Clinical Analysis of Inhaled Nitric Oxide Therapy in Preterm Infants at Different Gestational Ages: A National Retrospective Multicenter Study.

OBJECTIVE: This study aimed to investigate clinical features of inhaled nitric oxide (iNO) in preterm infants with a gestational age (GA) < 34 weeks in China. STUDY DESIGN: The clinical data of 434 preterm infants with GA < 34 weeks, treated with iNO in the neonatology departments of eight Class A tertiary hospitals in China over a 10-year period from January 2013 to December 2022, were included in this retrospective multicenter investigation. The infants were divided into three groups based on GA: 24 to 27 weeks (extremely preterm infants), 28 to 31 weeks (very preterm infants), and 32 to 33 weeks (moderate preterm infants). The use of iNO, perinatal data, incidence and mortality of indication for iNO treatment, therapeutic effects of iNO, incidence of short-term complications for iNO treatment, and mortality were compared among these three groups. RESULTS: Over the past 10 years, the proportion of iNO use was highest in extremely preterm infants each year. The lower the GA, the higher the iNO use rate: 4.20% for GA 24 to 27 weeks, 1.54% for GA 28 to 31 weeks, and 0.85% for GA 32 to 33 weeks. There was no significant difference in the therapeutic effect of iNO among the three groups. The incidence of neonatal pulmonary hemorrhage, neonatal shock, late-onset diseases, retinopathy of prematurity requiring intervention, intracranial hemorrhage (grade 3 or 4), periventricular leukomalacia, neonatal necrotizing enterocolitis (≥stage II), and moderate to severe bronchopulmonary dysplasia was highest in extremely preterm infants and increased with decreasing GA. Mortality was negatively correlated with GA and birth weight. The highest rate of iNO treatment in 24 to 27 weeks' preterm infants was due to hypoxic respiratory failure (HRF), whereas the highest rate of iNO treatment in 32 to 33 weeks' preterm infants was due to documented persistent pulmonary hypertension of the newborn (PPHN). The rates of iNO treatment due to HRF and documented PPHN were 54.3 and 60.6%, respectively, in extremely preterm infants, significantly higher than in very preterm and moderate preterm infants (all p < 0.05). Within the same GA group, the proportion of preterm infants treated with iNO for HRF was lower than that for documented PPHN (all p < 0.05), but there was no statistically significant difference in mortality between HRF and documented PPHN treated with iNO (all p > 0.05). CONCLUSION: Among preterm infants with GA < 34 weeks, the rate of iNO usage was highest in extremely preterm infants. However, iNO failed to improve the clinical outcome of extremely preterm infants with refractory hypoxemia, and there was no significant difference in the therapeutic effect of iNO among preterm infants with different GAs.

Circadian disruption promotes the neurotoxicity of oligomeric alpha-synuclein in mice.

Circadian disruption often arises prior to the onset of typical motor deficits in patients with Parkinson's disease (PD). It remains unclear whether such a prevalent non-motor manifestation would contribute to the progression of PD. Diffusible oligomeric alpha-synuclein (O-αSyn) is perceived as the most toxic and rapid-transmitted species in the early stages of PD. Exploring the factors that influence the spread and toxicity of O-αSyn should be helpful for developing effective interventions for the disease. The aim of this study was to explore the effects of circadian disruption on PD pathology and parkinsonism-like behaviors in a novel mouse model induced by O-αSyn. We discovered that O-αSyn could enter the brain rapidly following intranasal administration, resulting in the formation of nitrated-αSyn pathology and non-motor symptoms of the mice. Meanwhile, circadian disruption exacerbated the burden of nitrated-αSyn pathology and accelerated the loss of dopaminergic neurons in O-αSyn-treated mice. Subsequent experiments demonstrated that circadian disruption might act via promoting nitrative stress and neuroinflammation. These findings could highlight the circadian rhythms as a potential diagnostic and therapeutic target in early-stage PD.

Effect of moxibustion on plasma amino acid metabolism in rats with knee osteoarthritis. / è‰¾ç¸å¯¹è†å ³èŠ‚éª¨å ³èŠ‚ç‚Žå¤§é¼ è¡€æµ†æ°¨åŸºé ¸ä»£è°¢çš„å½±å“.

OBJECTIVES: To observe the effect of moxibustion at "Zusanli "(ST36) on the plasma amino acid metabolism in rats with knee osteoarthritis (KOA), and to explore the amino acid metabolism mechanism of moxibustion in repairing cartilage injury in KOA. METHODS: A total of 30 SD rats were randomly divided into normal, model and moxibustion groups, with 10 rats in each group. Rats in the model and moxibustion groups were injected with the mixture of L-cysteine and papain into bilateral knee joint cavity to make the KOA model. The moxibustion group received moxibustion at bilateral ST36 for 30 min, once daily for 30 days. At the end of the experiment, the swelling degree of knee joint was calculated, the mechanical pain threshold was measured by the Von Frey filament, the cartilage tissue injury was observed by HE staining, the matrix metalloproteinase-13 (MMP-13) content in the synovial tissue was detected by enzyme-linked immunosorbent assay (ELISA), and the differential amino acid metabolites in plasma were detected and screened by liquid chromatography-mass spectrometry (LC-MS). RESULTS: Compared with the normal group, the model group showed irregular cartilage surface, decreased number of chondrocytes, uneven distribution, and local clusters of chondrocytes；the contour of the tide line was blurred. The degree of joint swelling in the model group was higher than that in the normal group (P<0.01), the mechanical pain threshold was lower (P<0.01), and the content of MMP-13 in synovial tissue was higher (P<0.01). The contents of proline and tryptophan in the model group were down-regulated (P<0.01, P<0.05). Compared with the model group, the cartilage tissue damage and knee joint swelling were decreased(P<0.05), mechanical pain threshold was increased(P<0.05), MMP-13 content in synovial tissue and levels of glutamate and histidine expression were decreased (P<0.01, P<0.05). CONCLUSIONS: Moxibustion at ST36 significantly alleviated arthritis-related swelling and pain in KOA model rats, attenuated cartilage damage, and regulated levels of certain plasma amino acid metabolites. Moxibustion may regulate KOA cartilage synthesis and degradation through amino acid metabolic pathways such as proline, tryptophan, glutamate and histidine, exerting anti-inflammatory, analgesic, and protection of cartilage injury effects.

Effectiveness and Safety of Qishen Yiqi Dripping Pill in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention: 3-Year Results from a Multicentre Cohort Study.

OBJECTIVES: To evaluate the effectiveness and safety of Qishen Yiqi Dripping Pill (QSYQ) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). METHODS: This multicentre prospective cohort study was conducted at 40 centers in China. Patients with ACS after PCI entered either the QSYQ or Western medicine (WM) groups naturally based on whether they had received QSYQ before enrollment. QSYQ group received QSYQ (0.52 g, 3 times a day for 12 months) in addition to WM. The primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization. The secondary endpoint included rehospitalization due to ACS, heart failure, stroke, and other thrombotic events. Quality of life was assessed by the Seattle Angina Questionnaire (SAQ). RESULTS: A total of 936 patients completed follow-up of the primary endpoint from February 2012 to December 2018. Overall, 487 patients received QSYQ and WM. During a median follow-up of 566 days (inter quartile range, IQR, 517-602), the primary endpoint occurred in 46 (9.45%) and 65 (14.48%) patients in QSYQ and WM groups respectively [adjusted hazard ratio (HR) 0.60, 95% confidence interval (CI) 0.41-0.90; P=0.013]. The secondary endpoint occurred in 61 (12.53%) and 74 (16.48%) patients in QSYQ and WM groups, respectively (adjusted HR 0.76, 95% CI 0.53-1.09; P=0.136). In sensitivity analysis, the results still demonstrated that WM combined with QSYQ reduced the risk of the primary endpoint (HR 0.67, 95% CI 0.46-0.98; P=0.039). Moreover, QSYQ improved the disease perception domain of the SAQ (P<0.05). CONCLUSION: In patients with ACS after PCI, QSYQ combined with WM reduced the incidence of the primary endpoint. These findings provide a promising option for managing ACS after PCI and suggest the potential treatment for reducing the risk of primary endpoint included cardiac death, non-fatal myocardial infarction, and urgent revascularization through intermittent administration of QSYQ (Registration No. ChiCTR-OOC-14005552).

Photoinduced Decarboxylative Thioacylation of N-Hydroxyphthalimide Esters with Tetraalkylthiuram Disulfides.

Dithiocarbamate is a key structural sequence in pharmaceuticals and agrochemicals, and its synthesis is crucial in organic chemistry. Although significant progress has been made in related synthesis research, developing a practical and universal synthesis method remains fascinating. Herein, we report a new visible-light-induced decarboxylation coupling reaction between N-hydroxyphthalimide esters and tetraalkylthiuram disulfides, which uses Ir(ppy)3 as a photocatalyst to promote the generation of corresponding decarboxylation thioacylation product-dithiocarbamates in high yields. This redox-neutral protocol uses inexpensive and readily available starting material under mild reaction conditions, exhibiting broad substrate scope and wide functional group compatibility. This method can be further used for post modification of complex natural products and bioactive drugs.

Phospholipid peroxidation in macrophage confers tumor resistance by suppressing phagocytic capability towards ferroptotic cells.

Ferroptosis holds significant potential for application in cancer therapy. However, ferroptosis inducers are not cell-specific and can cause phospholipid peroxidation in both tumor and non-tumor cells. This limitation greatly restricts the use of ferroptosis therapy as a safe and effective anticancer strategy. Our previous study demonstrated that macrophages can engulf ferroptotic cells through Toll-like receptor 2 (TLR2). Despite this advancement, the precise mechanism by which phospholipid peroxidation in macrophages affects their phagocytotic capability during treatment of tumors with ferroptotic agents is still unknown. Here, we utilized flow sorting combined with redox phospholipidomics to determine that phospholipid peroxidation in tumor microenvironment (TME) macrophages impaired the macrophages ability to eliminate ferroptotic tumor cells by phagocytosis, ultimately fostering tumor resistance to ferroptosis therapy. Mechanistically, the accumulation of phospholipid peroxidation in the macrophage endoplasmic reticulum (ER) repressed TLR2 trafficking to the plasma membrane and caused its retention in the ER by disrupting the interaction between TLR2 and its chaperone CNPY3. Subsequently, this ER-retained TLR2 recruited E3 ligase MARCH6 and initiated the proteasome-dependent degradation. Using redox phospholipidomics, we identified 1-steaoryl-2-15-HpETE-sn-glycero-3-phosphatidylethanolamine (SAPE-OOH) as the crucial mediator of these effects. Conclusively, our discovery elucidates a novel molecular mechanism underlying macrophage phospholipid peroxidation-induced tumor resistance to ferroptosis therapy and highlights the TLR2-MARCH6 axis as a potential therapeutic target for cancer therapy.

HTB50-2 Inhibits Growth and Migration of Triple-negative Breast Cancer via FOSL2/FOXC1 Signaling Axis and Subsequent Ferroptosis.

BACKGROUND: The manipulation of ferroptosis in cancer cells is a possible therapeutic technique that has been investigated for use in the treatment of cancer. Consequently, ferroptosis-inducing medications have recently received increased interest in cancer therapy. In this research, we assessed the anticancer efficacy of 14ß-hydroxy- 3ß-(ß-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2), a natural product derived from the plant Helleborus thibetanus Franch, in Triple-Negative Breast Cancer (TNBC). Moreover, we also studied its potential mechanisms. METHODS: The biological effects of HTB50-2 in a series of breast cancer cell lines were analyzed using sulforhodamine B (SRB) and other methods. The migration ability was analyzed using three methods: wound healing assay, transwell assay, and Western blot. Meanwhile, the potential therapeutic value of HTB50-2 was evaluated in BALB/c mice by orthotopic transplantation. Transcriptome sequencing was conducted to explore the FOS-like antigen 2 (FOSL2) gene, and its role in ferroptosis was verified by Western blot and immunohistochemistry. The association of FOSL2 and ferroptosis-related genes was analyzed using NetworkAnalyst databases, and a TF-Gene interaction network was constructed. RESULTS: Ferroptosis was found to be induced in TNBC cells by HTB50-2. Furthermore, HTB50-2 inhibited tumor development by inducing ferroptosis in TNBC in vivo. Mechanistically, we demonstrated that a transcription factor FOSL2 mediated ferroptosis by HTB50-2. Additionally, it was found that Forkhead box C1 (FOXC1) was regulated by FOSL2 and correlated with ferroptosis. CONCLUSION: Our data suggest that HTB50-2 exerts its anti-cancer properties by ferroptosis via FOSL2/FOXC1 signaling pathway. Hence, HTB50-2 has an important application potential in the treatment of TNBC.

0.68% of solar-to-hydrogen efficiency and high photostability of organic-inorganic membrane catalyst.

Solar-driven flat-panel H2O-to-H2 conversion is an important technology for value-added solar fuel production. However, most frequently used particulate photocatalysts are hard to achieve stable photocatalysis in flat-panel reaction module due to the influence of mechanical shear force. Herein, a highly active CdS@SiO2-Pt composite with rapid CdS-to-Pt electron transfer and restrained photoexciton recombination was prepared to process into an organic-inorganic membrane by compounding with polyvinylidene fluoride (PVDF). This PVDF networked organic-inorganic membrane displays high photostability and excellent operability, achieving improved simulated sunlight-driven alkaline H2O-to-H2 conversion activity (213.48 mmol m-2 h-1) following a 0.68% of solar-to-hydrogen efficiency. No obvious variation in its appearance and micromorphology was observed even being recycled for 50-times, which considerably outperforms the existing membrane photocatalysts. Subsequently, a homemade panel H2O-to-H2 conversion system was fabricated to obtain a 0.05% of solar-to-hydrogen efficiency. In this study, we opens up a prospect for practical application of photocatalysis technology.

GBA-AAV mitigates sleep disruptions and motor deficits in mice with REM sleep behavior disorder.

Sleep disturbances, including rapid eye movement sleep behavior disorder (RBD), excessive daytime sleepiness, and insomnia, are common non-motor manifestations of Parkinson's disease (PD). Little is known about the underlying mechanisms, partly due to the inability of current rodent models to adequately mimic the human PD sleep phenotype. Clinically, increasing studies have reported that variants of the glucocerebrosidase gene (GBA) increase the risk of PD. Here, we developed a mouse model characterized by sleep-wakefulness by injecting α-synuclein preformed fibronectin (PFF) into the sublaterodorsal tegmental nucleus (SLD) of GBA L444P mutant mice and investigated the role of the GBA L444P variant in the transition from rapid eye movement sleep behavior disorder to PD. Initially, we analyzed spectral correlates of REM and NREM sleep in GBA L444P mutant mice. Importantly, EEG power spectral analysis revealed that GBA L444P mutation mice exhibited reduced delta power during non-rapid eye movement (NREM) sleep and increased theta power (8.2-10 Hz) in active rapid eye movement (REM) sleep phases. Our study revealed that GBA L444P-mutant mice, after receiving PFF injections, exhibited increased sleep fragmentation, significant motor and cognitive dysfunctions, and loss of dopaminergic neurons in the substantia nigra. Furthermore, the over-expression of GBA-AAV partially improved these sleep disturbances and motor and cognitive impairments. In conclusion, we present the initial evidence that the GBA L444P mutant mouse serves as an essential tool in understanding the complex sleep disturbances associated with PD. This model further provides insights into potential therapeutic approaches, particularly concerning α-synuclein accumulation and its subsequent pathological consequences.

Bifunctional Chiral Electrocatalysts Enable Enantioselective α-Alkylation of Aldehydes.

Herein, we describe an innovative approach to the asymmetric electrochemical α-alkylation of aldehydes facilitated by a newly designed bifunctional chiral electrocatalyst. The highly efficient bifunctional chiral electrocatalyst combines a chiral aminocatalyst with a redox mediator. It plays a dual role as a redox mediator for electrooxidation, while simultaneously providing remarkable asymmetric induction for the stereoselective α-alkylation of aldehydes. Additionally, this novel catalyst exhibits enhanced catalytic activity and excellent stereoselective control comparable to conventional catalytic systems. As a result, this strategy provides a new avenue for versatile asymmetric electrochemistry. The electrooxidation of diverse phenols enables the C-H/C-H oxidative α-alkylation of aldehydes in a highly chemo- and stereoselective fashion. Detailed mechanistic studies by control experiments and cyclic voltammetry analysis demonstrate possible reaction pathways and the origin of enantio-induction.

Anti-inflammation mechanisms of a homogeneous polysaccharide from Phyllanthus emblica L. on DSS induced colitis mice via the gut microbiota and metabolites alteration.

Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Pairwise machine learning-based automatic diagnostic platform utilizing CT images and clinical information for predicting radiotherapy locoregional recurrence in elderly esophageal cancer patients.

OBJECTIVE: To investigate the feasibility and accuracy of predicting locoregional recurrence (LR) in elderly patients with esophageal squamous cell cancer (ESCC) who underwent radical radiotherapy using a pairwise machine learning algorithm. METHODS: The 130 datasets enrolled were randomly divided into a training set and a testing set in a 7:3 ratio. Clinical factors were included and radiomics features were extracted from pretreatment CT scans using pyradiomics-based software, and a pairwise naive Bayes (NB) model was developed. The performance of the model was evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). To facilitate practical application, we attempted to construct an automated esophageal cancer diagnosis system based on trained models. RESULTS: To the follow-up date, 64 patients (49.23%) had experienced LR. Ten radiomics features and two clinical factors were selected for modeling. The model demonstrated good prediction performance, with area under the ROC curve of 0.903 (0.829-0.958) for the training cohort and 0.944 (0.849-1.000) for the testing cohort. The corresponding accuracies were 0.852 and 0.914, respectively. Calibration curves showed good agreement, and DCA curve confirmed the clinical validity of the model. The model accurately predicted LR in elderly patients, with a positive predictive value of 85.71% for the testing cohort. CONCLUSIONS: The pairwise NB model, based on pre-treatment enhanced chest CT-based radiomics and clinical factors, can accurately predict LR in elderly patients with ESCC. The esophageal cancer automated diagnostic system embedded with the pairwise NB model holds significant potential for application in clinical practice.

Systematic proteomics analysis revealed different expression of laminin interaction proteins in breast cancer: lower in luminal subtype and higher in claudin-low subtype.

Background: Breast cancer is a major public health concern. Proteomics enables identification of proteins with aberrant properties. Here, we identified proteins with abnormal expression levels in breast cancer tissues and systematically analyzed and validated the data to locate potential diagnostic and therapeutic targets. Methods: Protein expression level in breast cancer tissues and para-carcinoma tissues were detected by Isobaric Tags for Relative and Absolute Quantification (iTRAQ) technology and further screened through Gene Expression Profiling Interactive Analysis (GEPIA) database. Cellular components, protein domain and Reactome pathway analysis were performed to screen functional targets. Abnormal expression levels of functional targets were validated by Oncomine database, quantitative real time polymerase chain reaction (qRT-PCR) and proteomics detection. Protein correlation analysis was performed to explain the abnormal expression levels of potential targets in breast cancer. Results: Overall, 207 and 207 proteins were up- and down-regulated, respectively, in breast cancer tissues, and approximately 50% were also detected in the GEPIA database. The overlapping proteins were mainly extracellular proteins containing epidermal growth factor-like domain in leukocyte adhesion molecule (EGF-Lam) domain and enriched in laminin interaction pathway. Moreover, the downregulated laminin interaction proteins could be functional targets, which were also validated through Oncomine-Richardson and Oncomine-Curtis database. However, the lower expression level of laminin interaction proteins only fit for luminal breast cancer cells with no or low metastasis ability because the proteins achieved higher expression level in more invasive claudin-low breast cancer cells. In addition, when compared with corresponding in situ carcinoma tissues, above-mentioned proteins also showed higher expression levels in invasive carcinoma tissues. Finally, we have revealed the negative correlation between the laminin interaction proteins and the claudins. Conclusions: The laminin interaction protein, especially for laminins with ß1 and γ1 subunits and their integrin receptors with α1 and α6 subunits, showed lower expression levels in luminal breast cancer with no or lower metastatic ability, but showed higher expression levels in claudin-low breast cancer with higher metastatic ability; and their higher expression could be related to the low claudin expression.

Toehold Strand Displacement-Mediated Exponential HCR for Highly Sensitive and Specific Analysis of miRNA in Living Cells.

As an important disease biomarker, the development of sensitive detection strategies for miRNA, especially intracellular miRNA imaging strategies, is helpful for early diagnosis of diseases, pathological research, and drug development. Hybridization chain reaction (HCR) is widely used for miRNA imaging analysis because of its high specificity and lack of biological enzymes. However, the classic HCR reaction exhibits linear amplification with low efficiency, limiting its use for the rapid analysis of trace miRNA in living cells. To address this problem, we proposed a toehold-mediated exponential HCR (TEHCR) to achieve highly sensitive and efficient imaging of miRNA in living cells using ß-FeOOH nanoparticles as transfection vectors. The detection limit of TEHCR was as low as 92.7 fM, which was 8.8 × 103 times lower compared to traditional HCR, and it can effectively distinguish single-base mismatch with high specificity. The TEHCR can also effectively distinguish the different expression levels of miRNA in cancer cells and normal cells. Furthermore, TEHCR can be used to construct OR logic gates for dual miRNA analysis without the need for additional probes, demonstrating high flexibility. This method is expected to play an important role in clinical miRNA-related disease diagnosis and drug development as well as to promote the development of logic gates.

Efficacy of Lenvatinib Combined with PD-1 Inhibitor versus Sorafenib and PD-1 Inhibitor with or Without TACE for Hepatocellular Carcinoma with Extrahepatic Metastasis.

Background: Lenvatinib or Sorafenib combined with programmed cell death protein-1 (PD-1) inhibitor as recommend treatment of advanced hepatocellular carcinoma (HCC) with extrahepatic metastasis (EHM). We aimed to compared the prognosis of Lenvatinib plus PD-1 inhibitor (Len+PD-1) versus Sorafenib plus PD-1 (Sora+PD-1) as an initial therapy for HCC with EHM. Methods: Incorporating a sum of 229 HCC patients with EHM were encompassed within this study, with 127 in the Sora+PD-1 group and 102 in the Len+PD-1 group. Through propensity score matching (PSM), we compared overall survival (OS), progression-free survival (PFS), and patient safety between these two groups. Results: The median OS were 13.0 months and 14.2 months in the Sora+PD-1 group and Len+PD-1 group. The 6-, 12-, and 24-month OS rates were 92.9%, 58.9% and 5.6% in Sora+PD-1 group and 93.1%, 61.8% and 22.6% in Len+PD-1 group, respectively. The Len+PD-1 group had obviously better OS than the Sora+PD-1 group (P = 0.002). The 3-, 6-, and 12-month PFS rates were 76.4%, 27.6% and 1.6% in Sora+PD-1 group and 86.2%, 50.5% and 12.2% in Len+PD-1 group, respectively. Compared with Sora+PD-1 group, the Len+PD-1 group had obviously better PFS (P < 0.001). Analysis within subgroups showed that OS was significant in patients receiving TACE in Len+PD-1 group than Sora+PD-1 group (p = 0.003). Conclusion: Len+PD-1 group had longer OS and PFS than Sora+PD-1 group for patient with EHM. In addition, OS in patients received TACE was improved with Len+PD-1 treatment. For patients without TACE, there was no significance between Sora+PD-1 and Len+PD-1 groups.

[Microcirculatory visualization and metabolomics of Dalbergia cochinchinensis in ameliorating coronary microvascular dysfunction in rats].

This study employed microcirculation visualization and metabolomics methods to explore the effect and possible mechanism of Dalbergia cochinchinensis in ameliorating coronary microvascular dysfunction(CMD) induced by microsphere embolization in rats. Sixty SPF-grade male SD rats were randomized into sham, model, and low-, medium-, and high-dose [1.5, 3.0, and 6.0 g·kg~(-1)·d~(-1), respectively] D. cochinchinensis water extract groups. The rats in sham and model groups were administrated with equal volume of normal saline by gavage once a day for 7 consecutive days. The rat model of CMD was prepared by injecting polyethylene microspheres into the left ventricle, while the sham group was injected with an equal amount of normal saline. A blood flow meter was used to measure blood flow, and a blood rheometer to measure blood viscosity and fibrinogen content. An automatic biochemical analyzer and reagent kits were used to measure the serum levels of myocardial enzymes, glucose, and nitric oxide(NO). Hematoxylin-eosin(HE) staining was used to observe the pathological changes of myocardial tissue. DiI C12/C18 perfusion was used to infuse coronary microvessels, and the structural and morphological changes were observed using a confocal laser scanning microscope. AngioTool was used to analyze the vascular area, density, radius, and mean E lacunarity in the microsphere embolization area, and vascular blood flow resistance was calculated based on Poiseuille's law. Non-targeted metabolomics based on high performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed screen potential biomarkers and differential metabolites regulated by D. cochinchinensis and the involved metabolic pathways were enriched. The pharmacodynamic results showed that compared with the model group, D. cochinchinensis significantly increased mean blood flow, reduced plasma fibrinogen content, lowered the levels of myocardial enzymes such as creatine kinase(CK), creatine kinase-MB(CK-MB), and lactate dehydrogenase(LDH), alleviate myocardial injury, and protect damaged myocardium. In addition, D. cochinchinensis significantly increased serum NO content, promoted vascular smooth muscle relaxation, dilated blood vessels, lowered serum glucose(GLU) level, improved myocardial energy metabolism, and alleviated pathological changes in myocardial fibrosis and inflammatory cell infiltration. The results of coronary microcirculation perfusion showed that D. cochinchinensis improved the vascular morphology, increased the vascular area, density, and radius, reduced vascular mean E lacunarity and blood flow resistance, and alleviated vascular endothelial damage in CMD rats. The results of metabolomics identified 45 differential metabolites between sham and model groups, and D. cochinchinensis recovered the levels 25 differential metabolites, which were involved in 8 pathways including arachidonic acid metabolism, arginine biosynthesis, and sphingolipids metabolism. D. cochinchinensis can ameliorate coronary microcirculation dysfunction caused by microsphere embolization in rats, and it may alleviate the pathological changes of CMD rats by regulating inflammatory reaction, endothelial damage, and phospholipid metabolism.

Initiating PeriCBD to probe perinatal influences on neurodevelopment during 3-10 years in China.

Adverse perinatal factors can interfere with the normal development of the brain, potentially resulting in long-term effects on the comprehensive development of children. Presently, the understanding of cognitive and neurodevelopmental processes under conditions of adverse perinatal factors is substantially limited. There is a critical need for an open resource that integrates various perinatal factors with the development of the brain and mental health to facilitate a deeper understanding of these developmental trajectories. In this Data Descriptor, we introduce a multicenter database containing information on perinatal factors that can potentially influence children's brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development associated with perinatal factors among children aged 3-10 years. Ultimately, our goal is to help understand how different adverse perinatal factors specifically impact cognitive development and neurodevelopment. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD.

A complete oral regimen for induction therapy of patients with high-risk APL: An oral etoposide instead of intravenous infusion for cytoreductive chemotherapy.

There is an urgent need for an oral, efficient and safe regimen for high-risk APL under the pandemic of COVID-19. We retrospectively analysed 60 high-risk APL patients. For induction therapy (IT), in addition to all-trans retinoic acid (ATRA) and oral arsenic (RIF), 22 patients received oral etoposide (VP16) as cytotoxic chemotherapy (CC), and 38 patients received intravenous CC as historical control group. The median dose of oral VP16 was 1000 mg [interquartile rage (IQR), 650-1250]. One patient died during IT in the control group, 59 evaluable patients (100%) achieved complete haematological remission (CHR) after IT and complete molecular remission (CMR) after consolidation therapy. The median time to CHR and CMR was 36 days (33.8-44) versus 35 days (32-42; p = 0.75) and 3 months (0.8-3.5) versus 3.3 months (2.4-3.7; p = 0.58) in the oral VP16 group and in the control group. Two (9.1%) and 3 (7.9%) patients experienced molecular relapse in different group respectively. The 2-year estimated overall survival and event-free survival were 100% versus 94.7% (p = 0.37) and 90.9% versus 89.5% (p = 0.97) respectively. A completely oral, efficient and safe induction regimen including oral VP16 as cytoreductive chemotherapy combined with ATRA and RIF is more convenient to administer for patients with high-risk APL.

Dual miRNA-Triggered DNA Walker Assisted by APE1 for Specific Recognition of Tumor Cells.

The identification of a specific tumor cell is crucial for the early diagnosis and treatment of cancer. However, it remains a challenge due to the limited sensitivity and accuracy, long response time, and low contrast of the recent approaches. In this study, we develop a dual miRNA-triggered DNA walker (DMTDW) assisted by APE1 for the specific recognition of tumor cells. miR-10b and miR-155 were selected as the research models. Without miR-10b and miR-155 presence, the DNA walker remains inactive as its walking strand of W is locked by L1 and L2. After miR-10b and miR-155 are input, the DNA walker is triggered as miR-10b and miR-155 bind to L1 and L2 of W-L1-L2, respectively, unlocking W. The DNA walker is driven by endogenous APE1 that is highly catalytic and is highly expressed in the cytoplasm of tumor cells but barely expressed in normal cells, ensuring high contrast and reaction efficiency for specific recognition of tumor cells. Dual miRNA input is required to trigger the DNA walker, making this strategy with a high accuracy. The DMTDW strategy exhibited high sensitivity for miRNA analysis with a detection limit of 44.05 pM. Living cell-imaging experiments confirmed that the DMTDW could effectively respond to the fluctuation of miRNA and specifically identified MDA-MB-231 cells from different cell lines. The proposed DMTDW is sensitive, rapid, and accurate for specific tumor cell recognition. We believe that the DMTDW strategy can become a powerful diagnostic tool for the specific recognition of tumor cells.