence of various pathogens. However, how host cells protect PMI in response to PFT perforation in vivo remains obscure. Previously, we demonstrated that the HLH-30/TFEB-dependent intrinsic cellular defense (INCED) is elicited by PFT to maintain PMI in Caenorhabditis elegans intestinal epithelium. Yet, the molecular mechanism for the full activation of HLH-30/TFEB by PFT remains elusive. Here, we reveal that PRMT-7 (protein arginine methyltransferase-7) is indispensable to the nuclear transactivation of HLH-30 elicited by PFTs. We demonstrate that PRMT-7 participates in the methylation of HLH-30 on its RAG complex binding domain to facilitate its nuclear localization and activation. Moreover, we showed that PRMT7 is evolutionarily conserved to regulate TFEB cellular localization and repair plasma damage caused by PFTs in human intestinal cells. Together, our observations not only unveil a novel PRMT-7/PRMT7-dependent post-translational regulation of HLH-30/TFEB but also shed insight on the evolutionarily conserved mechanism of the INCED against PFT in metazoans.

Purpose: School is an important developmental setting for children. Adverse childhood experiences (ACEs) are linked to overall lower educational attainment and are more prevalent in children with Autism Spectrum Disorder (ASD) than in their neurotypical peers. The aim of this study is to test the association between ACEs and school outcomes among autistic children and whether mental health conditions explain this association., Methods: We combined 2016-2021 data from the National Surveys of Children's Health for children, ages 6-17, identified by parents as having ASD (N = 4,997), to examine the relationship between ACEs and school outcomes (grade progression, school attendance, and engagement). We analyzed depression and anxiety variables to investigate the extent to which mental health can explain the relationships between ACEs and school outcomes., Results: ACEs were significantly associated with school outcomes. With increased ACEs, autistic children experienced a significant decrease in the odds of school attendance, grade progression and school engagement (p < .05). Furthermore, although depression and anxiety symptoms were significantly associated with school outcomes, they cannot explain away the enduring, strong relationship between ACEs and level of grade progression, engagement, and school success index., Conclusion: Our findings suggest ACEs predict school success among autistic children, with mental health conditions appearing to mediate the relationship between ACEs and key factors in school success. Efforts should be made to proactively identify and address the impact of ACEs and associated mental health conditions among autistic students., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This research demonstrates changes in the behaviors and characteristics of sintered bricks while using industrial sludge ash (ISA) and waste glass (WG) as a replacement for clay in the brick manufacturing procedure. Owing to the limited amount of available land in Taiwan, it is becoming increasingly difficult to locate suitable sites for sanitary landfills, which is a common final disposal method for ash that is produced during thermal treatment in sludge factories. To meet the urgent need for land, the final waste disposal must convert this waste into a new resource. This research investigated the feasibility of using general industrial sludge ash waste, due to its abundance and high potential as a raw material in producing bricks. The result of this study shows that the bricks made from ISA and WG under a certain mixture proportion (ISA50%/WG40%/Clay10%) had excellent industrial potentials, such as compressive strength and water absorption rate. However, owing to the wide variety of components from different sources of ISA, the mixture proportion might vary accordingly. This study also analyzed the incineration index, proportion design, and process improvement, as well as investigating the possibility of increasing the total use of sludge ash as a resource. This study shows the potentials of utilizing wastes as raw materials in industrial manufacturing procedures. Therefore, more wastes can be tested and turned into resources in the future.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Introduction: Patients with primary glomerular disease (GN) have unique management needs. We describe the design of a user-centered, patient-facing electronic health (eHealth) tool to support GN management., Methods: We surveyed patients and GN expert nephrologists on disease management tasks, educational needs, and barriers and facilitators of eHealth tool use. Results were summarized and presented to patients, nephrologists, engineers, and a behavioral and implementation science expert in stakeholder meetings to jointly design an eHealth tool. Key themes from the meetings are described using rapid qualitative analysis., Results: Sixty-six patients with minimal change disease, focal segmental glomerulosclerosis, IgA nephropathy, and membranous nephropathy responded to the survey, as well as 25 nephrologists from the NIH-funded Cure Glomerulonephropathy study network. Overall, patients performed fewer management tasks and acknowledged fewer informational needs than recommended by nephrologists. Patients were more knowledgeable about eHealth tools than nephrologists. Nine patient stakeholders reflected on the survey findings and noted a lack of awareness of key recommended management tasks and receiving little guidance from nephrologists on using eHealth. Key themes and concepts from the stakeholder meetings about eHealth tool development included the need for customizable design, trustworthy sources, seamless integration with other apps and clinical workflow, and reliable data tracking. The final design of our eHealth tool, the UrApp System, has 5 core features: "Profile" generates personalized data tracking, educational information, facilitation with provider discussions and inputting other preferences; "Data Tracking" displays patient health data with the ability to communicate important trends to patients and nephrologists; "Resources" provides trusted education information in a personalized manner; "Calendar" displays key events and generate reminders; and "Journal" facilitates information documentation using written or audio notes., Conclusion: Our theory- and evidenced-based, stakeholder-engaged design process created designs for an eHealth tool to support the unique needs of patients with GN, optimized for effectiveness and implementation., Competing Interests: A.L.O. received research support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; K23DK123413) and honoraria from Bayer outside the submitted work. L.H.M. received research support from Boehringer-Ingelheim, consulting fees from Travere Therapeutics, Chinook Therapeutics, and Calliditas Therapeutics, and honorarium from HCP Live, Medscape, and PlatformQ outside the submitted work. J.C. received research support from Vertex Pharmaceuticals outside the submitted work. C.W. received research support from the NIDDK (K23DK118189), the Centers for Disease Control and Prevention, the European Society of Pediatric Nephrology – Pediatric Nephrology Research Consortium, Boehringer-Ingelheim, IQVIA, and Genetech outside the submitted work. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-β-carboline (THβC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC 50 values of 15.47 ± 1.31 and 19.31 ± 2.14 μM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC 50 values below 10 μM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Hericium erinaceus mycelium extract (HEM), containing erinacine A (HeA) and erinacine S (HeS), has shown promise in promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs), crucial for myelin production in the central nervous system (CNS). The main aim of this study was to characterize the protective effects of HEM and its components on OLs and myelin in demyelinating rodents by exposure to cuprizone (CPZ), a copper chelating agent commonly used to induce demyelination in the corpus callosum of the brain. Rats were fed by CPZ-containing diet and simultaneously orally administered HEM, HeA, or HeS on a daily basis for three weeks. We found that HEM and HeS preserved myelin and OLs in the corpus callosum of CPZ-fed rats, along with reduced microglia and astrocyte activation, and downregulated IL-1β expression. Furthermore, post-treatment with HeS, in mouse models with acute (6 weeks) or chronic (12 weeks) CPZ-induced demyelination demonstrated oral administration during the final 4 weeks (HeS4/6 or HeS4/12) effectively preserved myelin in the corpus callosum. Additionally, HeS4/6 and HeS4/12 inhibited anxious and depressive-like behaviors in CPZ-fed mice. In summary, simultaneous administration of HEM and HeS in rats during short-term CPZ intoxication preserved OLs and myelin. Furthermore, post-administration of HeS not only inhibited demyelination and gliosis but also alleviated anxiety and depression in both acute and chronic CPZ-fed mice. This study presents compelling evidence supporting the potential of HeS as a promising small active compound for protecting OLs and preserving myelin in demyelinating diseases associated with emotional disorders., Competing Interests: Declaration of Competing Interest The authors declare that they have no financial or personal associations with individuals or organizations that might pose a risk of undue influence or introduce bias into the paper's content. The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This study aims to explore the potential mechanism of action in the intervention of acute lung injury(ALI) based on the blood entry components of Ganke Granules in rats and in conjunction with network pharmacology, molecular docking, and animal experimental validation. The blood entry components of Ganke Granules in rats were imported into the SwissTargetPrediction platform to predict drug targets, and ALI-related targets were collected from the disease database. Intersections were taken, and protein-protein interaction(PPI) networks were constructed to screen the core targets, followed by Gene Ontology(GO) functional and Kyoto encyclopedia of genes and gnomes(KEGG) pathway enrichment analyses. A &quot;blood entry components-target-pathway-disease&quot; network was constructed, and the core components for disease intervention based on their topological parameters were screened. Molecular docking was used to predict the binding ability of the core components to key targets. The key targets of Ganke Granules in the intervention of ALI were verified by the lipopolysaccharide(LPS)-induced ALI mouse model. Through PPI topological parameter analysis, the top six key targets of STAT3, SRC, HSP90AA1, MAPK3, HRAS, and MAPK1 related to ALI were obtained. GO functional analysis showed that it was mainly related to ERK1 and ERK2 cascade, inflammatory response, and response to LPS. KEGG analysis showed that the main enrichment pathways were MAPK, neutrophil extracellular trap(NET) formation, and so on. Six core components(schizantherin B, schisandrin, besigomsin, harpagoside, isotectorigenin, and trachelanthamine) were filtered out by the &quot;blood entry components-target-pathway-disease&quot; network based on the analysis of topological parameters. Molecular docking results showed that the six core components and Tectoridin with the highest content in the granules had a high affinity with the key targets of MAPK3, SRC, MAPK1, and STAT3. In vivo experiment results showed that compared with the model group, Ganke Granules could effectively alleviate LPS-induced histopathological injury in the lungs of mice and reduce the percentage of inflammatory infiltration. The total protein content, nitric oxide(NO) level, myeloperoxidase(MPO) content, tumor necrosis factor-α(TNF-α), gamma interferon(IFN-γ), interleukin-1β(IL-1β), interleukin-6(IL-6), vascular endothelial growth factor(VEGF), and chemokine(C-X-C motif) ligand 1(CXCL1) chemokines in bronchoalveolar lavage fluid(BALF) were decreased, and the expression levels of lymphocyte antigen 6G(Ly6G), citrullinated histones 3(Cit-H3), and phosphorylated proteins SRC, ERK1/2, and STAT3 in lung tissue were significantly down-regulated. In conclusion, Ganke Granules could effectively inhibit the inflammatory response of ALI induced by LPS, protect lung tissue, regulate the release of inflammatory factors, and inhibit neutrophil infiltration and NET formation, and the mechanism of action may be related to inhibiting the activation of SRC/ERK1/2/STAT3 signaling pathway.

Human-specific insertions play important roles in human phenotypes and diseases. Here we reported a 446-bp insertion (Insert-446) in intron 11 of the TBC1D8B gene, located on chromosome X, and traced its origin to a portion of intron 6 of the EBF1 gene on chromosome 5. Interestingly, Insert-446 was present in the human Neanderthal and Denisovans genomes, and was fixed in humans after human-chimpanzee divergence. We have demonstrated that Insert-446 acts as an enhancer through binding transcript factors that promotes a higher expression of human TBC1D8B gene as compared with orthologs in macaques. In addition, over-expression TBC1D8B promoted cell proliferation and migration through "a dual finger" catalytic mechanism (Arg538 and Gln573) in the TBC domain in vitro and knockdown of TBC1D8B attenuated tumorigenesis in vivo. Knockout of Insert-446 prevented cell proliferation and migration in cancer and normal cells. Our results reveal that the human-specific Insert-446 promotes cell proliferation and migration by upregulating the expression of TBC1D8B gene. These findings provide a significant insight into the effects of human-specific insertions on evolution., (© 2023. Science China Press.)

Bumblebees play an important ecological economic role as pollinators in nature and agriculture. For reasons of biosecurity, many countries promote the cultivation of native bumblebee species for crop pollination instead of importing "alien" species. In South China, a few bumblebee species are considered useful in this way, particularly, Bombus atripes, Bombus bicoloratus and Bombus breviceps. However, whether they are suitable for artificial rearing and forming healthy colonies for pollination, remains unknown. In this project, queens from the 3 native species of Guizhou Province were collected and colonies were started under standardized conditions. The colonies were scored based on 19 parameters, including the stage of colony development, number and weight of offspring, and diet consumed. The data revealed that B. breviceps had the best performance, produced more workers and consumed the smallest diet. Next, we performed 16S rDNA sequencing of the bacterial communities found in the guts of offspring workers, and then a correlation analysis between colony performance and gut bacteria was conducted. Here, B. breviceps showed the highest diversity in gut bacterial composition, dominated by the bacteria Gilliamella, Snodgrassella, Enterobacter, and Lactobacillus Firm5. The higher the abundance of Snodgrassella, the better the performance of the colony in the foundation stage, and later Lactobacillus Firm5, Apibacter and Bifidobacterium were beneficial during the stages of rapid growth and colony decline. Although we do not understand all of the interactions yet, these correlations explain why B. breviceps demonstrated better colony performance. Our data provide valuable information for breeding local Bombus species and will contribute to developing strong colonies for crop pollination., (© 2024 Institute of Zoology, Chinese Academy of Sciences.)

Purpose: In this study, our objective was to investigate the potential utility of lymphocyte-C-reactive protein ratio (LCR) as a predictor of disease progression and a screening tool for intensive care unit (ICU) admission in adult patients with acute pancreatitis (AP)., Methods: We included a total of 217 adult patients with AP who were admitted to the First Affiliated Hospital of Harbin Medical University between July 2019 and June 2022. These patients were categorized into three groups: mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP), based on the presence and duration of organ dysfunction. Various demographic and clinical data were collected and compared among different disease severity groups., Results: Height, diabetes, lymphocyte count (LYMPH), lymphocyte percentage (LYM%), platelet count (PLT), D-Dimer, albumin (ALB), blood urea nitrogen (BUN), serum creatinine (SCr), glucose (GLU), calcium ion (Ca 2+ ), C-reactive protein (CRP), procalcitonin (PCT), hospitalization duration, ICU admission, need for BP, LCR, sequential organ failure assessment (SOFA) score, bedside index for severity in AP (BISAP) score, and modified Marshall score showed significant differences across different disease severity groups upon hospitalization. Notably, there were significant differences in LCR between the MAP group and the MSAP and SAP combined group, and the MAP and MSAP combined group and the SAP group, and adult AP patients with ICU admission and those without ICU admission upon hospitalization., Conclusion: In summary, LCR upon hospitalization can be utilized as a simple and reliable predictor of disease progression and a screening tool for ICU admission in adult patients with AP., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Xu et al.)

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated cell death. It has been shown that high glucose (HG) could induce ferroptosis in vascular endothelial cells (VECs), consequently contributing to the development of various diseases. This study synthesized and evaluated a series of novel ferrostatin-1 (Fer-1) derivatives fused with a benzohydrazide moiety to prevent HG-induced VEC ferroptosis. Several promising compounds showed similar or improved inhibitory effects compared to positive control Fer-1. The most effective candidate 12 exhibited better protection against erastin-induced ferroptosis and high glucose-induced ferroptosis in VECs. Mechanistic studies revealed that compound 12 prevented mitochondrial damage, reduced intracellular ROS accumulation, upregulated the expression of GPX4, and decreased the amounts of ferrous ion, LPO and MDA in VECs. However, compound 12 still exhibited undesirable microsomal stability like Fer-1, suggesting the need for further optimization. Overall, the present findings highlight ferroptosis inhibitor 12 as a potential lead compound for treating ferroptosis-associated vascular diseases., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Severe soft tissue infections caused by Aeromonas dhakensis, such as necrotizing fasciitis or cellulitis, are prevalent in southern Taiwan and around the world. However, the mechanism by which A. dhakensis causes tissue damage remains unclear. Here, we found that the haemolysin Ahh1, which is the major virulence factor of A. dhakensis, causes cellular damage and activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome signalling pathway. Deletion of ahh1 significantly downregulated caspase-1, the proinflammatory cytokine interleukin 1β (IL-1β) and gasdermin D (GSDMD) and further decreased the damage caused by A. dhakensis in THP-1 cells. In addition, we found that knockdown of the NLRP3 inflammasome confers resistance to A. dhakensis infection in both THP-1 NLRP3 -/- cells and C57BL/6 NLRP3 -/- mice. In addition, we demonstrated that severe soft-tissue infections treated with antibiotics combined with a neutralizing antibody targeting IL-1β significantly increased the survival rate and alleviated the degree of tissue damage in model mice compared control mice. These findings show that antibiotics combined with therapies targeting IL-1β are potential strategies to treat severe tissue infections caused by toxin-producing bacteria., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Inflammation is much more intrinsic to hernia then is what is generally appreciated. The occurrence of hernias is associated with swelling, stress and inflammation. Surgery remains an important intervention to treat hernias and for many years, post-surgical levels of inflammatory cytokines have been evaluated to compare the different strategies for their comparative advantages. All surgical procedures elicit some sort of inflammatory response and moreover the meshes used for hernia repair are also associated with elevated inflammatory response, although some favor predominantly a pro-inflammatory response while the other meshes favor anti-inflammatory response. An estimated more than 90% of hernia repairs involve some meshes with polypropylene considered as the gold standard. Efforts are underway to modulate polypropylene meshes associated inflammation through use of alternative materials as well as modifications to polypropylene meshes themselves. In the last one decade, miRNAs have entered hernia research and the data on a role of miRNAs in different hernias is slowly emerging, providing the first evidence of epigenetics in hernia. Some reports are connecting miRNAs with inflammation in hernia. All these aspects, such as, surgery-related to mesh-related inflammation as well as miRNA-related inflammation, are discussed in this article to present an up-to-date information on the topic., Competing Interests: Conflict of Interest No conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In the present study, a novel derivative, IOP-LA, was prepared by hybridizing antioxidant lipoic acid (LA) and our recently reported antioxidative marine phidianidine B-inspired indole/1,2,4-oxadiazole derivative. Our results demonstrated that IOP-LA could protect vascular endothelial cells (VECs) from oxidized low-density lipoprotein (oxLDL)-induced oxidative stress by activating the Nrf2 pathway, inhibit the production of atherosclerotic plaque, and promote the stability of atherosclerotic plaque in apoE -/- mice. Moreover, the protective effect of IOP-LA was superior to LA at the same concentration. Mechanistic studies revealed that IOP-LA significantly inhibited the increase of reactive oxygen species (ROS) levels and the translocation of nuclear factor kappa-B (NF-κB) nuclear induced by oxLDL through the nuclear factor erythroid2-related factor 2 (Nrf2) pathway. In summary, the data demonstrate that IOP-LA, as a new antioxidant, protects VECs from oxLDL-induced oxidative stress by activating the Nrf2 pathway. It is worth noting that this study provides a promising lead compound for the prevention and treatment of atherosclerosis., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Stigma has heavily impacted People Living with HIV (PLWH). Limited studies report on how social support affects HIV-related stigma and perceived stress, especially in Myanmar. During first seven months of 2020, a random sample of 248 eligible PLWH were contacted from a private, closed Facebook group with more than 18,000 Myanmar people, where 90% of the members were PLWH. Variables collected included demographics data, perceived stress, social support, and HIV stigma. After controlling for the effects of demographic variables, the path from HIV stigma to perceived stress (direct effect β  = 0.40) and though the mediation of social support was significant (indirect effect β  = 0.014). However, the mediating effect of social support was non-significant between HIV stigma and perceived stress. This exploratory study shows that social support did not have the expected effect of decreasing perceived stress in PLWH in Myanmar. Interventions to reduce HIV stigma to decrease perceived stress should consider other strategies, e.g., spirituality-based practice, to reduce perceived stress in Myanmar PLWH.

Rationale & Objective: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination., Study Design: Observational cohort study from July 1, 2021, to January 1, 2023., Setting & Participants: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy., Exposure: COVID-19 and COVID-19 vaccination., Outcome: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above., Analytical Approach: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening., Results: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m 2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m 2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m 2 ±0.15 SD vs-2.16mL/min/1.73m 2 ±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort., Limitations: Infrequent or short follow-up., Conclusions: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN., Plain-Language Summary: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Youth with intellectual and/or developmental disabilities (IDD) often struggle with depression and anxiety, which adversely impacts transition to adulthood. Integrated behavioral health care coordination, wherein care coordinators and behavioral health specialists collaborate to provide systematic, cost-effective, patient-centered care, is a promising strategy to improve access to behavioral health services and address factors that impact transition to adulthood, including depression/anxiety symptoms. Current care coordination models (e.g., Title V Maternal and Child Health Bureau [MCHB]) do not include behavioral health services. The CHECK (Coordinated HealthCarE for Complex Kids) mental health model, hereby refined and renamed BEhavioral Health Stratified Treatment (B.E.S.T.), is a behavioral health intervention delivery program designed for integration into care coordination programs. This study aims to determine whether an integrated behavioral health care coordination strategy (i.e., MCHB care coordination plus B.E.S.T.) would be more acceptable and lead to better youth health and transition outcomes, relative to standard care coordination (i.e., MCHB care coordination alone). Results would guide future investment in improving outcomes for youth with IDD. This study is a two-arm randomized clinical trial of 780 transition-aged youth with IDD (13-20 years) to evaluate the comparable efficacy of MCHB Care Coordination alone vs. MCHB Care Coordination plus B.E.S.T. on the following outcomes: 1) decreased symptoms and episodes of depression and anxiety over time; 2) improved health behaviors, adaptive functioning and health related quality of life; 3) increased health care transition (HCT) readiness; and 4) improved engagement and satisfaction with care coordination among stakeholders., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Bladder cancer is becoming one of the most common malignancies across the world. Although treatment strategy has been continuously improved, which has led to cisplatin-based chemotherapy becoming the standard medication, cancer recurrence and metastasis still occur in a high proportion of patients because of drug resistance. The high efficacy of regorafenib, a broad-spectrum kinase inhibitor, has been evidenced in treating a variety of advanced cancers. Hence, this study investigated whether regorafenib could also effectively antagonize the survival of cisplatin-resistant bladder cancer and elucidate the underlying mechanism. Two types of cisplatin-resistant bladder cancer cells, T24R1 and T24R2, were isolated from T24 cisplatin-sensitive bladder cancer cells. These cells were characterized, and T24R1- and T24R2-xenografted tumor mice were created to examine the therapeutic efficacy of regorafenib. T24R1 and T24R2 cells exhibited higher expression levels of epithelial-mesenchymal transition (EMT) and stemness markers compared to the T24 cells, and regorafenib could simultaneously inhibit the viability and the expression of EMT/stemness markers of both T24R1 and T24R2 cells. Moreover, regorafenib could efficiently arrest the cell cycle, promote apoptosis, and block the transmigration/migration capabilities of both types of cells. Finally, regorafenib could significantly antagonize the growth of T24R1- and T24R2-xenografted tumors in mice. These results demonstrated the therapeutic efficacy of regorafenib in cisplatin-resistant bladder cancers. This study, thus, provides more insights into the mechanism of action of regorafenib and demonstrates its great potential in the future treatment of cisplatin-resistant advanced bladder cancer patients.

Background: Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered., Methods: We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes., Results: Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1-positive and TIL-positive PD-L1-negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1-positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1-positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1-negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs., Conclusions: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Two new pregnane glycosides ( 1 and 2 ), together with four known ones ( 3 - 6 ), were isolated from the roots of Cynanchum auriculatum Royle ex Wight (Asclepiadaceae). On the basis of detailed spectroscopic analysis and chemical method, the structures of new compounds were characterized to be metaplexigenin 3- O - β -D-cymaropyranosyl- (1→4)- α -L-diginopyranosyl-(1→4)- β -D-cymaropyranoside ( 1 ), metaplexigenin 3- O - α -L-diginopyranosyl-(1→4)- β -D-cymaropyranoside ( 2 ). All the isolated compounds ( 1 - 6 ) were tested for their in vitro inhibitory activity against the growth of human colon cancer cell lines HCT-116. Compounds 5 and 6 showed significant cytoxicities with IC 50 values of 43.58 µM and 52.21 µM.

Competing Interests: Debbie Gipson received research funding through the University of Michigan from Reata, Travere, Novartis, Boehringer Ingelheim, and Goldfinch Bio and past consulting through the University of Michigan from Novartis, Vertex, and Genentech/Roche. Chia-shi Wang, Eloise Salmon, Rasheed Gbadegesin, Abhijit Naik, and Simone Sanna-Cherchi have no disclosures. Alessia Fornoni is one of the inventors on pending (PCT/US2019/032215; US 17/057,247; PCT/US2019/041730; PCT/US2013/036484; US 17/259,883; US17/259,883; JP501309/2021 and EU19834217.2; CN-201980060078.3; CA2,930,119; CA3,012,773; and CA2,852,904) or issued patents (US10,183,038 and US10,052,345) aimed at preventing and treating renal disease. She stands to gain royalties from their future commercialization. AF is vice president of L&F Health LLC and is a consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc., has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney disease from L&F Research, which was partially funded by L&F Health LLC. She also holds equities in Renal 3 River Corporation. Matthias Kretzler has received research support on behalf of the University of Michigan from Boehringer Ingelheim, Novo Nordisk, Certa, Poxel, Astellas, and Janssen, has received research funding from NIH, JDRF, Chan Zuckerburg Initiative, amfAR, AstraZeneca, Boehringer Ingelheim, Elpidera, Gilead, Goldfinch Bio, Eli Lilly, Angion Biomedica, Certa, Novo Nordisk, Janssen, Chinook, RenalytixAI, Regeneron Pharmaceuticals, Travere Therapeutics, and Ionis Pharmaceuticals, is on the editorial boards for J Am Soc Nephrology, Kidney Int, and Kidney Dis, and is on an advisory board for NephCure Kidney International. Sandra Merscher is an inventor on pending and issued patents aimed to diagnose or treat proteinuric renal diseases. She stands to gain royalties from their future commercialization. She holds equity interest in L&F Research and is a shareholder of ZyVersa Pharmaceuticals, Inc., who has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney diseases from L&F Research. Paul Hoover, Kelley Kidwell, Moin Saleem, Leonard Riella, Lawrence Holzman, Annette Jackson, and Opeyemi Olabisi have no disclosures. Paolo Cravedi is a consultant for Chinook therapeutics, Repertoire Immune Medicines, and Calliditas Therapeutics. Benjamin Freedman is an inventor on a patent and patent applications related to human kidney organoid differentiation and modeling of FSGS in this system (e.g., “three-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human micro-physiology, toxicology, and morphogenesis” [Japan, USA, and Australia], licensed to STEMCELL Technologies). He has ownership interest in Plurexa LLC. Hailey Desmond received research funding through the University of Michigan from Boehringer Ingelheim, Travere, Roche, Novartis, and Reata. Howard Trachtman is a consultant to Travere Therapeutics Inc., Walden, Boehringer Ingelheim (pending), Natera, Otsuka, and Aclipse. He is the board of the Kidney Health Initiative and the editorial board of Pediatric Nephrology and Kidney360.