Naringenin (4,5,7-trihydroxyflavonoid) is a naturally occurring bioflavonoid found in citrus fruits, which plays an important role in metabolic syndrome, neurological disorders, and cardiovascular diseases. However, the pharmacological mechanism and biological function of naringenin on anti-angiogenesis and anti-tumor immunity have not yet been elucidated. Our study firstly demonstrates that naringenin inhibits the growth of hepatocellular carcinoma (HCC) cells both in vivo and in vitro. Naringenin diminishes the ability of HCC cells to induce tube formation and migration of human umbilical vein endothelial cells (HUVECs) and suppresses neovascularization in chicken chorioallantoic membrane (CAM) assays. Meanwhile, in vivo results demonstrate that naringenin can significantly upregulate level of CD8⁺ T cells, subsequently increasing the level of immune-related cytokines in the tumor immune microenvironment. Mechanistically, we found that naringenin facilitate the K48-linked ubiquitination and subsequent protein degradation of vascular endothelial growth factor A (VEGFA) and mesenchymal-epithelial transition factor (c-Met), which reduces the expression of programmed death ligand 1 (PD-L1). Importantly, combination therapy naringenin with PD-L1 antibody or bevacizumab provided better therapeutic effects in liver cancer. Our study reveals that naringenin can effectively inhibit angiogenesis and anti-tumor immunity in liver cancer by degradation of VEGFA and c-Met in a K48-linked ubiquitination manner. This work enlightens the potential effect of naringenin as a promising therapeutic strategy against anti-angiogenesis and anti-tumor immunity in HCC.

Objective To develop an appropriate comprehensive scale for mild cognitive impairment in Parkinson dis-ease(PD-MCI)due to various diagnostic methods for PD-MCI and a lack of consensus on the applicable neuropsychological scales for PD-MCI.Methods A total of 92 non-dementia PD patients with a confirmed diagnosis were enrolled in this study,and all patients were assessed using the comprehensive scale of five cognitive domains recommended by the Chinese version of PD-MCI guidelines and Movement Disorder Society(MDS).Based on the norms of healthy controls assessed by the same scale,the patients were divided into non-cognitive impairment PD group and PD-MCI group.The t-test was used to observe the consistency between groups;the receiver operating characteristic(ROC)curve was used to investigate the cut-off value of each scale with the highest sensitivity and specificity in identifying the impairment in each cognitive domain of PD-MCI;a binary lo-gistic regression analysis was used to determine the specific contents of the comprehensive cognitive domain assessment scale for PD-MCI.Results This study showed that the ten-point comprehensive cognitive domain assessment scale based on long-time memory in Brief Visuospatial Memory Test,Clock Drawing Test,digit span backward test,Trail Making Test A,Verbal Flu-ency Test,Trail Making Test B,Similarities,Boston Naming Test,long-time recall memory in Auditory Verbal Learning Test,and short-time recall memory in Wechsler Memory Scale-IV Logical Memory Test had a significant diagnostic validity in predict-ing PD-MCI,with an area under the ROC curve of 0.971(95%CI 0.941?1.000).Conclusion The recommended cut-off value can be used to perform a subtype analysis of PD-MCI and observe the outcome and clinical specificity of different subtypes of PD-MCI,and therefore,it has a certain clinical significance.

Objective To establish the delimitation norm of cognitive domain assessment scales for Parkinson dis-ease(PD)in Beijing,China,and to investigate the optimal cut-off values for determining abnormal neuropsychological as-sessments.Methods A total of 33 normal middle-aged and elderly individuals in communities and 89 patients with non-dementia PD were included in this study,and all subjects underwent global cognitive function screening and cognitive do-main assessments.According to whether Montreal Cognitive Assessment(MoCA)score was greater than 25 points,the pa-tients with PD were divided into mild cognitive impairment group(PD-MCI group)and normal cognition group(PD-NC group).In order to compare the consistency between PD-related cognitive domain assessment scales and global cognitive function screening in the diagnosis of PD-MCI,different cut-off values below the appropriate norms(i.e.,1.00 standard deviation,1.28 standard deviations,1.64 standard deviations,1.96 standard deviations below the mean)were examined for sensitivity,specificity,positive predictive value,and negative predictive value to obtain the optimal cut-off value.Results The delimitation norm of PD-related cognitive domain assessment scales was established for Beijing,and the re-sults showed that 1.96 standard deviations had the highest consistency in the diagnosis of PD-MCI and PD-NC,with the best sensitivity and specificity.Conclusion This study establishes the delimitation norm of PD-related cognitive domain assess-ment scales and fills the blank of the unbounded value of most domestic PD cognitive impairment assessment scales,and it also proposes the optimal cut-off value of abnormal neuropsychological assessment,which provides a reference standard for the cognitive domain assessment of PD patients in China and helps clinicians to identify cognitive decline in PD patients and adopt intervention measures in the early stage.

Background::Total human immunodeficiency virus (HIV) DNA and integrated HIV DNA are widely used markers of HIV persistence. Droplet digital polymerase chain reaction (ddPCR) can be used for absolute quantification without needing a standard curve. Here, we developed duplex ddPCR assays to detect and quantify total HIV DNA and integrated HIV DNA.Methods::The limit of detection, dynamic ranges, sensitivity, and reproducibility were evaluated by plasmid constructs containing both the HIV long terminal repeat (LTR) and human CD3 gene (for total HIV DNA) and ACH-2 cells (for integrated HIV DNA). Forty-two cases on stable suppressive antiretroviral therapy (ART) were assayed in total HIV DNA and integrated HIV DNA. Correlation coefficient analysis was performed on the data related to DNA copies and cluster of differentiation 4 positive (CD4 +) T-cell counts, CD8 + T-cell counts and CD4/CD8 T-cell ratio, respectively. The assay linear dynamic range and lower limit of detection (LLOD) were also assessed. Results::The assay could detect the presence of HIV-1 copies 100% at concentrations of 6.3 copies/reaction, and the estimated LLOD of the ddPCR assay was 4.4 HIV DNA copies/reaction (95% confidence intervals [CI]: 3.6-6.5 copies/reaction) with linearity over a 5-log 10-unit range in total HIV DNA assay. For the integrated HIV DNA assay, the LLOD was 8.0 copies/reaction (95% CI: 5.8-16.6 copies/reaction) with linearity over a 3-log 10-unit range. Total HIV DNA in CD4 + T cells was positively associated with integrated HIV DNA ( r = 0.76, P <0.0001). Meanwhile, both total HIV DNA and integrated HIV DNA in CD4 + T cells were inversely correlated with the ratio of CD4/CD8 but positively correlated with the CD8 + T-cell counts. Conclusions::This ddPCR assay can quantify total HIV DNA and integrated HIV DNA efficiently with robustness and sensitivity. It can be readily adapted for measuring HIV DNA with non-B clades, and it could be beneficial for testing in clinical trials.

Objective:To analyze and discuss the characteristics of cardiopulmonary and cerebral resuscitation (CPCR) in patients after out-of-hospital cardiac arrest (OHCA).Methods:The data of OHCA patients admitted to the directly-managed branch of the Wuxi Emergency Medical Center, covering the period from December 26, 2016, at 7:45 to August 26, 2022, at 7:45. The analysis included the first electrocardiogram (ECG), clinical characteristics, pre-hospital emergency measures, and follow-up conditions in the hospital. Based on the Glasgow-Pittsburgh cerebral function grading at discharge, patients were divided into a CPCR group (grades 1-2) and a non-CPCR group (grades 3-5). The study compared the basic conditions, resuscitation times, and vital signs after resuscitation between the two groups to evaluate the factors affecting CPCR.Results:A total of 6 040 OHCA cases were treated, 3 002 cases received pre-hospital resuscitation. The initial ECG indicated a shockable rhythm in 185 cases, with a shockable rhythm rate of 6.16%. There were 293 pre-hospital survivors, with a pre-hospital survival rate of 9.76%. 170 cases survived to be discharged, with a discharge survival rate of 5.66%. Ultimately, 44 cases achieved CPCR, accounting for 25.88% of the cases that survived to discharge. There were statistically significant differences in terms of first-witness treatment, defibrillable rhythm ratio, defibrillation, response to pain stimulation after return of spontaneous circulation (ROSC), spontaneous breathing, light reflex, pulse oxygenation, and blood pressure between the CPCR and non-CPCR groups (all P<0.05). The CPCR group showed significantly higher proportions than the non-CPCR group in the defibrillatable rhythm (75.00% vs. 10.44%), undergoing defibrillation (70.46% vs. 9.24%), having spontaneous breathing after ROSC (86.36% vs. 17.27%), and having oxygen saturation >92% with systolic blood pressure >90 mmHg (86.36% vs. 39.76%).There were statistically significant differences between the CPCR and non-CPCR groups in the time from cardiac arrest (CA) to doctor reception, CA to first defibrillation, CA to ROSC, and CA to discharge or in-hospital death (all P<0.05). Conclusions:The patients with successful pre-hospital resuscitation and finally cerebral resuscitation were characterized by short times from OHCA to first medical contact (FMC) and from FMC to ROSC, appropriate pre-hospital vital sign management accompanied by partial neurological recovery, and comprehensive in-hospital neurological prognosis assessment.

Objective To evaluate the equity of health human resources allocation in traditional Chinese(TCM)hospitals from 2012 to 2021,and forecast the number of various health technicians,so as to provide theoretical basis for the reasonable allocation of health human resources of TCM health service.Methods The data of health personnel in TCM hospitals were collected,and Theil index and clustering degree were used to analyze the equity of health human resource allocation.The grey GM(1,1)model was used to predict the demand of health personnel in TCM hospitals.Results From 2012 to 2021,the health human resources of TCM hospitals in China showed an overall growth trend.According to the analysis of Theil index in each region,the contribution rate of Theil index showed that the difference between regions was the main factor causing the difference in personnel allocation.The concentration degree of TCM hospitals in terms of geographical allocation was eastern region,central region and western region,respectively.Conclusion The expansion of high-quality medical resources and the rational allocation of TCM resources should be promoted.Clear target responsibility,promote fine management,improve the fairness of medical personnel allocation;Based on traditional advantages,broaden training ideas,and effectively build a multi-dimensional training system for TCM talents.

Children and adults differ significantly in physiology,biochemistry and immune function,which leads to sig-nificant differences in blood transfusion strategies between children and adults.To guide the clinical transfusion practice of pediatric patients and improve the prognosis of children,the National Health Commission organized the formulation and re-lease of the health industry standard Guideline for Pediatric Transfusion(WS/T 795-2022).This paper will briefly introduce some concepts that help understand of the Standard and the preparation process of the Standard,and explain and interpret the preparation of the"scope","general provisions"and"factors to consider"of the Standard,hoping to contribute to the understanding and implementation of the Standard.

As research delves deeper into the mechanisms of tumor immune responses,studies reveal the importance of microbial com-munities within the tumor microenvironment in tumor progression and their interactions with the host immune system.Intratumoral micro-biota could influence the tumor microenvironment,thereby promoting or inhibiting tumor growth and development.Despite this import-ance,the specific role of intratumoral microbiota impacting cancer immunotherapeutic efficacy remains largely unexplored.A deeper under-standing of the characteristics and biological functions of tumor-specific microbiota heralds a potential revolutionary innovation in cancer treatment.In this review,we introduce the discovery and sources of intratumoral microbiota,also addressing its composition,and discuss tumor tissue characteristics.Moreover,we briefly review the history of cancer immunotherapy development with a particular focus on the research progress concerning the impact of intratumoral microbiota on cancer immunotherapy.Furthermore,we explore emerging strategies that combine targeting intratumoral microbiota with immunotherapy to enhance immune efficacy,inhibit tumor progression,and improve cure rates,anticipating that this approach could represent a new direction for enhancing treatment outcomes and prospects.

Background::Cluster of differentiation 8 (CD8 T) cells play critical roles in eradicating human immunodeficiency virus (HIV)-1 infection, but little is known about the effects of T cells expressing CD8 at low levels (CD8 low) or high levels (CD8 high) on HIV-1 replication inhibition after HIV-1 invasion into individual. Methods::Nineteen patients who had been acutely infected with HIV-1 (AHI) and 20 patients with chronic infection (CHI) for ≥2 years were enrolled in this study to investigate the dynamics of the quantity, activation, and immune responses of CD3 +CD8 low T cells and their counterpart CD3 +CD8 high T cells at different stages of HIV-1 infection. Results::Compared with healthy donors, CD3 +CD8 low T cells expanded in HIV-1-infected individuals at different stages of infection. As HIV-1 infection progressed, CD3 +CD8 low T cells gradually decreased. Simultaneously, CD3 +CD8 high T cells was significantly reduced in the first month of AHI and then increased gradually as HIV-1 infection progressed. The classical activation of CD3 +CD8 low T cells was highest in the first month of AHI and then reduced as HIV-1 infection progressed and entered the chronic stage. Meanwhile, activated CD38 -HLA-DR +CD8 low T cells did not increase in the first month of AHI, and the number of these cells was inversely associated with viral load ( r = -0.664, P = 0.004) but positively associated with the CD4 T-cell count ( r = 0.586, P = 0.014). Increased programmed cell death protein 1 (PD-1) abundance on CD3 +CD8 low T cells was observed from the 1st month of AHI but did not continue to be enhanced, while a significant T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif (ITIM) domains (TIGIT) abundance increase was observed in the 12th month of infection. Furthermore, increased PD-1 and TIGIT abundance on CD3 +CD8 low T cells was associated with a low CD4 T-cell count (PD-1: r = -0.456, P = 0.043; TIGIT: r = -0.488, P = 0.029) in CHI. Nonetheless, the nonincrease in PD-1 expression on classically activated CD3 +CD8 low T cells was inversely associated with HIV-1 viremia in the first month of AHI ( r = -0.578, P = 0.015). Notably, in the first month of AHI, few CD3 +CD8 low T cells, but comparable amounts of CD3 +CD8 high T cells, responded to Gag peptides. Then, weaker HIV-1-specific T-cell responses were induced in CD3 +CD8 low T cells than CD3 +CD8 high T cells at the 3rd and 12th months of AHI and in CHI. Conclusions::Our findings suggest that CD3 +CD8 low T cells play an anti-HIV role in the first month of infection due to their abundance but induce a weak HIV-1-specific immune response. Subsequently, CD3 +CD8 low T-cell number decreased gradually as infection persisted, and their anti-HIV functions were inferior to those of CD3 +CD8 high T cells.