Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy.

BACKGROUND: The E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways in various cancers, including prostate cancer. This need is particularly significant in prostate cancer. While androgen deprivation therapy (ADT) has demonstrated promising efficacy in prostate cancer, its long-term use can eventually lead to the development of castration-resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC). Notably, p300 has been identified as an important co-activator of the androgen receptor (AR), highlighting its significance in prostate cancer progression. Moreover, recent studies have revealed the involvement of p300 in AR-independent oncogenes associated with NEPC. Therefore, the blockade of p300 may emerge as an effective therapeutic strategy to address the challenges posed by both CRPC and NEPC. METHODS: We employed AI-assisted design to develop a peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading p300 in vitro and in vivo utilizing nano-selenium as a peptide drug delivery system. FINDINGS: Our p300-targeting peptide PROTAC drug demonstrated effective p300 degradation and cancer cell-killing capabilities in both CRPC, AR-negative, and NEPC cells. This study demonstrated the efficacy of a p300-targeting drug in NEPC cells. In both AR-positive and AR-negative mouse models, the p300 PROTAC drug showed potent p300 degradation and tumor suppression. INTERPRETATION: The design of peptide PROTAC drug targeting p300 is feasible and represents an efficient therapeutic strategy for CRPC, AR-negative prostate cancer, and NEPC. FUNDING: The funding details can be found in the Acknowledgements section.

Dietary effects of vitamin C on antioxidant capacity, intestinal microbiota and the resistance of pathogenic bacteria in cultured Silver pomfret (Pampus argenteus).

As most teleosts are unable to synthesize vitamin C, supplemental diets containing vitamin C diets play a crucial role in fish health. The aim of this study was to investigate the effect of dietary vitamin C on the intestinal enzyme activity and intestinal microbiota of silver pomfre (Pampus argenteus). Four experimental diets were supplemented with basic diets containing 300 mg of vitamin C/kg (group tjl3), 600 mg of vitamin C/kg (group tjl6), and 1200 mg of vitamin C/kg (group tjl12), as well as vitamin C-free supplemental basic diet (group tjl0), respectively. The four diets were fed to juvenile P. argenteus (average initial weight: 4.68 ± 0.93 g) for 6 weeks. The results showed that the activity of SOD (superoxide dismutase) and CAT (catalase) increased significantly while that of MDA (malondialdehyde) decreased significantly in group tjl3 compared to vitamin group tjl0. At the genus level, groups tjl0, tjl6, and tjl12 contained the same dominant microbial community, Stenotrophomonas, Photobacterium, and Vibrio, whereas group tjl3 was dominated by Stenotrophomonas, Delftia, and Bacteroides. Among the fish fed with a basic diet containing 300 mg of vitamin C/kg, the intestines exhibited a notable abundance of probiotic bacteria, including lactic acid bacteria (Lactobacillus) and Bacillus. The abundance of Aeromonas in groups tjl3 and tjl6 was lower than that of the vitamin C-free supplemental basic diet group, whereas Aeromonas was not detected in group tjl12. In addition, a causative agent of the disease outbreak in cultured P. argenteus, Photobacterium damselae subsp. Damselae (PDD) was the dominant microbiota community in groups tjl0, tjl6 and tjl12, whereas the abundance of PDD in group tjl3 was the lowest among the diets. Taken together, the diets supplied with vitamin C could influence the composition microbial community of P. argenteus. The low level of vitamin C (300 mg of vitamin C/kg per basic diet) supplementation could not only improve the antioxidant capacity but also resist the invasion of pathogenic bacteria.

Deciphering the mechanism of cimifugin in mitigating LPS-induced neuroinflammation in BV-2 cells.

PURPOSE: Sepsis often triggers a systemic inflammatory response leading to multi-organ dysfunction, with complex and not fully understood pathogenesis. This study investigates the therapeutic effects of cimifugin on BV-2 cells under sepsis-induced stress conditions. METHODS: We utilized a BV-2 microglial cell model treated with lipopolysaccharide (LPS) to mimic sepsis. Assessments included cellular vitality, inflammatory cytokine quantification (6 interleukin [6IL]-1ß, interleukin 6 [IL-6], and tumor necrosis factor-α [TNF-α]) via enzyme-linked-immunosorbent serologic assay, and analysis of mRNA expression using real-time polymerase chain reaction. Oxidative stress and mitochondrial function were also evaluated to understand the cellular effects of cimifugin. RESULTS: Cimifugin significantly attenuated LPS-induced inflammatory responses, oxidative stress, and mitochondrial dysfunction. It enhanced cell viability and modulated the secretion and gene expression of inflammatory cytokines IL-1ß, IL-6, and TNF-α. Notably, cimifugin activated the deacetylase sirtuin 1-nuclear factor erythroid 2-related factor 2 pathway, contributing to its protective effects against mitochondrial damage. CONCLUSION: Cimifugin demonstrates the potential of being an effective treatment for sepsis--induced neuroinflammation, warranting further investigation.

Compared with other methods, cyanoacrylate and lauromacrogol in treating esophagogastric varices did not increase the risk of postoperative infection.

BACKGROUND: Patients with cirrhosis commonly undergo endoscopic cyanoacrylate injection for gastric and esophageal variceal bleeding. However, postoperative infections can increase the risk of rebleeding and mortality. AIM: This study aimed to determine the risk of postoperative infections and its associated factors following cyanoacrylate injection treatment in these patients. METHODS: A retrospective analysis was conducted on 57 patients treated with ligation (ligation group), 66 patients treated with cyanoacrylate injection (injection group), and 91 patients treated with conservative treatment (control group) at the Nanchong Central Hospital. RESULTS: The rate of postoperative infection was similar among the cyanoacrylate, ligation, and conservative treatment groups, with no significant statistical difference observed (P = 0.97). Multivariate analysis identified postoperative Child-Pugh score and renal insufficiency as two independent risk factors for postoperative infection. The rebleeding rate in the injection group was significantly lower than in the other groups (P = 0.01). Mortality was significantly higher in the control group compared with the ligation and injection groups (P = 0.01). CONCLUSION: Cyanoacrylate combined with lauromacrogol injection did not significantly increase the risk of infection compared with ligation and conservative treatments, and it was more effective in reducing the risk of rebleeding. This method is safe, effective, and holds clinical value for broader application.

Metagenomic Next-Generation Sequencing based Fine Needle Aspiration in Patients with Suspected Infected Pancreatic Necrosis.

INTRODUCTION: Fine needle aspiration (FNA) is no longer recommended for diagnosing infected pancreatic necrosis (IPN) due to high false negative rate. Metagenome next-generation sequencing (mNGS) is a valuable tool for identifying potential pathogens. We hypothesized that adding mNGS to the standard FNA procedure may increase diagnostic accuracy. METHODS: This is a prospective, single-arm feasibility study enrolling acute necrotizing pancreatitis patients complicated by suspected IPN. CT-guided FNA was performed immediately after enrollment, and the drainages were subjected to culture and mNGS assays simultaneously. Confirmatory IPN within the following week of the index FNA procedure was the reference standard. The diagnostic performance of FNA-mNGS and the impact of mNGS results on treatment were evaluated. Historical controls were used for comparison of clinical outcomes. RESULTS: There was no significant difference between mNGS and culture in positive rate (75% vs. 70%, P = 0.723). The accuracy of FNA-mNGS was 80.0%, with a sensitivity of 82.35%, specificity of 66.67%, positive predictive value of 93.3%, and negative predictive value of 40.0%. The results of the mNGS led to treatment change in 16/20 patients (80%), including implementing PCD (n = 7), expanding antibiotic coverage (n = 2), PCD and expanding coverage (n = 4), narrowing antibiotic coverage (n = 1), and discontinuation of antibiotics (n = 2). The FNA-mNGS approach was not associated with improved clinical outcomes compared with the historical control group. CONCLUSIONS: The addition of mNGS to standard FNA has comparable diagnostic accuracy with culture-based FNA and may not be associated with improved clinical outcomes.

Correlation Analysis of Estrogen Levels and Psychological Status Among Patients with Uterine Fibroids.

Objective: This study aims to investigate the correlation between estrogen levels and psychological distress, focusing on depression and anxiety symptoms among patients diagnosed with uterine fibroids. Methods: The study employed a retrospective design and enrolled a cohort comprising 50 patients diagnosed with uterine fibroids and 50 healthy individuals as controls. Serum estradiol levels were quantified using a chemiluminescent immunoassay technique one month before surgery in the patient group. Depression and anxiety levels were evaluated using the Self-Rating Depression Scale (SDS) and the Self-Rating Anxiety Scale (SAS), respectively. Results: Significant differences in SDS scores, SAS scores, and serum estradiol levels emerged between the patient and control groups (P < .05). Patients exhibited higher SDS and SAS scores alongside elevated serum estradiol levels. Correlation analysis unveiled a negative association between SAS scores and estrogen levels among patients (r = -0.724, P = .013), suggesting a rise in anxiety levels with declining estrogen levels. Similarly, a negative correlation surfaced between SDS scores and estrogen levels among patients (r = -0.624, P = .016), indicating increased depressive symptoms as estrogen levels decrease. Conversely, no noteworthy correlations were demonstrated between anxiety or depressive symptoms and estrogen levels in the control group. Conclusion: Reduced estrogen levels were linked to heightened anxiety and depressive symptoms in patients with uterine fibroids. These findings suggest a plausible connection between estrogen hormone levels and psychological well-being, particularly concerning anxiety and depression. Further exploration of this association is warranted to shed light on potential therapeutic interventions targeting hormonal regulation to improve psychological distress in affected individuals.

Aridity affects soil organic carbon concentration and chemical stability by different forest types and soil processes across Chinese natural forests.

Forest soils play a critical role in carbon (C) reservoirs and climate change mitigation globally. Exploring the driving factors of soil organic carbon (SOC) concentration and stability in forests on a large spatial scale can help us evaluate the role of forest soils in regulating C sequestration. Based on SOC quantification and solid-state 13C nuclear magnetic resonance spectroscopy, we investigated the SOC concentration and SOC chemical stability (indicated by alkyl-to-O-alkyl ratio and hydrophobic-to-hydrophilic ratio) in top 0-5 and 5-10 cm soils from 65 Chinese natural forest sites and explored their driving factors. Results showed that SOC concentration in 0-5 cm soils were highest in mixed forests but SOC chemical stability in 0-5 cm soils were highest in coniferous forests, while SOC concentration and chemical stability in 5-10 cm soil layers did not differ across forest types. SOC concentration in 0-5 cm was directly related to soil pH and soil bacterial diversity. Structural equation models showed that aridity indirectly affected SOC concentration in 0-5 cm by directly affecting soil pH. While SOC chemical stability in 0-5 cm soils was higher with increased aridity. According to the correlations, the potential mechanisms could be attributed to higher proportion of coniferous forests in more arid forest sites, lower relative abundance of O-alkyl C, higher MgO and CaO contents, and higher bacterial diversity in soils from more arid forest sites. Our study reveals the important role of aridity in mediating SOC concentration and chemical stability in top 0-5 cm soils in Chinese natural forests on a large-scale field investigation. These results will help us better understand the different mechanisms underlying SOC concentration and stability in forests and assess the feedback of forest SOC to future climate change.

Structural characterization of Aspalatus linearis polysaccharide and its improving effect on acute alcoholic liver injury.

Polysaccharides from natural sources can regulate the composition of intestinal flora through the "gut-liver axis" pathway, potentially ameliorating alcoholic liver injury. Aspalathus linearis, also known as rooibos, is one such natural product that has shown promise in this regard. This study looked at the structural properties of A. linearis polysaccharide (ALP) and how well it would work to treat acute alcoholic liver impairment. This study looks at the composition of monosaccharides, functional groups, and molecular weight (Mw) of a newly discovered water-soluble polysaccharide, named ALP. The polysaccharide is composed of pyranose rings, amide groups, and sulfate groups linked by ß-glycosidic linkage. It has a relative Mw of 4.30 × 103 kDa and is composed of glucose, rhamnose, and some other monosaccharides. The study found that treating mice with the model of acute alcoholic liver disease with ALP could alleviate pathological symptoms, inhibit the release of inflammatory cytokines, and suppress indicators of oxidative stress. Experiments have shown that different doses of ALP can activate the P4502E1/Keap1-Nrf2-HO-1 signaling pathway. The regulation of inflammatory factors and downstream antioxidant enzymes occurs as a result. Based on these data, it is likely that ALP protects the liver via the "gut-liver axis" pathway by reducing oxidative stress-related damage, inflammation, and alcohol-related alterations to the gut microbiome. The results indicate that ALP mitigates injury caused by oxidative stress, inflammatory responses, and changes in the gut microbiota induced by alcohol through the "gut-liver axis" pathway, which provides protection to the liver. This provides preliminary evidence for the development of related drugs. PRACTICAL APPLICATION: Researchers extracted a polysaccharide from fresh leaves of Auricularia auricula. The polysaccharide was purified and determined to have a predominantly homogeneous molecular weight. An acute alcoholic liver damage mouse model was established, and it was concluded that the polysaccharide could ameliorate liver injury in mice through the "gut-liver axis" pathway. This novel polysaccharide can be used as an additive to develop functional foods with beneficial effects, which can positively impact the daily maintenance of consumers.

Pyrrole-containing hybrids as potential anticancer agents: An insight into current developments and structure-activity relationships.

Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side effects. Pyrrole and its derivatives are privileged heterocyclic compounds with significant diverse pharmacological effects. These compounds can target various aspects of cancer cells and have been applied in clinical settings or are undergoing clinical trials. As a result, pyrrole has emerged as a promising drug scaffold and has been further probed to get novel entities for the treatment of cancer. This article reviews recent research progress on anti-cancer drugs containing pyrrole. It focuses on the mechanism of action, biological activity, and structure-activity relationships of pyrrole derivatives, aiming to assist in designing and synthesizing innovative pyrrole-based anti-cancer compounds.

Synergistic modulation of the d-band center in Ni3S2 by selenium and iron for enhanced oxygen evolution reaction (OER) and urea oxidation reaction (UOR).

Efficient production of green hydrogen energy is crucial in addressing the energy crisis and environmental concerns. The oxygen evolution reaction (OER) poses a challenge in conventional overall water electrolysis due to its slow thermodynamically process. Urea oxidation reaction (UOR) offers an alternative anodic oxidation method that is highly efficient and cost-effective, with favorable thermodynamics and sustainability. Recently, there has been limited research on bifunctional catalysts that exhibit excellent activity for both OER and UOR reactions. In this study, we developed a selenium and iron co-doped nickel sulfide (SeFe-Ni3S2) catalyst that demonstrated excellent Tafel slopes of 53.9 mV dec-1 and 16.4 mV dec-1 for OER and UOR, respectively. Density Functional Theory (DFT) calculations revealed that the introduction of metal (iron) and nonmetallic elements (selenium) was found to coordinate the d-band center, resulting in improved adsorption/desorption energies of the catalysts and reduced the overpotentials and limiting potentials for OER and UOR, respectively. This activity enhancement can be attributed to the altered electronic coordination structure after the introduction of selenium (Se) and iron (Fe), leading to an increase in the intrinsic activity of the catalyst. This work offers a new strategy for bifunctional catalysts for OER and UOR, presenting new possibilities for the future development of hydrogen production and novel energy conversion technologies. It contributes towards the urgent search for technologies that efficiently produce green hydrogen energy, providing potential solutions to mitigate the energy crisis and protect the environment.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response.

BACKGROUND: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. METHODS: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). FINDINGS: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. INTERPRETATION: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. FUNDING: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Coordination-Driven Self-Assembly of Metal Ion-Antisense Oligonucleotide Nanohybrids for Chronic Bacterial Infection Therapy.

Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it is crucial to promptly explore and develop effective methodologies for bacterial infections. Herein, we propose a novel approach for synthesizing nanostructures based on antisense oligonucleotides (ASOs) through the coordination-driven self-assembly of Zn2+ with ASO molecules. This approach aims to provide effective synergistic therapy for chronic wound infections caused by Staphylococcus aureus (S. aureus). The resulting hybrid nanoparticles successfully preserve the structural integrity and biological functionalities of ASOs, demonstrating excellent ASO encapsulation efficiency and bioaccessibility. In vitro antibacterial experiments reveal that Zn-ASO NPs exhibit antimicrobial properties against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. This antibacterial ability is attributed to the high concentration of metal zinc ions and the generation of high levels of reactive oxygen species. Additionally, the ftsZ-ASO effectively inhibits the expression of the ftsZ gene, further enhancing the antimicrobial effect. In vivo antibacterial assays demonstrate that the Zn-ASO NPs promote optimal skin wound healing and exhibit favorable biocompatibility against S. aureus infections, resulting in a residual infected area of less than 8%. This combined antibacterial strategy, which integrates antisense gene therapy and metal-coordination-directed self-assembly, not only achieves synergistic and augmented antibacterial outcomes but also expands the horizons of ASO coordination chemistry. Moreover, it addresses the gap in the antimicrobial application of metal-coordination ASO self-assembly, thereby advancing the field of ASO-based therapeutic approaches.

Targeting starvation therapy for diabetic bacterial infections with endogenous enzyme-triggered hyaluronan-modified nanozymes in the infection microenvironment.

The high-glycemic microenvironment of diabetic wounds promotes bacterial proliferation, leading to persistent infections and delayed wound healing. This poses a significant threat to human health, necessitating the development of new nanodrug visualization platforms. In this study, we designed and synthesized cascade nano-systems modified with targeted peptide and hyaluronic acid for diabetic infection therapy. The nano-systems were able to target the site of infection using LL-37, and in the microenvironment of wound infection, the hyaluronic acid shell of the nano-systems was degraded by endogenous hyaluronidase. This precise degradation released a cascade of nano-enzymes on the surface of the bacteria, effectively destroying their cytoskeleton. Additionally, the metals in the nano-enzymes provided a photo-thermal effect, accelerating wound healing. The cascade nano-visualization platform demonstrated excellent bactericidal efficacy in both in vitro antimicrobial assays and in vivo diabetic infection models. In conclusion, this nano-system employs multiple approaches including targeting, enzyme-catalyzed therapy, photothermal therapy, and chemodynamic therapy to kill bacteria and promote healing. The Ag@Pt-Au-LYZ/HA-LL-37 formulation shows great potential for the treatment of diabetic wounds.

An observational study on the safety of teprotumumab based on FAERS database.

OBJECTIVE: Teprotumumab plays an important role in thyroid eye disease pathogenesis and progression. We intend to mine the adverse event (AE) signals from a relevant database, thereby contributing to the safe use of teprotumumab. METHODS: The data obtained from the ASCII data packages in the FAERS database from January 2020 to the second quarter of 2023 were imported into the SAS software (version 9.4) for data cleaning and analysis. Disproportionality analysis was performed using the reporting odds ratio (ROR) in conjunction with the United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) omnibus standard method to detect positive signals. PARTICIPANTS: This retrospective observational study relied on adverse drug reactions reported to the FDA through FAERS, which is a standard public system for spontaneous reporting. RESULTS: Collectively, 2171 AE reports for teprotumumab were collected, among which 108 significant signals were identified involving 17 system organ classes. The SOC of ear and labyrinth disorders included the most AE signals and reports. Muscle spasms, fatigue, headache, nausea, diarrhea, alopecia, blood glucose increased, hypoacusis, tinnitus, and diabetes mellitus were the top ten PTs ranked by the frequency of reporting, meanwhile, the two high-strength signals of thyroid-stimulating immunoglobulin increase (ROR 662.89, 95% CI 182.40-2409.19) and gingival recession (ROR 125.13, 95% CI 79.70-196.45) were not documented in the drug instruction. Meanwhile, we found a higher risk of increased blood glucose, deafness, and decreased appetite for male patients, and headache for female patients. CONCLUSIONS: Clinical application of teprotumumab should be closely monitored for ototoxicity, nail abnormalities, and menstrual changes, as well as for AEs not mentioned in the drug instruction, including gingival recession, thyroid-stimulating immunoglobulin increase, and so on.

Design, synthesis, and evaluation of antitumor activity of Mobocertinib derivatives, a third-generation EGFR inhibitor.

Mobocertinib, as a structural analog of the third generation TKI Osimertinib, can selectively act on the EGFRex20 mutation. We have structurally modified Mobocertinib to obtain new EGFR inhibitors. In this paper, we chose Mobocertinib as a lead compound for structural modification to investigate the effect of Mobocertinib derivatives on EGFRT790M mutation. We designed and synthesized 63 Mobocertinib derivatives by structural modification using the structural similarity strategy and the bioelectronic isoarrangement principle. Then, we evaluated the in vitro antitumor activity of the 63 Mobocertinib derivatives and found that the IC50 of compound H-13 against EGFRL858R/T790M mutated H1975 cells was 3.91 µM, and in further kinase activity evaluation, the IC50 of H-13 against EGFRL858R/T790M kinase was 395.2 nM. In addition, the preferred compound H-13 was able to promote apoptosis of H1975 tumor cells and block the proliferation of H1975 cells in the G0/G1 phase; meanwhile, it was able to significantly inhibit the migratory ability of H1975 tumor cells and inhibit the growth of H1975 cells in a time-concentration-dependent manner. In the in vivo anti-tumor activity study, the preferred compound H-13 had no obvious toxicity to normal mice, and the tumor inhibition effect on H1975 cell-loaded nude mice was close to that of Mobocertinib. Finally, molecular dynamics simulations showed that the binding energy between compound H-13 and 3IKA protein was calculated to be -162.417 ± 14.559 kJ/mol. In summary, the preferred compound H-13 can be a potential third-generation EGFR inhibitor.

Use of pressure muscle index to predict the contribution of patient's inspiratory effort during pressure support ventilation: a prospective physiological study.

Background: The successful implementation of assisted ventilation depends on matching the patient's effort with the ventilator support. Pressure muscle index (PMI), an airway pressure based measurement, has been used as noninvasive monitoring to assess the patient's inspiratory effort. The authors aimed to evaluate the feasibility of pressure support adjustment according to the PMI target and the diagnostic performance of PMI to predict the contribution of the patient's effort during ventilator support. Methods: In this prospective physiological study, 22 adult patients undergoing pressure support ventilation were enrolled. After an end-inspiratory airway occlusion, airway pressure reached a plateau, and the magnitude of change in plateau from peak airway pressure was defined as PMI. Pressure support was adjusted to obtain the PMI which was closest to -1, 0, +1, +2, and + 3 cm H2O. Each pressure support level was maintained for 20 min. Esophageal pressure was monitored. Pressure-time products of respiratory muscle and ventilator insufflation were measured, and the fraction of pressure generated by the patient was calculated to represent the contribution of the patient's inspiratory effort. Results: A total of 105 datasets were collected at different PMI-targeted pressure support levels. The differences in PMI between the target and the obtained value were all within ±1 cm H2O. As targeted PMI increased, pressure support settings decreased significantly from a median (interquartile range) of 11 (10-12) to 5 (4-6) cm H2O (p < 0.001), which resulted in a significant increase in pressure-time products of respiratory muscle [from 2.9 (2.1-5.0) to 6.8 (5.3-8.1) cm H2O•s] and the fraction of pressure generated by the patient [from 25% (19-31%) to 72% (62-87%)] (p < 0.001). The area under receiver operating characteristic curves for PMI to predict 30 and 70% contribution of patient's effort were 0.93 and 0.95, respectively. High sensitivity (all 1.00), specificity (0.86 and 0.78), and negative predictive value (all 1.00), but low positive predictive value (0.61 and 0.43) were obtained to predict either high or low contribution of patient's effort. Conclusion: Our results preliminarily suggested the feasibility of pressure support adjustment according to the PMI target from the ventilator screen. PMI could reliably predict the high and low contribution of a patient's effort during assisted ventilation.Clinical trial registration: ClinicalTrials.gov, identifier NCT05970393.

Methods and clinical biomarker discovery for targeted proteomics using Olink technology.

PURPOSE: This paper is to offer insights for designing research utilizing Olink technology to identify biomarkers and potential therapeutic targets for disease treatment. EXPERIMENTAL DESIGN: We discusses the application of Olink technology in oncology, cardiovascular, respiratory and immune-related diseases, and Outlines the advantages and limitations of Olink technology. RESULTS: Olink technology simplifies the search for therapeutic targets, advances proteomics research, reveals the pathogenesis of diseases, and ultimately helps patients develop precision treatments. CONCLUSIONS: Although proteomics technology has been rapidly developed in recent years, each method has its own disadvantages, so in the future research, more methods should be selected for combined application to verify each other.

Elucidating VSMC phenotypic transition mechanisms to bridge insights into cardiovascular disease implications.

Cardiovascular diseases (CVD) are the leading cause of death worldwide, despite advances in understanding cardiovascular health. Significant barriers still exist in effectively preventing and managing these diseases. Vascular smooth muscle cells (VSMCs) are crucial for maintaining vascular integrity and can switch between contractile and synthetic functions in response to stimuli such as hypoxia and inflammation. These transformations play a pivotal role in the progression of cardiovascular diseases, facilitating vascular modifications and disease advancement. This article synthesizes the current understanding of the mechanisms and signaling pathways regulating VSMC phenotypic transitions, highlighting their potential as therapeutic targets in cardiovascular disease interventions.