AcornHRD: an HRD algorithm highly associated with anthracycline-based neoadjuvant chemotherapy in breast cancer in China.

PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.

Role of Phenylethanolamine-N-methyltransferase on Nicotine-Induced Vasodilation in Rat Cerebral Arteries.

OBJECTIVE: The sympathetic-parasympathetic (or axo-axonal) interaction mechanism mediated that neurogenic relaxation, which was dependent on norepinephrine (NE) releases from sympathetic nerve terminal and acts on ß2-adrenoceptor of parasympathetic nerve terminal, has been reported. As NE is a weak ß2-adrenoceptor agonist, there is a possibility that synaptic NE is converted to epinephrine by phenylethanolamine-N-methyltransferase (PNMT) and then acts on the ß2-adrenoceptors to induce neurogenic vasodilation. METHODS: Blood vessel myography technique was used to measure relaxation and contraction responses of isolated basilar arterial rings of rats. RESULTS: Nicotine-induced relaxation was sensitive to propranolol, guanethidine (an adrenergic neuronal blocker), and Nω-nitro-l-arginine. Nicotine- and exogenous NE-induced vasorelaxation was partially inhibited by LY-78335 (a PNMT inhibitor), and transmural nerve stimulation depolarized the nitrergic nerve terminal directly and was not inhibited by LY-78335; it then induced the release of nitric oxide (NO). Epinephrine-induced vasorelaxation was not affected by LY-78335. However, these vasorelaxations were completely inhibited by atenolol (a ß1-adrenoceptor antagonist) combined with ICI-118,551 (a ß2-adrenoceptor antagonist). CONCLUSIONS: These results suggest that NE may be methylated by PNMT to form epinephrine and cause the release of NO and vasodilation. These results provide further evidence supporting the physiological significance of the axo-axonal interaction mechanism in regulating brainstem vascular tone.

Classification of multiple primary lung cancer in patients with multifocal lung cancer: assessment of a machine learning approach using multidimensional genomic data.

Background: Multiple primary lung cancer (MPLC) is an increasingly well-known clinical phenomenon. However, its molecular characterizations are poorly understood, and still lacks of effective method to distinguish it from intrapulmonary metastasis (IM). Herein, we propose an identification model based on molecular multidimensional analysis in order to accurately optimize treatment. Methods: A total of 112 Chinese lung cancers harboring at least two tumors (n = 270) were enrolled. We retrospectively selected 74 patients with 121 tumor pairs and randomly divided the tumor pairs into a training cohort and a test cohort in a 7:3 ratio. A novel model was established in training cohort, optimized for MPLC identification using comprehensive genomic profiling analyzed by a broad panel with 808 cancer-related genes, and evaluated in the test cohort and a prospective validation cohort of 38 patients with 112 tumors. Results: We found differences in molecular characterizations between the two diseases and rigorously selected the characterizations to build an identification model. We evaluated the performance of the classifier using the test cohort data and observed an 89.5% percent agreement (PA) for MPLC and a 100.0% percent agreement for IM. The model showed an excellent area under the curve (AUC) of 0.947 and a 91.3% overall accuracy. Similarly, the assay achieved a considerable performance in the independent validation set with an AUC of 0.938 and an MPLC predictive value of 100%. More importantly, the MPLC predictive value of the classification achieved 100% in both the test set and validation cohort. Compared to our previous mutation-based method, the classifier showed better κ consistencies with clinical classification among all 112 patients (0.84 vs. 0.65, p <.01). Conclusion: These data provide novel evidence of MPLC-specific genomic characteristics and demonstrate that our one-step molecular classifier can accurately classify multifocal lung tumors as MPLC or IM, which suggested that broad panel NGS may be a useful tool for assisting with differential diagnoses.

Glycyrrhetinic acid loaded in milk-derived extracellular vesicles for inhalation therapy of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and life-threatening lung disease for which treatment options are limited. Glycyrrhetinic acid (GA) is a triterpenoid with multiple biological effects, such as anti-inflammatory and anti-fibrotic properties. Herein, inhalable milk-derived extracellular vesicles (mEVs) encapsulating GA (mEVs@GA) were screened and evaluated for IPF treatment. The results indicated that the loading efficiency of GA in mEVs@GA was 8.65%. Therapeutic effects of inhalable mEVs@GA were investigated in vitro and in vivo. The mEVs@GA demonstrated superior anti-inflammatory effects on LPS-stimulated MHS cells. Furthermore, repeated noninvasive inhalation delivery of mEVs@GA in bleomycin-induced IPF mice could decrease the levels of transforming growth factors ß1 (TGF-ß1), Smad3 and inflammatory cytokines IL-6, IL-1ß and TNF-α. The mEVs@GA effectively diminished the development of fibrosis and improved pulmonary function in the IPF mice model at a quarter of the dose compared with the pirfenidone oral administration group. Additionally, compared to pirfenidone-loaded mEVs, mEVs@GA demonstrated superior efficacy at the same drug concentration in the pharmacodynamic study. Overall, inhaled mEVs@GA have the potential to serve as an effective therapeutic option in the treatment of IPF.

Macrophage hitchhiking for systematic suppression in postablative multifocal HCC.

BACKGROUND AND AIMS: HCC, particularly the multifocal HCC, features aggressive invasion and dismal prognosis. Locoregional treatments were often refractory to eliminate tumor tissue, resulting in residual tumor cells persisting and subsequent progression. Owing to problematic delivery to the tumor tissue, systemic therapies, such as lenvatinib (LEN) therapy, show limited clinical benefit in preventing residual tumor progression. Therefore, more advanced strategies for postablative multifocal HCC are urgently needed. APPROACH AND RESULTS: Motivated by the chemotaxis in tumor penetration of macrophages, we report a strategy named microinvasive ablation-guided macrophage hitchhiking for the targeted therapy toward HCC. In this study, the strategy leverages the natural inflammatory gradient induced by ablation to guide LEN-loaded macrophages toward tumor targeting, which increased by ~10-fold the delivery efficiency of LEN in postablative HCC in vivo. Microinvasive ablation-guided macrophage hitchhiking has demonstrated significant antitumor activity in various HCC models, including the hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice. The potential antitumor mechanism was explored using techniques such as flow cytometry, ELISA, and immunohistochemistry. We found that the strategy significantly suppressed tumor cell proliferation and neovascularization, and such enhanced delivery of LEN stimulated systemic immune responses and induced durable immune memory. CONCLUSIONS: The macrophage hitchhiking strategy demonstrates exceptional therapeutic efficacy and biosafety across various species, offering promising prospects for clinical translation in controlling residual tumor progression and improving outcomes following HCC ablation.

Exploring the Super-Relaxed State of Human Cardiac ß-Myosin by Molecular Dynamics Simulations.

Human ß-cardiac myosin plays a critical role in generating the mechanical forces necessary for cardiac muscle contraction. This process relies on a delicate dynamic equilibrium between the disordered relaxed state (DRX) and the super-relaxed state (SRX) of myosin. Disruptions in this equilibrium due to mutations can lead to heart diseases. However, the structural characteristics of SRX and the molecular mechanisms underlying pathogenic mutations have remained elusive. To bridge this gap, we conducted molecular dynamics simulations and free energy calculations to explore the conformational changes in myosin. Our findings indicate that the size of the phosphate-binding pocket can serve as a valuable metric for characterizing the transition from the DRX to SRX state. Importantly, we established a global dynamic coupling network within the myosin motor head at the residue level, elucidating how the pathogenic mutation E483K impacts the equilibrium between SRX and DRX through allosteric effects. Our work illuminates molecular details of SRX and offers valuable insights into disease treatment through the regulation of SRX.

Exploration of Solid Solutions and the Strengthening of Aluminum Substrates by Alloying Atoms: Machine Learning Accelerated Density Functional Theory Calculations.

In this paper, we studied the effects of a series of alloying atoms on the stability and micromechanical properties of aluminum alloy using a machine learning accelerated first-principles approach. In our preliminary work, high-throughput first-principles calculations were explored and the solution energy and theoretical stress of atomically doped aluminum substrates were extracted as basic data. By comparing five different algorithms, we found that the Catboost model had the lowest RMSE (0.24) and lowest MAPE (6.34), and this was used as the final prediction model to predict the solid solution strengthening of the aluminum matrix by the elements. Calculations show that alloying atoms such as K, Na, Y and Tl are difficult to dissolve in the aluminum matrix, whereas alloy atoms like Sc, Cu, B, Zr, Ni, Ti, Nb, V, Cr, Mn, Mo, and W exerted a strengthening influence. Theoretical studies on solid solutions and the strengthening effect of various alloy atoms in an aluminum matrix can offer theoretical guidance for the subsequent selection of suitable alloy elements. The theoretical investigation of alloy atoms in an aluminum matrix unveils the fundamental aspects of the solution strengthening effect, contributing significantly to the expedited development of new aluminum alloys.

Serum THBS2 is a potential biomarker for the diagnosis of non-small cell lung cancer.

OBJECTIVE: This study primarily aimed to analyze the levels of THBS2 in the serum of patients diagnosed with non-small cell lung cancer (NSCLC), and subsequently evaluate its potential as a diagnostic biomarker for NSCLC. METHODS: Serum samples were collected from 150 diagnosed NSCLC patients and 150 healthy individuals. The THBS2 concentration in these samples was determined using an enzyme-linked immunosorbent assay (ELISA). The study also investigated the correlation between THBS2 levels and various clinicopathological characteristics in NSCLC patients. The diagnostic sensitivity and specificity of serum THBS2 for NSCLC were assessed using receiver operating characteristic (ROC) curves and their corresponding area under the curve (AUC). RESULTS: Serum THBS2 levels in NSCLC patients were significantly elevated compared to those in healthy individuals. THBS2 levels showed a significant correlation with tumor differentiation grade, tumor size, TNM stage, lymph node metastasis, and distant metastasis. No significant correlation was identified between serum THBS2 levels and other parameters such as gender, age, height, weight, BMI, smoking history, and tumor histological type. At a cutoff value of 7.62 ng/mL, THBS2 could effectively differentiate NSCLC patients from healthy individuals, with a sensitivity of 85.31% and a specificity of 88.92%. The AUC for NSCLC diagnosis using THBS2 was 0.812, significantly surpassing the performance of traditional tumor markers tested, including CEA (0.728), and CYFRA 21­1 (0.685). CONCLUSIONS: Elevated serum THBS2 levels in NSCLC patients suggest its potential as a novel and reliable diagnostic biomarker for NSCLC. Its superior diagnostic performance could potentially outperform traditional tumor markers, leading to improved patient outcomes.

Effects of Different Molecular Weight Oxidized Dextran as Crosslinkers on Stability and Antioxidant Capacity of Curcumin-Loaded Nanoparticles.

Curcumin is a polyphenolic compound that has been widely investigated for its health benefits. However, the clinical relevance of curcumin is limited due to its low water solubility and inefficient absorption. Therefore, curcumin is often encapsulated in nanocarriers to improve its delivery and function. In this study, composite nanoparticles composed of stearic acid-modified chitosan (SA-CS) and sodium caseinate (NaCas) were formed using sodium periodate-oxidized dextran with different molecular weights as a crosslinking agent. The effects of oxidized dextran (Odex) with different molecular weights on the composite nanoparticles were compared. The optimal SA-CS/NaCas/Odex composite nanoparticle (NPO) was obtained using an Odex (150 kDa)-to-SA-CS mass ratio of 2:1. Its size, polydispersity index (PDI), and zeta potential (ZP) were 130.2 nm, 0.149, and 25.4 mV, respectively. The particles were highly stable in simulated gastric fluid (SGF) in vitro, and their size and PDI were 172.3 nm and 0.263, respectively. The encapsulation rate of NPO loaded with curcumin (Cur-NPO) was 93% under optimal ultrasonic conditions. Compared with free curcumin, the sustained release of Cur-NPO significantly reduced to 17.9%, and free-radical-scavenging ability improved to 78.7%. In general, the optimal prepared NPO exhibited good GI stability and has potential applications in the formulation of orally bioactive hydrophobic drugs.

Modeling the effects of phosphorylation on phase separation of the FUS low-complexity domain.

Aggregation of the RNA-binding protein fused in sarcoma (FUS) is a hallmark of neurodegenerative diseases. Phosphorylation of Ser/Thr in the FUS low-complexity domain (FUS-LC) may regulate phase separation of FUS and prevent pathological aggregation in cells. However, many details of this process remain elusive to date. In this work, we systematically investigated the phosphorylation of FUS-LC and the underlying molecular mechanism by molecular dynamics (MD) simulations and free energy calculations. The results clearly show that phosphorylation can destroy the fibril core structure of FUS-LC by breaking interchain interactions, particularly contacts involving residues like Tyr, Ser, and Gln. Among the six phosphorylation sites, Ser61 and Ser84 may have more important effects on the stability of the fibril core. Our study reveals structural and dynamic details of FUS-LC phase separation modulated by phosphorylation.

All-oil Constructs Stabilized by Cellulose Nanocrystal Surfactants.

Constructing all-oil systems with desired geometries and responsiveness would produce a new class of reconfigurable materials that can be used for applications that are not compatible with water or aqueous systems, a fascinating goal to achieve but severely limited by the lack of surfactants. Here, we demonstrate an efficient strategy to stabilize oil-oil interfaces by using the co-assembly between the cellulose nanocrystal and amine-functionalized polyhedral oligomeric silsesquioxane (POSS-NH2). Cellulose nanocrystal surfactants (CNCSs) form and assemble in situ at the interface, showing significantly enhanced binding energy and acid-dependent interfacial activity. When CNCSs jam at the interface, a robust assembly with exceptional mechanical properties can be achieved, allowing the 3D printing of all-oil devices on demand. Using CNCSs as emulsifiers, oil-in-oil high internal phase emulsions can be prepared by one-step homogenization and, when used as templates, porous materials that require water-sensitive monomers can be synthesized. These results open a new platform for stabilizing and structuring all-oil systems, providing numerous applications for microreactors, encapsulation, delivery, and tissue engineering scaffolds.

Effect of Temperatures and Graphene on the Mechanical Properties of the Aluminum Matrix: A Molecular Dynamics Study.

Graphene has become an ideal reinforcement for reinforced metal matrix composites due to its excellent mechanical properties. However, the theory of graphene reinforcement in graphene/aluminum matrix composites is not yet well developed. In this paper, the effect of different temperatures on the mechanical properties of the metal matrix is investigated using a classical molecular dynamics approach, and the effects of the configuration and distribution of graphene in the metal matrix on the mechanical properties of the composites are also described in detail. It is shown that in the case of a monolayer graphene-reinforced aluminum matrix, the simulated stretching process does not break the graphene as the strain increases, but rather, the graphene and the aluminum matrix have a shearing behavior, and thus, the graphene "pulls out" from the aluminum matrix. In the parallel stretching direction, the tensile stress tends to increase with the increase of the graphene area ratio. In the vertical stretching direction, the tensile stress tends to decrease as the percentage of graphene area increases. In the parallel stretching direction, the tensile stress of the system tends to decrease as the angle between graphene and the stretching direction increases. It is important to investigate the effect of a different graphene distribution in the aluminum matrix on the mechanical properties of the composites for the design of high-strength graphene/metal matrix composites.

The Acute Effects and Mechanism of Ketamine on Nicotine-Induced Neurogenic Relaxation of the Corpus Cavernosum in Mice.

The present study aimed to investigate the acute effects and the mechanism of ketamine on nicotine-induced relaxation of the corpus cavernosum (CC) in mice. This study measured the intra-cavernosal pressure (ICP) of male C57BL/6 mice and the CC muscle activities using an organ bath wire myograph. Various drugs were used to investigate the mechanism of ketamine on nicotine-induced relaxation. Direct ketamine injection into the major pelvic ganglion (MPG) inhibited MPG-induced increases in ICP. D-serine/L-glutamate-induced relaxation of the CC was inhibited by MK-801 (N-methyl-D-aspartate (NMDA) receptor inhibitor), and nicotine-induced relaxation was enhanced by D-serine/L-glutamate. NMDA had no effect on CC relaxation. Nicotine-induced relaxation of the CC was suppressed by mecamylamine (a non-selective nicotinic acetylcholine receptor antagonist), lidocaine, guanethidine (an adrenergic neuronal blocker), Nw-nitro-L-arginine (a non-selective nitric oxide synthase inhibitor), MK-801, and ketamine. This relaxation was almost completely inhibited in CC strips pretreated with 6-hydroxydopamine (a neurotoxic synthetic organic compound). Ketamine inhibited cavernosal nerve neurotransmission via direct action on the ganglion and impaired nicotine-induced CC relaxation. The relaxation of the CC was dependent on the interaction of the sympathetic and parasympathetic nerves, which may be mediated by the NMDA receptor.

Protocol for the identification and expression analysis of a cytoplasmic membrane-localized protein STING.

Here, we present a protocol for the detection of the two STING isoforms (erSTING and pmSTING) in human peripheral blood mononuclear cells or mouse splenocytes using Western blot and PCR. We detail steps to construct plasmids encoding each isoform and transfer them into mouse and human cell lines. Finally, we describe how to detect cell membrane localization of pmSTING using flow cytometry, immunoprecipitation, and immunofluorescence. This protocol is applicable for proteins with well-predicted topological structures. For complete details on the use and execution of this protocol, please refer to Li et al.1.

A large-scale screening and functional sorting of tumour microenvironment prognostic genes for breast cancer patients.

Purpose: The aim of this study was to systematically establish a comprehensive tumour microenvironment (TME)-relevant prognostic gene and target miRNA network for breast cancer patients. Methods: Based on a large-scale screening of TME-relevant prognostic genes (760 genes) for breast cancer patients, the prognostic model was established. The primary TME prognostic genes were selected from the constructing database and verified in the testing database. The internal relationships between the potential TME prognostic genes and the prognosis of breast cancer patients were explored in depth. The associated miRNAs for the TME prognostic genes were generated, and the functions of each primary TME member were investigated in the breast cancer cell line. Results: Compared with sibling controls, breast cancer patients showed 55 differentially expressed TME prognostic genes, of which 31 were considered as protective genes, while the remaining 24 genes were considered as risk genes. According to the lambda values of the LASSO Cox analysis, the 15 potential TME prognostic genes were as follows: ENPEP, CCDC102B, FEZ1, NOS2, SCG2, RPLP2, RELB, RGS3, EMP1, PDLIM4, EPHA3, PCDH9, VIM, GFI1, and IRF1. Among these, there was a remarkable linear internal relationship for CCDC102B but non-linear relationships for others with breast cancer patient prognosis. Using the siRNA technique, we silenced the expression of each TME prognostic gene. Seven of the 15 TME prognostic genes (NOS2, SCG2, RGS3, EMP1, PDLIM4, PCDH9, and GFI1) were involved in enhancing cell proliferation, destroying cell apoptosis, promoting cell invasion, or migration in breast cancer. Six of them (CCDC102B, RPLP2, RELB, EPHA3, VIM, and IRF1) were favourable for maintaining cell invasion or migration. Only two of them (ENPEP and FEZ1) were favourable for the processes of cell proliferation and apoptosis. Conclusions: This integrated study hypothesised an innovative TME-associated genetic functional network for breast cancer patients. The external relationships between these TME prognostic genes and the disease were measured. Meanwhile, the internal molecular mechanisms were also investigated.

Effect of annualized surgeon volume on major surgical complications for abdominal and laparoscopic radical hysterectomy for cervical cancer in China, 2004-2016: a retrospective cohort study.

BACKGROUND: Previous studies have suggested that higher surgeon volume leads to improved perioperative outcomes for oncologic surgery; however, the effect of surgeon volumes on surgical outcomes might differ according to the surgical approach used. This paper attempts to evaluate the effect of surgeon volume on complications or cervical cancer in an abdominal radical hysterectomy (ARH) cohort and laparoscopic radical hysterectomy (LRH) cohort. METHODS: We conducted a population-based retrospective study using the Major Surgical Complications of Cervical Cancer in China (MSCCCC) database to analyse patients who underwent radical hysterectomy (RH) from 2004 to 2016 at 42 hospitals. We estimated the annualized surgeon volumes in the ARH cohort and in the LRH cohort separately. The effect of the surgeon volume of ARH or LRH on surgical complications was examined using multivariable logistic regression models. RESULTS: In total, 22,684 patients who underwent RH for cervical cancer were identified. In the abdominal surgery cohort, the mean surgeon case volume increased from 2004 to 2013 (3.5 to 8.7 cases) and then decreased from 2013 to 2016 (8.7 to 4.9 cases). The mean surgeon case volume number of surgeons performing LRH increased from 1 to 12.1 cases between 2004 and 2016 (P < 0.01). In the abdominal surgery cohort, patients treated by intermediate-volume surgeons were more likely to experience postoperative complications (OR = 1.55, 95% CI = 1.11-2.15) than those treated by high-volume surgeons. In the laparoscopic surgery cohort, surgeon volume did not appear to influence the incidence of intraoperative or postoperative complications (P = 0.46; P = 0.13). CONCLUSIONS: The performance of ARH by intermediate-volume surgeons is associated with an increased risk of postoperative complications. However, surgeon volume may have no effect on intraoperative or postoperative complications after LRH.

Encapsulating gold nanoclusters into metal-organic frameworks to boost luminescence for sensitive detection of copper ions and organophosphorus pesticides.

Gold nanoclusters (Au NCs) with luminescence property are emerging as promising candidates in fluorescent methods for monitoring contaminants, but low luminescence efficiency hampers their extensive applications. Herein, GSH-Au NCs@ZIF-8 was designed by encapsulating GSH-Au NCs with AIE effect into metal-organic frameworks, achieving high luminescence efficiency and good stability through the confinement effect of ZIF-8. Accordingly, a fluorescent sensing platform was constructed for the sensitive detection of copper ions (Cu2+) and organophosphorus pesticides (OPs). Firstly, the as-prepared GSH-Au NCs@ZIF-8 could strongly accumulate Cu2+ due to the adsorption property of MOFs, accompanied by a significant fluorescence quenching effect with a low detection limit of 0.016 µM for Cu2+. Besides, thiocholine (Tch), the hydrolysis product of acetylthiocholine (ATch) by acetylcholinesterase (AchE), could coordinate with Cu2+ by sulfhydryl groups (-SH), leading to a significant fluorescence recovery, which was further used for the quantification of OPs owing to its inhibition to AChE activity. Furthermore, a hydrogel sensor was explored to accomplish equipment-free, visual, and quantitative monitoring of Cu2+ and OPs by a smartphone sensing platform. Overall, this work provides an effective and universal strategy for enhancing the luminescence efficiency and stability of Au NCs, which would greatly promote their applications in contaminants monitoring.

Case report: Targeted sequencing facilitates the diagnosis and management of rare multifocal pure ground-glass opacities with intrapulmonary metastasis.

Introduction: Treatments for multiple ground-glass opacities (GGOs) for which the detection rate is increasing are still controversial. Next-generation sequencing (NGS) may provide additional key evidence for differential diagnosis or optimal therapeutic schedules. Case presentation: We first reported a rare case in which more than 100 bilateral pulmonary GGOs (91.7% of the GGOs were pure GGOs) were diagnosed as both multiple primary lung cancer and intrapulmonary metastasis. We performed NGS with an 808-gene panel to assess both somatic and germline alterations in tissues and plasma. The patient (male) underwent three successive surgeries and received osimertinib adjuvant therapy due to signs of metastasis and multiple EGFR-mutated tumors. The patient had multiple pure GGOs, and eight tumors of four pathological subtypes were evaluated for the clonal relationship. Metastasis, including pure GGOs and atypical adenomatous hyperplasia, was found between two pairs of tumors. Circulating tumor DNA (ctDNA) monitoring of disease status may impact clinical decision-making. Conclusions: Surgery combined with targeted therapies remains a reasonable alternative strategy for treating patients with multifocal GGOs, and NGS is valuable for facilitating diagnostic workup and adjuvant therapy with targeted drugs through tissue and disease monitoring via ctDNA.

The predictive value of pressure recording analytical method for the duration of mechanical ventilation in children undergoing cardiac surgery with an XGBoost-based machine learning model.

Objective: Prolonged mechanical ventilation in children undergoing cardiac surgery is related to the decrease in cardiac output. The pressure recording analytical method (PRAM) is a minimally invasive system for continuous hemodynamic monitoring. To evaluate the postoperative prognosis, our study explored the predictive value of hemodynamic management for the duration of mechanical ventilation (DMV). Methods: This retrospective study included 60 infants who underwent cardiac surgery. Cardiac index (CI), the maximal slope of systolic upstroke (dp/dtmax), and cardiac cycle efficiency (CCE) derived from PRAM were documented in each patient 0, 4, 8, and 12 h (T0, T1, T2, T3, and T4, respectively) after their admission to the intensive care unit (ICU). A linear mixed model was used to deal with the hemodynamic data. Correlation analysis, receiver operating characteristic (ROC), and a XGBoost machine learning model were used to find the key factors for prediction. Results: Linear mixed model revealed time and group effect in CI and dp/dtmax. Prolonged DMV also have negative correlations with age, weight, CI at and dp/dtmax at T2. dp/dtmax outweighing CI was the strongest predictor (AUC of ROC: 0.978 vs. 0.811, p < 0.01). The machine learning model suggested that dp/dtmax at T2 ≤ 1.049 or < 1.049 in combination with CI at T0 ≤ 2.0 or >2.0 can predict whether prolonged DMV (AUC of ROC = 0.856). Conclusion: Cardiac dysfunction is associated with a prolonged DMV with hemodynamic evidence. CI measured by PRAM immediately after ICU admission and dp/dtmax 8h later are two key factors in predicting prolonged DMV.

Porcine deltacoronavirus E protein induces interleukin-8 production via NF-κB and AP-1 activation.

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and interleukin-6 (IL-6). Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present study, we found that interleukin-8 (IL-8) was upregulated by PDCoV infection. We then demonstrated that PDCoV E protein induced IL-8 production and that the TM domain and the C-terminal domain of the E protein were important for IL-8 production. Subsequently, we showed here that deleting the AP-1 and NF-κB binding motif in porcine IL-8 promoter abrogated its activation, suggesting that IL-8 expression was dependent on AP-1 and NF-κB. Furthermore, PDCoV E induced IL-8 production, which was also dependent on the NF-κB pathway through activating nuclear factor p65 phosphorylation and NF-κB inhibitor alpha (IκBα) protein phosphorylation, as well as inducing the nuclear translocation of p65, eventually resulting in the promotion of IL-8 production. PDCoV E also activated c-fos and c-jun, both of which are members of the AP-1 family. These findings provide new insights into the molecular mechanisms of PDCoV-induced IL-8 production and help us further understand the pathogenesis of PDCoV infection.