Tandem Proton Transfer in Carboxylated Supramolecular Polymer for Highly Efficient Overall Photosynthesis of Hydrogen Peroxide.

Proton supply is as critical as O2 activation for artificial photosynthesis of H2O2 via two-electron oxygen reduction reaction (2e- ORR). However, proton release via water dissociation is frequently hindered because of the sluggish water oxidation reaction (WOR), extremely limiting the efficiency of photocatalytic H2O2 production. To tackle this challenge, carboxyl-enriched supramolecular polymer (perylene tetracarboxylic acid - PTCA) is elaborately prepared by molecular self-assembly for overall photosynthesis of H2O2. Interestingly, the interconversion between carboxyl as Brønsted acid and its conjugated base realizes rapid proton circulation. Through this efficient tandem proton transfer process, the spatial effect of photocatalytic reduction and oxidation reaction is greatly enhanced with reduced reaction barrier. This significantly facilitates 2e- photocatalytic ORR to synthesize H2O2 and in the meanwhile promotes 4e- photocatalytic WOR to evolve O2. Consequently, the as-developed PTCA exhibits a remarkable H2O2 yield of 185.6 µM h-1 in pure water and air atmosphere under visible light illumination. More impressively, an appreciable H2O2 yield of 78.6 µM h-1 can be well maintained in an anaerobic system owing to in-situ O2 generation by 4e- photocatalytic WOR. Our study presents a novel concept for artificial photosynthesis of H2O2 via constructing efficient proton transfer pathway to enable rapid proton circulation.

Neuroimaging and clinical features of bilateral Wallerian degeneration of middle cerebellar peduncles subsequent to pontine infarction.

OBJECTIVE: Wallerian degeneration (WD) of the middle cerebellar peduncles (MCPs) following pontine infarction is a rare secondary degenerative neurological condition. Due to its infrequency, there is limited research on its characteristics. METHODS: This study aims to present three cases of WD of MCPs following pontine infarction and to analyze the prognosis, clinical manifestations, and neuroimaging features by amalgamating our cases with previously reported ones. RESULTS: The cohort consisted of 25 cases, comprising 18 men and 7 women aged 29 to 77 years (mean age: 66.2 years). The majority of patients (94%) exhibit risk factors for cerebrovascular disease, with hypertension being the primary risk factor. Magnetic resonance imaging (MRI) can detect WD of MCPs within a range of 21 days to 12 months following pontine infarction. This degeneration is characterized by bilateral symmetric hyperintensities on T2/FLAIR-weighted images (WI) lesions in the MCPs. Moreover, restricted diffusion, with hyperintensity on diffusion-weighted imaging (DWI) and low apparent diffusion coefficient (ADC) signal intensity may be observed as early as 21 days after the infarction. Upon detection of WD, it was observed that 20 patients (80%) remained asymptomatic during subsequent clinic visits, while four (16%) experienced a worsening of pre-existing symptoms. CONCLUSIONS: These findings underscore the importance of neurologists enhancing their understanding of this condition by gaining fresh insights into the neuroimaging characteristics, clinical manifestations, and prognosis of individuals with WD of bilateral MCPs.

Differentiation between primary central nervous system lymphomas and gliomas according to pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging.

Purpose: It is difficult to differentiate between primary central nervous system lymphoma and primary glioblastoma due to their similar MRI findings. This study aimed to assess whether pharmacokinetic parameters derived from dynamic contrast-enhanced MRI could provide valuable insights for differentiation. Methods: Seventeen cases of primary central nervous system lymphoma and twenty-one cases of glioblastoma as confirmed by pathology, were retrospectively analyzed. Pharmacokinetic parameters, including Ktrans, Kep, Ve, and the initial area under the Gd concentration curve, were measured from the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma. Statistical comparisons were made using Mann-Whitney U tests for Ve and Matrix Metallopeptidase-2, while independent samples t-tests were used to compare pharmacokinetic parameters in the mentioned regions and pathological indicators of enhancing tumor parenchyma, such as vascular endothelial growth factor and microvessel density. The pharmacokinetic parameters with statistical differences were evaluated using receiver-operating characteristics analysis. Except for the Wilcoxon rank sum test for Ve, the pharmacokinetic parameters were compared within the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma of the primary central nervous system lymphomas and glioblastomas using variance analysis and the least-significant difference method. Results: Statistical differences were observed in Ktrans and Kep within the enhancing tumor parenchyma and in Kep within the peritumoral parenchyma between these two tumor types. Differences were also found in Matrix Metallopeptidase-2, vascular endothelial growth factor, and microvessel density within the enhancing tumor parenchyma of these tumors. When compared with the contralateral normal parenchyma, pharmacokinetic parameters within the peritumoral parenchyma and enhancing tumor parenchyma exhibited variations in glioblastoma and primary central nervous system lymphoma, respectively. Moreover, the receiver-operating characteristics analysis showed that the diagnostic efficiency of Kep in the peritumoral parenchyma was notably higher. Conclusion: Pharmacokinetic parameters derived from dynamic contrast-enhanced MRI can differentiate primary central nervous system lymphoma and glioblastoma, especially Kep in the peritumoral parenchyma.

Study on the Infrared and Raman spectra of Ti3AlB2, Zr3AlB2, Hf3AlB2, and Ta3AlB2 by first-principles calculations.

In this paper, the crystal geometry, electronic structure, lattice vibration, Infrared and Raman spectra of ternary layered borides M3AlB2 (M = Ti, Zr, Hf, Ta) are studied by using first principles calculation method based on the density functional theory. The electronic structure of M3AlB2 indicates that they are all electrical conductors, and the d orbitals of Ti, Zr, Hf, and Ta occupy most of the bottom of the conduction band and most of the top of the valence band. Al and B have lower contributions near their Fermi level. The lightweight and stronger chemical bonds of atom B are important factors that correspond to higher levels of peak positions in the Infrared and Raman spectra. However, the vibration frequencies, phonon density of states, and peak positions of Infrared and Raman spectra are significantly lower because of heavier masses and weaker chemical bonds for M and Al atoms. And, there are 6 Infrared active modes A2u and E1u, and 7 Raman active modes, namely A1g, E2g, and E1g corresponding to different vibration frequencies in M3AlB2. Furthermore, the Infrared and Raman spectra of M3AlB2 were obtained respectively, which intuitively provided a reliable Infrared and Raman vibration position and intensity theoretical basis for the experimental study.

The Copper Efflux Regulator (CueR).

The copper efflux regulator (CueR) is a classical member of the MerR family of metalloregulators and is common in gram-negative bacteria. Through its C-terminal effector-binding domain, CueR senses cytoplasmic copper ions to regulate the transcription of genes contributing to copper homeostasis, an essential process for survival of all cells. In this chapter, we review the regulatory roles of CueR in the model organism Escherichia coli and the mechanisms for CueR in copper binding, DNA recognition, and interplay with RNA polymerase in regulating transcription. In light of biochemical and structural analyses, we provide molecular details for how CueR represses transcription in the absence of copper ions, how copper ions mediate CueR conformational change to form holo CueR, and how CueR bends and twists promoter DNA to activate transcription. We also characterize the functional domains and key residues involved in these processes. Since CueR is a representative member of the MerR family, elucidating its regulatory mechanisms could help to understand the CueR-like regulators in other organisms and facilitate the understanding of other metalloregulators in the same family.

Optimization of fracturing technology for unconventional dense oil reservoirs based on rock brittleness index.

The concept of volume fracturing has revolutionized the conventional limits of low permeability, expanded the effective resource space, and significantly enhanced oil well production in tight oil reservoir development. This paper elucidates the mechanism of volume fracturing technology for tight sandstone reservoirs by considering multiple factors such as the initiation range of multi-fractures, influence of far-well horizontal principal stress on fracture initiation and propagation, degree of natural fractures development, and mechanical parameters of reservoir rock. Through simulation based on the mechanical parameters of reservoir rock, a comparative analysis was conducted between the model-calculated rock fracture pressure value and measured data from fracturing construction wells in the study area. The results revealed that there was a discrepancy within 10% between the model calculations and actual data. By simulating the effects of different injection volumes of fracturing fluid, pumping rates, and perforation methods on the fracture geometry, optimal design parameters for volume fracturing technology were obtained. Additionally, we propose optimization ideas and suggestions for construction parameters applicable to field operations. The simulation results indicate that a minimum recommended fluid volume scale exceeding 1800 m3 is advised for the reservoir. Based on frictional calculations, it is recommended to have an on-site construction rate not less than 18.0 m3/min along with 36-48 holes/section for perforation purposes. The numerical simulation research presented in this paper provides a theoretical reference basis and practical guidance for the application of fracturing network technology in tight sandstone reservoirs.

Neutrophil percentage-to-albumin ratio is a potential marker of intravenous immunoglobulin resistance in Kawasaki disease.

Intravenous immunoglobulin (IVIG) resistance in Kawasaki disease (KD) was associated with coronary artery lesions. Neutrophil percentage-to-albumin ratio (NPAR) is an index of mortality in several inflammatory diseases. This study focused on the association of NPAR with IVIG- resistance in KD. Clinical and laboratory data of 438 children with KD before IVIG treatment were retrospectively analyzed. Notably, high NPAR was associated with older age, high WBC, NP, ALT, total bilirubin and CRP, as well as with high the incidence of IVIG-resistance, and with low hemoglobin (Hb), PLT, ALB and sodium levels. NPAR (OR: 2.366, 95% CI: 1.46-3.897, p = 0.001) and Hb (OR: 0.967, 95% CI: 0.944-0.989, p = 0.004) were independent risk factors for IVIG-resistance. NPAR showed linear relation with IVIG-resistance (p for nonlinear = 0.711) and the nonlinear correlation was found between IVIG-resistance and Hb (p for nonlinear = 0.002). The predictive performance of NPAR was superior to Beijing model (z = 2.193, p = 0.028), and not inferior to Chongqing model (z = 0.983, p = 0.326) and the combination of NPAR and Hb (z = 1.912, p = 0.056). These findings revealed that NPAR is a reliable predictor of IVIG-resistance.

The role of macrophages in fibrosis of chronic kidney disease.

Macrophages are widely distributed throughout various tissues of the body, and mounting evidence suggests their involvement in regulating the tissue microenvironment, thereby influencing disease onset and progression through direct or indirect actions. In chronic kidney disease (CKD), disturbances in renal functional homeostasis lead to inflammatory cell infiltration, tubular expansion, glomerular atrophy, and subsequent renal fibrosis. Macrophages play a pivotal role in this pathological process. Therefore, understanding their role is imperative for investigating CKD progression, mitigating its advancement, and offering novel research perspectives for fibrosis treatment from an immunological standpoint. This review primarily delves into the intrinsic characteristics of macrophages, their origins, diverse subtypes, and their associations with renal fibrosis. Particular emphasis is placed on the transition between M1 and M2 phenotypes. In late-stage CKD, there is a shift from the M1 to the M2 phenotype, accompanied by an increased prevalence of M2 macrophages. This transition is governed by the activation of the TGF-ß1/SMAD3 and JAK/STAT pathways, which facilitate macrophage-to-myofibroblast transition (MMT). The tyrosine kinase Src is involved in both signaling cascades. By thoroughly elucidating macrophage functions and comprehending the modes and molecular mechanisms of macrophage-fibroblast interaction in the kidney, novel, tailored therapeutic strategies for preventing or attenuating the progression of CKD can be developed.

Global incidence and characteristics of spinal cord injury since 2000-2021: a systematic review and meta-analysis.

BACKGROUND: This study employs systematic review and meta-analysis to explore the incidence and characteristics of spinal cord injury (SCI) between 2000 and 2021, aiming to provide the most recent and comprehensive data support for the prevention, diagnosis, treatment, and care of SCI. METHODS: Systematic searches were conducted on epidemiological studies of SCI published between January 1, 2000, and March 29, 2024. Meta-analysis, subgroup analysis, meta-regression, publication bias detection, and literature quality assessment were extensively utilized. RESULTS: The pooled results from 229 studies indicated that the overall incidence rate of SCI was 23.77 (95% CI, 21.50-26.15) per million people, with traumatic spinal cord injuries (TSCI) at a rate of 26.48 (95% CI, 24.15-28.93) per million people, and non-traumatic spinal cord injuries (NTSCI) at a rate of 17.93 (95% CI, 13.30-23.26) per million people. The incidence of TSCI exhibited a marked age-related increase and was significantly higher in community settings compared to hospital and database sources. Males experienced TSCI at a rate 3.2 times higher than females. Between 2000 and 2021, the incidence of TSCI remained consistently high, between 20 and 45 per million people, whereas NTSCI incidence has seen a steady rise since 2007, stabilizing at a high rate of 25-35 per million people. Additionally, the incidence of TSCI in developing countries was notably higher than that in developed countries. There were significant differences in the causes of injury, severity, injury segments, gender, and age distribution among the TSCI and NTSCI populations, but the proportion of male patients was much higher than that of female patients. Moreover, study quality, country type, and SCI type contributed to the heterogeneity in the meta-analysis. CONCLUSIONS: The incidence rates of different types of SCI remain high, and the demographic distribution of SCI patients is changing, indicating a serious disease burden on healthcare systems and affected populations. These findings underscore the necessity of adopting targeted preventive, therapeutic, and rehabilitative measures based on the incidence and characteristics of SCI.

A Novel Animal Model for Pulmonary Hypertension: Lung Endothelial-Specific Deletion of Egln1 in Mice.

Pulmonary arterial hypertension (PAH) is a devastating disease characterized by high blood pressure in the pulmonary arteries, which can potentially lead to heart failure over time. Previously, our lab found that endothelia-specific knockout of Egln1, encoding prolyl 4-hydroxylase-2 (PHD2), induced spontaneous pulmonary hypertension (PH). Recently, we elucidated that Tmem100 is a lung-specific endothelial gene using Tmem100-CreERT2 mice. We hypothesize that lung endothelial-specific deletion of Egln1 could lead to the development of PH without affecting Egln1 gene expression in other organs. Tmem100-CreERT2 mice were crossed with Egln1 flox/flox mice to generate Egln1 f/f ;Tmem100-CreERT2 (LiCKO) mice. Western blot and immunofluorescent staining were performed to verify the knockout efficacy of Egln1 in multiple organs of LiCKO mice. PH phenotypes, including hemodynamics, right heart size and function, pulmonary vascular remodeling, were evaluated by right heart catheterization and echocardiography measurements. Tamoxifen treatment induced Egln1 deletion in the lung endothelial cells (ECs) but not in other organs of adult LiCKO mice. LiCKO mice exhibited an increase in right ventricular systolic pressure (RVSP, ~35 mmHg) and right heart hypertrophy. Echocardiography measurements showed right heart hypertrophy, as well as cardiac and pulmonary arterial dysfunction. Pulmonary vascular remodeling, including increased pulmonary wall thickness and muscularization of distal pulmonary arterials, was enhanced in LiCKO mice compared to wild-type mice. Tmem100 promoter-mediated lung endothelial knockout of Egln1 in mice leads to development of spontaneous PH. LiCKO mice could serve as a novel mouse model for PH to study lung and other organ crosstalk.

Improving the Risk Prediction of the 2015 ATA Recurrence Risk Stratification in Papillary Thyroid Cancer.

BACKGROUND: Various prognostic factors are expected to refine the American Thyroid Association (ATA) recurrence risk stratification for patients with papillary thyroid cancer (PTC). However, it remains unclear to what extent integrating these factors improves patient treatment decision-making. METHODS: We developed two predictive models for structural incomplete response (SIR) at the one-year follow-up visit, based on comprehensive clinical data from a retrospective cohort of 2539 patients. Model 1 included the recurrence risk stratification and lymph node features (i.e., number and ratio of metastatic lymph nodes, N stage). Model 2 further incorporated preablation stimulated thyroglobulin (s-Tg). An independent cohort of 746 patients was used for validation analysis. We assessed the models' predictive performance compared to the recurrence risk stratification using the integrated discrimination improvement (IDI) and the continuous net reclassification improvement (NRI). The clinical utility of the models was evaluated using decision curve analysis. RESULTS: Both Model 1 and Model 2 outperformed the recurrence risk stratification in predicting SIR, with improved correct classification rates (Model 1: IDI=0.02, event NRI=42.31%; Model 2: IDI=0.07, event NRI=53.54%). The decision curves indicated that both models provided greater benefits over the risk stratification system in clinical decision-making. In the validation set, Model 2 maintained similar performance while Model 1 did not significantly improve correct reclassification. CONCLUSION: The inclusion of lymph node features and s-Tg showed potential to enhance the predictive accuracy and clinical utility of the existing risk stratification system for PTC patients.

Biomolecule-grafted GO enhanced the mechanical and biological properties of 3D printed PLA scaffolds with TPMS porous structure.

Graphene oxide (GO) exhibits excellent mechanical strength and modulus. However, its effectiveness in mechanically reinforcing polymer materials is limited due to issues with interfacial bonding and dispersion arising from differences in the physicochemical properties between GO and polymers. Surface modification using coupling agents is an effective method to improve the bonding problem between polymer and GO, but there may be biocompatibility issues when used in the biomedical field. In this study, the biomolecule L-lysine, was applied to improve the interfacial bonding and dispersion of GO in polylactic acid (PLA) without compromising biocompatibility. The PLA/L-lysine-modified GO (PLA/L-GO) bone scaffold with triply periodic minimal surface (TPMS) structure was prepared using fused deposition modeling (FDM). The FTIR results revealed successful grafting of L-lysine onto GO through the reaction between their -COOH and -NH2 groups. The macroscopic and microscopic morphology characterization indicated that the PLA/L-GO scaffolds exhibited an characteristics of dynamic diameter changes, with good interlayer bonding. It was noteworthy that the L-lysine modification promoted the dispersion of GO and the interfacial bonding with the PLA matrix, as characterized by SEM. As a result, the PLA/0.1L-GO scaffold exhibited higher compressive strength (13.2 MPa) and elastic modulus (226.8 MPa) than PLA/0.1GO. Moreover, PLA/L-GO composite scaffold exhibited superior biomineralization capacity and cell response compared to PLA/GO. In summary, L-lysine not only improved the dispersion and interfacial bonding of GO with PLA, enhancing the mechanical properties, but also improved the biological properties. This study suggests that biomolecules like L-lysine may replace traditional modifiers as an innovative bio-modifier to improve the performance of polymer/inorganic composite biomaterials.

In Fanconi Anemia, impaired accumulation of bone marrow neutrophils during emergency granulopoiesis induces hematopoietic stem cell stress.

Fanconi Anemia (FA) is an inherited disorder of DNA-repair due to mutation in one of 20+ interrelated genes that repair intra-strand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia (AML) may also occur. In prior studies, we found that Fanconi DNA-repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response. Specifically, Fancc-/- mice did not develop neutrophilia in response to emergency granulopoiesis stimuli, but instead exhibited apoptosis of bone marrow hematopoietic stem cells (HSCs) and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc-/- mice, with AML in survivors. In contrast, we found equivalent neutrophilia during emergency granulopoiesis in Fancc-/-Tp53+/- mice and wild type (WT) mice, without BMF. Since termination of emergency granulopoiesis is triggered by accumulation of bone marrow neutrophils, we hypothesize neutrophilia protects Fancc-/-Tp53+/- bone marrow from the stress of a sustained inflammation that is experienced by Fancc-/- mice. In the current work, we found that blocking neutrophil accumulation during emergency granulopoiesis led to BMF in Fancc-/-Tp53+/- mice, consistent with this hypothesis. Blocking neutrophilia during emergency granulopoiesis in Fancc-/-Tp53+/- mice (but not WT) impaired cell cycle checkpoint activity, also found in Fancc-/- mice. Mechanisms for loss of cell cycle checkpoints during infections challenges may define molecular markers of FA progression, or suggest therapeutic targets for bone marrow protection in this disorder.

The orchestration of cell-cycle reentry and ribosome biogenesis network is critical for cardiac repair.

Rationale: Myocardial infarction (MI) is a severe global clinical condition with widespread prevalence. The adult mammalian heart's limited capacity to generate new cardiomyocytes (CMs) in response to injury remains a primary obstacle in developing effective therapies. Current approaches focus on inducing the proliferation of existing CMs through cell-cycle reentry. However, this method primarily elevates cyclin dependent kinase 6 (CDK6) and DNA content, lacking proper cytokinesis and resulting in the formation of dysfunctional binucleated CMs. Cytokinesis is dependent on ribosome biogenesis (Ribo-bio), a crucial process modulated by nucleolin (Ncl). Our objective was to identify a novel approach that promotes both DNA synthesis and cytokinesis. Methods: Various techniques, including RNA/protein-sequencing analysis, Ribo-Halo, Ribo-disome, flow cytometry, and cardiac-specific tumor-suppressor retinoblastoma-1 (Rb1) knockout mice, were employed to assess the series signaling of proliferation/cell-cycle reentry and Ribo-bio/cytokinesis. Echocardiography, confocal imaging, and histology were utilized to evaluate cardiac function. Results: Analysis revealed significantly elevated levels of Rb1, bur decreased levels of circASXL1 in the hearts of MI mice compared to control mice. Deletion of Rb1 induces solely cell-cycle reentry, while augmenting the Ribo-bio modulator Ncl leads to cytokinesis. Mechanically, bioinformatics and the loss/gain studies uncovered that circASXL1/CDK6/Rb1 regulates cell-cycle reentry. Moreover, Ribo-Halo, Ribo-disome and circRNA pull-down assays demonstrated that circASXL1 promotes cytokinesis through Ncl/Ribo-bio. Importantly, exosomes derived from umbilical cord mesenchymal stem cells (UMSC-Exo) had the ability to enhance cardiac function by facilitating the coordinated signaling of cell-cycle reentry and Ribo-bio/cytokinesis. These effects were attenuated by silencing circASXL1 in UMSC-Exo. Conclusion: The series signaling of circASXL1/CDK6/Rb1/cell-cycle reentry and circASXL1/Ncl/Ribo-bio/cytokinesis plays a crucial role in cardiac repair. UMSC-Exo effectively repairs infarcted myocardium by stimulating CM cell-cycle reentry and cytokinesis in a circASXL1-dependent manner. This study provides innovative therapeutic strategies targeting the circASXL1 signaling network for MI and offering potential avenues for enhanced cardiac repair.

SART3 reads methylarginine-marked glycine- and arginine-rich motifs.

Glycine- and arginine-rich (GAR) motifs, commonly found in RNA-binding and -processing proteins, can be symmetrically (SDMA) or asymmetrically (ADMA) dimethylated at the arginine residue by protein arginine methyltransferases. Arginine-methylated protein motifs are usually read by Tudor domain-containing proteins. Here, using a GFP-Trap, we identify a non-Tudor domain protein, squamous cell carcinoma antigen recognized by T cells 3 (SART3), as a reader for SDMA-marked GAR motifs. Structural analysis and mutagenesis of SART3 show that aromatic residues lining a groove between two adjacent aromatic-rich half-a-tetratricopeptide (HAT) repeat domains are essential for SART3 to recognize and bind to SDMA-marked GAR motif peptides, as well as for the interaction between SART3 and the GAR-motif-containing proteins fibrillarin and coilin. Further, we show that the loss of this reader ability affects RNA splicing. Overall, our findings broaden the range of potential SDMA readers to include HAT domains.

Design, synthesis and biological evaluation of piperine derivatives as potent antitumor agents.

A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ± 6.05 µM, 11.86 ± 0.32 µM, and 10.50 ± 3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.

Design, synthesis, and evaluation of benzodioxolane compounds for antitumor activity.

This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies.

Investigating potential mechanisms of vitamin D against thyroid cancer via network pharmacology and experimental validation.

Thyroid cancer (TC) is one of the most common endocrine malignancies worldwide. Increasing evidence suggests that vitamin D (VD) has potential benefits in the treatment of TC. However, evidence regarding the targets and molecular mechanisms of VD in TC remains limited. In this study, we conducted network pharmacology, molecular docking, and experimental evaluation to explore the target genes, biological functions, and signaling pathways involved in this process. Network analysis revealed 77 potential target genes of VD against TC, and four hub target genes were identified: ESR1, KIT, CCND1, and PGR. Furthermore, we identified the biological processes (BP) and signaling pathways involving these potential target genes, and then determined the possible interaction between the hub targets and VD through molecular docking. Finally, through in vitro experiments, we found that VD effectively inhibits the proliferation of TC cells and downregulates the expression of the ESR1 gene. In conclusion, the effects of VD against TC involve multiple biological targets, BP, and signaling pathways. These findings provide scientific evidence for the application of VD in the treatment of TC.

Effect of Stroke Etiology on Endovascular Treatment for Acute Basilar-Artery Occlusion: A Post Hoc Analysis of the ATTENTION Randomized Trial.

BACKGROUND: Stroke etiology could influence the outcomes in patients with basilar-artery occlusion (BAO). This study aimed to evaluate the differences in efficacy and safety of best medical treatment (BMT) plus endovascular treatment (EVT) versus BMT alone in acute BAO across different stroke etiologies. METHODS: The study was a post hoc analysis of the ATTENTION trial (Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion), which was a multicenter, randomized trial at 36 centers in China from February 2021 to September 2022. Patients with acute BAO were classified into 3 groups according to stroke etiology (large-artery atherosclerosis [LAA], cardioembolism, and undetermined cause/other determined cause [UC/ODC]). The primary outcome was a favorable outcome (modified Rankin Scale score of 0-3) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 90-day mortality. RESULTS: A total of 340 patients with BAO were included, 150 (44.1%) had LAA, 72 (21.2%) had cardioembolism, and 118 (34.7%) had UC/ODC. For patients treated with BMT plus EVT and BMT alone, respectively, the rate of favorable outcome at 90 days was 49.1% and 23.8% in the LAA group (odds ratio, 3.08 [95% CI, 1.38-6.89]); 52.2% and 30.8% in the cardioembolism group (odds ratio, 2.45 [95% CI, 0.89-6.77]); and 37.5% and 17.4% in the UC/ODC group (odds ratio, 2.85 [95% CI, 1.16-7.01]), with P=0.89 for the stroke etiology×treatment interaction. The rate of symptomatic intracranial hemorrhage in EVT-treated patients with LAA, cardioembolism, and UC/ODC was 8.3%, 2.2%, and 3.2%, respectively, and none of the BMT-treated patients. Lower 90-day mortality was observed in patients with EVT compared with BMT alone across 3 etiology groups. CONCLUSIONS: Among patients with acute BAO, EVT compared with BMT alone might be associated with favorable outcomes and lower 90-day mortality, regardless of cardioembolism, LAA, or UC/ODC etiologies. The influence of stroke etiology on the benefit of EVT should be explored by further trials. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04751708.