Sponge-derived alkaloid AP-7 as a sensitizer to cisplatin in the treatment of multidrug-resistant NSCLC via Chk1-dependent mechanisms.

Multidrug resistance is a substantial obstacle in treating non-small cell lung cancer (NSCLC) with therapies like cisplatin (DDP)-based adjuvant chemotherapy and EGFR-tyrosine kinase inhibitors (TKIs). Aaptamine-7 (AP-7), a benzonaphthyridine alkaloid extracted from Aaptos aaptos sponge, has been shown to exhibit a broad spectrum of anti-tumor activity. However, the anti-cancer activity of AP-7 in combination with DDP and its molecular mechanisms in multidrug-resistant NSCLC are not yet clear. Our research indicates that AP-7 bolsters the growth inhibition activity of DDP on multidrug-resistant NSCLC cells. AP-7 notably disrupts DDP-induced cell cycle arrest and amplifies DDP-induced DNA damage effects in these cells. Furthermore, the combination of AP-7 and DDP downregulates Chk1 activation, interrupts the DNA damage repair-dependent Chk1/CDK1 pathway, and helps to overcome drug resistance and boost apoptosis in multidrug-resistant NSCLC cells and a gefitinib-resistant xenograft mice model. In summary, AP-7 appears to enhance DDP-induced DNA damage by impeding the Chk1 signaling pathway in multidrug-resistant NSCLC, thereby augmenting growth inhibition, both in vitro and in vivo. These results indicate the potential use of AP-7 as a DDP sensitizer in the treatment of multidrug-resistant NSCLC.

Integrating Spatial and Morphological Characteristics into Melanoma Prognosis: A Computational Approach.

In this study, the prognostic value of cellular morphology and spatial configurations in melanoma has been examined, aiming to complement traditional prognostic indicators like mitotic activity and tumor thickness. Through a computational pipeline using machine learning and deep learning methods, we quantified nuclei sizes within different spatial regions and analyzed their prognostic significance using univariate and multivariate Cox models. Nuclei sizes in the invasive band demonstrated a significant hazard ratio (HR) of 1.1 (95% CI: 1.03, 1.18). Similarly, the nuclei sizes of tumor cells and Ki67 S100 co-positive cells in the invasive band achieved HRs of 1.07 (95% CI: 1.02, 1.13) and 1.09 (95% CI: 1.04, 1.16), respectively. Our findings reveal that nuclei sizes, particularly in the invasive band, are potentially prognostic factors. Correlation analyses further demonstrated a meaningful relationship between cellular morphology and tumor progression, notably showing that nuclei size within the invasive band correlates substantially with tumor thickness. These results suggest the potential of integrating spatial and morphological analyses into melanoma prognostication.

Hemostasis Using Prothrombin Complex Concentrate in Patients Undergoing Cardiac Surgery: Systematic Review with Meta-Analysis.

OBJECTIVE: The purpose of present study was to comprehensívely explore the efficacy and safety of prothrombín complex concentrate (PCC) to treat massíve bleedíng in patíents undergoing cardiac surgery. METHODS: PubMed®, Embase, and Cochrane Líbrary databases were searched for studíes ínvestigating PCC administratíon duríng cardiac surgery published before September 10, 2022. Mean dífference (MD) wíth 95% confidence interval (CI) was applíed to analyze continuous data, and dichotomous data were analyzed as risk ratio (RR) with 95% CI. RESULTS: Twelve studies were included in the meta-analysis. Compared with other non-PCC treatment regimens, PCC was not assocíated with elevated mortality (RR=1.18, 95% CI=0.86-1.60, P=0.30, I2=0%), shorter hospital stay (MD=-2.17 days; 95% CI=-5.62-1.28, P=0.22, I2=91%), reduced total thoracic drainage (MD=-67.94 ml, 95% CI=-239.52-103.65, P=0.44, I2=91%), thromboembolíc events (RR=1.10, 95% CI=0.74-1.65, P=0.63, I2=39%), increase ín atríal fibríllatíon events (RR=0.73, 95% CI=0.52-1.05, P=0.24, I2=29%), and myocardial infarction (RR=1.10, 95% CI=0.80-1.51, P=0.57, I2=81%). However, PCC use was associated with reduced intensive care unit length of stay (MD=-0.81 days, 95% CI=-1.48- -0.13, P=0.02, I2=0%), bleeding (MD=-248.67 ml, 95% CI=-465.36- -31.97, P=0.02, I2=84%), and intra-aortic balloon pump/extracorporeal membrane oxygenation (RR=0.65, 95% CI=0.42-0.996, P=0.05, I2=0%) when compared with non-PCC treatment regimens. CONCLUSION: The use of PCC in cardiac surgery did not correlate with mortality, length of hospítal stay, thoracic drainage, atríal fibríllatíon, myocardíal ínfarction, and thromboembolíc events. However, PCC sígnificantly improved postoperatíve intensíve care unít length of stay, bleedíng, and intra-aortic balloon pump/ extracorporeal membrane oxygenation outcomes ín patients undergoing cardíac surgery.

Structures and Biological Activities of Secondary Metabolites from Xylaria spp.

The fungus genus Xylaria is an important source of drug discoveries in scientific fields and in the pharmaceutical industry due to its potential to produce a variety of structured novel and bioactive secondary metabolites. This review prioritizes the structures of the secondary metabolites of Xylaria spp. from 1994 to January 2024 and their relevant biological activities. A total of 445 new compounds, including terpenoids, nitrogen-containing compounds, polyketides, lactones, and other classes, are presented in this review. Remarkably, among these compounds, 177 compounds show various biological activities, including cytotoxic, antimicrobial, anti-inflammatory, antifungal, immunosuppressive, and enzyme-inhibitory activities. This paper will guide further investigations into the structures of novel and potent active natural products derived from Xylaria and their potential contributions to the future development of new natural drug products in the agricultural and medicinal fields.

Hemostasis Using Prothrombin Complex Concentrate in Patients Undergoing Cardiac Surgery: Systematic Review with Meta-Analysis

ABSTRACT Objective: The purpose of present study was to comprehensively explore the efficacy and safety of prothrombin complex concentrate (PCC) to treat massive bleeding in patients undergoing cardiac surgery. Methods: PubMed®, Embase, and Cochrane Library databases were searched for studies investigating PCC administration during cardiac surgery published before September 10, 2022. Mean difference (MD) with 95% confidence interval (CI) was applied to analyze continuous data, and dichotomous data were analyzed as risk ratio (RR) with 95% CI. Results: Twelve studies were included in the meta-analysis. Compared with other non-PCC treatment regimens, PCC was not associated with elevated mortality (RR=1.18, 95% CI=0.86-1.60, P=0.30, I2=0%), shorter hospital stay (MD=-2.17 days; 95% CI=-5.62-1.28, P=0.22, I2=91%), reduced total thoracic drainage (MD=-67.94 ml, 95% CI=-239.52-103.65, P=0.44, I2=91%), thromboembolic events (RR=1.10, 95% CI=0.74-1.65, P=0.63, I2=39%), increase in atrial fibrillation events (RR=0.73, 95% CI=0.52-1.05, P=0.24, I2=29%), and myocardial infarction (RR=1.10, 95% CI=0.80-1.51, P=0.57, I2=81%). However, PCC use was associated with reduced intensive care unit length of stay (MD=-0.81 days, 95% CI=-1.48- -0.13, P=0.02, I2=0%), bleeding (MD=-248.67 ml, 95% CI=-465.36- -31.97, P=0.02, I2=84%), and intra-aortic balloon pump/extracorporeal membrane oxygenation (RR=0.65, 95% CI=0.42-0.996, P=0.05, I2=0%) when compared with non-PCC treatment regimens. Conclusion: The use of PCC in cardiac surgery did not correlate with mortality, length of hospital stay, thoracic drainage, atrial fibrillation, myocardial infarction, and thromboembolic events. However, PCC significantly improved postoperative intensive care unit length of stay, bleeding, and intra-aortic balloon pump/ extracorporeal membrane oxygenation outcomes in patients undergoing cardiac surgery.

Synthesis of 3-Trifluoromethyl-1,2,4-triazolines and 1,2,4-Triazoles via Tandem Addition/Cyclization of Trifluoromethyl N-Acylhydrazones with Cyanamide.

A tandem addition/cyclization reaction between trifluoromethyl N-acylhydrazones and cyanamide is described, which provides a novel and efficient process for the synthesis of polysubstituted 3-trifluoromethyl-1,2,4-triazolines and their derivatives. The method has the advantages of mild reaction conditions, a broad substrate scope, good product yields, and atom economy.

A Fast and Automated FMT/XCT Reconstruction Strategy Based on Standardized Imaging Space.

The traditional finite element method-based fluorescence molecular tomography (FMT)/ X-ray computed tomography (XCT) imaging reconstruction suffers from complicated mesh generation and dual-modality image data fusion, which limits the application of in vivo imaging. To solve this problem, a novel standardized imaging space reconstruction (SISR) method for the quantitative determination of fluorescent probe distributions inside small animals was developed. In conjunction with a standardized dual-modality image data fusion technology, and novel reconstruction strategy based on Laplace regularization and L1-fused Lasso method, the in vivo distribution can be calculated rapidly and accurately, which enables standardized and algorithm-driven data process. We demonstrated the method's feasibility through numerical simulations and quantitatively monitored in vivo programmed death ligand 1 (PD-L1) expression in mouse tumor xenografts, and the results demonstrate that our proposed SISR can increase data throughput and reproducibility, which helps to realize the dynamically and accurately in vivo imaging.

Insight into the roles of electrolysis-activated persulfate oxidation in the waste activated sludge dewaterability: Effects and mechanism.

Sludge dewatering, as one of the most important steps of sludge treatment, can facilitate transportation and improve disposal efficiency by reducing the volume of sludge. This study investigated the effects of electrolysis-activated persulfate oxidation on improving sludge dewaterability. The results indicated that the sludge capillary suction time (CST) and water content of dewatered sludge cake (Wc) reduced from 93.7 s and 87.8% to 9.7 s and 68.3% respectively at the optimized process parameters: electrolysis voltage of 40 V, electrolysis time of 20 min, and 1.2 mmol/g TS S2O82-. Correlation analysis revealed that the enhancement of sludge dewaterability was closely associated with the increased floc size and zeta potential, decreased protein content in three-layers extracellular polymeric substances (EPS) and viscosity (R = -0.868, p = 0.002; R = -0.703, p = 0.035; R ≥ 0.961, p < 0.001; R = 0.949, p < 0.001). Four protein fluorescence regions in EPS were analyzed by three-dimensional excitation-emission matrix parallel factor (3D-EEM-PARAFAC). The protein secondary structure was changed after the treatment, and the reduction of α-helix/(ß-sheet + random coil) indicated that more hydrophobic sites were exposed. Analysis by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) and rheological test demonstrated that the hydrophilic functional groups of the sludge were decreased and the sludge mobility was significantly enhanced after the treatment with electrolysis-activated persulfate oxidation. Moreover, bound water was converted to free water during SO4·- and ·OH generated by electrolysis-activated persulfate degraded EPS and attacked sludge cells. Meanwhile, scanning electron microscopy (SEM) images revealed that the treated sludge formed porous channel structures, which promoted the flowability of the water. These findings provide a new insight based on electrolysis-activated persulfate oxidation in sludge treatment for enhancing sludge dewaterability.

ImmunoAIzer: A Deep Learning-Based Computational Framework to Characterize Cell Distribution and Gene Mutation in Tumor Microenvironment.

Spatial distribution of tumor infiltrating lymphocytes (TILs) and cancer cells in the tumor microenvironment (TME) along with tumor gene mutation status are of vital importance to the guidance of cancer immunotherapy and prognoses. In this work, we developed a deep learning-based computational framework, termed ImmunoAIzer, which involves: (1) the implementation of a semi-supervised strategy to train a cellular biomarker distribution prediction network (CBDPN) to make predictions of spatial distributions of CD3, CD20, PanCK, and DAPI biomarkers in the tumor microenvironment with an accuracy of 90.4%; (2) using CBDPN to select tumor areas on hematoxylin and eosin (H&E) staining tissue slides and training a multilabel tumor gene mutation detection network (TGMDN), which can detect APC, KRAS, and TP53 mutations with area-under-the-curve (AUC) values of 0.76, 0.77, and 0.79. These findings suggest that ImmunoAIzer could provide comprehensive information of cell distribution and tumor gene mutation status of colon cancer patients efficiently and less costly; hence, it could serve as an effective auxiliary tool for the guidance of immunotherapy and prognoses. The method is also generalizable and has the potential to be extended for application to other types of cancers other than colon cancer.

A Novel Adaptive Parameter Search Elastic Net Method for Fluorescent Molecular Tomography.

Fluorescence molecular tomography (FMT) is a new type of medical imaging technology that can quantitatively reconstruct the three-dimensional distribution of fluorescent probes in vivo. Traditional Lp norm regularization techniques used in FMT reconstruction often face problems such as over-sparseness, over-smoothness, spatial discontinuity, and poor robustness. To address these problems, this paper proposes an adaptive parameter search elastic net (APSEN) method that is based on elastic net regularization, using weight parameters to combine the L1 and L2 norms. For the selection of elastic net weight parameters, this approach introduces the L0 norm of valid reconstruction results and the L2 norm of the residual vector, which are used to adjust the weight parameters adaptively. To verify the proposed method, a series of numerical simulation experiments were performed using digital mice with tumors as experimental subjects, and in vivo experiments of liver tumors were also conducted. The results showed that, compared with the state-of-the-art methods with different light source sizes or distances, Gaussian noise of 5%-25%, and the brute-force parameter search method, the APSEN method has better location accuracy, spatial resolution, fluorescence yield recovery ability, morphological characteristics, and robustness. Furthermore, the in vivo experiments demonstrated the applicability of APSEN for FMT.

A sodium dichloroisocyanurate-based conditioning process for the improvement of sludge dewaterability and mechanism studies.

Sludge dewatering is necessary to reduce the volume of sludge for cost-effective transport and ultimate disposal. In this study, a novel combined chemical conditioning process was proposed to improve sludge dewatering performance in which sludge flocs were destructed by sodium dichloroisocyanurate (DCCNa) and re-flocculated by Al2(SO4)3 and the mechanism was elucidated. The results showed that sludge capillary suction time (CST) dropped to 15.4 s and moisture content of dewatered sludge cake (Mc) deceased to 71.01% respectively, after the application of combined conditioning with the optimal dosage of 200 mg DCCNa/g dry solids (DS) and 80 mg Al2(SO4)3/g DS. With chemical conditioning, sludge physicochemical properties were greatly changed. With the DCCNa application, the percentage of low-molecular-weight substances in soluble extracellular polymeric substances (S-EPS) increased. Also, the sludge zeta potential dropped from -16.85 mV to -25.45 mV and the median particle size (D50) decreased from 54.1 µm to 51.6 µm. However, the subsequent conditioning by Al2(SO4)3 dosing not only led to an increment of 18% in the portion of macromolecules in S-EPS, but also increased the zeta potential and D50 to -10.74 mV and 53.2 µm, respectively. The bound water content in sludge declined from 2.92 g/g DS to 1.98 g/g DS after combined conditioning. We concluded that DCCNa disintegrated the sludge flocs and microbial cells leading to the release of bound water, fine particles and organic substances with negative charge, and the fine colloidal particles can be flocculated into large dense aggregations with the dosing of Al2(SO4)3. In summary, the proposed combined conditioning provided a highly effective and environmental friendly approach to improve the sludge dewatering performance.

Enhancement of waste activated sludge dewaterability by ultrasound-activated persulfate oxidation: Operation condition, sludge properties, and mechanisms.

The study proposed the ultrasound-activated persulfate oxidation as a novel approach to enhance sludge dewaterability. The results demonstrated that the reduction of water content of dewatered sludge cake was 16.5% and the capillary suction time was reduced to 39.5 s at the optimal conditions of 1.0 mmol/g-TS S2O82- and ultrasound energy density of 2.0 kW L-1 within 15 min. The promotion of dewaterability was closely associated with the enlarged floc size, decreased viscosity, and near-neutral zeta potential. Meanwhile, the correlation analysis revealed that the protein in extracellular polymeric substances (EPS) governed sludge dewaterability, especially in loosely bound EPS. Three-dimensional excitation-emission matrix fluorescence spectroscopy, Fourier transform infrared spectroscopy and scanning electronic microscopy analysis revealed that ultrasound-activated persulfate oxidation treatment effectively degraded the gel-like EPS matrix and attacked cells, releasing the moisture which was trapped in EPS and cells. The aggregation of particles promoted the elimination of moisture. Furthermore, heavy metals in conditioned dewatered sludge cakes all satisfied the A level of agricultural land (GB4284-2018) requirements and the chemical speciation distribution of some heavy metals changed significantly.

An in-depth study on the deep-dewatering mechanism of waste activated sludge by ozonation pre-oxidation and chitosan re-flocculation conditioning.

At present, wastewater and sludge management departments are in urgent of the sludge deep-dewatering technique, which can substantially reduce sludge volume, enhance sludge calorific value and save costs. Ozonation pre-oxidation and chitosan (CT) re-flocculation conditioning have been verified to be an efficacious and environmental-friendly approach to realize sludge deep-dewatering. This paper focused on the novel insights into sludge properties under ozonation and CT conditioning. With 60 mg/gTS O3 and 20 mg/gTS CT, the water content of the conditioned sludge cake satisfied the deep-dewatering level (<60%). The ozone dosage of 60 mg/gTS effectually enhanced the release of soluble COD and retained the inherent organic matters simultaneously, and subsequently, CT could further reduce extracellular biopolymers, especially proteins. Fluorescence analysis indicated that the protein-like substances were largely decomposed into fulvic acid-like and humic acid-like substances after ozonation, and CT could further remove humic acid-like components. Macromolecules were observed to form by CT combining with ozonated extracellular polymers. Low-field NMR technique monitored sludge water states and suggested that water movability weakened after ozonation and enhanced again through CT conditioning. SEM images reflected that CT was available as junction link for ozonated polymers to aggregate into large flocs. Furthermore, the calorific value of conditioned sludge cake increased and sludge cake drying time was saved pronouncedly. The findings provided the systematic and comprehensive insights into the sludge properties in pre-oxidation and re-flocculation conditioning, which would aid in a better understanding of the in-depth dewatering mechanism and developing new dewatering technique.

Early Aortic Valve Replacement vs. Conservative Management in Asymptomatic Severe Aortic Stenosis Patients With Preserved Ejection Fraction: A Meta-Analysis.

Background: Aortic stenosis (AS) is the most common valvular disease in developed countries. Until now, the specific timing of intervention for asymptomatic patients with severe aortic stenosis and preserved ejection fraction remains controversial. Methods: A systematic search of four databases (Pubmed, Web of science, Cochrane library, Embase) was conducted. Studies of asymptomatic patients with severe AS or very severe AS and preserved left ventricular ejection fraction underwent early aortic valve replacement (AVR) or conservative care were included. The end points included all-cause mortality, cardiac mortality, and non-cardiac mortality. Results: Four eligible studies were identified with a total of 1,249 participants. Compared to conservative management, patients who underwent early AVR were associated with lower all-cause mortality, cardiac mortality, and non-cardiac mortality rate (OR 0.16, 95% CI 0.09-0.31, P < 0.00001; OR 0.12, 95% CI 0.02-0.62, P = 0.01; OR 0.36, 95% CI 0.21-0.63, P = 0.0003, respectively). Conclusions: Early AVR is preferable for asymptomatic severe AS patients with preserved ejection fraction.

Insight into a new two-step approach of ozonation and chitosan conditioning for sludge deep-dewatering.

Sludge deep-dewatering, capable of reducing water content (Wc) of sludge cake under 60%, is one of the current hot topics in sludge treatment. In this study, a new environmentally friendly two-step approach of ozonation and chitosan (CT) conditioning was proposed and examined to be practicable for sludge deep-dewatering. With 60 mg/gTS ozone and 20 mg/gTS CT conditioning, sludge capillary suction time (CST) and Wc of the dewatered sludge cake decreased from 196.3 s and 84.7% of raw sludge to 15.8 s and 57.5%, respectively. Ozonation treatment could efficiently crack sludge flocs and cells, and release biopolymers, causing the decreases in viscosity, zeta potential and particle size. Subsequently, CT ameliorated the sludge dewaterability successfully by neutralizing negative charges and flocculating colloids to promote the spread of interstitial water. Furthermore, the contents of heavy metals (As, Cd, Cr, Ni, Pb and Zn) in conditioned sludge cake decreased obviously except Cu, but all detected heavy metals contents satisfied the A level of agricultural land (GB4284-2018). For chemical speciation of heavy metals, the proportions of the acid soluble/exchangeable state and the reductive state increased apparently, implying higher toxicity and bioavailability, except Pb. Hence, pretreatments were required to reduce the environmental risk of heavy metals in conditioned sludge cake prior to a further utilization.

Kill two birds with one stone: curing accessory pathways and premature ventricular contractions with one ablation.

Radiofrequency catheter ablation has been used for treating cardiac arrhythmias, such as premature ventricular contractions and accessory pathway. We report two cases with successful ablation of left-sided accessory pathways and premature ventricular contractions from mitral annulus with one ablation. To our knowledge, no similar reports have been found so far.

Does Anterior Fat Pad Removal Reduce the Incidence of Atrial Fibrillation after CABG? A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Atrial fibrillation (AF) is a common complication after coronary artery bypass grafting (CABG). Several prospective randomized controlled trials (RCTs) have evaluated the effect of intact and removed anterior fat pads on the incidence of AF after CABG with conflicting results. We collected these RCTs and conducted a meta-analysis to determine whether anterior fat pad removal is effective in preventing the new onset of AF after CABG. METHODS AND RESULTS: Prospective RCTs were collected for analysis and the main outcomes include the occurrence of AF after CABG, total hospital stay, and major complications. Statistical analysis was conducted using RevMan 5.0.18 software (The Cochrane Collaboration), and pooled estimates of the effect were reported as risk ratios (RRs) or mean differences (MDs) with their 95% confidence intervals (CIs). The results of this meta-analysis indicate that anterior fat pad removal was not associated with a decreased risk of occurrence of AF after CABG (RR = 1.34, 95% CI: 0.88-2.03; P = 0.18), and it also did not increase the risk of major complications (RR = 1.05, 95% CI: 0.75-1.47; P = 0.79) or lengthen total hospital stay (MD = 0.06, 95% CI: -0.46 to 0.58; P = 0.83) compared with the control group. CONCLUSION: Anterior fat pad removal did not decrease the risk of the occurrence of AF after CABG despite its safety and convenience, and it should not be used to prevent new-onset AF after CABG unless new evidence is provided.

Successful ablation of atrioventricular nodal reentrant tachycardia in a patient with coexistent congenitally corrected transposition of the great vessels and situs inversus.

Congenitally corrected transposition of the great vessels (CTGV) is a rare congenital cardiac and great vessel abnormality. The anomalous inversion of the ventricles and great vessels makes performing catheter ablation difficult. We herein report a successful case of atrioventricular node reentrant tachycardia ablation in a patient with coexistent CTGV and situs inversus.

Landiolol hydrochloride for prevention of atrial fibrillation after cardiac surgery: a meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmic complication after cardiac surgery. Several studies have compared the efficacy of landiolol and placebo or other agents in preventing new-onset AF in patients after cardiac surgery. In this study, we conducted a meta-analysis to determine whether landiolol is effective in preventing new-onset AF after cardiac surgery. METHODS AND RESULTS: Five randomized controlled trials and two retrospective analyses were included in this study. The clinical outcomes of interest were the occurrence of AF after cardiac surgery and major complications. Meta-analysis was performed using RevMan 5.0.18 software, and pooled estimates of the effect were reported as risk ratios (RR) with 95% confidence intervals (CI). The results of this meta-analysis indicate that landiolol is significantly associated with a decreased risk of occurrence of AF after cardiac surgery (RR = 0.33; 95% CI: 0.23-0.48; P < 0.00001) and is not associated with an increased risk of major complications (RR = 0.79; 95% CI: 0.43-1.45; P = 0.45) compared with the control group. CONCLUSION: Landiolol administration in the perioperative period can reduce the occurrence of AF after cardiac surgery without increasing the risk of major complications. It can be used to prevent new-onset AF safely after cardiac surgery.