Paeoniflorin loaded liposomes modified with glycyrrhetinic acid for liver-targeting: preparation, characterization, and pharmacokinetic study

To enhance the retention times and therapeutic efficacy of paeoniflorin (PF), a liver-targeted drug delivery system has been developed using glycyrrhetinic acid (GA) as a ligand. The development and optimization of GA-modified PF liposomes (GPLs) have shown promising potential for targeted delivery to the liver, opening up new possibilities for liver disease treatment. This study aimed to identify the best prescriptions using single-factor experiments and response surface methodology. The formulation morphology was determined using transmission electron microscopy. Tissue distribution was observed through in vivo imaging, and pharmacokinetic studies were conducted. The results indicated that GPLs, prepared using the thin film dispersion method and response surface optimization, exhibited well-dispersed and uniformly sized particles. The in vitro release rate of GPLs was slower compared to PF monomers, suggesting a sustained release effect. The liver-targeting ability of GA resulted in stronger fluorescence signals in the liver for targeted liposomes compared to non-targeted liposomes. Furthermore, pharmacokinetic studies demonstrated that GPLs significantly prolonged the residence time of PF in the bloodstream, thereby contributing to prolonged efficacy. These findings suggest that GPLs are more effective than PF monomers in terms of controlling drug release and delivering drugs to specific targets, highlighting the potential of PF as a liver-protective drug.</p

Image_1_Clinicopathological characteristics, evolution, treatment pattern and outcomes of hormone-receptor-positive/HER2-low metastatic breast cancer.pdf

ObjectiveDespite the promising efficacy of the novel antibody-drug conjugate trastuzumab deruxtecan in treating Hormone Receptor (HoR)-positive/Human Epidermal Growth Factor Receptor 2 (HER2)-low metastatic breast cancer (MBC), its categorization as a distinct entity remains disputed, as does the divergence in its endocrine and chemotherapy outcomes. This study aimed to elucidate the clinical characteristics, primary/metastatic lesion HER2 expression, and treatment outcomes of HoR-positive/HER2-low patients.MethodsWe included HoR-positive/HER2-negative MBC patients who underwent 1st and 2nd line endocrine treatment from July 2010 to October 2022 at the Fudan University Shanghai Cancer Center, comparing the clinical pathological characteristics, HER2 expression in primary/metastatic lesions, treatment, and therapeutic effects of the HER2-low and HER2-zero groups.ResultsAmong the 458 HoR-positive/HER2-negative MBC patients, 54.37% (249/458) were HER2-low. The HER2-low group and the HER2-zero group had similar clinical pathological characteristics and similar progression-free survival (PFS) of 1st and 2nd line endocrine treatment (median PFS: 8.05 months vs 10.12 months, p=0.114, HR 1.257, 95% CI 0.771 to 1.028). The PFS of the HER2-low and HER2-zero groups was also similar, treated with different endocrine drugs (including aromatase inhibitors, tamoxifen/toremifene, fulvestrant, palbociclib, and everolimus). However, the HER2-low group had significantly shorter PFS during 1st and 2nd line chemotherapy compared to the HER2-zero group (median PFS: 8.64 vs 9.03 months, p=0.027, HR 0.841, 95% CI 0.721-0.980). Additionally, 41.18% (63/153) of patients exhibited a change in HER2 expression between primary and metastatic lesions. Notably, patients whose HER2 status changed from zero to low expression had significantly prolonged PFS during chemotherapy compared to those who maintained low HER2 expression (median PFS: 14.29 vs 11.27 months, p=0.048, HR 0.597, 95% CI 0.358-0.996).ConclusionIn HoR-positive MBC, patients with low and zero HER2 expression have similar clinical characteristics and respond similarly to endocrine treatment, but the chemotherapy effect is worse in the HER2-low patients. Moreover, the transformation of HER2 status from primary to metastatic lesions may have potential influence on chemotherapy outcomes. Therefore, the expression and heterogeneity of HER2 should be considered in clinical decisions.</p

Table_1_Risk scores of incident mild cognitive impairment in a Beijing community-based older cohort.docx

Objective: It is very important to identify individuals who are at greatest risk for mild cognitive impairment (MCI) to potentially mitigate or minimize risk factors early in its course. We created a practical MCI risk scoring system and provided individualized estimates of MCI risk.Methods: Using data from 9,000 older adults recruited for the Beijing Ageing Brain Rejuvenation Initiative, we investigated the association of the baseline demographic, medical history, lifestyle and cognitive data with MCI status based on logistic modeling and established risk score (RS) models 1 and 2 for MCI. We evaluated model performance by computing the area under the receiver operating characteristic (ROC) curve (AUC). Finally, RS model 3 was further confirmed and improved based on longitudinal outcome data from the progression of MCI in a sub-cohort who had an average 3-year follow-up.Results: A total of 1,174 subjects (19.8%) were diagnosed with MCI at baseline, and 72 (7.8%) of 849 developed MCI in the follow-up. The AUC values of RS models 1 and 2 were between 0.64 and 0.70 based on baseline age, education, cerebrovascular disease, intelligence and physical activities. Adding baseline memory and language performance, the AUC of RS model 3 more accurately predicted MCI conversion (AUC = 0.785).Conclusion: A combination of risk factors is predictive of the likelihood of MCI. Identifying the RSs may be useful to clinicians as they evaluate their patients and to researchers as they design trials to study possible early non-pharmaceutical interventions to reduce the risk of MCI and dementia.</p

Data_Sheet_1_Altered expression of inflammation-associated molecules in striatum: an implication for sensitivity to heavy ion radiations.docx

Background and objectiveHeavy ion radiation is one of the major hazards astronauts face during space expeditions, adversely affecting the central nervous system. Radiation causes severe damage to sensitive brain regions, especially the striatum, resulting in cognitive impairment and other physiological issues in astronauts. However, the intensity of brain damage and associated underlying molecular pathological mechanisms mediated by heavy ion radiation are still unknown. The present study is aimed to identify the damaging effect of heavy ion radiation on the striatum and associated underlying pathological mechanisms.Materials and methodsTwo parallel cohorts of rats were exposed to radiation in multiple doses and times. Cohort I was exposed to 15 Gy of 12C6+ ions radiation, whereas cohort II was exposed to 3.4 Gy and 8 Gy with 56Fe26+ ions irradiation. Physiological and behavioural tests were performed, followed by 18F-FDG-PET scans, transcriptomics analysis of the striatum, and in-vitro studies to verify the interconnection between immune cells and neurons.ResultsBoth cohorts revealed more persistent striatum dysfunction than other brain regions under heavy ion radiation at multiple doses and time, exposed by physiological, behavioural, and 18F-FDG-PET scans. Transcriptomic analysis revealed that striatum dysfunction is linked with an abnormal immune system. In vitro studies demonstrated that radiation mediated diversified effects on different immune cells and sustained monocyte viability but inhibited its differentiation and migration, leading to chronic neuroinflammation in the striatum and might affect other associated brain regions.ConclusionOur findings suggest that striatum dysfunction under heavy ion radiation activates abnormal immune systems, leading to chronic neuroinflammation and neuronal injury.</p

Supplementary information files for What have we learnt from quantitative case reports of acute lateral ankle sprains injuries and episodes of ‘giving-way’ of the ankle joint, and what shall we further investigate?

Supplementary information files for article What have we learnt from quantitative case reports of acute lateral ankle sprains injuries and episodes of ‘giving-way’ of the ankle joint, and what shall we further investigate? Lateral ankle sprains are a commonly incurred injury in sports. They have a high recurrence rate and can lead to the development of persistent injury associated symptoms. We performed a quantitative synthesis of published case reports documenting the kinematics of acute lateral ankle sprains and episodes of “giving-way” of the ankle joint to provide a comprehensive description of the mechanisms. A systematic literature search was conducted to screen records within MEDLINE® and EMBASE® . Additional strategies included manual search of specific journals as well as contacting researchers in relevant communities to retrieve unpublished data. Twenty-four cases were included in the quantitative synthesis; 11 from individual case reports and 13 from four separate case series. Two authors independently reviewed all articles and extracted ankle joint kinematic data. Excessive ankle inversion was the most pronounced kinematic pattern observed across all included cases, with a mean peak inversion angle of 67.5° (range 2.0 to 142) and a mean peak inversion velocity of 974°/s (range 468 to 1752). This was followed by internal rotation and plantar flexion, respectively. A homogeneous linear function revealed a mean inversion velocity across all cases of 337°/s (range 117 to 1400; R2 =0.78; p<0.0001). </p

What have we learnt from quantitative case reports of acute lateral ankle sprains injuries and episodes of ‘giving-way’ of the ankle joint, and what shall we further investigate?

Lateral ankle sprains are a commonly incurred injury in sports. They have a high recurrence rate and can lead to the development of persistent injury associated symptoms. We performed a quantitative synthesis of published case reports documenting the kinematics of acute lateral ankle sprains and episodes of “giving-way” of the ankle joint to provide a comprehensive description of the mechanisms. A systematic literature search was conducted to screen records within MEDLINE® and EMBASE® . Additional strategies included manual search of specific journals as well as contacting researchers in relevant communities to retrieve unpublished data. Twenty-four cases were included in the quantitative synthesis; 11 from individual case reports and 13 from four separate case series. Two authors independently reviewed all articles and extracted ankle joint kinematic data. Excessive ankle inversion was the most pronounced kinematic pattern observed across all included cases, with a mean peak inversion angle of 67.5° (range 2.0 to 142) and a mean peak inversion velocity of 974°/s (range 468 to 1752). This was followed by internal rotation and plantar flexion, respectively. A homogeneous linear function revealed a mean inversion velocity across all cases of 337°/s (range 117 to 1400; R2 = 0.78; p < 0.0001).</p