Search

Na Guo,* Yanyan Miao,* Mingzhong Sun Department of Hepatopathy, The Sixth People’s Hospital of Qingdao, Qingdao 266033, Shandong Province, China *These authors contributed equally to this work Objective: The aim of this study was to systematically investigate the safety and efficacy of the combination of transcatheter hepatic arterial chemoembolization (TACE) and cinobufotalin injection for advanced hepatocellular carcinoma (HC). Methods: Clinical trials were searched from Web of Science, Cochrane Library, PubMed, Embase, Chinese Medical Citation Index (CMCI), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP), and Wanfang database. Outcome measures including therapeutic efficacy, quality of life, liver function, immune function, and adverse events were extracted and evaluated. Results: After final assessment, 27 studies including 2,079 advanced HC patients were involved in this study. Compared with TACE alone, the combination of TACE with cinobufotalin injection adjuvant therapy significantly prolonged the patients’ 1-, 1.5-, 2-, and 3-year overall survival (OS) rate (1-year OS, OR=2.84, 95% CI=2.20–3.67, P

Qing-wei Zhang,1 Jia-yu Song,2 Jiang-hua Yu,1 Ming-zhen Sun,2 Si-yuan Tang,1 Shao-zhe Yang,1 Lei-jia Cao,1 Hui-fen Wang,1 Li-na Cui,1 Xiu-hong Fu1 1Department of Obstetrics and Gynaecology, Luohe Central Hospital, Luohe, 462000, Henan, China; 2Department of Pharmacology, Luohe Medical College, Luohe, 462000, Henan, China Purpose: In this paper, the association between polymorphisms of IFN-γ+874T/A (rs2430561), IFN-γR1 -56 T/C (rs2234711), IFN-γR1 +95 C/T (rs7749390), and IFN-γR1 -611A/G (rs 1327474) and human papillomavirus (HPV) susceptibility was investigated in rural women from Luohe, Henan, China. Patients and methods: A total of 520 rural women were enrolled from Luohe, including 260 with HPV infection and mild dysplasia or less and 260 without HPV infection. Single-nucleotide polymorphisms (SNPs) of IFN-γ +874T/A, IFN-γR1 -56 T/C, IFN-γR1 +95 C/T and IFN-γR1 -611A/G were genotyped using TaqMan Pre-Designed SNP Genotyping Assays. Serum IFN-γ levels were measured using Human IFN-γ Quantikine ELISA Kit. Multivariate logistic regression analysis was performed to identify the SNPs associated with HPV susceptibility. Serum IFN-γ levels were compared between different genotypes. Results: The polymorphism of IFN-γ +874T/A was associated with HPV susceptibility and +874A carriers had an increased risk. Moreover, the odds ratio was higher in +874 AA carriers than in +874 AT carriers (1.672 vs 2.874). Serum IFN-γ levels were highest in IFN-γ +874 TT carriers, intermediate in AT carriers, and lowest in AA carriers (2.86±1.14 vs 1.57±0.79 vs 0.41±0.22 pg/mL, all P

© 2015 Safaee et al.CD97 is a novel glioma antigen that confers an invasive phenotype and poor survival in patients with glioblastoma (GBM), the most aggressive primary malignant brain tumor. The short isoform of CD97, known as EGF(1,2,5), has been shown t

Choroid plexus carcinoma (CPCs) is a rare, malignant, primary brain tumor with a poor prognosis. Currently, there is no consensus on the use of adjuvant therapy, and few large-scale studies focus exclusively on the pediatric population. We performed a comprehensive systematic review of pediatric CPCs to determine the effects of various adjuvant therapy modalities on overall survival (OS). A literature search was performed to identify studies reporting children with CPC who underwent surgical resection. Only patients who had clearly received adjuvant therapy, or were described as not selected for adjuvant therapy were analyzed in our comparison groups. Kaplan–Meier and multivariate Cox regression survival analyses were performed to determine the effects of different types of adjuvant therapies on OS. A total of 135 children (age ≤ 18 years) with CPC who had known adjuvant therapy status and OS were identified from 53 articles. Kaplan–Meier analysis showed that while adjuvant therapy overall improved OS (p = 0.001), different modes of adjuvant therapies had varying effects on OS (p = 0.034). Specifically, combined chemo-radiotherapy as well as chemotherapy alone improved OS (p = 0.001), but radiation did not (p = 0.129). Multivariate Cox proportional hazard model adjusting for confounding factors showed that combined therapy was associated with better OS compared to chemotherapy alone (HR: 0.291, p = 0.027). Both chemotherapy alone and combined chemo-radiation improved OS independent of age, gender, tumor location and extent of resection, while radiation alone did not.

Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesio

Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell p

Improving liver regeneration (LR) remains a medical issue, and there is currently a lack of safe and effective drugs for LR. Rhizoma Dioscoreae (SanYak, SY) is a traditional Chinese medicine. However, the underlying action mechanism of SY treatment for LR is yet to be fully elucidated. To explore the mechanism by which SY affects LR, we have conducted a series of methods for network pharmacological analysis, molecular docking, and in vivo experimental validation in mice. Overall, 9 compounds and 30 predicted target genes of SY were found to be associated with the therapeutic effects of LR. Compared with the model group, hematoxylin and eosin staining revealed that the mice with preoperative drug intervention possessed fewer postoperative hepatocyte bubbles and relatively regular morphology. Furthermore, the serum alanine transaminase and aspartate aminotransferase levels were reduced, immunohistochemistry revealed elevated proliferating cell nuclear antigen positivity rate, and Western blotting demonstrated that the phospho-protein kinase B (AKT)/AKT ratio was downregulated and that vascular endothelial growth factor A (VEGFA) expression levels were upregulated. This study explored dioscin, the main active ingredient of SY, and its potential therapeutic effects on LR. It repairs damaged liver following surgery and promotes liver cell proliferation. The action mechanism comprises reducing AKT phosphorylation levels and upregulating VEGFA expression levels. Thus, this study provides a new direction for further research on the mechanism of SY promoting LR.

Isochronous Mass Spectrometry is a practical approach for studying decays of short-lived isomers. However, solely relying on the time stamps between the isomer and ground state does not provide clear sign of decay. To address this issue, we proposed a method for extracting decay time point by analyzing the residuals of time stamps within a window of (20μs, 180μs) after the start of data acquisition. Decay events out of the window were disregarded due to poor accuracy of revolution time. In this paper, we propose a novel approach based on the discrete Fourier transform technique, which was tested by simulation data. We found that the accuracy of the decay time point can be improved, leading to an expanded window of (15μs, 185μs). Furthermore, as the novel method was applied to experimental data, additional five decay events were identified. The newly determined half-life of 94m Ru 44+ is consistent with the previous value., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Glioblastoma (GBM) is the most common malignant primary brain tumor and remains incurable. Previous work has shown that systemic administration of Decitabine (DAC) induces sufficient expression of cancer-testis antigens (CTA) in GBM for targeting by adoptive T-cell therapy in vivo. However, the mechanisms by which DAC enhances immunogenicity in GBM remain to be elucidated. Using New York esophageal squamous cell carcinoma 1 (NY-ESO-1) as a representative inducible CTA, we demonstrate in patient tissue, immortalized glioma cells, and primary patient-derived gliomaspheres that basal CTA expression is restricted by promoter hypermethylation in gliomas. DAC treatment of glioma cells specifically inhibits DNA methylation silencing to render NY-ESO-1 and other CTA into inducible tumor antigens at single-cell resolution. Functionally, NY-ESO-1 T-cell receptor-engineered effector cell targeting of DAC-induced antigen in primary glioma cells promotes specific and polyfunctional T-cell cytokine profiles. In addition to induction of CTA, DAC concomitantly reactivates tumor-intrinsic human endogenous retroviruses, interferon response signatures, and MHC-I. Overall, we demonstrate that DAC induces targetable tumor antigen and enhances T-cell functionality against GBM, ultimately contributing to the improvement of targeted immune therapies in glioma., Significance: This study dissects the tumor-intrinsic epigenetic and transcriptional mechanisms underlying enhanced T-cell functionality targeting decitabine-induced cancer-testis antigens in glioma. Our findings demonstrate concomitant induction of tumor antigens, reactivation of human endogenous retroviruses, and stimulation of interferon signaling as a mechanistic rationale to epigenetically prime human gliomas to immunotherapeutic targeting., (©2024 The Authors; Published by the American Association for Cancer Research.)

Aim: To investigate the morphological characteristics of retinal vessels in patients with different severity of diabetic retinopathy (DR) and in patients with or without diabetic macular edema (DME)., Methods: The 239 eyes of DR patients and 100 eyes of healthy individuals were recruited for the study. The severity of DR patients was graded as mild, moderate and severe non-proliferative diabetic retinopathy (NPDR) according to the international clinical diabetic retinopathy (ICDR) disease severity scale classification, and retinal vascular morphology was quantitatively analyzed in ultra-wide field images using RU-net and transfer learning methods. The presence of DME was determined by optical coherence tomography (OCT), and differences in vascular morphological characteristics were compared between patients with and without DME., Results: Retinal vessel segmentation using RU-net and transfer learning system had an accuracy of 99% and a Dice metric of 0.76. Compared with the healthy group, the DR group had smaller vessel angles (33.68±3.01 vs 37.78±1.60), smaller fractal dimension (Df) values (1.33±0.05 vs 1.41±0.03), less vessel density (1.12±0.44 vs 2.09±0.36) and fewer vascular branches (206.1±88.8 vs 396.5±91.3), all P <0.001. As the severity of DR increased, Df values decreased, P =0.031. No significant difference between the DME and non-DME groups were observed in vascular morphological characteristics., Conclusion: In this study, an artificial intelligence retinal vessel segmentation system is used with 99% accuracy, thus providing with relatively satisfactory performance in the evaluation of quantitative vascular morphology. DR patients have a tendency of vascular occlusion and dropout. The presence of DME does not compromise the integral retinal vascular pattern., Competing Interests: Conflicts of Interest: Deng XY, None; Liu H, None; Zhang ZX, None; Li HX, None; Wang J, None; Chen YQ, None; Mao JB, None; Sun MZ, None; Shen LJ, None., (International Journal of Ophthalmology Press.)

Objective: To evaluate the application value of portable pulse oximeter in adult obstructive sleep apnea (OSA). Methods: This study prospectively enrolled adult patients who underwent polysomnography (PSG) due to snoring at the Respiratory and Sleep Medicine Department of Peking University People's Hospital from July 2022 to July 2023. During PSG monitoring, CS-WOxi was continuously used to monitor blood oxygen levels. The consistency between 3% oxygen desaturation index (ODI 3 ) measured by portable pulse oximeter and ODI 3 of polysomnography was evaluated using difference test, Pearson's correlation coefficient, and Bland-altman method. Receiver operating characteristic curve was used to determine the optimal threshold for diagnosing OSA. Results: A total of 184 subjects were included, including 121 males (65.8%) and 63 females (34.2%). The mean age was 46.0 (34.3, 59.0) years, body mass index was 26.0 (23.3, 29.6) kg/m², and the apnea-hypopnea index was 18.2 (5.8, 40.8) events/h. There was a significant difference between CS-ODI 3 and PSG-ODI 3 [17.1(6.2, 42.7) vs. 14.0(2.9, 32.6), P <0.001], and the Pearson correlation coefficient was 0.93 ( P <0.001). There was a good correlation between CS-ODI 3 and PSG-AHI ( r =0.92, P <0.001). Bland-Altman consistency test showed that the average difference between the two was 0.7 events/h, and the 95% consistency limit was (-17.9, 19.3 events/h). When the CS-ODI 3 ≥5 events/h was used to identify OSA, the sensitivity was 94.4%, the specificity was 80.0%, and the accuracy was 91.3%. When PSG-AHI≥5 events/h was used as the diagnostic criteria, the area under the receiver operating characteristic curve was 0.933. Conclusion: Portable pulse oximeter can monitor pulse oxygen saturation accurately and has good sensitivity and specificity for OSA high-risk patients, and is a reliable tool for OSA screening.

Purinergic receptor P2Y11, a G protein-coupled receptor that is stimulated by extracellular ATP, has been demonstrated to be related to the chemotaxis of granulocytes, apoptosis of neutrophils, and secretion of cytokines in vitro. P2Y11 mutations were associated with narcolepsy. However, little is known about the roles of P2RY11 in the occurrence of narcolepsy and inflammatory response in vivo. In this study, we generated a zebrafish P2Y11 mutant using CRISPR/Cas9 genome editing and demonstrated that the P2Y11 mutant replicated the narcolepsy-like features including reduced HCRT expression and excessive daytime sleepiness, suggesting that P2Y11 is essential for HCRT expression. Furthermore, we accessed the cytokine expression in the mutant and revealed that the P2RY11 mutation disrupted the systemic inflammatory balance by reducing il4, il10 and tgfb, and increasing il6, tnfa, and il1b. In addition, the P2RY11-deficient larvae with caudal fin injuries exhibited significantly slower migration and less recruitment of neutrophils and macrophages at damaged site, and lower expression of anti-inflammatory cytokines during tissue damage. All these findings highlight the vital roles of P2RY11 in maintaining HCRT production and secreting anti-inflammatory cytokines in the native environment, and suggested that P2RY11-deficient zebrafish can serve as a reliable and unique model to further explore narcolepsy and inflammatory-related diseases with impaired neutrophil and macrophage responses., (© 2024. The Author(s).)

Destruction of erythropoiesis process leads to various diseases, including thrombocytopenia, anaemia, and leukaemia. miR-429-CT10 regulation of kinase-like (CRKL) axis involved in development, progression and metastasis of cancers. However, the exact role of miR-429-CRKL axis in leukaemic cell differentiation are still unknown. The current work aimed to uncover the effect of miR-429-CRKL axis on erythropoiesis. In the present study, CRKL upregulation was negatively correlated with miR-429 downregulation in both chronic myeloid leukaemia (CML) patient and CR patient samples. Moreover, CRKL expression level was significantly decreased while miR-429 expression level was increased during the erythroid differentiation of K562 cells following hemin treatment. Functional investigations revealed that overexpression and knockdown of CRKL was remarkably effective in suppressing and promoting hemin-induced erythroid differentiation of K562 cells, whereas, miR-429 exhibited opposite effects to CRKL. Mechanistically, miR-429 regulates erythroid differentiation of K562 cells by downregulating CRKL via selectively targeting CRKL-3'-untranslated region (UTR) through Raf/MEK/ERK pathway. Conversely, CRKII had no effect on erythroid differentiation of K562 cells. Taken together, our data demonstrated that CRKL (but not CRKII) and miR-429 contribute to development, progression and erythropoiesis of CML, miR-429-CRKL axis regulates erythropoiesis of K562 cells via Raf/MEK/ERK pathway, providing novel insights into effective diagnosis and therapy for CML patients., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Indications Corridor and Limits of Exposure: The expanded retrosigmoid approach with splitting of the horizontal cerebellar fissure provides a more direct and shorter route for central and dorsolateral pontine lesions while minimizing retraction of tracts, nuclei, and cerebellum. 1-4., Anatomic Essentials Need for Preoperative Planning and Assessment: The middle cerebellar peduncle is partially covered by the petrosal surface of the cerebellum. The horizontal cerebellar fissure (petrosal fissure) divides the petrosal surface of the cerebellar hemisphere into superior and inferior parts. Splitting the petrosal fissure separates the superior and inferior petrosal surfaces and exposes the posterolateral middle cerebellar peduncle (posterior and lateral to the root entry zone of CN5). 1-4., Essentials Steps of the Procedure: Expanded retrosigmoid craniotomy is performed, including unroofing of the sigmoid sinus; petrosal fissure is split to expose the posterolateral middle cerebellar peduncle; entry point for resection of the cavernoma is identified; nims stimulator stimulator is used to confirm the absence of tracts and nuclei; myelotomy is performed; and cavernoma and its draining vein (but not the developmental venous anomaly) are removed using a combination of traction and countertraction against gliotic plane., Pitfalls/avoidance of Complications: Wide splitting of the horizontal cerebellar fissure minimizes retraction or resection of the cerebellum and offers the best angle of attack. Knowledge of brainstem anatomy and use of intraoperative navigation are critical to avoid complications., Variants and Indications for Their Use: Far lateral through the middle cerebellar peduncle is a variant that can be used to resect pontine cavernomas if a caudocranial trajectory is preferred.The patient consented to the procedure and to the publication of her image., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Etomidate (ET) is a widely used intravenous imidazole general anesthetic, which depresses the cerebellar neuronal activity by modulating various receptors activity and synaptic transmission. In this study, we investigated the effects of ET on the cerebellar climbing fiber-Purkinje cells (CF-PC) plasticity in vitro in mice using whole-cell recording technique and pharmacological methods. Our results demonstrated that CF tetanic stimulation produced a mGluR1-dependent long-term depression (LTD) of CF-PC excitatory postsynaptic currents (EPSCs), which was enhanced by bath application of ET (10 µM). Blockade of mGluR1 receptor with JNJ16259685, ET triggered the tetanic stimulation to induce a CF-PC LTD accompanied with an increase in paired-pulse ratio (PPR). The ET-triggered CF-PC LTD was abolished by extracellular administration of an N-methyl-(D)-aspartate (NMDA) receptor antagonist, D-APV, as well as by intracellular blockade of NMDA receptors activity with MK801. Furthermore, blocking cannabinoids 1 (CB1) receptor with AM251 or chelating intracellular Ca 2+ with BAPTA, ET failed to trigger the CF-PC LTD. Moreover, the ET-triggered CF-PC LTD was abolished by inhibition of protein kinase A (PKA), but not by inhibition of protein kinase C inhibiter. The present results suggest that ET acts on postsynaptic NMDA receptor resulting in an enhancement of the cerebellar CF-PC LTD through CB1 receptor/PKA cascade in vitro in mice. These results provide new evidence and possible mechanism for ET anesthesia to affect motor learning and motor coordination by regulating cerebellar CF-PC LTD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stable K562 cells expressing the ETV6-MECOM fusion protein were used to investigate the effects of the ETV6-MECOM oncoprotein. K562-ETV6-MECOM cells were undifferentiated and had reduced colony formation, increased cell migration and invasion, and increased sphere number and diameter in a spheroid formation assay, presenting epithelial-to-mesenchymal transition (EMT) traits. The expression of E-cadherin, a hallmark of EMT, was significantly downregulated at the transcriptional and translational level in K562-ETV6-MECOM cells to explore the mechanistic basis of EMT. Stepwise truncation, DNA sequence deletion, mutation analysis for E-cadherin promoter transactivation, and a dual luciferase assay indicated that the regulatory region of ETV6-MECOM is located in the DNA motif -1116 TTAAAA -1111 of E-cadherin promoter. Moreover, a chromatin immunoprecipitation assay showed that this oncoprotein binds to the DNA motif -1116 TTAAAA -1111 with the anti-EVI1 antibody. Although ETV6-MECOM upregulated the expressions of EMT master regulators, including SNAIL, SLUG, ZEB2, and TWIST2, their knockdown had no effect on EMT-related properties. However, overexpression of E-cadherin eliminated EMT traits in the presence of the ETV6-MECOM oncoprotein. These data confirmed that the ETV6-MECOM oncoprotein, not SNAIL, SLUG, ZEB2, or TWIST2, plays a critical role in inducing EMT traits in leukemia K562 cells. ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif -1116 TTAAAA -1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors.)

Pleiotropic drug resistance (PDR) family proteins have been extensively studied for their roles in transporting hydrophobic substances, including carotenoids. Overexpression of the PDR family regulator Pdr3p was recently found to boost the biosynthesis of carotenoids, which could not be explained by enhanced product secretion due to the meager extracellular proportions. To provide insights into the possible mechanism, comparative transcriptomics, reverse metabolic engineering, and electrophoretic mobility shift assay (EMSA) were conducted. Transcriptomic data suggested an unexpected correlation between Pdr3p overexpression and the transcriptional levels of GAL promoter-driven genes. This assumption was verified using mCherry and the lycopene synthetic pathway as the reporters. qRT-PCR and EMSA provided further evidence for the activation of GAL promoters by Pdr3p binding to their upstream activation sequences (UASs). This work gives insight into the mechanism of Pdr3p-promoted carotenoid production and highlights the complicated metabolic networking between transcriptional factors and promoters in yeast.

Aerogels prepared using freeze-drying methods have the potential to be insulation materials or absorbents in the fields of industry, architecture, agriculture, etc., for their low heat conductivity, high specific area, low density, degradability, and low cost. However, their native, poor water resistance caused by the hydrophilicity of their polymer matrix limits their practical application. In this work, a novel, controllable, and efficient templating method was utilized to construct a highly hydrophobic surface for freeze-drying aerogels. The influence of templates on the macroscopic morphology and hydrophobic properties of materials was investigated in detail. This method provided the economical and rapid preparation of a water-resistant aerogel made from polyvinyl alcohol (PVA) and montmorillonite (MMT), putting forward a new direction for the research and development of new, environmentally friendly materials.

Introduction: Previous studies have indicated a correlation between perceived stress and cognitive decline. However, it remains unknown whether high levels of perceived stress can result in motoric cognitive risk (MCR) syndrome. This study investigated the relationship between perceived stress and MCR in a community-based population., Methods: The study cohort comprised 852 elderly individuals from the Rugao Longitudinal Aging Cohort. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10), while MCR was defined as the coexistence of subjective memory complaints (SMCs) and slow gait speed., Results: The average age of the study participants is 79.84 ± 4.34 years. The mean score of PSS-10 among participants is 10.32 (range = 0-33; [SD] = 5.71), with a median score of 10.00 (6.00, 14.00). The prevalence of MCR is 9.3%. In the logistic regression analysis, for each 1-SD (5.71) increase in the global PSS-10 score, the risk of MCR increased by 40% (95% CI 1.09-1.80). Additionally, in the aspect of two components of MCR, with a 1-SD increase (5.71) in the global PSS-10 score, there was a 50% (95% CI 1.29-1.75) increase in the risk of SMCs and a 27% (95% CI 1.04-1.55) increase in the risk of slow gait speed. In terms of specific walking speed, there was a reverse correlation between the global PSS-10 score and walking speed (r = -0.14, p &lt; 0.001)., Conclusions: This study provided preliminary evidence that high levels of perceived stress were associated with the risk of MCR in a community-dwelling population., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The sleep deficiency and sleep disturbance of critically ill patients may result in adverse outcomes, negative effects on early rehabilitation, and may persist well beyond the intensive care unit (ICU). It has been paid more and more attention in clinical practice. The sleep problems of critically ill patients are associated with suffered critical illness, ICU environments, and coexisting sleep disorders before critical illness. Poor sleep quality, insufficient sleep duration, severe sleep fragmentation and irregular circadian rhythms during critical care illness have been extensively described. In addition, ICU patients have been specifically shown to experience atypical sleep and pathologic wakefulness. So the sleep in critical ill patients should be evaluated. Sleep can be evaluated by both subjective assessment and objective measurements, including polysomnography and actigraphy. According to individual situation, comprehensive, interdisciplinary, and personalized interventions, which include treating critical illness, improving ICU environment to reduce interference to sleep, nonpharmacological treatment to relax and stabilize sleep, and treating coexisting sleep disorders, should be taken to improve the patient's sleep and then to promote the early rehabilitation of critically ill patients.

Objective: To evaluate the association between digestive tract cancer and anatomical severity of coronary artery disease. Methods: This study enrolled 142 patients with digestive tract cancer who underwent coronary angiography in the Department of Cardiology of the First Medical Center of Chinese PLA General Hospital from 2009 to 2020 as the cancer group. The patients in cancer group were matched with 426 non-cancer patients who underwent coronary angiography at our hospital during the same period in a 1∶3 ratio based on gender and age. All enrolled patients had no previous history of percutaneous coronary intervention or coronary artery bypass grafting surgery. The severity of coronary artery disease was documented and assessed using the SYNTAX score based on angiogram. High SYNTAX score (SXhigh) was defined as SYNTAX score≥22 (upper quartile), while low SYNTAX score (SXlow) was SYNTAX score<22. High NLR (NLRhigh) was NLR≥2.287 (median), while low NLR (NLRlow) was NLR<2.287. The association between digestive tract cancer and severity of coronary artery disease was analyzed using logistic regression analysis. Results: This study included a total of 568 patients, with a mean age of (66.6±8.7) years. Among them, 430 patients (75.7%) were male. The cancer group consisted of 142 patients with digestive tract cancers, with a mean age of (66.5±8.4) years. The non-cancer group consisted of 426 patients, with a mean age of (66.7±8.8) years. The proportion of SXhigh in patients with digestive tract cancers (33.1%, 47 patients) was higher than that in non-cancer patients (23.9%, 102 patients) ( P =0.032). Compared to non-cancer patients, SXhigh in patients with digestive tract cancers was higher ( OR : 1.614, 95% CI : 1.051-2.481, P =0.029). Subgroup analysis stratified by NLR levels revealed that in the NLRhigh group, patients with digestive tract cancers exhibited a higher severity of coronary artery disease compared to non-cancer patients, with an OR of 1.948 (95% CI : 1.005-3.779, P =0.048). In the NLRlow group, there was no significant relationship between digestive tract cancers and the severity of coronary artery disease, with an OR of 1.277 (95% CI : 0.586-2.781, P =0.538). Conclusions: Digestive tract cancer is associated with the severity of coronary artery disease, and patients with digestive tract cancers have a higher risk of severe coronary artery disease than non-cancer patients. Additionally, there is an association between digestive tract cancers and the severity of coronary artery disease under conditions of high levels of inflammation.

Background and Aims: Knowledge of how intrinsic capacity (IC) shape functional ability (FA) trajectories in later life remains unclear. We investigated the changes in IC and their impact on 5-years FA trajectories in the Chinese older population., Methods: A total of 1640 older adults from the Rugao Longitudinal Ageing Study were included and analyzed. FA was assessed by The Lawton Instrumental Activities of Daily Living Scale (IADLs). We used cognition, psychology, locomotion, sensory capacity, and vitality to capture the multiple domains of IC according to the ICOPE method. The IC was derived retrospectively from variables collected before this was described by WHO., Results: At baseline, a higher IC was associated with higher IADLs (β = 0.98, 95% CI 0.90, 1.06, P < 0.001). Individuals with declines in IC between wave1 and wave2 experienced a faster decline in IADLs over time (β = - 0.28, 95% CI - 0.40, - 0.16, P < 0.001) after considering covariates. One or more impairment IC scores at baseline strongly predicted death (HR = 1.20, 95% CI 1.11, 1.30, P < 0.001). In addition, according to the IC scores at baseline, we stratify IC in low, middle, and high, compared with those in the high IC score, those in the low were associated with a 2.56-fold (95% CI 1.64, 4.01, P < 0.001) higher risk of mortality, after adjustment for variables., Conclusion: Changes in IC shape FA trajectories. IC impairment is associated with an increased risk of death. Assessing intrinsic capacity would facilitate early identification of older adults at high risk of adverse outcomes and prompt targeted interventions., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Using a novel method of isochronous mass spectrometry, the masses of ^{62}Ge, ^{64}As, ^{66}Se, and ^{70}Kr are measured for the first time, and the masses of ^{58}Zn, ^{61}Ga, ^{63}Ge, ^{65}As, ^{67}Se, ^{71}Kr, and ^{75}Sr are redetermined with improved accuracy. The new masses allow us to derive residual proton-neutron interactions (δV&#95;{pn}) in the N=Z nuclei, which are found to decrease (increase) with increasing mass A for even-even (odd-odd) nuclei beyond Z=28. This bifurcation of δV&#95;{pn} cannot be reproduced by the available mass models, nor is it consistent with expectations of a pseudo-SU(4) symmetry restoration in the fp shell. We performed ab initio calculations with a chiral three-nucleon force (3NF) included, which indicate the enhancement of the T=1 pn pairing over the T=0 pn pairing in this mass region, leading to the opposite evolving trends of δV&#95;{pn} in even-even and odd-odd nuclei.

Objective: This study aims to clarify how the stimulation of acupuncture points is achieved by needles with different surface texture during acupuncture; it also seeks to lessen injury at the insertion site and increase the therapeutic efficacy of acupuncture, by simulating the mechanical effects of various needle surface patterns on Zusanli (ST36) without changing the radius of acupuncture needles., Methods: Five acupuncture needle models with different surface patterns, including the smooth needle, the lined needle, the ringed needle, the left-hand threaded needle and the right-hand threaded needle, and a layered model of the Zusanli acupoint were used to investigate how to reduce tissue damage and increase stimulation during acupuncture treatment. Puncturing of the skin as well as lifting-inserting and twisting needle manipulations were simulated using these models, and the degree of damage and force of stimulation caused by the acupuncture needles with different surface patterns during acupuncture were compared., Results: The smooth needle and the lined needle caused the least tissue damage during insertion, while the left-hand threaded and the right-hand threaded needles caused the most damage. The ringed needle, the left-hand threaded needle and the right-hand threaded needle stimulated the acupoint tissue more during lifting-inserting manipulations, while the lined needle and the smooth needle produced less stimulation. The stimulation of the lined needle on the acupoint tissue was the largest during twisting manipulation, whereas the left-hand threaded needle and the right-hand threaded needle had smaller effects. In lifting-inserting and twisting manipulations, both the left-hand threaded needle and right-hand threaded needle provided more stimulation, but the torsion direction in which they produced better stimulation was the opposite., Conclusion: According to the simulation results, the ringed pattern enhances stimulation best in the lifting-inserting manipulation, whereas the lined pattern enhances stimulation best in the twisting manipulation. Both the right-hand and left-hand thread patterns have certain enhancing effects in these two operations. Taking the geometric properties of the pattern into account, the left-hand thread pattern and the right-hand thread pattern have the geometric characteristics of both the lined pattern and the ringed pattern. To conclude, a pattern perpendicular to the movement direction during the acupuncture manipulation creates more stimulation. These results have significance for future needle design. Please cite this article as: Sun MZ, Wang X, Li YC, Yao W, Gu W. Mechanical effects of needle texture on acupoint tissue. J Integr Med. 2023; 21(3): 254-267., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Shanghai Changhai Hospital. Published by Elsevier B.V. All rights reserved.)

Both azido (N 3 ) and trifluoromethyl (CF 3 ) groups are key moieties of numerous valuable molecules that are extensively applied in drug discovery, chemical biology, and synthetic chemistry. However, the asymmetric construction of chiral quaternary stereocenters bearing both N 3 and CF 3 groups is still unexplored. Herein, we report a kind of bench-stable and easily adjustable benziodazolone-based azidating reagents. These reagents were used to achieve an enantioselective copper-catalyzed azidation of N -unprotected 3-trifluoromethylated oxindoles to provide diverse enantioenriched 3-N 3 -3-CF 3 oxindoles.

Background: Migratory disc herniations can mimic neoplasms clinically and on imaging. Far lateral lumbar disc herniations usually compress the exiting nerve root and can be challenging to distinguish from a nerve sheath tumor due to the proximity of the nerve and characteristics on magnetic resonance imaging (MRI). These lesions can occasionally present in the upper lumbar spine region at the L1-2 and L2-3 levels., Observations: The authors describe 2 extraforaminal lesions in the far lateral space at the L1-2 and L2-3 levels, respectively. On MRI, both lesions tracked along the corresponding exiting nerve roots with avid postcontrast rim enhancement and edema in the adjacent muscle tissue. Thus, they were initially concerning for peripheral nerve sheath tumors. One patient underwent fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) screening and demonstrated moderate FDG uptake on PET-CT scan. In both cases, intraoperative and postoperative pathology revealed fibrocartilage disc fragments., Lessons: Differential diagnosis for lumbar far lateral lesions that are peripherally enhancing on MRI should include migratory disc herniation, regardless of the level of the disc herniations. Accurate preoperative diagnosis can aid in decision making for management, surgical approach, and resection.

Lymphatic metastasis is the most common form in breast cancer (BC) progression. Previously, we observed that lnc045874, a most conservative homology of Homo Sapiens NONHSAT021545 (lnc021545), miR-330-3p, and EREG may have some effects in mouse hepatocarcinoma cell lines with different lymphatic metastasis potentials. Through data from TCGA and GEO database analysis, we speculated that miR-330-3p might be a tumor promoter, while EREG could be a tumor suppressor in BC. MiR-330-3p was upregulated, while lnc021545 and EREG were downregulated in 50 BC tissues. MiR-330-3p advanced the metastatic behaviors of BC cells, whereas lnc021545 and EREG resulted in the opposite effects. The three molecules' expressions were correlated respectively and showed that miR-330-3p targeted lnc021545 and EREG to affect their expressions. Lnc021545/miR-330-3p axis affected BC metastasis by regulating EREG in epithelial-to-mesenchymal transition. In 50 BC patients, these three molecules and their cooperation are associated with aggressive tumor phenotypes, patient outcomes, and trastuzumab therapy. We finally discovered that lnc021545, miR-330-3p, and EREG formed a multi-gene co-regulation system that affected the metastasis of BC and the cooperation reflects the synergistic effects of the three molecules, recommending that their cooperation may provide a more accurate index for anti-metastasis therapeutic and prognostic evaluation of BC.

CYP2D6 is one of the most important metalloenzymes involved in the biodegradation of many drug molecules in the human body. It has been found that multiple substrate binding can lead to substrate inhibition of CYP2D6 metabolizing dextromethorphan (DM), but the corresponding theoretical mechanism is rarely reported. Therefore, we chose DM as the probe and performed molecular dynamics simulations and quantum mechanical calculations on CYP2D6-DM systems to investigate the mechanism of how the multiple substrate binding leads to the substrate inhibition of CYP2D6 metabolizing substrates. According to our results, three gate residues (Arg221, Val374, and Phe483) for the catalytic pocket are determined. We also found that the multiple substrate binding can lead to substrate inhibition by reducing the stability of CYP2D6 binding DM and increasing the reactive activation energy of the rate-determining step. Our findings would help to understand the substrate inhibition of CYP2D6 metabolizing the DM and enrich the knowledge of the drug-drug interactions for the cytochrome P450 superfamily.

Cellular senescence serves as a powerful tumor suppressing mechanism that inhibits the proliferation of cancer cells bearing oncogenic mutations at the initial stage of cancer development. RNA-binding proteins (RBPs) play important roles in cancer progression and treatment through distinct functions. However, functions and mechanisms of RNA binding proteins in regulating senescence remain elusive. Here we reported that the RNA binding protein RBM4 contributed to cellular senescence. Depletion of RBM4 induced senescence in different types of cells, including multiple cancer cells. Meanwhile, RBM4 ablation inhibited cancer cell progression both in vitro and in vivo. Specifically, knockdown of RBM4 significantly increased the level of SERPINE1, a known promoter of senescence, thereby inducing the senescence of lung cancer cells. Mechanistically, miR-1244 bound to the 3'-UTR of SERPINE1 to suppress its expression, whereas depletion of RBM4 reduced the level of miR-1244 by promoting the degradation of primary miR-1244 transcripts (pri-miR1244), thus increasing the expression of SERPINE1 and inducing subsequent senescence. Moreover, either SERPINE1 inhibitor or miR-1244 mimics attenuated the RBM4 depletion-induced senescence. Altogether, our study revealed a novel mechanism of RBM4 in the regulation of cancer progression through controlling senescence, providing a new avenue for targeting RBM4 in cancer therapeutics., (© 2023. The Author(s).)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Clear cell renal cell carcinoma (ccRCC) accounts for 80% of renal cell carcinomas (RCCs), and its morbidity and prognosis are unfavorable. Surgical resection is the first-line treatment for ccRCC, but the oncogenesis of ccRCC is very complex. With the development of high-throughput sequencing technology, it is necessary to analyze the transcriptome to determine more effective treatment methods. The tumor microenvironment (TME) is composed of tumor cells, various immune-infiltrating cells, fibroblasts, many cytokines, and catalysts. It is a complex system with a dynamic balance that plays an essential role in tumor growth, invasion, and metastasis. Previous studies have confirmed that potassium channels can affect the immune system, especially T lymphocytes that require potassium channel activation. However, the effect of potassium channels on the TME of ccRCC remains to be studied. Therefore, this study aims to construct a prognostic signature for ccRCC patients based on potassium ion channel-related genes (PCRGs), assess patient risk scores, and divide patients into high- and low-risk groups based on the cutoff value. In addition, we investigated whether there were differences in immune cell infiltration, immune activator expression, somatic mutations, and chemotherapeutic responses between the high- and low-risk groups. Our results demonstrate that the PCRG signature can accurately assess patient prognosis and the tumor microenvironment and predict chemotherapeutic responses. In summary, the PCRG signature could serve as an auxiliary tool for the precision treatment of ccRCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zeng, Li, He, Sun, Huang, Wang, Zhuo, Chen, Chen, Guo and Huang.)

Survivors of traumatic brain injury (TBI) have an unpredictable clinical course. This unpredictability makes clinical resource allocation for clinicians and anticipatory guidance for patients difficult. Historically, experienced clinicians and traditional statistical models have insufficiently considered all available clinical information to predict functional outcomes for a TBI patient. Here, we harness artificial intelligence and apply machine learning and statistical models to predict the Functional Independence Measure (FIM) scores after rehabilitation for traumatic brain injury (TBI) patients. Tree-based algorithmic analysis of 629 TBI patients admitted to a large acute rehabilitation facility showed statistically significant improvement in motor and cognitive FIM scores at discharge., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Say, Chen, Sun, Li and Lu.)

Background: Post-traumatic hydrocephalus (PTH) is a complication of traumatic brain injury (TBI) that requires treatment and postoperative care. The shunt is one of the main treatments for PTH, which presents with dysfunction and infection. Considering brain injury, hydrocephalus shunt malfunction, and infection, family caregivers need to be responsible for caring for PTH patients, recognizing shunt malfunction and infection, and managing those patients accordingly from hospital to home. Understanding the experiences and needs of caregivers is beneficial for knowing their competency and quality of health care, ameliorating and ensuring future transition care. The study aimed to explore the feelings, experiences, and needs of family caregivers when caring for patients with TBI, PTH and shunts., Methods: This was exploratory research of a purposive sample of 12 family caregivers of adult patients with TBI, PTH and shunts in five neurosurgery departments at a general hospital in Zhengzhou, Henan Province, China, using a semi-structured interview method. Data were collected from October 2021 to March 2022 before being analyzed by content analysis methods., Results: Caregivers required professional and social knowledge and support in the areas of TBI, PTH and shunts, caregiving interventions, psychological care needs, and health insurance, just as caregivers do, but unlike other general caregivers, care for patients with TBI, PTH, and shunt is fraught with uncertainty and the need to manage shunt setting, and caregivers often experience 'complex emotional reaction' during the transitional period, where care needs and complex emotions may lead to a lack of caregiver confidence, which in turn may affect caregiving behaviors, and experiences that affect care may be mediated through caregiving confidence. The perceived availability of resources, particularly those that are still available to them when they return home, has a significant impact on participants' emotional response and sense of confidence., Conclusions: The emotional response and the impact of stressor caregivers after TBI, PTH, and shunt was important, and sometimes confidence in care appeared to be an intermediate and useful factor that needed to be considered as health professionals prepared to develop care resources on how to manage and empower patients with TBI, PTH, and shunt. Meanwhile, there may be gaps and inequities in supportive care for patients diagnosed with TBI, PTH, and shunt in China., (© 2022. The Author(s).)

Propionate is an effective mould inhibitor widely used as a food preservative. In this study, we used zebrafish to explore the adverse effects of long-term exposure to low concentrations of sodium propionate and the underlying molecular mechanisms (from larvae to adult). When exposed for 3 months, we found that blood glucose, total cholesterol, and triglyceride levels increased, and zebrafish developed a hyperglycaemic state. New tank test results showed depression in zebrafish reduced 5-hydroxytryptamine levels in the brain and damaged the dopamine system. At the same time, the results of the color preference test showed that zebrafish had cognitive impairments. In addition, Hypothalamic-Pituitary-Adrenal axis analysis revealed abnormal gene expression, increased cortisol levels, and reduced glucocorticoid receptor mRNA levels, which were consistent with depressive behavior. We also observed abnormal transcription of inflammatory and apoptotic factors. Overall, we found that chronic exposure to sodium propionate induces depressive symptoms. This may be related to the activation of the HPA axis by the hyperglycaemic state, thereby inducing inflammation and disrupting the dopaminergic system. In summary, this study provides theoretical and technical support for the overlap of the emotional pathogenesis associated with diabetes., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Coronary artery disease (CAD) is associated with cancer. The role of inflammation in the association of CAD with cancer remains unclear. The study investigated whether inflammation could impact the relationship between CAD and lung cancer., Methods: The study involved 96 newly diagnosed lung cancer patients without receiving anti-cancer therapy and 288 matched non-cancer patients. All the patients underwent coronary angiography and were free from previous percutaneous coronary intervention or coronary artery bypass grafting. SYNTAX score (SXscore) were used to assess severity of CAD. High SXscore (SXhigh) grade was defined as SXscore > 16 (highest quartile). Neutrophil-to-lymphocyte ratio (NLR) served as an inflammatory biomarker. NLR-high grade referred to NLR > 2.221 (median)., Results: Among 384 study patients, 380 patients (98.96%) had NLR value (median: 2.221, interquartile range: 1.637-3.040). Compared to non-cancer patients, lung cancer patients had higher rate of SXhigh among total study patients ( P = 0.014) and among patients with NLR-high ( P = 0.006), but had not significantly higher rate of SXhigh among patients with NLR-low ( P = 0.839). Multivariate logistic regression analysis showed that SXhigh was associated with lung cancer [odds ratio (OR) = 1.834, 95% CI: 1.063-3.162, P = 0.029]. Subgroup analysis showed that SXhigh was associated with lung cancer among patients with NLR-high (OR = 2.801, 95% CI: 1.355-5.794, P = 0.005), however, the association between SXhigh and lung cancer was not significant among patients with NLR-low (OR = 0.897, 95% CI: 0.346-2.232, P = 0.823)., Conclusions: Inflammation could lead different association between anatomical severity of CAD and lung cancer. Severity of CAD was significantly associated with increased risk of lung cancer among patients with high inflammation rather than among patients with low inflammation., (© 2022 JGC All rights reserved; www.jgc301.com.)

Purpose: To investigate the effects of Periplaneta americana L. on ulcerative colitis (UC) induced by a combination of chronic stress (CS) and 2,4,6-trinitrobenzene sulfonic acid enema (TNBS) in rats., Methods: The experiment UC model with CS was established in rats by a combination of chronic restraint stress, excess failure, improper, and TNBS. The body weight, disease activity index (DAI), colonic mucosal injury index (CMDI), histopathological score (HS) and pro-inflammatory mediators were measured. The content of corticotropin-releasing hormone (CRH) in hypothalamus or adrenocorticotropic hormone (ACTH) and corticosteroids (CORT) in plasma were evaluated by enzyme-linked immunosorbent assay. The proportion of T lymphocyte subsets was detected by flow cytometry, and gut microbiota was detected by 16S rDNA amplicon sequencing., Results: Weight loss, DAI, CMDI, HS and proinflammatory mediators were reversed in rats by P. americana L. treatment after UC with CS. Increased epidermal growth factor (EGF) was observed in P. americana L. groups. In addition, P. americana L. could reduce the content of CRH and ACTH and regulate the ratio of CD3+, CD3+CD8+ and CD3+CD4+CD25+/CD4+ in spleen. Comparably, P. americana L. changes composition of gut microbiota., Conclusions: The ethanol extract of Periplaneta Americana L. improves UC induced by a combination of CS and TNBS in rats.

Sodium propionate is widely used as a preservative in food. The widespread use of preservatives is known to cause both environmental and public health problems. This study aimed to investigate the effects of sodium propionate on the developmental behavior and glucose metabolism of zebrafish. Our results showed that sodium propionate had no significant effect on the embryonic morphological development of zebrafish embryos but changed the head eye area. Then we found sodium propionate disturbed the thigmotaxis behavior, impaired neural development. Moreover, changes in clock gene expression disrupted the circadian rhythm of zebrafish. Circadian genes regulated insulin sensitivity and secretion in various tissues. Then our results showed that the disorder of circadian rhythm in zebrafish affected glucose metabolism and insulin resistance, which damaged the development of retina. Therefore, the safety of propionate should be further evaluated., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

A better understanding of tumor metastasis is urgently required for the treatment and prognosis of hepatocarcinoma patients. Current work contributes a novel ceRNA feedback regulation pathway composed of epiregulin (EREG), microRNA-330-3p (miR-330-3p) and long non-coding RNA 021545 (lncRNA021545) in regulating hepatocarcinoma malignancy via epithelial-mesenchymal transition (EMT) process. Closely correlated, the deficiencies of EREG and lncRNA021545 and the overexpression of miR-330-3p were involved in the clinical progression of hepatocarcinoma. In vitro results showed that 1) lncRNA021545 downregulation promoted, 2) miR-330-3p dysexpression positively correlated, and 3) EREG dysexpression reversely correlated with the migratory and invasive properties of hepatocarcinoma HCCLM3 and Huh7 cell lines. By directly binding to EREG and lncRNA021545, miR-330-3p expression change reversely correlated with their expressions in HCCLM3 and Huh7 cells, which was also confirmed in primary tumors from HCCLM3-xenograft mice in responding to miR-330-3p change. LncRNA021545 and EREG positively regulated each other, and lncRNA021545 negatively regulated miR-330-3p, while, EREG dysregulation unchanged miR-330-3p expression in hepatocarcinoma cells. Furthermore, systemic in vitro cellular characterizations showed that the malfunctions of the three molecules mediated the invasiveness of hepatocarcinoma cells via EMT process through affecting the expressions of E-cadherin, N-cadherin, vimentin, snail and slug, which was further confirmed by in vivo miR-330-3p promotion on the tumorigenicity and metastasis of HCCLM3 bearing nude mice and by in vitro miR-330-3p promotion on the migration and invasion of hepatocarcinoma cells to be antagonized by EREG overexpression through acting on EMT process. Our work indicates, that by forming a circuit signaling feedback pathway, the homeostatic expressions of lncRNA021545, miR-330-3p and EREG are important in liver health. Its collapse resulted from the downregulations of lncRNA021545 and EREG together with miR-330-3p overexpression promote hepatocarcinoma progression by enhancing the invasiveness of tumor cells through EMT activation. These discoveries suggest that miR-330-3p/lncRNA021545/EREG axis plays a critical role in hepatocarcinoma progression and as a candidate for its treatment., Competing Interests: None., (AJCR Copyright © 2022.)

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells in vitro . Our results indicate that 8FNC arrests the AGS cell cycle in the G2/M phase, reduces the mitochondrial membrane potential of AGS cells, and drives the initiation of apoptotic body formation in 8FNC-induced apoptosis. Moreover, 8FNC exhibits strong inhibitory effects on AGS cell migration. Studies on the molecular mechanisms of the cytotoxic activities of 8FNC revealed that it may play a significant role in the inhibitory effect on AGS human gastric cancer cells through the PI3K/AKT signaling pathway. In conclusion, 8FNC may become a promising lead compound in the development of potential clinical drug candidates for the treatment of gastric cancer.

To analyze the application feasibility of Tiaoshen Jianpi acupuncture and moxibustion in hospice care for terminal cancer patients. Tiaoshen Jianpi acupuncture and moxibustion adjusts the spirit to regulate emotions and fortifies the spleen to supplement and boost foundation of acquired (postnatal) constitution. And it could relieve adverse reactions after radiotherapy and chemotherapy, alleviate pain and regulate emotions in hospice care for terminal cancer patients, so as to promote the progress of hospice care for terminal cancer patients.

CYP2D6 is an important enzyme of the cytochrome P450 superfamily, and catalyzes nearly 25% of the drugs sold in the market. For decades, the interactions and metabolism between CYP2D6 and substrates have been a hot topic. However, the key factors of the catalytic regioselectivity for CYP2D6 still remain controversial. Here, we construct four systems to explore the interaction between dextromethorphan (DM) and CYP2D6. A new binding mode of CYP2D6 is defined, and two key residues (residue Asp301 and residue Glu216) are discovered working simultaneously to stabilize the DM at the reactive site by forming water bridge hydrogen bonds when CYP2D6 binds DM. Our results also indicate that the substrate concentration could mediate the binding mode between the substrate and CYP2D6 by decreasing the volume of the catalytic pocket, which is not conducive to the O-demethylation of DM but benefits the N-demethylation of DM. These results could shed light on the process of CYP2D6 binding to the substrate, and help to better understand the regioselectivity of CYP2D6 catalyzing the substrates.