Synthesis of novel 4-substituted isatin Schiff base derivatives as potential autophagy inducers and evaluation of their antitumour activity.

Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC50 = 4.83 µM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC50 of 69.01 µM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.

Cognitive shadows in perimenopause: linking subjective cognitive decline (SCD) to menopausal symptom severity.

OBJECTIVE: As women approach perimenopause, the incidence of Subjective Cognitive Decline (SCD) rises. This study aims to investigate the association between SCD and the severity of perimenopausal symptoms. SETTING: Conducted at The Affiliated Hospital of Guizhou Medical University Menopause Clinic from November 2022 to June 2023. Participants, aged 40-55 years, were classified as perimenopausal using the STRAW + 10 criteria. METHODS: SCD was assessed separately using the Chinese version of the SCD-Q9 scale and the SCD International Working Group (SCD-I) conceptual framework, while perimenopausal symptoms were evaluated with the Modified Kupperman Index (MKI). Linear relationships between MKI scores and SCD-Q9 scores were clarified using both univariate and multivariate linear regression analyses. Additionally, a multivariate Logistic regression analysis was conducted to examine the association between MKI scores and SCD classification based on SCD-I criteria. MAIN OUTCOME MEASURES: The primary outcomes were the Modified Kupperman Index scores, SCD-Q9 questionnaire scores, and the diagnosis of SCD based on SCD-I criteria. RESULTS: Among 101 participants, the average MKI score was 18.90 ± 9.74, and the average SCD-Q9 score was 4.57 ± 2.29. Both univariate and multivariate linear regressions demonstrated a positive correlation between these scores. A multivariate Logistic regression analysis, using MKI as the independent variable and SCD-I criteria classification as the dependent variable, revealed a significant positive association. CONCLUSIONS: A notable association exists between SCD and perimenopausal symptoms severity. This underscores the potential clinical importance of addressing perimenopausal symptoms to mitigate SCD risks in women. Further studies should focus on clarifying the causality between these factors.

ZNF26-Associated Genes as Prognostic Signatures in Colorectal Cancer with Broad Therapeutic Implications.

The identification of biomarkers correlated with colorectal cancer (CRC) prognosis holds substantial importance from both clinical and scientific perspectives. Zinc finger protein 26 (ZNF26) has not been previously investigated or documented in solid tumors; thus, further research is necessary to ascertain its prognostic value in CRC. Gene expression profiles and clinicopathological data were acquired from The Cancer Genome Atlas (TCGA) database. Subsequently, expression correlation was assessed utilizing the TCGA CRC cohort. The prognostic value of ZNF26 was evaluated through Kaplan-Meier (KM) and ROC curve analyses. Following this, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to perform enrichment analysis between high- and low-ZNF26 expression groups. The association between immune cells, immune checkpoint genes, and ZNF26 expression levels was examined. Lastly, the research findings were further validated using CRC tissue samples. The results revealed that, in comparison to healthy controls, CRC significantly reduced ZNF26 expression. Elevated ZNF26 expression was associated with poorer overall survival in CRC patients. Additionally, high ZNF26 expression exhibited an inverse relationship with the immunological score and immune checkpoint gene expression in CRC patients. The findings from the TCGA data analysis were corroborated by the PCR results obtained from CRC tissue samples. ZNF26 is markedly upregulated in colorectal cancer tissues, potentially serving as a biomarker for CRC.

Effect of dexamethasone pretreatment using deep learning on the surgical effect of patients with gastrointestinal tumors.

To explore the application efficacy and significance of deep learning in anesthesia management for gastrointestinal tumors (GITs) surgery, 80 elderly patients with GITs who underwent surgical intervention at our institution between January and September 2021 were enrolled. According to the preoperative anesthesia management methodology, patients were rolled into a control (Ctrl) group (using 10 mg dexamethasone 1-2 hours before surgery) and an experimental (Exp) group (using a deep learning-based anesthesia monitoring system on the basis of the Ctrl group), with 40 cases in each group. A comprehensive comparative analysis was performed between the two cohorts, encompassing postoperative cognitive evaluations, Montreal Cognitive Assessment (MoCA) scores, gastrointestinal functionality, serum biomarkers (including interleukin (IL)-6, C-reactive protein (CRP), and cortisol levels), length of hospitalization, incidence of complications, and other pertinent metrics. The findings demonstrated that anesthesia monitoring facilitated by deep learning algorithms effectively assessed the anesthesia state of patients. Compared to the Ctrl group, patients in the Exp group showed significant differences in cognitive assessments (word recall, number connection, number coding) (P<0.05). Additionally, the Exp group exhibited a notably increased MoCA score (25.3±2.4), significantly shorter time to first flatus postoperatively (35.8±13.7 hours), markedly reduced postoperative pain scores, significantly shortened time to tolerate a liquid diet postoperatively (19.6±5.2 hours), accelerated recovery of serum-related indicators, and a significantly decreased mean length of hospital stay (11.4±3.2 days) compared to the Ctrl group. In summary, administering dexamethasone under the anesthesia management of GITs surgery based on gradient boosting decision tree (GBDT) and pharmacokinetics pharmacodynamics (PKPD) models can promote patient recovery, reduce the incidence of postoperative cognitive impairment (POCD), and improve patient prognosis.

The emerging role of extracellular vesicles in the diagnosis and treatment of autism spectrum disorders.

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by restricted, repetitive behavioral patterns and deficits in social interactions. The prevalence of ASD has continued to rise in recent years. However, the etiology and pathophysiology of ASD remain largely unknown. Currently, the diagnosis of ASD relies on behavior measures, and there is a lack of reliable and objective biomarkers. In addition, there are still no effective pharmacologic therapies for the core symptoms of ASD. Extracellular vesicles (EVs) are lipid bilayer nanovesicles secreted by almost all types of cells. EVs play a vital role in cell-cell communications and are known to bear various biological functions. Emerging evidence demonstrated that EVs are involved in many physiological and pathological processes throughout the body and the content in EVs can reflect the status of the originating cells. EVs have demonstrated the potential of broad applications for the diagnosis and treatment of various brain diseases, suggesting that EVs may have also played a role in the pathological process of ASD. Besides, EVs can be utilized as therapeutic agents for their endogenous substances and biological functions. Additionally, EVs can serve as drug delivery tools as nano-sized vesicles with inherent targeting ability. Here, we discuss the potential of EVs to be considered as promising diagnostic biomarkers and their potential therapeutic applications for ASD.

Integrative analysis of senescence-related genes identifies robust prognostic clusters with distinct features in hepatocellular carcinoma.

INTRODUCTION: Senescence refers to a state of permanent cell growth arrest and is regarded as a tumor suppressive mechanism, whereas accumulative evidence demonstrate that senescent cells play an adverse role during cancer progression. The scarcity of specific and reliable markers reflecting senescence level in cancer impede our understanding of this biological basis. OBJECTIVES: Senescence-related genes (SRGs) were collected for integrative analysis to reveal the role of senescence in hepatocellular carcinoma (HCC). METHODS: Consensus clustering was used to subtype HCC based on SRGs. Several computational methods, including single sample gene set enrichment analysis (ssGSEA), fuzzy c-means algorithm, were performed. Data of drug sensitivities were utilized to screen potential therapeutic agents for different senescence patients. Additionally, we developed a method called signature-related gene analysis (SRGA) for identification of markers relevant to phenotype of interest. Experimental strategies consisting quantitative real-time PCR (qRT-PCR), ß-galactosidase assay, western blot, and tumor-T cell co-culture system were used to validate the findings in vitro. RESULTS: We identified three robust prognostic clusters of HCC patients with distinct survival outcome, mutational landscape, and immune features. We further extracted signature genes of senescence clusters to construct the senescence scoring system and profile senescence level in HCC at bulk and single-cell resolution. Senescence-induced stemness reprogramming was confirmed both in silico and in vitro. HCC patients with high senescence were immune suppressed and sensitive to Tozasertib and other drugs. We suggested that MAFG, PLIN3, and 4 other genes were pertinent to HCC senescence, and MAFG potentially mediated immune suppression, senescence, and stemness. CONCLUSION: Our findings provide insights into the role of SRGs in patients stratification and precision medicine.

Evolutional heterochromatin condensation delineates chromocenter formation and retrotransposon silencing in plants.

Heterochromatic condensates (chromocenters) are critical for maintaining the silencing of heterochromatin. It is therefore puzzling that the presence of chromocenters is variable across plant species. Here we reveal that variations in the plant heterochromatin protein ADCP1 confer a diversity in chromocenter formation via phase separation. ADCP1 physically interacts with the high mobility group protein HMGA to form a complex and mediates heterochromatin condensation by multivalent interactions. The loss of intrinsically disordered regions (IDRs) in ADCP1 homologues during evolution has led to the absence of prominent chromocenter formation in various plant species, and introduction of IDR-containing ADCP1 with HMGA promotes heterochromatin condensation and retrotransposon silencing. Moreover, plants in the Cucurbitaceae group have evolved an IDR-containing chimaera of ADCP1 and HMGA, which remarkably enables formation of chromocenters. Together, our work uncovers a coevolved mechanism of phase separation in packing heterochromatin and silencing retrotransposons.

Kopsileuconines A-D: bisindole alkaloids with cytotoxic activity from Kopsia hainanensis.

Kopsileuconines A-D (1-4), four monoterpenoid bisindole alkaloids with unprecedented skeletons, along with their biosynthetically related precursors (5-8) were isolated from the roots of Kopsia hainanensis. Compound 1 possessed an undescribed C-6-C-5' dimerization pattern of aspidofractinine-type alkaloids. Compounds 2-4 were rhazinilam-kopsine (2) and rhazinilam-aspidofractinine type (3 and 4) bisindole alkaloids with undescribed skeletons, respectively. Their structures with absolute configurations were fully accomplished by extensive spectroscopic analysis, quantum-chemical calculations, and X-ray crystallography. A plausible biosynthetic pathway for 1-4 was proposed. Compound 2 exhibited a significant inhibitory effect against human lung cancer cell lines PC9 (EGFR mutant), with an IC50 value of 15.07 ± 1.19 µM.

METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence.

METTL3 is the catalytic subunit of the methyltransferase complex, which mediates m6A modification to regulate gene expression. In addition, METTL3 regulates transcription in an enzymatic activity-independent manner by driving changes in high-order chromatin structure. However, how these functions of the methyltransferase complex are coordinated remains unknown. Here we show that the methyltransferase complex coordinates its enzymatic activity-dependent and independent functions to regulate cellular senescence, a state of stable cell growth arrest. Specifically, METTL3-mediated chromatin loops induce Hexokinase 2 expression through the three-dimensional chromatin organization during senescence. Elevated Hexokinase 2 expression subsequently promotes liquid-liquid phase separation, manifesting as stress granule phase separation, by driving metabolic reprogramming. This correlates with an impairment of translation of cell-cycle related mRNAs harboring polymethylated m6A sites. In summary, our results report a coordination of m6A-dependent and -independent function of the methyltransferase complex in regulating senescence through phase separation driven by metabolic reprogramming.

Histone chaperone HIRA, Promyelocytic Leukemia (PML) protein and p62/SQSTM1 coordinate to regulate inflammation during cell senescence.

Cellular senescence, a stress-induced stable proliferation arrest associated with an inflammatory Senescence-Associated Secretory Phenotype (SASP), is a cause of aging. In senescent cells, Cytoplasmic Chromatin Fragments (CCFs) activate SASP via the anti-viral cGAS/STING pathway. PML protein organizes PML nuclear bodies (NBs), also involved in senescence and anti-viral immunity. The HIRA histone H3.3 chaperone localizes to PML NBs in senescent cells. Here, we show that HIRA and PML are essential for SASP expression, tightly linked to HIRA's localization to PML NBs. Inactivation of HIRA does not directly block expression of NF-κB target genes. Instead, an H3.3-independent HIRA function activates SASP through a CCF-cGAS-STING-TBK1-NF-κB pathway. HIRA physically interacts with p62/SQSTM1, an autophagy regulator and negative SASP regulator. HIRA and p62 co-localize in PML NBs, linked to their antagonistic regulation of SASP, with PML NBs controlling their spatial configuration. These results outline a role for HIRA and PML in regulation of SASP.

Research progress on targeted therapy and immunotherapy for esophageal cancer / 药学实践与服务

Esophageal cancer is a malignant tumor with high incidence and mortality rate in the world and its pathogenic factors are complex and diverse. There are no obvious symptoms in the early stage, and most patients are in the middle to late stage at the initial diagnosis. The prognosis of esophageal cancer is poor. The treatment mode of conventional surgical resection combined with chemoradiotherapy can no longer meet the current treatment needs of disease, and new treatment strategies are urgently needed. Molecular targeted therapy and immunotherapy are new treatment methods that have emerged in recent years, which have broken the therapeutic bottleneck and have been proven to play important roles in the treatment of esophageal cancer. The current research progress of the main targets and their related targeted drugs in molecular targeted therapy and immunotherapy for esophageal cancer were reviewed in this article, which provided reference for the application of precision medicine in the field of esophageal cancer.

Chinese expert consensus on diagnosis, treatment and prevention of venous thrombus embolism associated with chest trauma (2022 version) / 中华创伤杂志

Chest trauma is one of the most common injuries. Venous thromboembolism (VTE) as a common complication of chest trauma seriously affects the quality of patients′ life and even leads to death. Although there are some consensus and guidelines on the prevention and treatment of VTE at home and abroad, the current literatures lack specificity considering the diagnosis, treatment and prevention of VTE in patients with chest trauma have their own characteristics, especially for those with blunt trauma. Accordingly, China Chest Injury Research Society and editorial board of Chinese Journal of Traumatology organized relevant domestic experts to jointly formulate the Chinese expert consensus on the diagnosis, treatment and prevention of chest trauma venous thromboembolism associated with chest trauma (2022 version). This consensus provides expert recommendations of different levels as academic guidance in terms of the characteristics, clinical manifestations, risk assessment, diagnosis, treatment, and prevention of chest trauma-related VTE, so as to offer a reference for clinical application.

Cancer-associated ischemic stroke: pathophysiology, clinical characteristics, and treatment / 国际脑血管病杂志

Cancer can mediate the onset of ischemic stroke directly or through cancer-associated hypercoagulability. The clinical manifestations of cancer-associated ischemic stroke (CAIS) are very heterogeneous according to the underlying cause. Generally speaking, CAIS is manifested as multiple vascular territory ischemic lesions on imaging, and fibrinogen degradation products such as blood D-dimer are significantly increased. The treatment of CAIS is quite tricky. Given that the risk of bleeding is not higher than that of the general population, cancer is not a contraindication for intravenous thrombolysis and mechanical thrombectomy. Anticoagulant therapy of CAIS should be individualized according to the benefits and risks. Low molecular weight heparin is still the first choice, and new oral anticoagulants have good prospects. This article reviews the pathogenesis, clinical features and treatment progress of CAIS.

Review and analysis of policies for private hospitals during the 13th Five-Year Plan period in China / 中华医院管理杂志

During the 13th Five-Year Plan period, China issued a series of policies for private hospitals, which made an important impact on the running of medical institutions by social forces. One hundred and sixty-one policy documents for private hospitals were sorted out from January 2016 to January 2020, national policies and measures in terms of access approval, comprehensive supervision, fiscal and taxation support, supporting policies, talent development, open innovation, and resource sharing were being reviewed. It found that the characteristics of China′s policies were consistent in content, comprehensive in coverage, and supported the development of traditional Chinese and Western medicine.From 2016 to 2020, the total number of private medical institutions in China maintained growth, however, there were some practical problems, such as insufficient professional and technical capacity, low coordination development with public healthcare, and incomplete supervision and evaluation system. Therefore, during the 14th Five-Year Plan period, we should realize the transformation from private hospital management to modern governance, integrate private hospital development policies, optimize the system of approval and access, standardize the supervision and evaluation system, enhance the sharing of development resources, strengthen the construction of professionals, adhere to the concept of fairness, openness, and innovation, so as to promote the sustainable development of private hospitals.

Analysis of sarcopenia and influencing factors in hospitalized elderly patients / 中华老年医学杂志

Objective:To analyze features of sarcopenia and its influencing factors in hospitalized patients at our department.Methods:This was a cross-sectional study.A total of 180 patients aged 80.3±6.7 years admitted to the geriatrics department of our hospital were consecutively recruited.Patients were divided into the non-sarcopenia group(n=80, 44.4%)and the sarcopenia group(n=100, 55.6%)based on the diagnostic criteria for sarcopenia of the Asian Sarcopenia Working Group.All subjects were evaluated by using the comprehensive geriatric assessment.Differences in comorbidity, physical function, nutrition, cognitive function, psychological characteristics, geriatric syndromes, medication and other aspects were analyzed between the two groups.The correlation of the above factors with sarcopenia was analyzed.Results:Scores on the Charlson comorbidity index and the cumulative illness rating scale were higher in the sarcopenia group than in the non-sarcopenia group(2.6±1.7 vs.2.1±1.1, 11.3±4.1 vs.7.9±1.8, P<0.05). Scores on mini-nutrition assessment and mini-cog, grip, chair-rising test(five times), timed get-up and go test(3 m), walking speed, and short physical performance battery were lower in the sarcopenia group than in the non-sarcopenia group[(12.8±2.1) vs.(11.2±1.7), (2.3±1.0) vs.(4.4±0.9), (21.2±5.8)kg vs.(27.6±6.2)kg, (31.4±15.3)s vs.(13.2±4.0)s, (24.2±9.5)s vs.(12.0±2.9)s, (0.6±0.2)m/s vs.(0.9±0.3)m/s, (6.1±1.9) vs.(9.8±1.3), respectively, P<0.05]. The incidences of geriatric syndromes such as incontinence, visual impairment, hearing impairment, sleeping disorders, oral problems, chronic pain, anxiety, depression and falls were higher in sarcopenia patients than in non-sarcopenia patients.Logistic regression analysis showed that body mass index, walking speed and the number of geriatric syndromes were risk factors for sarcopenia( OR=1.401, 1.286 and 3.654, P<0.05). Conclusions:The incidence of sarcopenia is high in hospitalized elderly patients.Comprehensive geriatric assessment can be used to achieve a more complete understanding of the characteristics and influencing factors for patients with sarcopenia and will help provide a basis for appropriate treatment plans.