ABSTRACT
When main-sequence stars expand into red giants, they are expected to engulf close-in planets1-5. Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants6-8 has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars9. Here we present the discovery that the giant planet 8 Ursae Minoris b10 orbits a core-helium-burning red giant. At a distance of only 0.5 AU from its host star, the planet would have been engulfed by its host star, which is predicted by standard single-star evolution to have previously expanded to a radius of 0.7 AU. Given the brief lifetime of helium-burning giants, the nearly circular orbit of the planet is challenging to reconcile with scenarios in which the planet survives by having a distant orbit initially. Instead, the planet may have avoided engulfment through a stellar merger that either altered the evolution of the host star or produced 8 Ursae Minoris b as a second-generation planet11. This system shows that core-helium-burning red giants can harbour close planets and provides evidence for the role of non-canonical stellar evolution in the extended survival of late-stage exoplanetary systems.
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Errors in clinical decision-making are disturbingly common. Recent studies have found that 10 to 15% of all clinical decisions regarding diagnoses and treatment are inaccurate. Here, we experimentally study the ability of structured information-sharing networks among clinicians to improve clinicians' diagnostic accuracy and treatment decisions. We use a pool of 2,941 practicing clinicians recruited from around the United States to conduct 84 independent group-level trials, ranging across seven different clinical vignettes for topics known to exhibit high rates of diagnostic or treatment error (e.g., acute cardiac events, geriatric care, low back pain, and diabetes-related cardiovascular illness prevention). We compare collective performance in structured information-sharing networks to collective performance in independent control groups, and find that networks significantly reduce clinical errors, and improve treatment recommendations, as compared to control groups of independent clinicians engaged in isolated reflection. Our results show that these improvements are not a result of simple regression to the group mean. Instead, we find that within structured information-sharing networks, the worst clinicians improved significantly while the best clinicians did not decrease in quality. These findings offer implications for the use of social network technologies to reduce errors among clinicians.
Subject(s)
Clinical Decision-Making , Information Dissemination , Humans , Aged , Medical Errors/prevention & controlABSTRACT
Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.
Subject(s)
Cell Culture Techniques , Microfluidics , Animals , DNA , Humans , Mice , Models, BiologicalABSTRACT
While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.
Subject(s)
ATP Citrate (pro-S)-Lyase/metabolism , Acetyl Coenzyme A/metabolism , BRCA1 Protein/metabolism , Cell Nucleus/enzymology , DNA Breaks, Double-Stranded , Recombinational DNA Repair , A549 Cells , ATP Citrate (pro-S)-Lyase/genetics , Acetylation , Animals , BRCA1 Protein/genetics , Cell Nucleus/drug effects , Female , G2 Phase Cell Cycle Checkpoints , Genomic Instability , Glucose/metabolism , HCT116 Cells , HeLa Cells , Histones/metabolism , Humans , Melanoma, Experimental/enzymology , Melanoma, Experimental/genetics , Melanoma, Experimental/pathology , Mice, Inbred C57BL , Phosphorylation , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Protein Binding , Protein Processing, Post-Translational , RNA Interference , Recombinational DNA Repair/drug effects , S Phase Cell Cycle Checkpoints , Serine , Time Factors , Transfection , Tumor Suppressor p53-Binding Protein 1/metabolismABSTRACT
Heart diseases are a major cause of morbidity and mortality worldwide. Understanding the molecular mechanisms underlying these diseases is essential for the development of effective diagnostic and therapeutic strategies. The FHL family consists of five members: FHL1, FHL2, FHL3, FHL4, and FHL5/Act. These members exhibit different expression patterns in various tissues including the heart. FHL family proteins are implicated in cardiac remodeling, regulation of metabolic enzymes, and cardiac biomechanical stress perception. A large number of studies have explored the link between FHL family proteins and cardiac disease, skeletal muscle disease, and ovarian metabolism, but a comprehensive and in-depth understanding of the specific molecular mechanisms targeting FHL on cardiac disease is lacking. The aim of this review is to explore the structure and function of FHL family members, to comprehensively elucidate the mechanisms by which they regulate the heart, and to explore in depth the changes in FHL family members observed in different cardiac disorders, as well as the effects of mutations in FHL proteins on heart health.
Subject(s)
Heart Diseases , Muscular Diseases , Humans , Muscle Proteins/metabolism , Muscular Diseases/genetics , Heart Diseases/genetics , Mutation , Intracellular Signaling Peptides and Proteins/genetics , LIM Domain Proteins/geneticsABSTRACT
Silicon monoxide (SiO) has attracted considerable interest as anode material for lithium-ion batteries (LIBs). However, their poor initial Coulombic efficiency (ICE) and conductivity limit large-scale applications. Prelithiation and carbon-coating are common and effective strategies in industry for enhancing the electrochemical performance of SiO. However, the involved heat-treatment processes inevitably lead to coarsening of active silicon phases, posing a significant challenge in industrial applications. Herein, the differences in microstructures and electrochemical performances between prelithiated SiO with a pre-coated carbon layer (SiO@C@PLi) and SiO subjected to carbon-coating after prelithiation (SiO@PLi@C) are investigated. A preliminary carbon layer on the surface of SiO before prelithiation is found that can suppress active Si phase coarsening effectively and regulate the post-prelithiation phase content. The strategic optimization of the sequence where prelithiation and carbon-coating processes of SiO exert a critical influence on its regulation of microstructure and electrochemical performances. As a result, SiO@C@PLi exhibits a higher ICE of 88.0%, better cycling performance and lower electrode expansion than SiO@PLi@C. The pouch-type full-cell tests demonstrate that SiO@C@PLi/Graphite||NCM811 delivers a superior capacity retention of 91% after 500 cycles. This work provides invaluable insights into industrial productions of SiO anodes through optimizing the microstructure of SiO in prelithiation and carbon-coating processes.
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RATIONALE & OBJECTIVE: Individuals with a low estimated glomerular filtration rate (eGFR) are at a high risk of death. However, the causes underpinning this association are largely uncertain. This study aimed to assess the causal relationship of low eGFR with all-cause and cause-specific mortality. STUDY DESIGN: Retrospective cohort study incorporating Mendelian randomization (MR). SETTING & PARTICIPANTS: Individual-level data from 436,214 White participants (54.3% female; aged 56.8±8.0 years) included in the UK Biobank. EXPOSURES: eGFR estimated using cystatin C (eGFRcyst). OUTCOMES: The outcomes of interest included all-cause mortality, cardiovascular mortality, cancer mortality, infection mortality, and other-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards analysis for the conventional observational analyses; linear and nonlinear MR analyses implemented using genetic allele scores as instrumental variables representing kidney function to estimate the effect of kidney function on the survival outcomes. RESULTS: During a median follow-up of 12.1 years, there were 30,489 deaths, 6,098 of which were attributed to cardiovascular events, 15,538 to cancer, 1,516 to infection, and 7,227 to other events. In the conventional observational analysis, eGFRcyst exhibited a nonlinear association with all the outcomes. MR analysis suggested that a genetically predicted lower eGFRcyst was linearly associated with a higher rate of cardiovascular mortality (HR, 1.43; 95% CI, 1.18-1.75) across the entire measurement range (every 10-mL/min/1.73m2 decrement). Nonetheless, no causal associations between eGFRcyst and all-cause mortality (HR, 1.07; 95% CI, 0.98-1.17) or any types of noncardiovascular mortality were detected. LIMITATIONS: Potential misclassification of the actual cause of death, a nonrepresentative sample, and potential error in the interpretation of the magnitude of associations generated in MR analyses. CONCLUSIONS: These findings suggest a potential causal association between low eGFR and cardiovascular mortality in the general population, but no causal relationship with all-cause mortality or noncardiovascular mortality was observed. Further studies in other populations are warranted to confirm these findings. PLAIN-LANGUAGE SUMMARY: This study investigated the existence of a causal relationship between lower kidney function and death of different causes. Using data from 436,214 people in the United Kingdom, we applied conventional statistical analyses and those incorporating genetic data to implement Mendelian randomization, an approach that estimates causal associations. The observational analysis showed a nonlinear association between kidney function and various types of mortality outcomes. However, Mendelian randomization analysis suggested a linear increase in the risk of cardiovascular mortality with lower kidney function, but no causal link between the level of kidney function and all-cause or noncardiovascular mortality was identified. Managing kidney health may help reduce cardiovascular mortality, but caution is needed in interpreting the magnitudes of these results. Further validation in other populations and in those with advanced kidney failure is needed.
Subject(s)
Cause of Death , Glomerular Filtration Rate , Mendelian Randomization Analysis , Humans , Female , Middle Aged , Male , Retrospective Studies , Cardiovascular Diseases/mortality , Cardiovascular Diseases/genetics , Cystatin C/blood , United Kingdom/epidemiology , Cohort Studies , Aged , Kidney Function TestsABSTRACT
BACKGROUND: A combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated excellent clinical efficacy and safety in treating a variety of cancers, including urothelial carcinoma (UC). However, its efficacy and safety in patients with muscle-invasive upper tract urothelial carcinoma (UTUC) who are undergoing radical surgery remain uncertain. The purpose of this retrospective study was to examine the effectiveness and safety of tislelizumab combined with gemcitabine plus cisplatin (TGC) as a first-line postoperative adjuvant treatment in this population. METHODS: This single-center, real-world study retrospectively analyzed the data from 71 patients with muscle-invasive UTUC who had radical nephroureterectomy (RNU) at the Affiliated Hospital of Xuzhou Medical University between November 1, 2020, and November 1, 2023. Among the 71 patients, 30 received adjuvant therapy of TGC within 90 days after RNU and 41 underwent surveillance. No patients receive preoperative neoadjuvant therapy. The TGC therapy group received adjuvant therapy every 3 weeks postoperatively until the first recurrence, first metastasis, or death due to any reason, whichever occurred first. The patients were followed up telephonically and through outpatient visits to record and evaluate their disease-free survival (DFS) and treatment-related adverse events (TRAEs). RESULTS: This study assessed the DFS of 41 and 30 patients in the surveillance group and TGC therapy group, respectively. The median DFS of the surveillance group was 16.5 [95% confidence interval (CI), 14.7-18.3] months, while the median DFS of the TGC group has not yet reached [hazard ratio (HR) 0.367 (95% CI, 0.169-0.796); p = 0.008], with 21 patients still undergoing follow-up. Compared with the surveillance group, the TGC therapy group had dramatically improved DFS after RNU and reduced risk by 63.3%. Of the 30 patients receiving combination therapy, 28 experienced TRAEs; all TRAEs were consistent with the frequently reported events in the chemotherapy-alone regimens, and there were no treatment-related deaths. CONCLUSION: This study demonstrates that TGC therapy exhibits excellent clinical efficacy in patients undergoing radical surgery, significantly improving DFS and displaying great safety.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Cisplatin/therapeutic use , Gemcitabine , Carcinoma, Transitional Cell/drug therapy , Carcinoma, Transitional Cell/surgery , Retrospective Studies , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/surgery , Deoxycytidine/adverse effects , Muscles , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
BACKGROUND: In the management of urothelial carcinoma, patient selection for immunotherapy, particularly with immune checkpoint inhibitors such as PD-1 (programmed cell death protein 1), is important for treatment efficacy. Inflammatory markers are useful for predicting treatment outcomes and immune-related adverse events (irAEs). This study aims to retrospectively explore the associations between inflammatory markers and outcomes in patients with postoperative urothelial carcinoma undergoing tislelizumab (PD-1 inhibitor) adjuvant therapy. METHODS: A retrospective analysis was conducted on 133 patients with postoperative urothelial carcinoma who received tislelizumab adjuvant therapy at the Affiliated Hospital of Xuzhou Medical University from April 2020 to August 2023. The prognostic effects of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) on disease-free survival (DFS) and overall survival (OS) were assessed using Cox regression models. The correlation between inflammatory markers and the onset of irAEs was analyzed using logistic regression models. RESULTS: NLR < 5 and MLR < 0.31 were significantly associated with better outcomes compared to NLR >5 and MLR >0.31, respectively. Multivariate analysis revealed that an NLR < 5 was independently associated with better DFS and OS. However, there was no significant effect on the DFS and OS between PLR < 135 and PLR >135. Patients who experienced irAEs had longer DFS and OS. Multivariate analysis demonstrated that irAEs were an independent prognostic risk factor for DFS and OS. There was no significant difference in the occurrence of irAEs among different NLR, PLR, and MLR groups. CONCLUSION: In patients with postoperative urothelial carcinoma receiving tislelizumab adjuvant therapy, the assessment of NLR and MLR before treatment may serve as valuable predictive markers of clinical outcome.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Immune Checkpoint Inhibitors , Retrospective Studies , Carcinoma, Transitional Cell/pathology , Urinary Bladder Neoplasms/pathology , Platelet Count , Prognosis , Lymphocytes/pathology , Neutrophils/pathologyABSTRACT
The primordial to primary follicle transition (PPT) in the ovary is critical to maintain sustainable reproductive resources in female mammals. However, it is unclear how granulosa cells (GCs) of the primary follicle participate in regulating PPT. This study focused on exploring the role of transcription factor Sp1 (SP1) in regulating PPT based on the fact that SP1 is pivotal for pregranulosa cell proliferation before primordial follicle formation. The results showed that mice fertility was prolonged when Sp1 was specifically depleted from GCs (GC- Sp1 -/- ). Besides, the PPT in GC- Sp1 -/- mice was reduced, resulting in more primordial follicles being preserved. Single-cell RNA-seq also indicated that the level of cholesterol metabolism was downregulated in GC- Sp1 -/- mice. Additionally, the PPT was promoted by either overexpression of ferredoxin-1 (FDX1), one of the key genes in mediating cholesterol metabolism or supplementing cholesterol for cultured fetal ovaries. Collectively, SP1 in GCs participates in the metabolism of cholesterol partially by regulating the transcription of Fdx1 during the PPT.
Subject(s)
Granulosa Cells , Ovarian Follicle , Female , Mice , Animals , Ovarian Follicle/metabolism , Granulosa Cells/metabolism , Ovary/metabolism , Mammals , Lipid MetabolismABSTRACT
Diabetic cardiomyopathy (DCM) represents a distinct myocardial disorder elicited by diabetes mellitus, characterized by aberrations in myocardial function and structural integrity. This pathological condition predominantly manifests in individuals with diabetes who do not have concurrent coronary artery disease or hypertension. An escalating body of scientific evidence substantiates the pivotal role of programmed cell death (PCD)-encompassing apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis-in the pathogenic progression of DCM, thereby emerging as a prospective therapeutic target. Additionally, numerous non-coding RNAs (ncRNAs) have been empirically verified to modulate the biological processes underlying programmed cell death, consequently influencing the evolution of DCM. This review systematically encapsulates prevalent types of PCD manifest in DCM as well as nascent discoveries regarding the regulatory influence of ncRNAs on programmed cell death in the pathogenesis of DCM, with the aim of furnishing novel insights for the furtherance of research in PCD-associated disorders relevant to DCM.
Subject(s)
Apoptosis , Diabetic Cardiomyopathies , RNA, Untranslated , Diabetic Cardiomyopathies/pathology , Diabetic Cardiomyopathies/metabolism , Diabetic Cardiomyopathies/genetics , Humans , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Animals , Autophagy , Necroptosis/genetics , Pyroptosis/geneticsABSTRACT
OBJECTIVE: This prospective observational study aimed to evaluate the efficacy of radiofrequency ablation (RFA) in treating ≤ 2 cm thyroid nodules with Bethesda IV cytology and C-TIRADS 4A categorization. Additionally, the factors influencing the completed absorption of ablation (CAA) were examined. METHODS: A total of 62 cases with 62 nodules underwent ultrasound-guided RFA and were included in the study. The volume reduction rate (VRR), CAA, and incomplete absorption of ablation (IAA) were assessed at the 1st, 3rd, 6th, and subsequent 6-month follow-ups. Clinical and ultrasound features were compared between the CAA and IAA groups at the 12th month follow-up. RESULTS: The average VRR at the 1st, 3rd, 6th, 12th month, and last follow-up were -88.6%, 16.0%, 59.7%, 82.0%, and 98.2%, respectively. More than half of the nodules achieved a 90% VRR after 1 year of RFA, with 88.7% demonstrating CAA at the end of the study (follow-up duration of 14 to 63 months). Nodules with grade 3 vascularity and those associated with chronic thyroiditis showed delayed CAA at the 12th month follow-up (p = 0.036 and 0.003, respectively). CONCLUSION: RFA is an effective technique for treating ≤ 2 cm thyroid nodules with Bethesda IV cytology and C-TIRADS 4A categorization. Nodules with grade 3 blood supply and patients with chronic thyroiditis exhibited an impact on the completed absorption following RFA. CLINICAL RELEVANCE STATEMENT: Our study has shown that radiofrequency ablation is an effective treatment for ≤ 2 cm thyroid nodules classified as Bethesda IV cytology. However, we identified that high vascularity of the nodule and chronic thyroiditis are adverse factors affecting the completed absorption of the ablation. KEY POINTS: â¢Radiofrequency ablation (RFA) is an effective technique for treatment of ≤ 2 cm Bethesda IV category thyroid nodules. â¢Higher blood supply and chronic thyroiditis influence the completed absorption after RFA.
Subject(s)
Catheter Ablation , Hashimoto Disease , Radiofrequency Ablation , Thyroid Nodule , Thyroiditis , Humans , Thyroid Nodule/diagnostic imaging , Thyroid Nodule/surgery , Radiofrequency Ablation/methods , Treatment Outcome , Ultrasonography , Retrospective Studies , Catheter Ablation/methodsABSTRACT
Much progress has been made in advancing antiretroviral (ART) adherence, yet disparities remain. To explore relationships of syndemic conditions - co-occurring health conditions caused by combinations of biological, social, and structural factors - to ART adherence among African American men, we used data from longitudinal assessments of 302 African American men enrolled in a study designed to increase physical activity and healthy eating. Syndemic conditions included alcohol dependency, drug dependency, depression, post-traumatic stress disorder, and unstable housing. A syndemic conditions variable was operationalized to indicate the presence of 0-5 conditions. About 55% of participants had 1 or more syndemic conditions. Age and marriage were positively associated with ART adherence, whereas number of syndemic conditions was negatively associated with adherence during the 12-month period. The interaction of being married and the syndemic conditions variable significantly predicted greater adherence. Similarly, the interaction of more education and the syndemic conditions variable predicted greater adherence. In multiple regression models, the syndemic conditions variable remained significant (-0.018) in predicting adherence; however, there was no significant interaction among the 5 conditions. This study lends evidence to syndemics literature indicating deleterious consequences of negative life experiences on health outcomes.
Subject(s)
Anti-HIV Agents , Black or African American , HIV Infections , Medication Adherence , Syndemic , Urban Population , Adult , Humans , Male , Middle Aged , Alcoholism/epidemiology , Anti-HIV Agents/therapeutic use , Black or African American/statistics & numerical data , Black or African American/psychology , Depression/epidemiology , HIV Infections/drug therapy , HIV Infections/psychology , Longitudinal Studies , Medication Adherence/statistics & numerical data , Medication Adherence/psychology , Socioeconomic Factors , Stress Disorders, Post-Traumatic/epidemiology , Substance-Related Disorders/epidemiologyABSTRACT
This study employs cold-wall chemical vapor deposition to achieve the growth of MoTe2thin films on 4-inch sapphire substrates. A two-step growth process is utilized, incorporating MoO3and Te powder sources under low-pressure conditions to synthesize MoTe2. The resultant MoTe2thin films exhibit a dominant 1T' phase, as evidenced by a prominent Raman peak at 161 cm-1. This preferential 1T' phase formation is attributed to controlled manipulation of the second-step growth temperature, essentially the reaction stage between Te vapor and the pre-deposited MoOxlayer. Under these optimized growth conditions, the thickness of the continuous 1T'-MoTe2films can be precisely tailored within the range of 3.5-5.7 nm (equivalent to 5-8 layers), as determined by atomic force microscopy depth profiling. Hall-effect measurements unveil a typical hole concentration and mobility of 0.2 cm2Vs-1and 7.9 × 1021cm-3, respectively, for the synthesized few-layered 1T'-MoTe2films. Furthermore, Ti/Al bilayer metal contacts deposited on the few-layered 1T'-MoTe2films exhibit low specific contact resistances of approximately 1.0 × 10-4Ω cm2estimated by the transfer length model. This finding suggests a viable approach for achieving low ohmic contact resistance using the 1T'-MoTe2intermediate layer between metallic electrodes and two-dimensional semiconductors.
ABSTRACT
Activation and transdifferentiation of hepatic stellate cells (HSC) into migratory myofibroblasts is a key process in liver fibrogenesis. Cell migration requires an active remodeling of the cytoskeleton, which is a tightly regulated process coordinated by Rho-specific guanine nucleotide exchange factors (GEFs) and the Rho family of small GTPases. Rho-associated kinase (ROCK) promotes assembly of focal adhesions and actin stress fibers by regulating cytoskeleton organization. GEF exchange protein directly activated by cAMP 1 (EPAC1) has been implicated in modulating TGFß1 and Rho signaling; however, its role in HSC migration has never been examined. The aim of this study was to evaluate the role of cAMP-degrading phosphodiesterase 4 (PDE4) enzymes in regulating EPAC1 signaling, HSC migration, and fibrogenesis. We show that PDE4 protein expression is increased in activated HSCs expressing alpha smooth muscle actin and active myosin light chain (MLC) in fibrotic tissues of human nonalcoholic steatohepatitis cirrhosis livers and mouse livers exposed to carbon tetrachloride. In human livers, TGFß1 levels were highly correlated with PDE4 expression. TGFß1 treatment of LX2 HSCs decreased levels of cAMP and EPAC1 and increased PDE4D expression. PDE4 specific inhibitor, rolipram, and an EPAC-specific agonist decreased TGFß1-mediated cell migration in vitro. In vivo, targeted delivery of rolipram to the liver prevented fibrogenesis and collagen deposition and decreased the expression of several fibrosis-related genes, and HSC activation. Proteomic analysis of mouse liver tissues identified the regulation of actin cytoskeleton by the kinase effectors of Rho GTPases as a major pathway impacted by rolipram. Western blot analyses confirmed that PDE4 inhibition decreased active MLC and endothelin 1 levels, key proteins involved in cytoskeleton remodeling and contractility. The current study, for the first time, demonstrates that PDE4 enzymes are expressed in hepatic myofibroblasts and promote cytoskeleton remodeling and HSC migration. © 2023 The Pathological Society of Great Britain and Ireland.
Subject(s)
Actins , Cyclic Nucleotide Phosphodiesterases, Type 4 , Animals , Humans , Mice , Actins/metabolism , Cell Movement , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cytoskeleton/metabolism , Cytoskeleton/pathology , Fibrosis , Hepatic Stellate Cells/metabolism , Liver Cirrhosis/pathology , Proteomics , Rolipram/metabolismABSTRACT
OBJECTIVES: Lymphocyte subsets are the predictors of disease diagnosis, treatment, and prognosis. Determination of lymphocyte subsets is usually carried out by flow cytometry. Despite recent advances in flow cytometry analysis, most flow cytometry data can be challenging with manual gating, which is labor-intensive, time-consuming, and error-prone. This study aimed to develop an automated method to identify lymphocyte subsets. METHODS: We propose a knowledge-driven combined with data-driven method which can gate automatically to achieve subset identification. To improve accuracy and stability, we have implemented a Loop Adjustment Gating to optimize the gating result of the lymphocyte population. Furthermore, we have incorporated an anomaly detection mechanism to issue warnings for samples that might not have been successfully analyzed, ensuring the quality of the results. RESULTS: The evaluation showed a 99.2â¯% correlation between our method results and manual analysis with a dataset of 2,000 individual cases from lymphocyte subset assays. Our proposed method attained 97.7â¯% accuracy for all cases and 100â¯% for the high-confidence cases. With our automated method, 99.1â¯% of manual labor can be saved when reviewing only the low-confidence cases, while the average turnaround time required is only 29â¯s, reducing by 83.7â¯%. CONCLUSIONS: Our proposed method can achieve high accuracy in flow cytometry data from lymphocyte subset assays. Additionally, it can save manual labor and reduce the turnaround time, making it have the potential for application in the laboratory.
Subject(s)
Flow Cytometry , Lymphocyte Subsets , Lymphocyte Subsets/classification , Lymphocyte Subsets/cytology , Flow Cytometry/methods , Flow Cytometry/standards , Automation, Laboratory , Reproducibility of Results , HumansABSTRACT
OBJECTIVE: This study aims to investigate the efficacy and safety of snare traction-assisted endoscopic submucosal dissection (ESD) for the management of circumferential superficial esophageal cancer. METHODS: A total of 68 patients who underwent ESD for circumferential superficial esophageal cancer were included in this study. All the patients were divided into two groups based on whether the snare traction was used or not; the snare traction group (S-ESD, group n = 35) and the control group (C-ESD, group n = 33). RESULTS: There was no significant difference in the size of the resected area between the groups [21.98 (18.30, 27.00) cm2 vs 24.00 (15.28, 30.72) cm2, P = 0.976]. The snare traction group had a shorter dissection time [92.00 (74.00, 121.00) min vs 110.00 (92.50, 137.00) min, P = 0.017] and a faster resection speed [0.28 ± 0.13 cm2/min vs 0.22 ± 0.11cm2/min, P = 0.040] compared to the control group. There were no statistically significant differences between the two groups in terms of hospital stay, cost, en bloc resection rate, R0 resection rate, curative resection rate, bleeding rate, perforation rate, stricture rate, and recurrence rate (P > 0.05). CONCLUSION: Snare traction-assisted ESD is a safe and efficient approach for the treatment of circumferential superficial esophageal cancer. Its advantages includes shorter procedure so the anesthesia requirement, clear operative filed view, improved mucosal dissection efficiency, simple, and easily accessible equipment.
Subject(s)
Endoscopic Mucosal Resection , Esophageal Neoplasms , Humans , Endoscopic Mucosal Resection/methods , Endoscopic Mucosal Resection/instrumentation , Endoscopic Mucosal Resection/adverse effects , Esophageal Neoplasms/surgery , Esophageal Neoplasms/pathology , Male , Female , Middle Aged , Aged , Treatment Outcome , Traction/methods , Retrospective Studies , Operative Time , Esophagoscopy/methodsABSTRACT
OBJECTIVE: To investigate the safety and prognosis of enbloc or piecemeal removal after enbloc resection of a gastric GIST by comparing the clinical data of endoscopic en block resection and piecemeal removal (EP) and en block resection and complete removal (EC) of gastric GISTs. METHODS: A total of 111 (43 endoscopic piecemeal, and 68 complete removal) patients with gastric GIST's ≥ 2 cm in diameter who underwent endoscopic therapy from January 2016 to June 2020 at the First Affiliated Hospital of Zhengzhou University were retrospectively analyzed. In all cases, it was ensured that the tumor was intact during the resection, however, it was divided into EP group and EC group based on whether the tumor was completely removed or was cut into pieces which were then removed. The patients' recurrence-free survival rate and recurrence-free survival (RFS) were recorded. RESULTS: There was no statistically significant difference in RFS rates between the two groups (P = 0.197). The EP group had relatively high patient age, tumor diameter, risk classification, and operation time. However, there was no statistically significant difference in the number of nuclear fission images, postoperative hospitalization time, postoperative fasting time, complication rate and complication grading between the two groups (P > 0.05). CONCLUSION: Endoscopic piecemeal removal after en block resection of gastric GIST is safe and effective and achieves similar clinical outcomes as complete removal after en block resection.
Subject(s)
Gastrointestinal Stromal Tumors , Humans , Gastrointestinal Stromal Tumors/surgery , Gastrointestinal Stromal Tumors/pathology , Female , Male , Middle Aged , Retrospective Studies , Aged , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Adult , Treatment Outcome , Gastroscopy/methodsABSTRACT
BACKGROUND: Noninvasive prenatal testing (NIPT) for fetal aneuploidy relies on the analysis of fetoplacental cell-free DNA (cfDNA) found in maternal plasma. A minimum cfDNA fetal fraction (FF) is required for reliable test performance, but some methods may have suboptimal accuracy for FF measurement. This study investigated the accuracy of a single-nucleotide polymorphism- (SNP-) based NIPT method to assess FF. METHODS: FF measurements using SNP-based NIPT in consecutive samples from singleton male pregnancies were compared with FF measured using a "gold standard" Y-chromosome method. RESULTS: In a cohort of 106,846 samples, the SNP-based FF method showed a standard deviation (SD) of 0.42%. Compared to the Y chromosome FF method, a correlation coefficient, r, of 0.995, and bias of 0.17% were observed. The SD was not substantially different across specific FF ranges or for samples with high-risk NIPT results. CONCLUSIONS: The SNP-based NIPT method estimates FF with good accuracy, with a SD three to eight times better than other NIPT methods (0.42% vs. 1.3%-3.4%). FF is an important quality control parameter and should be routinely reported as part of NIPT.
ABSTRACT
BACKGROUND: We examined the association of objective measures of cardiometabolic risk with progression to a high-risk for advanced fibrosis in patients with MASLD at initially low- and indeterminate-risk for advanced fibrosis. METHODS: We performed a retrospective cohort study of primary care patients with MASLD between 2012 and 2021. We evaluated patients with MASLD and low- or indeterminate-risk Fibrosis-4 Index (FIB-4) scores and followed them until the outcome of a high-risk FIB-4 (>2.67), or the end of the study period. Exposures of interest were body mass index (BMI), systolic blood pressure (SBP), hemoglobin A1c, cholesterol, estimated glomerular filtration rate (eGFR), and smoking status. Variables were categorized by the threshold for primary care therapy intensification. Unadjusted and adjusted Cox regression models were developed for the outcome of time to a high-risk FIB-4 value. RESULTS: The cohort included 1,347 patients with a mean follow-up of 3.6 years (SD 2.7). Of the cohort, 258 (19%) had a subsequent FIB-4 > 2.67. In the fully adjusted Cox regression models, mean SBP > 150 mm Hg (1.57; 95%CI 1.02-2.41) and eGFR < 59 ml/min (HR 2.78; 95%CI 2.17-3.58) were associated with an increased hazard of a high-risk FIB-4, while receiving a statin prescription (HR 0.51; 95%CI 0.39-0.66) was associated with a lower risk. CONCLUSIONS: Nearly 1 in 5 primary care patients with MASLD transitioned to a high-risk FIB-4 score during 3.6 years of follow-up, and uncontrolled blood pressure and reduced kidney function were associated with an increased hazard of a FIB-4 at high-risk for advanced fibrosis.