Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective: To examine the correlation between frailty and lifestyle factors among middle-aged and elderly populations, so as to provide insights into the management of frailty among middle-aged and elderly populations. Methods : Middle-aged and elderly residents at ages of 45 ot 69 years were recruited using the convenient sampling method from seven townships in Changxing County of Zhejiang Province from 2019 to 2020. The demographic characteristics and lifestyle factors were collected using questionnaires, and the frailty was measured using the Chinese version of Tilburg Frailty Indicator ( TFI ). Factors affecting frailty were identified among middle-aged and elderly populations using the multivariable logistic regression model. Results: A total of 7 170 residents were surveyed, including 2 780 males ( 38.77% ) and 4 390 females ( 61.23% ), which had a median age of 56 (interquartile range, 10) years. The median frailty score was 2 (interquartile range, 3 ) among the study subjects, and the median frailty score was 2 ( interquartile range, 2 ) among residents at ages of 45 to 59 years, and 2 (interquartile range, 3) among residents at ages of 60 to 69 years. The overall detection of frailty was 16.07%, and the detection of frailty was 13.52% among subjects at ages of 45 to 59 years and 21.01% among subjects at ages of 60 to 69 years. Multivariable logistic regression analysis identified physical activity ( OR=0.826, 95%CI: 0.719-0.949 ) and sleep quality ( OR: 3.376-11.493, 95%CI: 2.907-15.808 ) as factors affecting frailty among middle-aged and elderly residents. Following age stratification, physical activity ( OR=0.817, 95%CI: 0.681-0.981 ) and sleep quality ( OR: 3.076-11.566, 95%CI: 2.518-18.216 ) as factors affecting frailty among subjects at ages of 45 to 59 years, while sleep quality ( OR: 3.777-11.827, 95%CI: 3.002-18.547 ) significantly correlated with frailty among residents at ages of 60 to 69 years. Conclusion Physical activity and sleep quality are associated with the risk of frailty among middle-aged and elderly populations.

Objective:This study has investigated the value of detecting cerebrospinal fluid (CSF) MyD88L265P mutation and interleukin-10 (IL-10) levels in the prognosis of PCNSL.Methods:We retrospectively analyzed the clinical data, CSF characteristics (including cytology, cell counting, total protein, and the level of cytokine IL-10) and treatment process of 39 PCNSL patients newly diagnosed by surgery and pathology (18 males and 21 females, aged 40-73 years) from August 2013 to December 2016 in Hua Shan Hospital North. MyD88L265P mutation was detected by digital PCR in 39 paraffin-embedded tissues and 35 cerebrospinal fluid samples. Log-rank test was used for univariate analysis and Cox regression for multivariate analysis to establish the prognosis model of PCNSL which might be related to PCNSL first progress-free survival (PFS) and overall survival (OS).Results:The median age of the 39 PCNSL patients was 59 years old, with 30.8% (12/39) intraocular involvement. The mutation rate of MyD88L265P in tissues and cerebrospinal fluid was 74.4% (29/39) and 40.0% (14/35), respectively. 51.9% (14/27) patients were observed with MyD88L265P mutation in both tissues and CFS. Univariate analysis showed that intraocular involvement, high level of IL-10 in CFS (≥45 pg/ml), and MyD88L265P mutation in CFS are factors significantly influencing median progression-free survival (mPFS) of patients ( P<0.05). Patients with intraocular involvement had shorter OS than those without involvement which was statistically significant ( HR=6.5,95% CI 1.7-47.3, P<0.05). And multivariate analysis showed that intraocular involvement ( HR=2.4, 95% CI 1.3-7.8, P<0.05) and CFS MyD88L265P mutation ( HR=2.1, 95% CI 1.1-5.7, P<0.05) were independent prognostic factors for PFS. Conclusion:The presence of intraocular involvement and MyD88L265P mutation in CFS indicated poor prognosis of PCNSL patients. High CSF IL-10 level was not an independent factor affecting prognosis.

［18F］6-fluoro-3, 4-dihydroxy-L-phenylalanine(［18F］F-DOPA)has been used as a radiotracer for Parkinson′s disease over 30 years. The previously reported electrophilic synthesis method has low radiochemical yield(RCY), low specific activity(SA)and other defects. Recent reported nucleophilic synthesis of ［18F］F-DOPA could overcome the disadvantages. In this paper, the nucleophilic synthetic methods for ［18F］F-DOPA are reviewed.

Objective To evaluate the relationship between concurrent myocardial bridge at anterior descending branch and the formation of coronary atherosclerosis plaques by using transluminal attenuation gradient (TAG). Methods A total of 198 patients underwent coronary CTA in Renji Hospital of Shanghai Jiaotong University School of Medcine from June 2017 to March 2018 and the results showed the anterior descending myocardial bridge. The data were retrospectively analyzed. All patients completed the coronary CTA with 320?row detector CT. According to the manifestations of myocardial bridge on CTA,the patients were divided into deep and superficial myocardial bridge groups. According to whether the patients were complicated with coronary atherosclerotic plaques, they were divided into isolated myocardial bridge group and myocardial bridge with coronary atherosclerotic plaque group. The thickness and length of myocardial bridge, the volume of coronary atherosclerotic plaques at the site of myocardial bridge, the pre?bridge and post?bridge TAG values, and the K ratio were recorded. Independent sample t test (normal distribution) or Mann?Whitney U test (skewed distribution) was used to compare the difference of measurement data among different groups. χ2 test was used to compare the difference of enumeration data among different groups. Pearson correlation test was used to analyze the correlation among pre?bridge and post?bridge TAG values,K ratio,thickness and length of myocardial bridge and plaque volume. The influence of above indexes on plaque occurrence was analyzed by binary logistic regression analysis. The relationship between main influence indexes and plaque formation was analyzed by receiver operating characteristic curve (ROC). Results Ninety nine patients had isolated myocardial bridge,99 with myocardial bridge and coronary atherosclerotic plaques,27 with superficial myocardial bridge and 171 with deep myocardial bridge. All atherosclerotic plaques occurred in pre?bridge and the mean volume of plaques was (91.6±83.0)mm3. The differences in sex, age, height, body weight and body mass index werenot statistically significant between isolated myocardial bridge group and myocardial bridge with coronary atherosclerotic plaque group (all P>0.05). The difference in pre?bridge TAG value was statistically significant between the isolated myocardial bridge group and myocardial bridge with coronary atherosclerotic plaque group (all P<0.05), but not statistically significant in post?bridge TAG value and K ratio (all P>0.05). The difference in pre?bridge and post?bridge TAG values and K value was not statistically significant between the superficial group and the deep group (all P>0.05). There was a weak negative correlation (r=-0.205,-0.316,-0.339,respectively,P<0.05) between the plaque volume and pre?bridge&post?bridge TAG values and K ratio. The pre?bridge TAG value significantly affected the plaque formation (P=0.014) and the odds ratio was 0.884 (95% CI 0.801 to 0.976). While other factors had no significant effects on plaque formation (all P>0.05). The area under curveof plaque formation promoted by pre?bridge TAG value was 0.582. When the diagnostic critical value was －37.26 HU/mm, the sensitivity and specificity of pre?bridge TAG value in plaque formation were 31.31% and 81.82%, respectively. Conclusion The TAG value of anterior descending bridge is an independent risk factor for plaque occurrence. The abnormal TAG value of anterior descending myocardial bridge can be detected early by CTA.

Objective To explore the application value of histogram quantitative analysis based on diffusion kurtosis imaging (DKI) in detecting prostate cancer (PCa) and assessing tumor aggressiveness. Methods One hundred and twenty patients were retrospectively enrolled in Zhongnan Hospital of Wuhan University from November 2014 to November 2016,with diagnosis confirmed by prostate biopsy,definitive Gleason score(GS) results and prostate MRI examinations. There were 90 tumor foci in 67 prostate cancer patients, including 23 cases with GS≤6 (37 tumor foci), 7 GS 3+4=7(7 tumor foci), 3 GS 4+3=7(3 tumor foci).Thirty four cases who were with GS≥8(43 tumor foci)were divided into low-grade PCa(37 GS≤6)and high-grade PCa(53 GS≥7).Fifty three patients were diagnosed with benign prostatic hyperplasia(BPH).All patients underwent conventional prostate MRI examination and multi b value DKI examination. The apparent diffusion coefficient(Dapp)corrected by non-Gaussian model,apparent kurtosis coefficient(Kapp)and ADC value were obtained for histogram analysis.Student's t test was executed to compare the differences of ADCs,Dappand Kappvalues between prostate cancer(PCa)and BPH,low-grade PCa and high-grade PCa.ROC curves were used to evaluate the diagnostic value of ADCs,Dappand Kappvalues in differentiating PCa from BPH and differentiating high-grade PCa from low-grade PCa. Pearson correlation was used to assess the correlations between the histogram quantitative parameters of ADCs,Dappand Kappvalues and Gleason score. Results Except skew of Kapp, the other histogram quantitative parameters of Kappbetween PCa and BPH were statistically significant (all P<0.05). Except the skew of Kapp, the other histogram quantitative parameters of Kappbetween low-grade PCa and high-grade PCa were statistically significant(all P<0.05).The median,mean and standard deviation of ADC,Dappand Kapphave good diagnostic value in detecting PCa from BPH and differing high-grade PCa from low-grade PCa.The area under ROC curve was ranging from 0.558 to 0.985.There were moderate to high correlations between median,mean of ADC(r=-0.701 and-0.676, respectively),median,mean of Dapp(r=-0.712 and-0.701,respectively),median,standard deviation,and kurtosis of Kapp(r=0.458,0.516 and-0.528,respectively)and Gleason score(all P<0.05).Conclusion The DKI parameters combined with histogram quantitative analysis is helpful in detecting prostate cancer and assessing tumor aggressiveness.

Aim To assess the effects of Banqiao Codonopisis Pilosula(BCP)decoction on learning and memory dysfunction in AD model rats induced by high activity GSK-3β and its possible mechanism.Methods The SD rats(4 months old,♂)were divided into five groups,namely,sham-operated group(blank group),AD model group,BCP high-dose(2.16 g·kg-1·d-1)group,BCP medium-dose(1.08 g·kg-1·d-1)group,and BCP lower-dose(0.54 g·kg-1·d-1)group.Treatment group received BCP decoction by gavage once a day for 14 days,while other groups were offered drinking water by gavage once a day for 14 days.The autonomous behavior activities of all rats were observed and recorded after gavage.In the last seven days by gavage,Morris water maze test was used to test the spatial learning and memory ability of the five groups.After five days training,treatment groups and AD model group were injected wortmannin(WT,PI3K specific inhibitor)and GF-109203X(GFX,PKC specific inhibitor)(100 μmol·L-1 of each,total volume of 10 μL)into the right lateral ventricle of the rats.The blank group was only injected 2％DMSO.The spatial memory retention was detected by water maze 24 hours after lateral ventricle injection.Then,changes in the spatial learning memory of rats were observed.The level of Tau phosphorylation in SD rat hippocampus and the expression and activity changes of related protein kinase GSK-3β were detected by Western blot and immunohistochemistry.The changes of Nissl bodies in SD rat hippocampus were observed by Nissl′s staining.Results After intragastric administration of BCP,the rat autonomous behavior activities in each group all showed a declining trend,and the differences in low-dose and middle-dose groups had statistical significance compared with blank group.The Morris water maze tests showed that the latency navigation of model group was significantly longer than that of blank group(P<0.01),while that of the BCP three doses groups was shorter than that of model group(P<0.05).Compared with the same group,the latency navigation of the three groups after gavage BCP low,middle and high dose was significant shorter than that without gavage(P<0.05).Western blot results showed that the activity of GSK-3β in AD model group was up-regulated compared with the blank group.However,BCP inhibited activity of GSK-3β.Western blot and immunohistochemistry results showed the level of Tau phosphorylation in AD model group was increased compared with the blank group in the area of CA3(P<0.05).Compared with AD model group,the level of Tau phosphorylation was decreased in treatment group.Nissl′s staining results showed that dendritic spines in AD model group was significantly attenuated compared with the blank group(P<0.05).Far more dendritic spines were observed in treatment group than in AD model group.The number of Nissl′s bodies in neuron cells of hippocampus in hippocampal CA3 was obviously larger in treatment groups than in AD model group.These effect of BCP was dose-dependent.Conclusions BCP can prevent the learning and memory dysfunction in AD model rats induced by high activity of GSK-3β.The mechanism may be related to inhibiting GSK-3β activity and then reducing the level of phosphorylation of Tau and improving neural development.