Population Pharmacokinetics of Sacituzumab Govitecan in Patients with Metastatic Triple-Negative Breast Cancer and Other Solid Tumors.

BACKGROUND AND OBJECTIVE: Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an antibody with affinity for Trop-2 coupled to SN-38 via hydrolyzable linker. SG is approved for patients with metastatic triple-negative breast cancer (mTNBC) who have received two or more prior chemotherapies (at least one in a metastatic setting) and for patients with pretreated hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. METHODS: In these analyses, the pharmacokinetics of SG, free SN-38, and total antibody (tAB) were characterized using data from 529 patients with mTNBC or other solid tumors across two large clinical trials (NCT01631552; ASCENT, NCT02574455). Three population pharmacokinetic models were constructed using non-linear mixed-effects modeling; clinically relevant covariates were evaluated to assess their impact on exposure. Models for SG and tAB were developed independently whereas free SN-38 was sequentially generated via a first-order release process from SG. RESULTS: Pharmacokinetics of the three analytes were each described by a two-compartment model with estimated body weight-based scaling exponents for clearance and volume. Typical parameter estimates for clearance and steady-state volume of distribution were 0.133 L/h and 3.68 L for SG and 0.0164 L/h and 4.26 L for tAB, respectively. Mild-to-moderate renal impairment, mild hepatic impairment, age, sex, baseline albumin level, tumor type, UGT1A1 genotype, or Trop-2 expression did not have a clinically relevant impact on exposure for any of the three analytes. CONCLUSIONS: These analyses support the approved SG dosing regimen of 10 mg/kg as intravenous infusion on days 1 and 8 of 21-day cycles and did not identify a need for dose adjustment based on evaluated covariates or disease characteristics.

Structural insights into ion selectivity and transport mechanisms of Oryza sativa HKT2;1 and HKT2;2/1 transporters.

Plant high-affinity K+ transporters (HKTs) play a pivotal role in maintaining the balance of Na+ and K+ ions in plants, thereby influencing plant growth under K+-depleted conditions and enhancing tolerance to salinity stress. Here we report the cryo-electron microscopy structures of Oryza sativa HKT2;1 and HKT2;2/1 at overall resolutions of 2.5 Å and 2.3 Å, respectively. Both transporters adopt a dimeric assembly, with each protomer enclosing an ion permeation pathway. Comparison between the selectivity filters of the two transporters reveals the critical roles of Ser88/Gly88 and Val243/Gly243 in determining ion selectivity. A constriction site along the ion permeation pathway is identified, consisting of Glu114, Asn273, Pro392, Pro393, Arg525, Lys517 and the carboxy-terminal Trp530 from the neighbouring protomer. The linker between domains II and III adopts a stable loop structure oriented towards the constriction site, potentially participating in the gating process. Electrophysiological recordings, yeast complementation assays and molecular dynamics simulations corroborate the functional importance of these structural features. Our findings provide crucial insights into the ion selectivity and transport mechanisms of plant HKTs, offering valuable structural templates for developing new salinity-tolerant cultivars and strategies to increase crop yields.

In Situ Photogenerated Radicals of Hydroxyl Substituted Pyrene-Based Triphenylamines with Enhanced Transport and Free Doping/Post-Oxidation for Efficient Perovskite Solar Cells.

The high-performance hole transporting material (HTM) is one of the most important components for the perovskite solar cells (PSCs) in promoting power conversion efficiency (PCE). However, the low conductivity of HTMs and their additional requirements for doping and post-oxidation greatly limits the device performance. In this work, three novel pyrene-based derivatives containing methoxy-substituted triphenylamines units (PyTPA, PyTPA-OH and PyTPA-2OH) are designed and synthesized, where different numbers of hydroxyl groups are connected at the 2- or 2,7-positions of the pyrene core. These hydroxyl groups at the 2- or 2,7-positions of pyrene play a significantly role to enhance the intermolecular interactions that are able to generate in situ radicals with the assistance of visible light irradiation, resulting in enhanced hole transferring ability, as well as an enhanced conductivity and suppressed recombination. These pyrene-core based HTMs exhibit excellent performance in PSCs, which possess a higher PCE than those control devices using the traditional spiro-OMeTAD as the HTM. The best performance can be found in the devices with PyTPA-2OH. It has an average PCE of 23.44% (PCEmax = 23.50%), which is the highest PCE among the reported PSCs with the pyrene-core based HTMs up to date. This research offers a novel avenue to design a dopant-free HTM by the combination of the pyrene core, methoxy triphenylamines, and hydroxy groups.

Patient and public involvement (PPI) in systematic reviews: frequency, determinants, stages, barriers, and dissemination.

OBJECTIVE: To investigate the frequency, determinants, stages, and barriers of patient and public involvement (PPI) in systematic reviews, and to explore its association with the dissemination of reviews. STUDY DESIGN AND SETTING: We examined systematic reviews that required the inclusion of a PPI declaration, published in The BMJ between January 1, 2015, and December 31, 2022. Multivariable analysis was used to assess the association between PPI and key variables. We investigated the association between PPI and the dissemination of reviews using Altmetric scores, citations, and full-text views. RESULTS: A total of 217 systematic reviews were included, of which 56 (25.8%, 95% CI 20.0% to 31.6%) included PPI, with a steady increase from 5.9% (1/17) in 2015 to 44.4% (4/35) in 2022. Of the 217 systematic reviews, 160 (73.7%) involved methodologists as co-authors. Factors significantly associated with a higher proportion of PPI included the publication year after 2019 (adjusted odds ratio [aOR] 2.46, 95% confidence interval [CI] 1.26 to 4.83), the involvement of methodologists (aOR 3.08; 95% CI 1.27 to 7.47), and being led by researchers from high-income countries (aOR 5.47; 95% CI 1.23 to 24.30). Reviews that included PPI had higher Altmetric scores per month (6.6 vs. 3.4, P=0.002) and more monthly full-text (1048.6 vs. 636.5, P<0.001) and PDF (217.7 vs. 129.0, P<0.001) views than reviews without PPI. However, there was no difference in the monthly citations (2.2 vs. 2.0, P=0.365) between reviews with and without PPI. CONCLUSION: The proportion of systematic reviews reporting PPI in The BMJ has increased over time, possibly due to journal policies, but it still remains at a low level. Reviews led by researchers from high-income countries or involving methodologists are associated with a higher frequency of PPI within The BMJ. Furthermore, reviews incorporating PPI within The BMJ have a higher potential for broad dissemination.

LncRNA EBLN3P Accelerates Cell Proliferation and Invasion of Colon Cancer through Modulating the miR-519d-3p/ZFP91 Axis.

Purpose: The study aims to explore the roles and underlying mechanisms of long noncoding RNAs endogenous bornavirus-like nucleoprotein (lncRNA EBLN3P) in colon cancer, emphasizing the potential impact of these insights on advancing colon cancer treatment strategies. By shedding light on lncRNA EBLN3P's involvement, this research could contribute to the development of novel therapeutic approaches, enhancing the efficacy of interventions for colon cancer patients. Methods: We employed quantitative reverse transcription polymerase chain reaction to assess the levels of lncRNA EBLN3P, zinc finger protein (ZFP91), and miR-519d-3p, alongside CCK-8 and EdU assays for cell proliferation, flow cytometry for apoptosis, and Transwell and wound healing assays for migration and invasion. The in vivo function of lncRNA EBLN3P was investigated through a xenograft model, and protein levels were evaluated via Western blot analysis. Results: LncRNA EBLN3P was found to be upregulated in colon cancer tissues and cells, promoting cell proliferation and metastasis while inhibiting apoptosis. Downregulation of lncRNA EBLN3P reduced tumor size, volume, and weight in a mouse model. MiR-519d-3p, which negatively interacts with lncRNA EBLN3P, was found to be downregulated in colon cancer tissues and cell lines. Its upregulation hindered cancer cell proliferation and metastasis while enhancing apoptosis. ZFP91, a binding partner of miR-519d-3p, was upregulated in colon cancer and inversely related to miR-519d-3p levels. Rescue experiments indicated that the effects of lncRNA EBLN3P silencing could be reversed by miR-519d-3p suppression, but were mitigated by ZFP91 downregulation. Conclusion: LncRNA EBLN3P facilitates colon cancer progression via the miR-519d-3p/ZFP91 axis, presenting a novel understanding of lncRNA EBLN3P's role and offering potential therapeutic insights for colon cancer treatment. This study fills a critical gap by linking lncRNA EBLN3P with the miR-519d-3p/ZFP91 axis in the context of colon cancer, thereby broadening our understanding of the molecular mechanisms underlying colon cancer progression.

Comparative characteristics of early-onset vs. late-onset advanced colorectal cancer: a nationwide study in China.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC, diagnosed in patients under the age of 50 years) has been increasing around the world. Here, we aimed to systematically identify distinctive features of EOCRC. METHODS: From 2020 to 2021, we conducted a nationwide survey in 19 hospitals, collecting data on advanced CRC patients' demographics, clinical features, disease knowledge, medical experiences, expenditures, and health-related quality of life (HRQOL). We compared these features between EOCRC and late-onset colorectal cancer (LOCRC, ≥ 50 years old) groups and analyzed the association between EOCRC and HRQOL using multivariate linear regression. FINDINGS: In total, 991 patients with EOCRC and 3581 patients with LOCRC were included. Compared to the LOCRC group, the EOCRC group had higher levels of education, were more informed about the risk factors for CRC, were more likely to have widespread metastases throughout the body, were more inclined to undergo gene testing, and were more likely to opt for targeted therapy, radiotherapy, and chemotherapy. However, HRQOL in the EOCRC group was similar to that of the LOCRC group, and no significant association was observed between EOCRC and HRQOL (beta: -0.753, P value: 0.307). INTERPRETATION: In Chinese patients, EOCRC patients had more aggressive features. Despite undergoing more intensified treatments and gene testing, they had similar HRQOL compared with LOCRC. These findings advocate for a more tailored approach to treatment, especially for young CRC patients with advanced TNM stages and metastasis.

Arginine alleviates Clostridium perfringens α toxin-induced intestinal injury in vivo and in vitro via the SLC38A9/mTORC1 pathway.

Introduction: Clostridium perfringens α toxin is a main virulence factor responsible for gut damage in animals. Arginine is a functional amino acid exhibiting significant immunoregulatory activities. However, the effects and immunoregulatory mechanisms of arginine supplementation on α toxin-induced intestinal injury remain unclear. Methods: In vivo, 256 male Arbor Acres chickens were randomly assigned to a 2×2 factorial arrangement, involving diet treatments (with or without 0.3% arginine supplementation) and immunological stress (with or without α toxin challenge). In vitro, IEC-6 cells were treated with or without arginine in the presence or absence of α toxin. Moreover, IEC-6 cells were transfected with siRNA targeting mTOR and SLC38A9 to explore the underlying mechanisms. Results and discussion: The results showed that in vivo, arginine supplementation significantly alleviated the α toxin-induced growth performance impairment, decreases in serum immunoglobulin (Ig)A and IgG levels, and intestinal morphology damage. Arginine supplementation also significantly reduced the α toxin-induced increase in jejunal proinflammatory cytokines interleukin (IL)-1ß, IL-6 and IL-17 mRNA expression. Clostridium perfringens α toxin significantly decreased jejunal mechanistic target of rapamycin (mTOR) and solute carrier family 38 member 9 (SLC38A9) mRNA expression, while arginine supplementation significantly increased mTOR and SLC38A9 mRNA expression. In vitro, arginine pretreatment mitigated the α toxin-induced decrease in cell viability and the increase in cytotoxicity and apoptosis. Arginine pretreatment also alleviated the α toxin-induced upregulation of mRNA expression of inflammation-related cytokines IL-6, C-X-C motif chemokine ligand (CXCL)10, CXCL11 and transforming growth factor-ß (TGF-ß), as well as apoptosis-related genes B-cell lymphoma-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-extra large (Bcl-XL) and cysteinyl aspartate specific proteinase 3 (Caspase-3) and the ratio of Bax to Bcl-2. Arginine pretreatment significantly increased the α toxin-induced decrease in mTOR, SLC38A9, eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) and ribosomal protein S6 kinase (S6K) mRNA expression. Knockdown SLC38A9 and mTOR largely abrogated the positive effects of arginine pretreatment on α toxin-induced intracellular changes. Furthermore, SLC38A9 silencing abolished the increased mTOR mRNA expression caused by arginine pretreatment. In conclusion, arginine administration attenuated α toxin-induced intestinal injury in vivo and in vitro, which could be associated with the downregulation of inflammation via regulating SLC38A9/mTORC1 pathway.

POLE2 promotes osteosarcoma progression by enhancing the stability of CD44.

Osteosarcoma (OS) is the most prevalent primary malignancy of bone in children and adolescents. It is extremely urgent to develop a new therapy for OS. In this study, the GSE14359 chip from the GEO database was used to screen differentially expressed genes in OS. DNA polymerase epsilon 2 (POLE2) was confirmed to overexpress in OS tissues and cell lines by immunohistochemical staining, qPCR and Western blot. Knockdown of POLE2 inhibited the proliferation and migration of OS cells in vitro, as well as the growth of tumors in vivo, while the apoptosis rate was increased. Bioinformatics analysis revealed that CD44 and Rac signaling pathway were the downstream molecule and pathway of POLE2, which were inhibited by knockdown of POLE2. POLE2 reduced the ubiquitination degradation of CD44 by acting on MDM2. Moreover, knockdown of CD44 inhibited the tumor-promoting effects of POLE2 overexpression on OS cells. In conclusion, POLE2 augmented the expression of CD44 via inhibiting MDM2-mediated ubiquitination, and then activated Rac signaling pathway to influence the progression of OS, indicating that POLE2/CD44 might be potential targets for OS treatment.

Identification and characterization of a PL35 GAGs lyase with 4-O-sulfated N-acetylgalactosamine (A-type)-rich structures producing property.

Glycosaminoglycan (GAG) lyases are important tools for investigating the structure of GAGs and preparing low-molecular-weight GAGs. The PL35 family, a recently established polysaccharide lyase family, should be further investigated. In this study, we discovered a new GAG lyase, CHa1, which belongs to the PL35 family. When expressed heterologously in Escherichia coli (BL21), CHa1 exhibited high expression levels and solubility. The optimal activity was observed in Tris-HCl buffer (pH 7.0) or sodium phosphate buffer (pH 8.0) at 30 °C. The specific activities towards HA, CSA, CSC, CSD, CSE, and HS were 3.81, 13.03, 36.47, 18.46, 6.46, and 0.50 U/mg protein, respectively. CHa1 digests substrate chains randomly that acting as an endolytic lyase and shows a significant preference for GlcA-containing structures, prefers larger oligosaccharides (≥UDP8) and can generate a series of oligosaccharides composed mainly of the A unit when digesting CSA. These oligosaccharides include ΔC-A, ΔC-A-A, ΔC-A-A-A, ΔC-A-A-A-A, and ΔC-A-A-A-A-A. The residues Tyr257 and His421 play crucial roles in the catalytic process, and Ser211, Asn212, Asn213, Trp214, Gln216, Lys360, Arg460 and Gln462 may participate in the binding process of CHa1. This study on CHa1 contributes to our understanding of the PL35 family and provides valuable tools for investigating the structure of GAGs.

Research hotspots and trend of wrist arthroscopy: A bibliometrics analysis from 2013 to 2023.

BACKGROUND: Wrist arthroscopy technology is a surgical technology invented in recent years and widely used in clinical treatment of various wrist diseases. This study uses the methods of bibliometrics and visual analysis to understand the global research status, research hotspots, and future development trends of wrist arthroscopy. METHODS: The relevant literature of global publications on wrist arthroscopy from 2013 to 2023 was extracted from the Web of Science Core Collection database, and the annual output, cooperation, hot spots, research status, and development trend of this field were analyzed by using the bibliometric software (VOSviewers, CiteSpace, and the R package "Bibliometrix"). RESULTS: A total of 635 articles were included, from 2013 to 2023, the number of publications related to wrist arthroscopy showed an overall upward trend, the USA, France, and China are the top 3 countries in terms of the number of publications, whereas Mayo Clinic is the institution with the highest number of publications, Ho PC holds a core position in this field, keyword analysis indicates that the research hotspots are the applications of wrist arthroscopy in triangular fibrocartilage complex injuries, scaphoid nonunion, and avascular necrosis of the lunate. CONCLUSION SUBSECTIONS: Wrist arthroscopy has shown tremendous potential in treating various wrist diseases. However, there are still some challenges in its research domain. With continuous deep research, strengthened international collaboration, and ongoing technological advancements, wrist arthroscopy has the potential to become the standard treatment in hand surgery, offering more efficient and safer treatment options for patients worldwide.

Enhancing healthy aging with small molecules: A mitochondrial perspective.

The pursuit of enhanced health during aging has prompted the exploration of various strategies focused on reducing the decline associated with the aging process. A key area of this exploration is the management of mitochondrial dysfunction, a notable characteristic of aging. This review sheds light on the crucial role that small molecules play in augmenting healthy aging, particularly through influencing mitochondrial functions. Mitochondrial oxidative damage, a significant aspect of aging, can potentially be lessened through interventions such as coenzyme Q10, alpha-lipoic acid, and a variety of antioxidants. Additionally, this review discusses approaches for enhancing mitochondrial proteostasis, emphasizing the importance of mitochondrial unfolded protein response inducers like doxycycline, and agents that affect mitophagy, such as urolithin A, spermidine, trehalose, and taurine, which are vital for sustaining protein quality control. Of equal importance are methods for modulating mitochondrial energy production, which involve nicotinamide adenine dinucleotide boosters, adenosine 5'-monophosphate-activated protein kinase activators, and compounds like metformin and mitochondria-targeted tamoxifen that enhance metabolic function. Furthermore, the review delves into emerging strategies that encourage mitochondrial biogenesis. Together, these interventions present a promising avenue for addressing age-related mitochondrial degradation, thereby setting the stage for the development of innovative treatment approaches to meet this extensive challenge.

Risk factors for cognitive impairment in patients with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) patients have been found to be at risk of concurrent cognitive dysfunction in previous studies, which has now become an important public health issue of widespread concern. AIM: To investigate the risk factors for concurrent cognitive dysfunction in patients with CKD. METHODS: This is a prospective cohort study conducted among patients with CKD between October 2021 and March 2023. A questionnaire was formulated by literature review and expert consultation and included questions about age, sex, education level, per capita monthly household income, marital status, living condition, payment method, and hypertension. RESULTS: Logistic regression analysis showed that patients aged 60-79 years [odds ratio (OR) = 1.561, P = 0.015] and ≥ 80 years (OR = 1.760, P = 0.013), participants with middle to high school education (OR = 0.820, P = 0.027), divorced or widowed individuals (OR = 1.37, P = 0.032), self-funded patients (OR = 2.368, P = 0.008), and patients with hypertension (OR = 2.011, P = 0.041) had a higher risk of cognitive impairment. The risk of cognitive impairment was lower for those with a college degree (OR = 0.435, P = 0.034) and married individuals. CONCLUSION: The risk factors affecting cognitive dysfunction are age, 60-79 years and ≥ 80 years; education, primary school education or less; marital status, divorced or widowed; payment method, self-funded; hypertension; and CKD.

Rational Design of an In-Situ Polymer-Inorganic Hybrid Solid Electrolyte Interphase for Realising Stable Zn Metal Anode under Harsh Conditions.

The in-depth understanding of the composition-property-performance relationship of solid electrolyte interphase (SEI) is the basis of developing a reliable SEI to stablize the Zn anode-electrolyte interface, but it remains unclear in rechargeable aqueous zinc ion batteries. Herein, a well-designed electrolyte based on 2 M Zn(CF3SO3)2-0.2 M acrylamide-0.2 M ZnSO4 is proposed. A robust polymer (polyacrylamide)-inorganic (Zn4SO4(OH)6.xH2O) hybrid SEI is in situ constructed on Zn anodes through controllable polymerization of acrylamide and coprecipitation of SO4 2- with Zn2+ and OH-. For the first time, the underlying SEI composition-property-performance relationship is systematically investigated and correlated. The results showed that the polymer-inorganic hybrid SEI, which integrates the high modulus of the inorganic component with the high toughness of the polymer ingredient, can realize high reversibility and long-term interfacial stability, even under ultrahigh areal current density and capacity (30 mA cm-2~30 mAh cm-2). The resultant Zn||NH4V4O10 cell also exhibits excellent cycling stability. This work will provide a guidance for the rational design of SEI layers in rechargeable aqueous zinc ion batteries.

The Role and Mechanism of Nicotinamide Riboside in Oxidative Damage and a Fibrosis Model of Trabecular Meshwork Cells.

Purpose: To investigate the potential effects and mechanism of nicotinamide riboside (NR) on the oxidative stress and fibrosis model of human trabecular meshwork (HTM) cell line cells. Methods: HTM cells were pretreated with NR, followed by the induction of oxidative injury and fibrosis by hydrogen peroxide (H2O2) and TGF-ß2, respectively. Cell viability was tested using Hoechst staining and MTT assays, cell proliferation was assessed by EdU assay, and cell apoptosis was detected by flow cytometry and western blotting. DCFH-DA and DHE probes were used to measure the level of reactive oxygen species (ROS), and MitoTracker staining was used to measure the mitochondrial membrane potential (MMP). Fibrotic responses, including cell migration and deposition of extracellular matrix (ECM) proteins, were detected via Transwell assays, qRT-PCR, and immunoblotting. Results: NR pretreatment improved the viability, proliferation, and MMP of H2O2-treated HTM cells. Compared to cells treated solely with H2O2, HTM cells treated with both NR and H2O2, exhibited a reduced rate of apoptosis and generation of ROS. Compared with H2O2 pretreatment, NR pretreatment upregulated expression of the JAK2/Stat3 pathway but inhibited mitogen-activated protein kinase (MAPK) pathway expression. Moreover, 10-ng/mL TGF-ß2 promoted cell proliferation and migration, which were inhibited by NR pretreatment. Both qRT-PCR and immunoblotting showed that NR inhibited the expression of fibronectin in a TGF-ß2-induced fibrosis model. Conclusions: NR has a protective effect on oxidative stress and fibrosis in HTM cells, which may be related to the JAK2/Stat3 pathway and MAPK pathway. Translational Relevance: Our research provides the ongoing data for potential therapy of NAD+ precursors in glaucoma.

Association of depressive symptoms with risk of incidence low back pain in middle-aged and older Chinese adults.

BACKGROUND: Elevated Depressive symptoms (DS) and low back pain (LBP) pose significant and growing public health challenges, and China is no exception. This study innovatively examined the relationship between specific DS and distinct patterns of DS and incident LBP. METHODS: This study extracted data from 4713 participants aged 45+ years from the China and Health Retirement Longitudinal Study (CHARLS), followed-up for incidence LBP (June 2011-September 2020). DS was assessed by the 10-item Center for Epidemiological Studies Depression Scale (CESD-10). The incident LBP was determined by self-reported. Latent class analysis (LCA) was employed to categorize patterns of DS. Cox proportional hazards regression models were used to examine the association between DS and incident LBP. RESULTS: Over the 9.25-year follow-up period, 2234 incident LBP cases were identified. There was a significant independent association between positive DS and incident LBP with an HR of 1.73 (95 % CI = 1.55-1.94). Of the 10-item DS, difficulty concentrating (adjusted HR = 1.16, 95 % CI = 1.03-1.31), effortfulness (adjusted HR = 1.32, 95 % CI = 1.18-1.49), hopelessness (adjusted HR = 1.13, 95 % CI = 1.02-1.25), restless sleep (adjusted HR = 1.17, 95 % CI = 1.06-1.30), and loneliness (adjusted HR = 1.18, 95 % CI = 1.02-1.36), each independently associated with incident LBP. Regarding patterns of DS, compared to the "healthy" pattern of DS, four patterns showed significant association with incident LBP, especially the cumulative pattern of DS. LIMITATIONS: DS and LBP were assessed based on self-reported. CONCLUSIONS: In middle-aged and older Chinese adults, 5 specific DS (difficulty concentrating, effortfulness, hopelessness, restless sleep, and loneliness) and distinct patterns of DS indicate varied risks of developing LBP.

A comprehensive multi-omics analysis identifies a robust scoring system for cancer-associated fibroblasts and intervention targets in colorectal cancer.

BACKGROUND: Cancer-associated fibroblasts (CAF) play a critical role in promoting tumor growth, metastasis, and immune evasion. While numerous studies have investigated CAF, there remains a paucity of research on their clinical application in colorectal cancer (CRC). METHODS: In this study, we collected differentially expressed genes between CAF and normal fibroblasts (NF) from previous CRC studies, and utilized machine learning analysis to differentiate two distinct subtypes of CAF in CRC. To enable practical application, a CAF-related genes (CAFGs) scoring system was developed based on multivariate Cox regression. We then conducted functional enrichment analysis, Kaplan-Meier plot, consensus molecular subtypes (CMS) classification, and Tumor Immune Dysfunction and Exclusion (TIDE) algorithm to investigate the relationship between the CAFGs scoring system and various biological mechanisms, prognostic value, tumor microenvironment, and response to immune checkpoint blockade (ICB) therapy. Moreover, single-cell transcriptomics and proteomics analyses have been employed to validate the significance of scoring system-related molecules in the identity and function of CAF. RESULTS: We unveiled significant distinctions in tumor immune status and prognosis not only between the CAF clusters, but also across high and low CAFGs groups. Specifically, patients in CAF cluster 2 or with high CAFGs scores exhibited higher CAF markers and were enriched for CAF-related biological pathways such as epithelial-mesenchymal transition (EMT) and angiogenesis. In addition, CAFGs score was identified as a risk index and correlated with poor overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and recurrence-free survival (RFS). High CAFGs scores were observed in patients with advanced stages, CMS4, as well as lymphatic invasion. Furthermore, elevated CAFG scores in patients signified a suppressive tumor microenvironment characterized by the upregulation of programmed death-ligand 1 (PD-L1), T-cell dysfunction, exclusion, and TIDE score. And high CAFGs scores can differentiate patients with lower response rates and poor prognosis under ICB therapy. Notably, single-cell transcriptomics and proteomics analyses identified several molecules related to CAF identity and function, such as FSTL1, IGFBP7, and FBN1. CONCLUSION: We constructed a robust CAFGs score system with clinical significance using multiple CRC cohorts. In addition, we identified several molecules related to CAF identity and function that could be potential intervention targets for CRC patients.

Berberine alleviates concanavalin A-induced autoimmune hepatitis in mice by modulating the gut microbiota.

BACKGROUND: Autoimmune hepatitis (AIH) is an immune-mediated liver disease of unknown etiology accompanied by intestinal dysbiosis and a damaged intestinal barrier. Berberine (BBR) is a traditional antibacterial medicine that has a variety of pharmacological properties. It has been reported that BBR alleviates AIH, but relevant mechanisms remain to be fully explored. METHODS: BBR was orally administered at doses of 100 mg⋅kg-1⋅d-1 for 7 days to mice before concanavalin A-induced AIH model establishment. Histopathological, immunohistochemical, immunofluorescence, western blotting, ELISA, 16S rRNA analysis, flow cytometry, real-time quantitative PCR, and fecal microbiota transplantation studies were performed to ascertain BBR effects and mechanisms in AIH mice. RESULTS: We found that liver necrosis and apoptosis were decreased upon BBR administration; the levels of serum transaminase, serum lipopolysaccharide, liver proinflammatory factors TNF-α, interferon-γ, IL-1ß, and IL-17A, and the proportion of Th17 cells in spleen cells were all reduced, while the anti-inflammatory factor IL-10 and regulatory T cell proportions were increased. Moreover, BBR treatment increased beneficial and reduced harmful bacteria in the gut. BBR also strengthened ileal barrier function by increasing the expression of the tight junction proteins zonula occludens-1 and occludin, thereby blocking lipopolysaccharide translocation, preventing lipopolysaccharide/toll-like receptor 4 (TLR4)/ NF-κB pathway activation, and inhibiting inflammatory factor production in the liver. Fecal microbiota transplantation from BBR to model mice also showed that BBR potentially alleviated AIH by altering the gut microbiota. CONCLUSIONS: BBR alleviated concanavalin A-induced AIH by modulating the gut microbiota and related immune regulation. These results shed more light on potential BBR therapeutic strategies for AIH.

Effective health management strategies for patients undergoing valve replacement: a bibliometric analysis of the current research status and future directions.

Background: Valvular heart disease is a major health concern worldwide. The effective management of patients undergoing valve replacement determines their prognosis. Bibliometric analysis of studies on managing patients with artificial heart valves has not been previously performed. Methods: This study analyzed 2,771 publications related to patient management after valve replacement published in the Web of Science Core Collection database between January 1, 2013, and December 31, 2022. Bibliometric analysis was performed using CiteSpace and VOSviewer considering countries, institutions, authors, journals, references, and keywords. Results: The countries with the most significant contributions in this field were the United States of America (USA), Germany, and Italy. Leon MB from Columbia University, USA was the most influential author. Transcatheter aortic valve replacement was a current research hotspot, while anticoagulation management was a key area of interest. Combining anticoagulation therapy with internet-linked tools and portable health devices may offer new research avenues. Frailty assessment and intervention were potential future research areas. Conclusions: This bibliometric analysis provides clinicians and researchers with useful insights for developing novel ideas and directions to manage the health of patients undergoing valve replacement.