Neurodegenerative diseases constitute a group of chronic disorders characterized by the progressive loss of neurons. Major neurodegenerative conditions include Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Pathologically, these diseases are marked by the accumulation of aggregates formed by pathological proteins such as amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. These proteins assemble into amyloid fibrils that undergo prion-like propagation and dissemination, ultimately inducing neurodegeneration. Understanding the biology of these protein aggregates is fundamental to elucidating the pathophysiology of neurodegenerative disorders. In this review, we summarize the molecular mechanisms underlying the aggregation and transmission of pathological proteins, the processes through which these protein aggregates trigger neurodegeneration, and the interactions between different pathological proteins. We also provide an overview of the current diagnostic approaches and therapeutic strategies targeting pathological protein aggregates.
Humans ; Neurodegenerative Diseases/metabolism* ; alpha-Synuclein/metabolism* ; Amyloid beta-Peptides/metabolism* ; tau Proteins/metabolism* ; Protein Aggregation, Pathological/metabolism* ; DNA-Binding Proteins/metabolism* ; Animals ; Protein Aggregates/physiology*

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

Objective: To understand sleep quarity among primary and middle school students in Shenzhen City, so as to provide data support for sleeping quality improvement. Methods: A survey was conducted among 8 742 children selected from two 12 year schools in Longhua District of Shenzhen City, by purposive sampling method from December 22, 2020 to January 15, 2021. The general information was investigated with the self designed questionnaire, and sleep disturbance was investigated and evaluated with the Sleep Disturbance Scale for Children (SDSC). And Chi square test was applied for data analysis. Results: About 47.61 % of primary and middle school students in Shenzhen City reported sleep disturbance, 10.84% of students had moderate to severe sleep disturbance. The overall rate of sleep disturbance and moderate and to severe sleep disturbance among primary school students (48.03%, 10.04%), junior middle schools (45.89%, 11.30%), senior middle schools (52.61%, 16.83%) were found of statistically significant differences ( χ 2=8.89, 27.05, P <0.05). The time to fall asleep for primary school students, junior school students and senior school students at night during the study period were 22:00-23:00 (90.35%), 22:00-23:00 (62.37%), and 23:00-01:00 (61.44%), respectively, and the time to fall asleep of the different stages students were found of statistically significant differences ( χ 2=1 470.17, P <0.01). About 41.04% of students could fall asleep within 15 minutes and 50.57% could fall asleep within 15 to 30 minutes, and the differences in the latency for different stages students to fall asleep at night were of statistical significance ( χ 2=82.92, P <0.01); 8.03% of primary and middle school students had a night sleep time of over 9 hours, and 45.97 % had a night sleep time of 8-9 hours, and the differences in the night sleep time among different stages students were of statistical significance ( χ 2=1 292.86, P <0.01). Conclusions The main sleep problems among primary and secondary school students in Shenzhen City are insufficient sleep and poor sleep quality. The relevant departments should emphasize the sleep health education among children and their parents, so as to improve their sleep quality.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Objective:To elucidate the quasispecies variation of 3′ half-length genome in HIV-1 CRF103_01B-infected patients in Beijing using single genome amplification (SGA).Methods:This study enrolled six CRF103_01B-infected patients who were diagnosed during a drug resistance monitoring for newly diagnosed cases or newly treated cases with antiviral therapy in Beijing from 2017 to 2020. RNA was extracted from their plasma samples, and 3′ end of cDNA was diluted by serial dilution method after reverse transcription. Nested PCR was used to amplify the 3′ half-length genome sequences of HIV-1 quasispecies. MEGA 11 was used to construct Neighbor-Joining (NJ) tree and calculate the intrahost genetic distance. Genetic variation in HIV-1 quasispecies was visualized by online Highlighter tool. BootScan analysis was performed using Simplot 3.5 software to analyze inter-quasispecies recombination. Virus tropism was predicted by online Geno2pheno tool.Results:Among the six CRF103_01B-infected patients, five were men who have sex with men. A total of 144 3′ half-length genome SGA sequences (19-36 sequences/case) were obtained. The NJ tree based on the 3′ half-length genome of HIV-1 quasispecies revealed different degrees of genetic diversity. The HIV-1 quasispecies in BL4748-00 case of acute infection has the least variation with the intrahost distance of 0.002±0.000, showing genetic homogeneity. The quasispecies sequences from BL4981-00, BL3150-00 and BL3558-00 cases formed at least three subclusters, respectively, with different evolutionary directions, and their intrahost distance ranked from 0.031±0.004 to 0.016±0.002 (BL3150-00>BL3558-00>BL4981-00). The quasispecies sequences from the couple BL3022-00 (female) and BL3023-00 clustered into a large monophyletic cluster (bootstrap value=100%), and the intrahost distance of the latter (0.025±0.003) was higher than that of the former (0.019±0.002). Inter-quasispecies recombination was observed in BL3558-00 case. The quasispecies from the six patients were CCR5-tropic viruses.Conclusions:The diversity of quasispecies variation in CRF103_01B-infected patients is related to disease progress. Genetic homogeneity is observed in acute HIV infection, while multiple evolutionary directions are detected in chronic infection. Co-infection or superinfection cases are not found, but there are recombination events among quasispecies in some cases.

【Objective】 To analyze the distribution of unexpected antibodies in tumor patients retrospectively and explore the clinical significance. 【Methods】 Unexpected antibody screening was performed on inpatients with blood preparation and blood transfusion in our hospital from January 2004 to December 2022, with 1 176 cases tested positive, and the types of unexpected antibodies and distribution characteristics were statistically analyzed. 【Results】 Unexpected antibodies were screened in 1 176 cases, with the positive rate at 1.05% (1 176/111 483). The unexpected antibodies were mainly anti-E 16.33%(192/1 176), anti-M 7.99% (94/1 176), anti-Mur 5.70% (67/1 176) and anti-Le^a 4.76% (56/1 176). Among the 1 176 cases, gastrointestinal tumors accounted for 27.99% (329/1 176), gynecological tumors accounted for 24.84% (292/1 176), respiratory tumors accounted for 16.67% (196/1 176) . 【Conclusion】 The influencing factors of unexpected antibodies in tumor patients were disease type, blood transfusion history and blood type. Therefore, it is necessary for clinical departments to carry out unexpected antibody screening and perform Rh blood type matched transfusion for tumor patients to avoid alloantibody production.

Objective:To evaluate the effectiveness and safety of concurrent chemoradiotherapy combined with nimotuzumab in the treatment of patients with inoperable esophageal squamous cell carcinoma (ESCC).Methods:A retrospective analysis was conducted on the clinical data of 503 patients with inoperable ESCC who underwent concurrent chemoradiotherapy in the Department of Radiation Oncology, Changzhou No. 2 People′s Hospital Affiliated to Nanjing Medical University and Department of Radiation Oncology, Affiliated Hospital of Jiangnan University from 2014 to 2020. Among these patients, 69 received concurrent chemoradiotherapy combined with nimotuzumab (the combined therapy group) and 434 received concurrent chemoradiotherapy alone (the concurrent chemoradiotherapy group). Patients of both groups were matched at a ratio of 1∶2 using the propensity score matching (PSM) method. As a result, 168 patients were determined for clinical analysis, including 61 in the combined therapy group and 107 in the concurrent chemoradiotherapy group. The short-term efficacy and adverse reactions of both groups were compared. The overall survival (OS) curves and progression-free survival (PFS) curves were plotted using the Kaplan-Meier method for the Log-rank test.Results:The two groups showed no statistical difference ( P > 0.05) in clinical baseline characteristics after the PSM. The objective response rate (ORR) of the combined therapy group was significantly higher than that of the concurrent chemoradiotherapy group with statistically significant differences (85.2% vs. 71.0%, χ2 = 4.33, P = 0.037). There was no statistical difference (98.4% vs. 91.6%, P > 0.05) in the disease control rate (DCR) between the two groups. The combined therapy group had median PFS of 28.07 months and 1-, 3-, and 5-year PFS ratios of 78.2%, 37.5% and 29.1%, respectively. The concurrent chemoradiotherapy group had mPFS of 19.54 months and 1-, 3-, and 5-year PFS ratios of 72.9%, 28.3% and 21.3%, respectively. Both groups showed statistically significant differences in PFS ( χ2 = 4.49, P = 0.034). The combined group had median OS of 34.93 months and 1-, 3-, and 5-year OS ratios of 88.5%, 46.8% and 37.4%, respectively. The concurrent chemoradiotherapy group had mOS of 24.30 months and 1-, 3-, and 5-year OS ratios of 81.3%, 35.2% and 28.0%, respectively. Both groups showed statistically significant differences in OS (χ 2= 5.11, P = 0.024), but did not show statistical differences ( P > 0.05) in the severity degree of each adverse effect during the treatment. Conclusions:Concurrent chemoradiotherapy combined with nimotuzumab can improve the ORR and prolong the PFS and OS of patients with inoperable ESCC compared with concurrent chemoradiotherapy alone. Furthermore, combining with nimotuzumab does not increase adverse effects and can be tolerated by patients with high safety.

Objective:To preliminary explore the potential application value of ultrasound shear wave elastography (SWE) in assessing functional defecation disorders compared with anorectal manometry and X-ray defecography.Methods:From July 2022 to December 2022, the results of SWE, anorectal manometry and X-ray defecography of 39 patients with functional defecation disorders visited Sir Run Run Shaw Hospital, School of Medicine of Zhejiang University were retrospectively analyzed. Non-parametric tests were used to analyze the changes in elastic modulus values of anorectal muscle groups at different phase.Chi-square test and Bland-Altman plots were used to assess the consistency between SWE, X-ray defecography and anorectal manometry in evaluating spastic pelvic floor syndrome, as well as the changes in the anorectal angle measured by SWE and X-ray defecography (from resting phase to contraction phase, resting phase to strain phase (Valsalval maneuver).Results:The elastic modulus values measured by SWE of the puborectalis muscle, internal anal sphincter, and external anal sphincter of patients with functional defecation disorders during strain phase were 32.4 kPa (19.1 kPa, 60.3 kPa), 25.3 kPa (17.0 kPa, 53.8 kPa), and 28.6 kPa (21.3 kPa, 55.1 kPa), respectively, which had no statistically significant differences compared to elastic modulus values in resting phase (33.5 kPa (22.1 kPa, 44.9 kPa), 28.9 kPa (22.4 kPa, 45.1 kPa), and 32.4 kPa (23.1 kPa, 49.4 kPa), all P>0.05). The consistency between SWE and X-ray defecography in the diagnosis of spastic pelvic floor syndrome was poor (Kappa=0.190). The consistency between SWE and anorectal manometry in the diagnosis of dyssynergic defecation was poor (Kappa=0.160). The differences in the changes of anorectal angle detected by SWE and X-ray defecography were within the 95% consistency limit ( P=0.429 and 0.582). Conclusion:SWE is sensitive in evaluating changes in anorectal angle, and it shows good consistency with defecography in assessing angle changes.

Esophageal squamous cell carcinoma (ESCC) is the most predominant pathological type of esophageal cancer in China. In recent years, with the development of molecular targeted drugs, targeted therapy has become a hot research topic in the field of ESCC treatment. Nimotuzumab is the first humanized monoclonal antibody targeting epidermal growth factor receptor (EGFR) in China, which has been approved for the treatment of early or locally advanced nasopharyngeal carcinoma. Several phase Ⅱ-Ⅲ clinical trials have explored the use of nimotuzumab in the treatment of ESCC, confirming its significant efficacy and survival benefit in the treatment of advanced ESCC, as well as its favorable safety profile.

Objective:To evaluate the efficacy and tolerability of the dual therapy of dolutegravir (DTG) plus lamivudine (3TC) as a switch simplified strategy in treatment-experienced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients.Methods:Treatment-experienced HIV/AIDS patients who switched to a dual therapy containing DTG (50 mg, once daily) plus 3TC (300 mg, once daily) were included in Beijing You′an Hospital, Capital Medical University from September 2016 to May 2019. HIV RNA, CD4 + T lymphocyte count, blood lipid indexes, renal function indexes were collected when patients changed the treatment regimen (baseline) and after 48 weeks of treatment. Efficacy (HIV RNA<50 copies/mL) and safety of the dual therapy were analyzed. Statistical comparisons were performed using the Wilcoxon matched-pairs signed rank test. Results:The reasons for 33 patients switching the treatment regimen were virologic failure (four cases, 12.1%), simplification of regimen (11 cases, 33.3%), and drug toxicity (18 cases, 54.5%). The patients were treated with anti-retroviral therapy (ART) for 2.13 (1.05, 4.23) years before regimens switching. Twenty-nine (87.9%) patients were virologically suppressed at baseline, and four (12.1%) patients were virological failure. After switching to DTG plus 3TC, all 33 patients showed HIV RNA<50 copies/mL after 48 weeks of treatment. The baseline CD4 + T lymphocyte count was 543 (363, 595)/μL. After switching the treatment regimens for 48 weeks, CD4 + T lymphocyte count was significantly increased to 625 (455, 651)/μL, and the difference was statistically significant ( Z=3.14, P=0.002). Compared with baseline, low-density lipoprotein-cholesterol was increased after 48 weeks of treatment (2.35(1.80, 3.08) mmol/L vs 3.12(2.74, 3.87) mmol/L), while triglyceride (2.21(1.27, 4.37) mmol/L vs 1.61(1.20, 2.22) mmol/L), the ratio of total cholesterol to high-density lipoprotein-cholesterol (5.02 (4.13, 6.40) vs 4.70 (3.55, 5.35)) and estimated glomerular filtration rate (106.4(78.2, 118.2) mL/(min·1.73 m 2) vs 88.6 (75.7, 107.9) mL/(min·1.73 m 2)) were decreased. The differences were all statistically significant ( Z=4.89, 2.37, 2.09 and 2.83, respectively, all P<0.050). No patient discontinued due to adverse events. Conclusions:The use of dual therapy containing DTG and 3TC is effective and well-tolerated in treatment-experienced HIV/AIDS patients under any prior ART without significant adverse events.