Purpose To investigate the effect of autophagy intervention on ferroptosis and drug resistance of colorectal canc-er cells and its molecular mechanism.Methods The human colorectal cancer cell lines HCT-8,COLO205,HCT-116,SW620,and SW480 were cultured.HCT-116 cells with moder-ate expression of LC3 were screened,and the expression differ-ences of LC3,p62,Keap1,Nrf2,GPX4 proteins,Fe2+,GSH,and MDA between them and OXA-resistant HCT-116/OXA cell lines were detected.The expression levels of LC3,p62,Keap1,Nrf2,GPX4,Fe2+,GSH and MDA were assessed in HCT-116/OXA cells through the intervention of autophagy and ferroptosis intervention agent combined with oxaliplatin.The proliferative activity and sensitivity to oxaliplatin in each group were detected by CCK-8 assay.Cell growth and invasion ability of each group were detected by plate cloning and Trans well assay.Results LC3,p62 and GPX4 expression levels of HCT-116 cells in the 5 groups were moderate.Compared with HCT-116 cells,HCT-116/OXA was less sensitive to oxaliplatin,and the proteins of p62,Nrf2 and GPX4 were highly expressed,LC3 and Keap1 were lowly expressed,and the expression of Fe2+,GSH and MDA were increased(P＜0.05).The levels of LC3,Keap1 protein,Fe2+and MDA in Rapa and Rapa+Fer-1 groups were higher than those in Fer-1 and control groups,while p62,Nrf2,GPX4 and GSH levels were lower.The expressions of GPX4 pro-tein and GSH in Rapa+Fer-1 group were lower than those in Rapa group(P＜0.05).In the autophagy inhibitor group,LC3,p62,Nrf2,GPX4 and GSH were highly expressed in the CQ and CQ+Erastin groups compared with the control and Eras-tin groups,while Keap1 protein,Fe2+and MDA were low.The levels of GPX4 protein and GSH in Erastin group were lower than those in the other three groups,and the levels of Fe2+and MDA were higher than those in the other three groups(P＜0.05).The combination of autophagy activator OXA showed that Rapa intervention group had higher chemical sensitivity to OXA,less number of migrating cells and lower cell proliferation activity than the other three groups.The sensitivity of Rapa+Fer-1 group to oxaliplatin was lower than that of Rapa group,but higher than that of Fer-1 group and control group(P＜0.05).There was no significant difference between Fer-1 group and con-trol group(P＜0.05).Compared with the control group,the cell activity,migration capacity and clonogenesis capacity of Erastin,CQ+Erastin and CQ groups were decreased when auto-phagy inhibitor was combined with OXA,and the Erastin group was the lowest,while the CQ+Erastin group was higher than the Erastin group,and lower than the CQ group(P＜0.05).Con-clusion In colorectal cancer,autophagy is involved in the regu-lation of ferroptosis,and intervention in autophagy can regulate ferroptosis in colorectal cancer cells through the p62-Keap1/Nrf2-GPX4 pathway,thereby reversing oxaliplatin resistance.

Objective:To evaluate the 10-year protective effect and immunogenicity of quadrivalent human papillomavirus (HPV) vaccine in Chinese women aged 20 to 45 years.Methods:From October 2019 to April 2020, a long-term follow-up study was conducted on the subjects of the Phase III clinical trial of the quadrivalent HPV vaccine (NCT00834106). Participants underwent a questionnaire survey, venous blood sampling, gynecological examination, cervical exfoliated cell pathology examination, and serum neutralizing antibody titers for HPV-6, 11, 16, and 18 were measured using a pseudovirus neutralization assay. The results of the cytological examination and the positive rate and titers of serum antibodies of different cervical exfoliated cells were compared.Results:A total of 889 subjects were followed up, including 240 in the control group, 453 in the vaccination group and 196 in the post-trial vaccination group. The age of the control group was (40±7) years old, which was higher than that of the supplementary vaccination group and the vaccination group [(38±4) and (38±6) years old, respectively] ( P<0.05). There were no statistically significant differences in condom use and sexual frequency among all groups (all P values>0.05). The abnormal proportion of cervical exfoliation cytopathology in the vaccination group was 3.7% (17/453), which was significantly lower than that in the control group [9.6% (23/240)] and post-trial vaccination group [5.6% (11/196)] ( P<0.05). There were two cases of cervical intraepithelial neoplasia (CIN) grade 1 in the vaccination group, two cases of CIN grade 1 and three cases of CIN grade 2 and above in the control group, and no CIN grade 1 and above cases in the post-trial vaccination group. The positive rate of HPV-18 antibody was 35.5% (161/453) in the vaccination group and 76.0% (149/196) in the post-trial vaccination group, which was significantly lower than that of other types ( P<0.05). The neutralizing antibody GMT ratio between the vaccination group and the control group ranged from 2.62 to 25.33 (9.05 to 83.08). Conclusion:Protective neutralizing antibodies are sustained in Chinese women aged 20 to 45 years after ten years of vaccination with quadrivalent HPV vaccine.

Objective:To evaluate the 10-year protective effect and immunogenicity of quadrivalent human papillomavirus (HPV) vaccine in Chinese women aged 20 to 45 years.Methods:From October 2019 to April 2020, a long-term follow-up study was conducted on the subjects of the Phase III clinical trial of the quadrivalent HPV vaccine (NCT00834106). Participants underwent a questionnaire survey, venous blood sampling, gynecological examination, cervical exfoliated cell pathology examination, and serum neutralizing antibody titers for HPV-6, 11, 16, and 18 were measured using a pseudovirus neutralization assay. The results of the cytological examination and the positive rate and titers of serum antibodies of different cervical exfoliated cells were compared.Results:A total of 889 subjects were followed up, including 240 in the control group, 453 in the vaccination group and 196 in the post-trial vaccination group. The age of the control group was (40±7) years old, which was higher than that of the supplementary vaccination group and the vaccination group [(38±4) and (38±6) years old, respectively] ( P<0.05). There were no statistically significant differences in condom use and sexual frequency among all groups (all P values>0.05). The abnormal proportion of cervical exfoliation cytopathology in the vaccination group was 3.7% (17/453), which was significantly lower than that in the control group [9.6% (23/240)] and post-trial vaccination group [5.6% (11/196)] ( P<0.05). There were two cases of cervical intraepithelial neoplasia (CIN) grade 1 in the vaccination group, two cases of CIN grade 1 and three cases of CIN grade 2 and above in the control group, and no CIN grade 1 and above cases in the post-trial vaccination group. The positive rate of HPV-18 antibody was 35.5% (161/453) in the vaccination group and 76.0% (149/196) in the post-trial vaccination group, which was significantly lower than that of other types ( P<0.05). The neutralizing antibody GMT ratio between the vaccination group and the control group ranged from 2.62 to 25.33 (9.05 to 83.08). Conclusion:Protective neutralizing antibodies are sustained in Chinese women aged 20 to 45 years after ten years of vaccination with quadrivalent HPV vaccine.

Objective:To investigate the change of chemical exchange saturation transfer (CEST) imaging in the bilateral substantia nigra (SN) and red nucleus (RN) of Parkinson disease (PD), and to explore the value of CEST-MRI for the clinical application of PD.Methods:This was a cross-sectional study. A total of 45 PD patients (PD group) and 21 sex-, age-, and cognitive-function matched normal control subjects (NC group) were retrospectively enrolled from December 2012 to July 2015 in Beijing Hospital. All subjects underwent brain CEST-MRI and routine MRI. Based on the MATLAB software package, the 4-pool Lorentz fitting model was applied to analyze the signal change of CEST imaging, which could acquire the mean amplitudes of the 4-pool parameters including Amide, nuclear overhauser enhancement (NOE), direct water saturation (DS) and magnetization transfer (MT) in the bilateral SN and RN. Independent samples t test and Mann-Whitney U test were used to compare CEST parameters between the PD group and the NC group and controlled by Bonferroni correction. The combined model was constructed based on parameters with inter-group differences after correction. The receiver operating characteristic curve and area under the curve (AUC) were used to evaluate the diagnostic efficiency of the CEST parameters and the combined model. Results:Compared with the NC group, the left SN Amide value, left RN Amide value, and right SN NOE value were reduced in the PD group, and the difference was statistically significant ( t=-3.59, corrected P=0.026; t=-3.77, corrected P=0.016; Z=-3.27, corrected P=0.017). The left SN Amide value, the left RN Amide value, the right SN NOE value, and the combined model all had good diagnostic efficacy in the differentiation of the PD group from the HC group (AUCs of 0.78, 0.79, 0.75, and 0.81, respectively). The combined model had the highest AUC value (0.81) and specificity (97.78%), the Amide value of left SN had the highest sensitivity (93.33%). Conclusions:Quantitative analysis of CEST-MRI based on the 4-pool Lorentz fitting model shows significant differences in the CEST quantitative indicators of the SN and RN between the PD group and the NC group, demonstrating good potential for clinical application in the diagnosis of PD.

Objective:To investigate the incidence of various non-motor symptoms (NMS) in early stage of Parkinson′s disease (PD) patients and the differences between the body-first and brain-first subtypes.Methods:A total of 121 patients with PD (Hoehn-Yahr stage 1-2) were recruited from PD Clinic, Department of Neurology, Beijing Hospital from January 2012 to January 2015. The general information and clinical features of the patients were collected. The minimal diagnostic criteria of parasomnias described in the International Classification of Sleep Disorders-Revised were used to diagnose rapid eye movement sleep behavior disorder (RBD).According to the sequence of RBD and motor symptoms, the patients were divided into 2 groups: body-first subtype and brain-first subtype. NMS was evaluated by the Non-Motor Symptom Questionnaire (NMSQuest). The clinical features and the incidence of various NMS were compared between the 2 groups. The Unified Parkinson′s Disease Rating Scale (UPDRS) was used to evaluate the severity of the disease, and its third part (UPDRS-Ⅲ) was used to evaluate the motor function of the patients. Hamilton Rating Scale for Depression (HAMD) and Hamilton Rating Scale for Anxiety (HAMA) were used to evaluate the depression and anxiety status of the patients. The sleep status of patients was assessed by Parkinson′s Disease Sleep Scale (PDSS). The quality of life of the patients was assessed by 39-item Parkinson′s Disease Questionnaire (PDQ-39).Results:Of all the patients, 49.59% (60/121) had the body-first subtype and 50.41% (61/121) had the brain-first subtype of PD. There was no significant difference in UPDRS-Ⅲ score between the 2 groups. The average number of NMS in all PD patients was 10.97±4.88. Body-first subtype patients had higher NMS incidence than brain-first subtype in difficulty in swallowing [46.7% (28/60) vs 23.0% (14/61), χ 2=7.507, P=0.006], nausea and vomiting [16.7% (10/60) vs 3.3% (2/61), χ 2=6.069, P=0.014], constipation [85.0% (51/60) vs 55.7% (34/61), χ 2=12.393, P<0.001], fecal incontinence [8.3% (5/60) vs 0 (0/61), χ 2=5.302, P=0.021], difficulty in remembering recent events [58.3% (35/60) vs 32.8% (20/61), χ 2=7.962, P=0.005], loss of interest [43.3% (26/60) vs 24.6% (15/61), χ 2=4.743, P=0.029], inattention [45.0% (27/60) vs 19.7% (12/61), χ 2=8.884, P=0.003], depression [55.0% (33/60) vs 34.4% (21/61), χ 2=5.181, P=0.023], intense vivid dreams [73.3% (44/60) vs 39.3% (24/61), χ 2=14.196, P<0.001] and restless legs [53.3% (32/60) vs 27.9% (17/61), χ 2=8.140, P=0.004]. The differences were significant. Body-first subtype and NMSQuest ( r=-0.489, P<0.001), UPDRS ( r=-0.189, P=0.038), HAMD ( r=-0.231, P=0.011), HAMA ( r=-0.298, P=0.001) and PDQ-39 scores ( r=-0.276, P=0.002) were negatively correlated. Body-first subtype and PDSS score was positively correlated. NMSQuest (Δ R2=0.265, P<0.001) was the main determinant of PDQ-39 score. Conclusions:PD patients are accompanied by various NMS, which is a major factor affecting the quality of life. Compared with brain-first subtype, body-first subtype might have more NMS burden and higher incidence rate in most NMS in early PD patients.

Objective:To explore the difference of clinical characteristics between senile Parkinson's disease(PD)with depression and unipolar depression.Methods:From March 2019 to March 2020, 53 patients with Parkinson's disease depression and 57 patients with unipolar depression who were admitted to the neurology department of Beijing Hospital were continuously collected.The gender, age and education level of the patients were recorded.The course of disease and other general data of the patients with Parkinson's disease were also recorded.Depression and anxiety of the patients were evaluated by Beck Depression Inventory(BDI)and Generalized Anxiety Disorder Scale(GAD-7). Quality of life of patients with Parkinson's disease was evaluated by 8-item Parkinson's disease questionnaire(PDQ-8). Differences in the assessment results and quality of life scores between the two groups were analyzed.Results:The incidence of depression comorbid with anxiety in elderly PD patients was 52.8%(28/53), lower than that in elderly unipolar depression patients comorbid with anxiety [84.2%(48/57)]( χ2=12.664, P<0.001). The scores of activity inhibition [(1.8±0.8)points]and hyposexuality [(0.4±1.0)points]in elderly PD patients with comorbid depression were higher than that in patients with unipolar depression [(1.1±0.8)points, (0.0±0.0)points]( t=4.399, 2.942, P<0.001, =0.005). Moreover, the incidence of activity inhibition(98.1%)and hyposexuality(15.1%)in PD patients with comorbid depression was higher than that in patients with unipolar depression(78.9%, 0.0%)( χ2=9.680, 9.279, both P=0.002). The scores of self-blame [(1.0±0.8)points]and pain [(1.0±0.8)points]in elderly patients with unipolar depression were higher than those in PD patients with comorbid depression [(0.5±0.7)points, (0.9±0.7)points]( t=-3.902, -2.486, P<0.001, =0.014). Moreover, the incidence of self-blame(66.7%), irritability(78.9%)and image distortion(56.1%)in elderly patients with unipolar depression was higher than that in PD patients(35.8%, 56.6%, 35.8%)( χ2=10.447, 6.320, 4.547, P=0.001, 0.012, 0.033). The scores of PDQ-8 in PD patients with comorbid depression and anxiety [14.8(10.8, 19.0)points]( Z=-3.544, P<0.001)were higher than those in PD patients with depression only [7.0(4.8, 11.0)points]. Conclusions:The focus of depression in elderly PD patients is different from that in elderly unipolar depression patients.Elderly patients with unipolar depression are more likely to be comorbid with anxiety.Depression reduces the quality of life in PD patients, and the comorbidity of anxiety further reduces the overall quality of life in PD patients with depression.

Objective:To systematically search and summarize the best evidence for the implementation and management of parenteral nutrition in critically ill patients.Methods:Based on the evidence-based medicine evidence structure, relevant evidence on the implementation and management of parenteral nutrition in critically ill patients was searched from top to bottom in Chinese and English databases such as China National Knowledge Infrastructure (CNKI) , VIP, British Medical Journal (BMJ) Best Practice, UpToDate and so on. The search period was from January 1, 2017 to July 31, 2022. Using the quality level of evidence and grade of recommendation system of the Joanna Briggs Institute (JBI) Evidence-Based Health Care Center in Australia, two researchers conducted literature quality evaluation and evidence summary.Results:A total of 19 articles were included, including 2 clinical decisions, 3 clinical practice guidelines, 11 expert consensuses, 2 systematic reviews, and 1 retrospective case-control study. A total of 9 themes were summarized, including the establishment of a multidisciplinary team, indications for parenteral nutrition, nutritional assessment, parenteral nutrition start time, parenteral nutrition stop time, selection and evaluation of vascular pathways, selection of infusion devices, observation of infusion processes and complications, with a total of 29 best evidences.Conclusions:The safe implementation and management of parenteral nutrition support for critically ill patients is of great significance for improving patient health outcomes. Medical and nursing staff should establish a standardized evidence-based parenteral nutrition support process to improve the safety of parenteral nutrition implementation in critically ill patients.

Objective:To investigate the grey matter alterations of Parkinson′s disease (PD) patients with and without sleep disorders, and to explore the relationship between different sleep-related problems and clinical variables as well as grey matter volume (GMV) in PD.Methods:Forty-six PD patients and 38 healthy controls (HCs) were recruited from January 2018 to December 2021 in the Department of Neurology, Beijing Hospital. PD patients were divided into PD with sleep disorders (PD-S, n=26) and PD without sleep disorders (PD-nS, n=20) subgroups (cutoff points of 82 for Parkinson′s Disease Sleep Scale or less than 5 for each item was considered as an indicator of substantial sleep disorder). The Mini-Mental State Examination (MMSE), the third part of the Unified Parkinson′s Disease Rating Scale (UPDRS-Ⅲ), Hamilton Rating Scale for Anxiety (HAMA), Hamilton Rating Scale for Depression (HAMD), Non-Motor Symptoms Questionnaire (NMSQ), and Parkinson′s Disease Questionnaire-39 (PDQ-39) were used to evaluate cognitive function, motor symptoms, anxious and depressive symptoms, non-motor symptoms, and the quality of life of the patients. Optimized voxel-based morphometry was applied to the magnetic resonance imaging brain images in all participants,and multiple linear regression analysis was used to test the correlation between GMV and sleep quality in patients with PD. Results:Compared with the HCs, PD-nS patients showed decreased GMV in bilateral limbic lobe, parahippocampal gyrus, amygdala, cingulate gyrus, hippocampus, right cerebellum, bilateral frontotemporal lobe, bilateral occipital lobe and the left parietal lobe. PD-S group exhibited reduced GMV in bilateral limbic lobe, parahippocampal gyrus, amygdala, right cerebellum, bilateral frontotemporal lobe and bilateral parietal-occipital lobe, compared to the HCs. Compared with PD-nS, PD-S patients revealed higher depressive (HAMD score: 12.19±5.59 vs 6.95±3.19, t=-4.01, P<0.001), anxious (HAMA score: 12.04±5.32 vs 7.25±4.68, t=-3.18, P=0.003), and non-motor symptoms scores (NMSQ score: 12.92±5.18 vs 9.90±4.10, t=-2.14, P=0.038), poorer quality of life (PDQ-39 score: 35.31±22.01 vs 22.40±9.00, t=-2.71, P=0.010), and reduced GMV in the left insula, frontal, and parietal lobe ( P<0.001, uncorrected, cluster>100). There was a marked relationship between sleep quality and the reduced GMV of the right medial temporal gyrus (β=0.006, 95% CI 0.002-0.010, P=0.003), left middle frontal gyrus (β=0.006, 95% CI 0.002-0.010, P=0.002), the right cerebellum (β=0.014, 95% CI 0.005-0.023, P=0.003), and the right medial occipital gyrus (β=0.017, 95% CI 0.011-0.024, P<0.001). Significant grey matter changes were associated with nocturnal restlessness, mainly within the left limbic lobe, bilateral occipital lobe, the right cerebellum, and parietal lobe (β=0.008, 95% CI 0.006-0.010, P<0.001). Furthermore, nocturia in PD was related to certain grey matter atrophy, including bilateral limbic lobe, the right inferior parietal gyrus, and bilateral frontal lobe (β=0.010, 95% CI 0.008-0.013, P<0.001). The symptom of daytime dozing was correlated with GMV reduction in the right occipital lobe, the left temporal lobe (β=0.014, 95% CI 0.010-0.019, P<0.001). There were also several compensatory brain regions, including bilateral frontal lobe, the left limbic lobe and cingulate ( P<0.001, uncorrected, cluster>60). Conclusions:Sleep disturbance is common in PD, which is related to the anxious and depressive symptoms, non-motor symptoms, and the quality of life. PD patients with different sleep disorders show grey matter alterations in severeal brain regions, which are associated with sleep quality, nocturnal restlessness, psychosis, and daytime dozing.

Background: Endoscopic submucosal dissection (ESD) has become the preferred treatment of early colorectal cancer. PDCD4 and autophagy have important clinical significance in the pathogenesis of colorectal cancer. Aims: To explore the expressions and significance of apoptosis factor PDCD4 and autophagy factors LC3Ⅱ and p62 in colorectal cancer. Methods: Fifty-four early colorectal adenocarcinoma patients treated by ESD from Jan. 2015 to Nov. 2020 at Binzhou Medical University Hospital were collected. The expressions of PDCD4, LC3Ⅱ and p62 were detected by immunohistochemistry, and the correlations with clinicopathological factors were analyzed. The differential expression of PDCD4 in pan-cancer was analyzed by bioinformatics analysis. Results: Expression of PDCD4 was associated with the long-diameter of paracancer adenoma (P<0.05), and expressions of LC3Ⅱ and p62 were associated with the long-diameters of adenocarcinoma and paracancer adenoma (P<0.05). The positive expression of PDCD4 in P-NIMM was located in the nucleus, while the positive expression in adenocarcinoma was located in cytoplasm. The nucleus/cytoplasm ratio of PDCD4 was significantly higher in P-NIMM than in P-LGIN, P-HGIN and adenocarcinoma (P<0.05), and the nucleus/cytoplasm ratio of PDCD4 was significantly higher in P-LGIN, P-HGIN than in adenocarcinoma (P<0.05). The positive expression rates of LC3Ⅱ and p62 were significantly higher in adenocarcinoma than in P-NIMM and P-LGIN (P<0.05). In P-LGIN, P-HGIN and adenocarcinoma, the expression of PDCD4 was negatively correlated with the expressions of LC3Ⅱ and p62 (P<0.05). The bioinformatics analysis showed that expression of PDCD4 was significantly reduced in a variety of malignant tumors including colorectal cancer (P<0.05). Conclusions: The inhibition of apoptosis and activation of autophagy may promote the occurrence of colorectal cancer, and its mechanism may be related to the intracellular transposition of PDCD4 that inhibits cell apoptosis and enhances autophagy, and activating cellular autophagy may further accelerate the degradation of PDCD4 and thus reducing its cancer inhibiting effect.

Objective To compare the differences in incidence of rapid eye movement sleep behavior disorder（RBD）on Parkinson’s disease（PD） and multiple system atrophy parkinsonism type（MSAP），and to investigate the correlation factors of the RBD screening questionnaire （RBDSQ） scores.Methods Thirty-four PD patients and 30 MSAP patients without dementia within 5 years of onset were included. Baseline data were collected in detail，and UPDRS Ⅲ score，HY staging score and RBDSQ score were performed between the two groups to compare the difference in the incidence of RBD between the two groups，as well as the correlation factors of RBDSQ score.Results The incidence of RBD in prodrome MSA （40.0%） was significantly higher than that in prodrome PD （2.9%，χ2=11.330，P=0.001）.The incidence of RBD in the clinical stage of MSAP（63.3%）was significantly higher than that in the clinical stage of PD（29.4%，χ2=7.401，P=0.007）.The RBDSQ score of MSAP patients was significantly higher than that of PD patients （6.6±3.9 vs.4.7±3.4，Z=-2.084，P=0.037）.There was no clear correlation between RBDSQ scores in PD group or MSAP group and disease course，UPDRS Ⅲ score，MMSE score and disease progression rate. Conclusion Compared with PD group，the incidence of RBD in prodrome and clinical MSAP group was significantly higher than that in PD group. In MSAP patients and PD patients with normal cognitive function，there was no clear correlation between RBDSQ score and UPDRS Ⅲ score and MMSE score.