Synthesis, biological activities and mechanistic studies of C20-ketone pachysandra alkaloids as anti-hepatocellular carcinoma agents.

The pachysandra alkaloids found in Sarcococca ruscifolia demonstrate notable anti-hepatocellular carcinoma activity. Despite their efficacy, the structural diversity of these compounds remains limited, and their precise antitumor mechanism is still unclear. In pursuit of identifying novel lead compounds with high efficacy and low toxicity for combating hepatocellular carcinoma, twenty-three compounds of C20-ketone pachysandra alkaloid derivatives were designed and synthesized by using 3-dimethylamine pachysandra alkaloids as scaffolds. Subsequent in vitro anticancer activity experiments showed that synthetic pachysandra alkaloids had a stronger effect on HepG2 cells than did their natural counterparts, with low toxicity and high selectivity. The most potent derivative, 6k, had an IC50 value of 0.75 µM, demonstrating 25.7-fold greater anticancer activity than sarcovagine D against HepG2 cells. Through network pharmacology and molecular docking analysis, it was revealed that synthetic pachysandra alkaloids may exert their effects by inhibiting the JAK2/STAT3 pathway, thereby preventing the proliferation of liver cancer cells. Further research through scratch tests, immunofluorescence experiments, and Western blot analysis revealed that compound 6k effectively inhibited the migration of HepG2 cells and induced mitochondria-mediated intrinsic apoptosis of HepG2 cells by regulating the JAK2/STAT3 signaling pathway. The aforementioned results indicate that compound 6k could be developed as a potential candidate for the treatment of hepatocellular carcinoma.

Characteristics and Functions of Dominant Yeasts Together with Their Applications during Strong-Flavor Baijiu Brewing.

Yeasts are pivotal brewing microbes that are associated with the flavor and quality of Chinese baijiu, yet research on dominant yeasts in strong-flavor baijiu brewing remains limited. In this study, Saccharomyces cerevisiae, Pichia kudriavzevii, and Kazachstania bulderi were identified as predominated yeasts in strong-flavor baijiu. Each strain showed distinct characteristics in ethanol resistance, thermal tolerance, and lactic acid tolerance, severally. S. cerevisiae FJ1-2 excelled in ethanol and ethyl ester production, P. kudriavzevii FJ1-1 in ethyl acetate, and K. bulderi FJ1-3 in lactic acid generation. Subsequently, the reinforced Fuqu of each yeast were severally prepared for application in baijiu brewing to verify their functions. Results revealed that the relative abundance of fortified yeast in each group rose. Pichia, Kazachstania, and Saccharomyces emerged as the core microbe for each group, respectively, by co-occurrence network analysis, influencing the microbiota to regulate flavor substances. In short, P. kudriavzevii FJ1-1 enhanced ethyl acetate. K. bulderi FJ1-3 improved ethyl caproate production and decreased levels of ethyl acetate and higher alcohols by modulating yeast community between Pichia and Saccharomyces. This is a systematic endeavor to study the functions of yeasts of strong-flavor baijiu, providing a solid basis for improving baijiu quality.

Protective effects of fructose-1,6-bisphosphate postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing valve replacement: a randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Pharmacological postconditioning can protect against myocardial ischaemia-reperfusion injury during cardiac surgery with extracorporeal circulation. The aim of this study was to observe the protective effects of fructose-1,6-bisphosphate (FDP) postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing cardiac valve replacement with extracorporeal circulation. METHODS: Patients undergoing elective mitral valve replacement and/or aortic valve replacement were divided into normal saline postconditioning group (NS group) and FDP postconditioning group (FDP group). The primary outcome was the plasma concentration of creatine kinase-MB (CK-MB). The secondary outcomes were the plasma concentrations of lactate dehydrogenase, CK, high-sensitivity C-reactive protein, alpha-hydroxybutyrate dehydrogenase and cardiac troponin I, the spontaneous cardiac rhythm recovery profile, the extracorporeal circulation time and duration of surgery, intensive care unit and postoperative hospitalization. RESULTS: Forty patients were randomly assigned to receive intervention and included in the analysis. The serum concentrations of CK-MB, lactate dehydrogenase, CK, cardiac troponin I, alpha-hydroxybutyrate dehydrogenase and high-sensitivity C-reactive protein at T1∼4 were lower in the FDP group than in the NS group (P < 0.001). Compared with the NS group, the dosage of dopamine administered 1-90 min after cardiac resuscitation, the spontaneous cardiac rhythm recovery time and the incidence of ventricular fibrillation were lower in the FDP group (P < 0.001, P < 0.001 and P = 0.040, respectively). The values of ST- changes were increased more significantly in the NS group than in the FDP group (median [standard deviation] 1.3 [0.3] mm vs 0.7 [0.2] mm; P < 0.001). Compared with the NS group, the time of recovery of ST-segment deviations was shorter in the FDP group (50.3 [12.3] min vs 34.6 [6.9] min; P < 0.001). CONCLUSIONS: The FDP postconditioning could improve both myocardial ischaemia-reperfusion injury and the spontaneous cardiac rhythm recovery during cardiac valve surgery with extracorporeal circulation.

Designing photothermal catalytic systems in multi-component MOFs for enhanced conversion of carbon dioxide.

We integrated a pair of donor-acceptor photothermal units, a Lewis acidic site, and a nucleophilic catalytic site into a multi-component metal-organic framework, resulting in an efficient photothermal catalytic system for the conversion of CO2 to cyclic carbonates.

Biomimetic Colored Coating toward Robust Display under Hostile Conditions.

Structural colors particularly of the angle-independent category stemming from wavelength-dependent light scattering have aroused increasing interest due to their considerable applications spanning displays and sensors to detection. Nevertheless, these colors would be heavily altered and even disappear during practical applications, which is related with the variation of refractive index mismatch by liquid wetting/infiltrating. Inspired by bird feathers, we propose a simple deposition toward the coating with angle-independent structural color and superamphiphobicity. The coating is composed of ∼200 nm-sized channel-type structures between hollow silica and air nanostructures, exhibiting a robust sapphire blue color independent of intense liquid intrusion, which duplicates the characteristics of the back feather of Eastern Bluebird. A high color saturation and superamphiphobicity of the biomimetic coating are optimized by manipulating the coating parameters or adding black substances. Excellent durability under harsh conditions endows the coating with long-term service life in various extreme environments.

Supramolecular assemblies with aggregation-induced emission for in situ active imaging-guided photodynamic therapy of cancer cells.

Photodynamic therapy (PDT) has attracted widespread attention as a novel non-invasive anticancer approach. However, the diminished photosensitivity and limited oxygen exposure caused by the aggregation of traditional photosensitizers greatly impair its overall therapeutic efficacy. Herein, a series of water-soluble aggregation-induced emission luminogens (AIEgens) with triphenylamine as skeleton were synthesized and exhibited bright Near-infrared (NIR) emission and strong reactive oxygen species (ROS) generation. Through host-guest complexation between the multicharged triphenylamine units on AIEgens and cucurbit[10]uril (CB[10]) host molecule, supramolecular nanoassemblies were constructed and exhibited negligible phototoxicity to normal cells due to their limited oxygen contact. In contrast, the efficient release of AIEgens from nanoassemblies through competitive binding of overexpressed peptides in cancer cells with CB[10], enabled the full exploitation of the photosensitivity of AIEgens to produce highly efficient ROS, achieving selective ablation of cancer cells. Moreover, due to the restriction of intramolecular motion (RIM) upon anchored on organelle membranes through electrostatic interactions, the cationic AIEgens with weak fluorescence in physiological environment exhibited intense fluorescence emission, thus realizing imaging-guided PDT. This work may open up an avenue for the development of simple and feasible smart responsive nanomaterials for cancer treatment using supramolecular host-guest complexation strategy.

Huaxi integrated blood management reduces the red blood cell transfusion for on-pump cardiac surgery: A quasi-experimental study.

OBJECTIVE: As many as half of patients undergoing on-pump cardiac surgery require red blood cell transfusion, emphasizing the need for effective strategies that can reduce this need. We conducted this analysis to assess the effectiveness of Huaxi Integrated Blood Management strategy at our medical center. DESIGN: Before and after study. PARTICIPANTS: Patients who underwent on-pump cardiac surgery were included from January 2019 to December 2021. Two cohorts were compared, one before implementation of the strategy (1 January 2019 until 31 May 2020) and one after implementation (1 June 2020 until 31 December 2021). MEASUREMENTS: We evaluated temporal trends in blood transfusion, safety, and efficacy of this strategy. Primary outcomes were the incidence and volume of intra- and postoperative blood transfusions of packed red blood cells. Secondary outcomes are intraoperative and postoperative transfusion of other blood products, all-cause mortality during hospitalization, and incidence of new-onset complications. MAIN RESULTS: Our results demonstrated that this integrated strategy effectively decreased both the perioperative packed red blood cell transfusion volume and incidence for patients who underwent the on-pump cardiac surgery. Following the implementation, the incidence of packed red blood cell transfusions decreased by 8.1% during the intraoperative period and by 12.3% during the postoperative period. The mean volume of such transfusions decreased by 0.28 units during the intraoperative period and by 0.49 units during the postoperative period. Hemoglobin concentrations were significantly higher after implementation, and the maximal mean increase was 4.72 g/l on postoperative day 1. Similar benefit of the strategy was observed across subgroups of patients who underwent different types of surgery. CONCLUSIONS: The Huaxi Integrated Blood Management strategy may be effective at reducing the need for packed red blood cell transfusion and enhancing patient care.

Cadmium causes cerebral mitochondrial dysfunction through regulating mitochondrial HSF1.

Mitochondria, as the powerhouse of the cell, play a vital role in maintaining cellular energy homeostasis and are known to be a primary target of cadmium (Cd) toxicity. The improper targeting of proteins to mitochondria can compromise the normal functions of the mitochondria. However, the precise mechanism by which protein localization contributes to the development of mitochondrial dysfunction induced by Cd is still not fully understood. For this research, Hy-Line white variety chicks (1-day-old) were used and equally distributed into 4 groups: the Control group (fed with a basic diet), the Cd35 group (basic diet with 35 mg/kg CdCl2), the Cd70 group (basic diet with 70 mg/kg CdCl2) and the Cd140 group (basic diet with 140 mg/kg CdCl2), respectively for 90 days. It was found that Cd caused the accumulation of heat shock factor 1 (HSF1) in the mitochondria, and the overexpression of HSF1 in the mitochondria led to mitochondrial dysfunction and neuronal damage. This process is due to the mitochondrial HSF1 (mtHSF1), causing mitochondrial fission through the upregulation of dynamin-related protein 1 (Drp1) content, while inhibiting oligomer formation of single-stranded DNA-binding protein 1 (SSBP1), resulting in the mitochondrial DNA (mtDNA) deletion. The findings unveil an unforeseen role of HSF1 in triggering mitochondrial dysfunction.

Mindful breathing for cancer pain: efficacy of a single 20-minute session - a randomised controlled study.

OBJECTIVES: Cancer pain is a prevalent and challenging symptom affecting a significant number of patients globally, with inadequate control remaining a substantial challenge despite advancements in pain management. Non-pharmacological interventions, including mindfulness-based approaches, have shown promise in alleviating cancer-related pain. This study aimed to explore the efficacy of a single session of 20-minute mindful breathing in reducing pain among patients with cancer. METHODS: A randomised controlled study was conducted at the University of Malaya Medical Centre, Malaysia, involving adult cancer inpatients with a pain score of ≥4/10. Participants were randomly assigned to a 20-minute mindful breathing intervention or a 20-minute supportive listening control group. Outcome measures included pain intensity, pain unpleasantness and Hospital Anxiety and Depression Scale score, assessed before and after the intervention. RESULTS: The 20-minute mindful breathing sessions demonstrated significant efficacy in reducing pain intensity, pain unpleasantness and anxiety compared with the control group. CONCLUSION: This research broadens the repertoire of cancer pain management by highlighting the rapid and holistic benefits of a single session of 20-minute mindful breathing. The findings suggest the potential integration of brief mindfulness exercises into routine cancer care to enhance pain management and overall well-being.

Effectiveness of chest pain center accreditation on the hospital outcome of acute aortic dissection: a nationwide study in China.

BACKGROUND: The National Chest Pain Center Program (NCPCP) is a nationwide, quality enhancement program aimed at raising the standard of care for patients experiencing acute chest pain in China. The benefits of chest pain center (CPC) accreditation on acute coronary syndrome have been demonstrated. However, there is no evidence to indicate whether CPC accreditation improves outcomes for patients with acute aortic dissection (AAD). METHODS: We conducted a retrospective observational study of patients with AAD from 1671 hospitals in China, using data from the NCPCP spanning the period from January 1, 2016 to December 31, 2022. The patients were divided into 2 groups: pre-accreditation and post-accreditation admissions. The outcomes examined included in-hospital mortality, misdiagnosis, and Stanford type A AAD surgery. Multivariate logistic regression was employed to explore the relationship between CPC accreditation and in-hospital outcomes. Furthermore, we stratified the hospitals based on their geographical location (Eastern/Central/Western regions) or administrative status (provincial/non-provincial capital areas) to assess the impact of CPC accreditation on AAD patients across various regions. RESULTS: The analysis encompassed a total of 40,848 patients diagnosed with AAD. The post-accreditation group exhibited significantly lower rates of in-hospital mortality and misdiagnosis (12.1% vs. 16.3%, P < 0.001 and 2.9% vs. 5.4%, P < 0.001, respectively) as well as a notably higher rate of Stanford type A AAD surgery (61.1% vs. 42.1%, P < 0.001) compared with the pre-accreditation group. After adjusting for potential covariates, CPC accreditation was associated with substantially reduced risks of in-hospital mortality (adjusted OR 0.644, 95% CI 0.599-0.693) and misdiagnosis (adjusted OR 0.554, 95% CI 0.493-0.624), along with an increase in the proportion of patients undergoing Stanford type A AAD surgery (adjusted OR 1.973, 95% CI 1.797-2.165). Following CPC accreditation, there were significant reductions in in-hospital mortality across various regions, particularly in Western regions (from 21.5 to 14.1%). Moreover, CPC accreditation demonstrated a more pronounced impact on in-hospital mortality in non-provincial cities compared to provincial cities (adjusted OR 0.607 vs. 0.713). CONCLUSION: CPC accreditation is correlated with improved management and in-hospital outcomes for patients with AAD.

Numerical simulation and in vitro experimental study of the hemodynamic performance of vena cava filters with helical forms.

Inferior vena cava filter (IVCF) implantation is a common method of thrombus capture. By implanting a filter in the inferior vena cava (IVC), microemboli can be effectively blocked from entering the pulmonary circulation, thereby avoiding acute pulmonary embolism (PE). Inspired by the helical flow effect in the human arterial system, we propose a helical retrievable IVCF, which, due to the presence of a helical structure inducing a helical flow pattern of blood in the region near the IVCF, can effectively avoid the deposition of microemboli in the vicinity of the IVCF while promoting the cleavage of the captured thrombus clot. It also reduces the risk of IVCF dislodging and slipping in the vessel because its shape expands in the radial direction, allowing its distal end to fit closely to the IVC wall, and because its contact structure with the inner IVC wall is curved, increasing the contact area and reducing the risk of the vessel wall being punctured by the IVCF support structure. We used ANSYS 2023 software to conduct unidirectional fluid-structure coupling simulation of four different forms of IVCF, combined with microthrombus capture experiments in vitro, to explore the impact of these four forms of IVCF on blood flow patterns and to evaluate the risk of IVCF perforation and IVCF dislocation. It can be seen from the numerical simulation results that the helical structure does have the function of inducing blood flow to undergo helical flow dynamics, and the increase in wall shear stress (WSS) brought about by this function can improve the situation of thrombosis accumulation to a certain extent. Meanwhile, the placement of IVCF will change the flow state of blood flow and lead to the deformation of blood vessels. In in vitro experiments, we found that the density of the helical support rod is a key factor affecting the thrombus trapping efficiency, and in addition, the contact area between the IVCF and the vessel wall has a major influence on the risk of IVCF displacement.

Anchoring PdOx clusters on defective alumina for improved catalytic methane oxidation.

Evolution of the Pd active centers in size and spatial distribution leads to an irreversible deactivation in many high-temperature catalytic processes. This research demonstrates the use of a defective alumina (Al2O3-x) as catalyst support to anchor Pd atoms and suppress the growth of Pd clusters in catalytic methane oxidation. A combination of operando spectroscopy and density functional theory (DFT) calculations provide insights into the evolution of Pd species and reveals distinct catalytic methane oxidation mechanisms on Pd single atoms, clusters, and nanoparticles (NPs). Among these Pd species, the cluster active centers are found to be the most favorable participants in methane oxidation due to their high dispersion, high content of Pd2+ oxidation state, and resistance to deactivation by carbonates, bicarbonates, and water. The Pd/Al2O3-x catalyst shows increased stability with respect to a Pd/Al2O3 counterpart during simulated aging in alternating reducing and oxidizing conditions due to stronger interactions with the support. This study demonstrates that defect engineering of non-reducible supports can constrain the evolution of active centers, which holds promising potential for widespread utilization across diverse industrial catalytic processes, including various hydrogenation and oxidation reactions.

A High-Entropy Oxyhydroxide with a Graded Metal Network Structure for Efficient and Robust Alkaline Overall Water Splitting.

Designing high-entropy oxyhydroxides (HEOs) electrocatalysts with controlled nanostructures is vital for efficient and stable water-splitting electrocatalysts. Herein, a novel HEOs material (FeCoNiWCuOOH@Cu) containing five non-noble metal elements derived by electrodeposition on a 3D double-continuous porous Cu support is created. This support, prepared via the liquid metal dealloying method, offers a high specific surface area and rapid mass/charge transfer channels. The resulting high-entropy FeCoNiWCuOOH nanosheets provide a dense distribution of active sites. The heterostructure between Cu skeletons and FeCoNiWCuOOH nanosheets enhances mass transfer, electronic structure coupling, and overall structural stability, leading to excellent activities in the oxygen evolution reaction (OER), hydrogen evolution reaction (HER), and water splitting reaction. At 10 mA cm-2, the overpotentials for OER, HER, and water splitting in 1.0 m KOH solution are 200, 18, and 1.40 V, respectively, outperforming most current electrocatalysts. The catalytic performance remains stable even after operating at 300 mA cm-2 for 100, 100, and over 1000 h, correspondingly. This material has potential applications in integrated hydrogen energy systems. More importantly, density functional theory (DFT) calculations demonstrate the synergy of the five elements in enhancing water-splitting activity. This work offers valuable insights for designing industrial water electrolysis systems.

MOSDNET: A multi-omics classification framework using simplified multi-view deep discriminant representation learning and dynamic edge GCN with multi-task learning.

The integration of multi-omics data offers a robust approach to understanding the complexity of diseases by combining information from various biological levels, such as genomics, transcriptomics, proteomics, and metabolomics. This integrated approach is essential for a comprehensive understanding of disease mechanisms and for developing more effective diagnostic and therapeutic strategies. Nevertheless, most current methodologies fail to effectively extract both shared and specific representations from omics data. This study introduces MOSDNET, a multi-omics classification framework that effectively extracts shared and specific representations. This framework leverages Simplified Multi-view Deep Discriminant Representation Learning (S-MDDR) and Dynamic Edge GCN (DEGCN) to enhance the accuracy and efficiency of disease classification. Initially, MOSDNET utilizes S-MDDR to establish similarity and orthogonal constraints for extracting these representations, which are then concatenated to integrate the multi-omics data. Subsequently, MOSDNET constructs a comprehensive view of the sample data by employing patient similarity networks. By incorporating similarity networks into DEGCN, MOSDNET learns intricate network structures and node representations, which enables superior classification outcomes. MOSDNET is trained through a multitask learning approach, effectively leveraging the complementary knowledge from both the data integration and classification components. After conducting extensive comparative experiments, we have conclusively demonstrated that MOSDNET outperforms leading state-of-the-art multi-omics classification models in terms of classification accuracy. Simultaneously, we employ MOSDNET to identify pivotal biomarkers within the multi-omics data, providing insights into disease etiology and progression.

Identification of immune-inflammation targets for intracranial aneurysms: A multiomics and epigenome-wide study integrating summary-data-based mendelian randomization, single-cell-type expression analysis, and DNA methylation regulation.

BACKGROUND: Dysfunction of the immune system and inflammation plays a vital role in developing intracranial aneurysms (IAs). However, the progress of genetic pathophysiology is complicated and not entirely elaborated. This study aimed to explore the genetic associations of immune- and inflammation-related genes (IIRGs) with IAs and their subtypes using Mendelian randomization, colocalization test, and integrated multiomics functional analysis. METHODS: We conducted a summary-data-based Mendelian randomization (SMR) analysis using data from several genome-wide association studies of gene expression (31,684 European individuals) and protein quantitative trait loci (35,559 Icelanders), as well as information on IAs and their subtypes from The International Stroke Genetics Consortium (IGSC) for discovery phase and the FinnGen study for replication. This analysis aimed to determine the causal relationship between IIRGs and the risk of IAs and their subtypes. Further functional analyses, including DNA methylation regulation (1980, European individuals), single-cell-type expression analysis, and protein-protein interaction, were conducted to detect the specific cell type with enriched expression and discover potential drug targets. RESULTS: After integrating multi-omics evidence from expression quantitative trait loci (eQTL)and protein quantitative trait loci(pQTL), we found that tier 1: RELT [odds ratio (OR): 0.14, 95% confidence interval (CI): 0.04-0.50], TNFSF12 (OR: 1.24, 95% CI: 1.24-1.43), tier 3:ICAM5 (OR: 0.89, 95% CI: 0.82-0.96), and ERAP2 (OR: 1.07, 95% CI: 1.02-1.12) were associated with the risk of IAs; tier 3: RELT (OR: 0.11, 95% CI: 0.02-0.54), ERAP2 (OR: 1.08, 95% CI: 1.02-1.13), and TNFSF12 (OR: 1.24, 95% CI: 1.05-1.47) were associated with the risk of aneurysmal subarachnoid hemorrhage (aSAH); and tier 1:RELT (OR: 0.04, 95% CI: 0.01-0.30) was associated with the risk of unruptured intracranial aneurysms (uIAs). Further functional analyses showed that RELT was regulated by cg06382664 and cg18850434 and ICAM5 was regulated by cg04295144 in IAs; RELT was regulated by cg06382664, cg08770935, cg16533363, and cg18850434 in aSAH; and RELT was regulated by cg06382664 and cg21810604 in uIAs. In addition, we found that H6PD (OR: 1.13, 95% CI: 1.01-1.28), NT5M (OR: 1.91, 95% CI: 1.21-3.01), and NPTXR (OR: 1.13, 95% CI: 1.01-1.26) were associated with IAs; NT5M (OR: 2.13, 95% CI: 1.23-3.66) was associated aSAH; and AP4M1 (OR: 0.06, 95% CI: 0.01-0.42) and STX7 (OR: 3.97, 95% CI: 1.41-11.18) were related to uIAs. STX7 and TNFSF12 were mainly enriched in microglial cells, whereas H6PD, STX7, and TNFSF12 were mainly enriched in astrocytes. CONCLUSIONS: After integrating multi-omics evidence, we eventually identified IIRGs: RELT, TNFSF12, ICAM5 and ERAP2 were the novel therapy targets for IAs. These new results confirmed a vital role of immune and inflammation in the etiology of IAs, contributing to enhance our understanding of the immune and inflammatory mechanisms in the pathogenesis of IAs and revealing the complex genetic causality of IAs.

The Chemokine CCL2 Promotes Excitatory Synaptic Transmission in Hippocampal Neurons via GluA1 Subunit Trafficking.

The CC chemokine ligand 2 (CCL2, also known as MCP-1) and its cognate receptor CCR2 have well-characterized roles in chemotaxis. CCL2 has been previously shown to promote excitatory synaptic transmission and neuronal excitability. However, the detailed molecular mechanism underlying this process remains largely unclear. In cultured hippocampal neurons, CCL2 application rapidly upregulated surface expression of GluA1, in a CCR2-dependent manner, assayed using SEP-GluA1 live imaging, surface GluA1 antibody staining, and electrophysiology. Using pharmacology and reporter assays, we further showed that CCL2 upregulated surface GluA1 expression primarily via Gαq- and CaMKII-dependent signaling. Consistently, using i.p. injection of lipopolysaccharide to induce neuroinflammation, we found upregulated phosphorylation of S831 and S845 sites on AMPA receptor subunit GluA1 in the hippocampus, an effect blocked in Ccr2-/- mice. Together, these results provide a mechanism through which CCL2, and other secreted molecules that signal through G-protein coupled receptors, can directly regulate synaptic transmission.

Targeting SOX4/PCK2 signaling suppresses neuroendocrine trans-differentiation of castration-resistant prostate cancer.

BACKGROUND: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer (PCa), is characterized by loss of AR signaling and resistance to AR-targeted therapy. While it is well reported that second-generation AR blockers induce neuroendocrine (NE) trans-differentiation of castration-resistant prostate cancer (CRPC) to promote the occurrence of NEPC, and pluripotent transcription factors might be potential regulators, the underlying molecular mechanisms remain unclear. METHODS: We analyzed the data from public databsets to screen candidate genes and then focused on SOX4, a regulator of NE trans-differentiation. The expression changes of SOX4 and its relationship with tumor progression were validated in clinical tumor tissues. We evaluated malignant characteristics related to NEPC in prostate cancer cell lines with stable overexpression or knockdown of SOX4 in vitro. Tumor xenografts were analyzed after inoculating the relevant cell lines into nude mice. RNA-seq, ATAC-seq, non-targeted metabolomics analysis, as well as molecular and biochemical assays were carried out to determine the mechanism. RESULTS: We screened public datasets and identified that expression of SOX4 was significantly elevated in NEPC. Overexpressing SOX4 in C4-2B cells increased cell proliferation and migration, upregulated the expression of NE marker genes, and inhibited AR expression. Consistently, inhibition of SOX4 expression in DU-145 and PC-3 cells reduced the above malignant phenotypes and repressed the expression of NE marker genes. For the in vivo assay, we found that knockdown of SOX4 inhibited tumor growth of subcutaneous xenografts in castrated nude mice which were concomitantly treated with enzalutamide (ENZ). Mechanically, we identified that one of the key enzymes in gluconeogenesis, PCK2, was a novel target of SOX4. The activation of carbohydrate metabolism reprogramming by SOX4 could promote NE trans-differentiation via the SOX4/PCK2 pathway. CONCLUSIONS: Our findings reveal that SOX4 promotes NE trans-differentiation both in vitro and in vivo via directly enhancing PCK2 activity to activate carbohydrate metabolism reprogramming. The SOX4/PCK2 pathway and its downstream changes might be novel targets for blocking NE trans-differentiation.

ScLNet: A cornea with scleral lens OCT layers segmentation dataset and new multi-task model.

Objective: To develop deep learning methods with high accuracy for segmenting irregular corneas and detecting the tear fluid reservoir (TFR) boundary under the scleral lens. Additionally, this study aims to provide a publicly available cornea with scleral lens OCT dataset, including manually labeled layer masks for training and validation of segmentation algorithms. This study introduces ScLNet, a dataset comprising cornea with Scleral Lens (ScL) optical coherence tomography (OCT) images with layer annotations, and a multi-task network designed to achieve rapid, accurate, automated segmentation of scleral lens with regular and irregular corneas. Methods: We created a dataset comprising 31,360 OCT images with scleral lens annotations. The network architecture includes an encoder with multi-scale input and a context coding layer, along with two decoders for specific tasks. The primary task focuses on predicting ScL, TFR, and cornea regions, while the auxiliary task, aimed at predicting the boundaries of ScL, TFR, and cornea, enhances feature extraction for the main task. Segmentation results were compared with state-of-the-art methods and evaluated using Dice similarity coefficient (DSC), intersection over union (IoU), Matthews correlation coefficient (MCC), Precision, and Hausdorff distance (HD). Results: ScLNet achieves 98.22 % DSC, 96.50 % IoU, 98.13 % MCC, 98.35 % Precision, and 3.6840 HD (in pixels) in segmenting ScL; 97.78 % DSC, 95.66 % IoU, 97.71 % MCC, 97.70 % Precision, and 3.7838 HD (in pixels) in segmenting TFR; and 99.22 % DSC, 98.45 % IoU, 99.15 % MCC, 99.14 % Precision, and 3.5355 HD (in pixels) in segmenting cornea. The layer interfaces recognized by ScLNet closely align with expert annotations, as evidenced by high IoU scores. Boundary metrics further confirm its effectiveness. Conclusion: We constructed a dataset of corneal OCT images with ScL wearing, which includes regular and irregular cornea patients. The proposed ScLNet achieves high accuracy in extracting ScL, TFR, and corneal layer masks and boundaries from OCT images of the dataset.

Predictive Value of Pretreatment Neutrophil to Albumin Ratio in Response to Neoadjuvant Chemotherapy of Breast Cancer.

Background: The immune system appears to play a crucial role in how breast cancer responds to chemotherapy. In this study, we investigated a peripheral marker of immune and inflammation named the neutrophil to albumin ratio (NAR) to explore its potential relationship with pathological complete response (pCR) in locally advanced breast cancer patients who underwent neoadjuvant chemotherapy (NAC). Methods: We conducted a retrospective analysis of 212 consecutive breast cancer patients who received NAC. The NAR was calculated by examining the complete blood cell count and albumin level in peripheral blood before starting NAC. Through ROC curve analysis, we determined the optimal cutoff value for NAR as 0.0877. We used Pearson's chi-square test or Fisher's exact test to evaluate the relationship between NAR and pCR, as well as other clinical and pathological characteristics. Logistic regression models were employed for univariate and multivariate analyses. Results: The results of both univariate and multivariate logistic regression analyses showed that NAR was associated with tumor pathological regression. The NAR high group had a higher pCR rate compared to the NAR low group (OR 3.127 [95% CI 1.545-6.328]; p = 0.002). Conclusion: According to this study, it was observed that patients with breast cancer who had high levels of NAR were more likely to achieve pCR when undergoing NAC.

Dietary crude protein and protein solubility manipulation enhances intestinal nitrogen absorption and mitigates reactive nitrogen emissions through gut microbiota and metabolome reprogramming in sheep.

Dietary nutrient manipulation (e.g. protein fractions) could lower the environmental footprints of ruminants, especially reactive nitrogen (N). This study investigated the impacts of dietary soluble protein (SP) levels with decreased crude protein (CP) on intestinal N absorption, hindgut N metabolism, fecal microbiota and metabolites, and their linkage with N metabolism phenotype. Thirty-two male Hu sheep, with an age of six months and an initial BW of 40.37 ± 1.18 kg, were randomly assigned to four dietary groups. The control diet (CON), aligning with NRC standards, maintained a CP content of 16.7% on a dry matter basis. Conversely, the experimental diets (LPA, LPB, and LPC) featured a 10% reduction in CP compared with CON, accompanied by SP adjustments to 21.2%, 25.9%, and 29.4% of CP, respectively. Our results showed that low-protein diets led to significant reductions in the concentrations of plasma creatinine, ammonia, urea N, and fecal total short-chain fatty acids (SCFA) (P < 0.05). Notably, LPB and LPC exhibited increased total SCFA and propionate concentrations compared with LPA (P < 0.05). The enrichment of the Prevotella genus in fecal microbiota associated with energy metabolism and amino acid (AA) biosynthesis pathways was evident with SP levels in low-protein diets of approximately 25% to 30%. Moreover, LPB and LPC diets demonstrated a decrease in fecal NH 4 + -N and NO 2 - -N contents as well as urease activity, compared with CON (P < 0.05). Concomitantly, reductions in fecal glutamic acid dehydrogenase gene (gdh), nitrite reductase gene (nirS), and nitric oxide reductase gene (norB) abundances were observed (P < 0.05), pointing towards a potential reduction in reactive N production at the source. Of significance, the up-regulation of mRNA abundance of AA and peptide transporters in the small intestine (duodenum, jejunum, and ileum) and the elevated concentration of plasma AA (e.g. arginine, methionine, aspartate, glutamate, etc.) underscored the enhancement of N absorption and N efficiency. In summary, a 10% reduction in CP, coupled with an SP level of approximately 25% to 30%, demonstrated the potential to curtail reactive N emissions through fecal Prevotella enrichment and improve intestinal energy and N utilization efficiency.