PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. CONCLUSION: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.

Comparison of immediate vs. delayed guided tissue regeneration in Infrabony defect of second molars after adjacent third molar extraction: a retrospective study.

BACKGROUND: The distal aspect of the second molar (d-M2) often exhibits infrabony defects due to the adjacent third molar. Although the defects can be treated by guided tissue regeneration (GTR) after removing the third molar, the optimal timing remains uncertain following third molar removal in clinical decision-making. This study aimed to compare delayed and immediate GTR treatments to assist in clinical decision-making. METHODS: D-M2 infrabony defects with a minimum 1-year follow-up were collected and divided into three groups: Immediate GTR group, which underwent third molar extraction and received GTR simultaneously; Delayed GTR group, which underwent delayed GTR at least 3 months after third molar extraction; and Control group, which underwent only scaling and root planing during third molar extraction. The clinical and radiographic parameters related to the infrabony defect before GTR and post-surgery were evaluated using the Kruskal-Wallis test or one-way ANOVA, followed by post-hoc Dunn's test or the Bonferroni test for pairwise comparisons. RESULTS: A total of 109 d-M2 infrabony defects were assessed. No significant differences were found between the two GTR groups, although both of them showed significant reductions in infrabony defect depth: the immediate GTR group (2.77 ± 1.97 mm vs. 0.68 ± 1.03 mm, p < 0.001) and the delayed GTR group (2.98 ± 1.08 mm vs. 0.68 ± 1.03 mm, p < 0.001) compared to the control group. CONCLUSION: GTR can effectively improve d-M2 infrabony defects when the third molar is removed, whether simultaneously or delayed. Patients may experience less discomfort with immediate GTR treatment as it requires only one surgery.

Rhamnolipids-based bio-supramolecular solvents as green and sustainable media for extraction of pyrethroid insecticides in water and food matrices.

A novel bio-supramolecular solvent (bio-SUPRAS) based on rhamnolipids (RLs) was designed for efficient extraction of pyrethroid insecticides in water and food matrices. Benefiting from RLs as amphiphiles equipped with the attractive properties of bio-degradable, low toxicity and high stability, bio-SUPRAS was spontaneously generated through salt induced coagulation. The bio-SUPRAS was characterized by cryo-scanning electron microscope and main factors influencing the extraction performance were investigated in detail. Under the optimized conditions, the method was found to have desirable limits of detection (5∼10 µg l-1), good precision (RSDs<16.9 %) and satisfactory recovery (75.2 %∼94.3 %). More importantly, the extraction mechanism was studied by density functional theory systematically. Following greenness assessment, the technique was successfully used for enrichment of pyrethroid pesticides in real samples before HPLC-UV analysis. Thus, the method showed the outstanding merits of eco-efficient, green, time-saving, and had favorable application prospect to remove trace analytes from intricate sample matrices.

Delayed cerebrovascular reactivity in individuals with spinal cord injury in the right inferior parietal lobe: a breath-hold functional near-infrared spectroscopy study.

Cerebrovascular reactivity (CVR) reflects the ability of blood vessels to dilate or constrict in response to a vasoactive stimulus, and allows researchers to assess the brain's vascular health. Individuals with spinal cord injury (SCI) are at an increased risk for autonomic dysfunction in addition to cognitive impairments, which have been linked to a decline in CVR; however, there is currently a lack of brain-imaging studies that investigate how CVR is altered after SCI. In this study, we used a breath-holding hypercapnic stimulus and functional near-infrared spectroscopy (fNIRS) to investigate CVR alterations in individuals with SCI (n = 20, 14M, 6F, mean age = 46.3 ± 10.2 years) as compared to age- and sex-matched able-bodied (AB) controls (n = 25, 19M, 6F, mean age = 43.2 ± 12.28 years). CVR was evaluated by its amplitude and delay components separately by using principal component analysis and cross-correlation analysis, respectively. We observed significantly delayed CVR in the right inferior parietal lobe in individuals with SCI compared to AB controls (linear mixed-effects model, fixed-effects estimate = 6.565, Satterthwaite's t-test, t = 2.663, p = 0.008), while the amplitude of CVR was not significantly different. The average CVR delay in the SCI group in the right inferior parietal lobe was 14.21 s (sd: 6.60 s), and for the AB group, the average delay in the right inferior parietal lobe was 7.08 s (sd: 7.39 s). CVR delays were also associated with the duration since injury in individuals with SCI, in which a longer duration since injury was associated with a shortened delay in CVR in the right inferior parietal region (Pearson's r-correlation, r = -0.59, p = 0.04). This study shows that fNIRS can be used to quantify changes in CVR in individuals with SCI, and may be further used in rehabilitative settings to monitor the cerebrovascular health of individuals with SCI.

Designing green and recyclable switchable supramolecular deep eutectic solvents for efficient extraction of flavonoids from Scutellariae Radix and mechanism exploration.

A green and recyclable switchable supramolecular deep eutectic solvent (SS-DES) was designed and prepared for effective extraction of flavonoids from Scutellariae Radix. The novel SS-DES has both excellent extraction performance of DES and the host guest inclusion of cyclodextrin, thereby showing superior extraction efficiency and selectivity. The characteristic of polarity switching can endow the SS-DES with achieving homogeneous extraction and rapid two-phase separation, shorting per-treatment time largely. Parameters affecting the extraction performance were investigated by the response surface methodology. The results indicated that the SS-DES showed better extraction yield of total flavonoids (157.95 mg/g) compared with pure DES (135 mg/g) and traditional organic solvent (60 % ethanol, 104.87 mg/g). Moreover, the switching mechanism of SS-DES was characterized by FT-IR and 1H NMR, and the extraction mechanism was studied by density functional theory and molecular docking analysis. After evaluating the ecological impact of the method, the cytotoxicity of SS-DES was investigated and the result displayed that its toxicity was very low or even negligible with the EC50>2000 mg/L. After being adsorbed by macroporous AB-8 resin, the regenerated SS-DES was recycled 5 times and the extraction efficiency still remained above 90 %, indicating the desirable reusability. Therefore, the proposed method was efficient and sustainable, and revealed favorable application prospect for the extraction of bio-active compounds from plant materials.

Effects of Tasks on Functional Brain Connectivity Derived from Inter-Individual Correlations: Insights from Regional Homogeneity of Functional MRI Data.

Research on brain functional connectivity often relies on intra-individual moment-to-moment correlations of functional brain activity, typically using techniques like functional MRI (fMRI). Inter-individual correlations are also employed on data from fMRI and positron emission tomography (PET). Many past studies have not specified tasks for participants, keeping them in an implicit "resting" condition. This lack of task specificity raises questions about how different tasks impact inter-individual correlation estimates. In our analysis of fMRI data from 100 unrelated participants, scanned during seven task conditions and in a resting state, we calculated Regional Homogeneity (ReHo) for each task as a regional measure of brain functions. We found that changes in ReHo due to different tasks were relatively small compared with the variations across brain regions. Cross-region variations of ReHo were highly correlated between different tasks. Similarly, whole-brain inter-individual correlation patterns were remarkably consistent across the tasks, showing correlations greater than 0.78. Changes in inter-individual correlations between tasks were primarily driven by connectivity in the visual, somatomotor, default mode network, and the interactions between them. The subtle yet statistically significant differences in functional connectivity may be linked to specific brain regions associated with the studied tasks. Future studies should consider task design when exploring inter-individual connectivity in specific brain systems.

Therapeutic potential of single-nucleotide polymorphism-mediated IL6R inhibitors in ankylosing spondylitis treatment.

Objective: Interleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS. Methods: The C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability. Results: According to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.996, P = 5.12 × 10-08) and ukb-a-88 (OR: 0.994, 95% CI 0.993-0.996, P = 6.25 × 10-15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.997, P = 1.25 × 10-06) and ukb-a-88 (OR: 0.995, 95% CI 0.994-0.997, P = 7.81 × 10-09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy. Conclusion: This MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.

Advances in the Study of Non-Coding RNA in the Signaling Pathway of Pulmonary Fibrosis.

Pulmonary fibrosis is a group of chronic, progressive, and irreversible interstitial lung diseases, which are common to most end-stage lung diseases and are one of the most difficult diseases of the respiratory system. In recent years, due to the frequent occurrence of air pollution and smog, the incidence of pulmonary fibrosis in China has increased year by year, the morbidity and mortality rates of pulmonary fibrosis have gradually increased and the age of the disease tends to be younger. However, the pathogenesis of pulmonary fibrosis is not yet fully understood and is needed to further explore new drug targets. Studies have shown that non-coding RNAs play an important role in regulating the process of pulmonary fibrosis, non-coding RNAs and their specifically expressed can promote or inhibit the process. Here, we review the role of some in the regulation of pulmonary fibrosis signaling pathways and provide new ideas for the clinical diagnosis and treatment of pulmonary fibrosis.

Network-wise analysis of movie-specific information in dynamic functional connectivity using COBE.

Movie watching during functional magnetic resonance imaging has emerged as a promising tool to measure the complex behavior of the brain in response to a stimulus similar to real-life situations. It has been observed that presenting a movie (sequence of events) as a stimulus will lead to a unique time course of dynamic functional connectivity related to movie stimuli that can be compared across the participants. We assume that the observed dynamic functional connectivity across subjects can be divided into following 2 components: (i) specific to a movie stimulus (depicting group-level behavior in functional connectivity) and (ii) individual-specific behavior (not necessarily common across the subjects). In this work, using the dynamic time warping distance measure, we have shown the extent of similarity between the temporal sequences of functional connectivity while the underlying movie stimuli were same and different. Further, the temporal sequence of functional connectivity patterns related to a movie is enhanced by suppressing the subject-specific components of dynamic functional connectivity using common and orthogonal basis extraction. Quantitative analysis using the F-ratio measure reveals significant differences in dynamic functional connectivity within the somatomotor network and default mode network, as well as between the occipital network and somatomotor networks.

What is the association of preoperative biopsy with recurrence and survival in retroperitoneal sarcoma? A systematic review by the Australia and New Zealand Sarcoma Association clinical practice guidelines working party.

Preoperative biopsy for retroperitoneal sarcoma (RPS) enables appropriate multidisciplinary treatment planning. A systematic review of literature from 1990 to June 2022 was conducted using the population, intervention, comparison and outcome model to evaluate the local recurrence and overall survival of preoperative biopsy compared to those that had not. Of 3192 studies screened, five retrospective cohort studies were identified. Three reported on biopsy needle tract seeding, with only one study reporting biopsy site recurrence of 2 %. Two found no significant difference in local recurrence and one found higher 5-year local recurrence rates in those who had not been biopsied. Three studies reported overall survival, including one with propensity matching, did not show a difference in overall survival. In conclusion, preoperative core needle biopsy of RPS is not associated with increased local recurrence or adverse survival outcomes.

Reduced Volume Expansion of Micron-Sized SiOx via Closed-Nanopore Structure Constructed by Mg-Induced Elemental Segregation.

The inherently huge volume expansion during Li uptake has hindered the use of Si-based anodes in high-energy lithium-ion batteries. While some pore-forming and nano-architecting strategies show promises to effectively buffer the volume change, other parameters essential for practical electrode fabrication, such as compaction density, are often compromised. Here we propose a new in situ Mg doping strategy to form closed-nanopore structure into a micron-sized SiOx particle at a high bulk density. The doped Mg atoms promote the segregation of O, so that high-density magnesium silicates form to generate closed nanopores. By altering the mass content of Mg dopant, the average radii (ranged from 5.4 to 9.7 nm) and porosities (ranged from 1.4 % to 15.9 %) of the closed pores are precisely adjustable, which accounts for volume expansion of SiOx from 77.8 % to 22.2 % at the minimum. Benefited from the small volume variation, the Mg-doped micron-SiOx anode demonstrates improved Li storage performance towards realization of a 700-(dis)charge-cycle, 11-Ah-pouch-type cell at a capacity retention of >80 %. This work offers insights into reasonable design of the internal structure of micron-sized SiOx and other materials that undergo conversion or alloying reactions with drastic volume change, to enable high-energy batteries with stable electrochemistry.

Explorations of using a convolutional neural network to understand brain activations during movie watching.

Neuroimaging studies increasingly use naturalistic stimuli like video clips to trigger complex brain activations, but the complexity of such stimuli makes it difficult to assign specific functions to the resulting brain activations, particularly for higher-level content like social interactions. To address this challenge, researchers have turned to deep neural networks, e.g., convolutional neural networks (CNNs). CNNs have shown success in image recognition due to their different levels of features enabling high performance. In this study, we used pre-trained VGG-16, a popular CNN model, to analyze video data and extract hierarchical features from low-level shallow layers to high-level deeper layers, linking these activations to different levels of activation of the human brain. We hypothesized that activations in different layers of VGG-16 would be associated with different levels of brain activation and visual processing hierarchy in the brain. We were also curious about which brain regions would be associated with deeper convolutional layers in VGG-16. The study analyzed a functional MRI (fMRI) dataset where participants watched the cartoon movie Partly Cloudy. Frames of the videos were fed into VGG-16, and activation maps from different kernels and layers were extracted. Time series of the average activation patterns for each kernel were created and fed into a voxel-wise model to study brain activations. Results showed that lower convolutional layers (1st convolutional layer) were mostly associated with lower visual regions, but some kernels (6, 19, 24, 42, 55, and 58) surprisingly showed associations with activations in the posterior cingulate cortex, part of the default mode network. Deeper convolutional layers were associated with more anterior and lateral portions of the visual cortex (e.g., the lateral occipital complex) and the supramarginal gyrus. Analyzing activation features associated with different brain regions showed the promise and limitations of using CNNs to link video content to brain functions.

PEI, a new transfection method, augments the inhibitory effect of RBM5 on prostate cancer.

PEI is a cationic polymer, serving as a non-viral transfection carrier grounded in nanotechnology that enhances transfection efficiency via the proton sponge effect. RBM5 is an RNA-binding protein that can inhibit tumor development. This study involved the transfection of RBM5 in prostate cancer cells with PEI, Lipo2000, and their combination. Transwell and wound healing assays were used to observe invasion and migration of prostate cancer cells and flow cytometry was used to observe the apoptosis. Detect the expression of invasion and migration-related protein MMP9 through western blotting experiment. An activity detection kit was used to detect the activity of apoptotic protein caspase-3. We found that there was no significant difference in transfection efficiency when PEI and Lipo2000 were used alone but it significantly improved when they are combined. RBM5 reduced invasion, migration, and proliferation of prostate cancer and enhanced apoptosis. MMP9 expression was reduced, and the activity of caspase-3 was increased. PEI transfection could improve the inhibition of RBM5 on tumors more than Lipo2000. The inhibitory effect is more obvious when the two are used together. RBM5 transfected with PEI can amplify its inhibitory effect on prostate cancer, and this effect is more evident when combined with Lipo2000.

Brain activation during the N-back working memory task in individuals with spinal cord injury: a functional near-infrared spectroscopy study.

Cognitive impairments have frequently been reported in individuals with spinal cord injury (SCI) across different domains such as working memory, attention, and executive function. The mechanism of cognitive impairment after SCI is not well understood due to the heterogeneity of SCI sample populations, and may possibly be due to factors such as cardiovascular dysfunction, concomitant traumatic brain injury (TBI), hypoxia, sleep disorders, and body temperature dysregulation. In this study, we implement the Neuropsychiatric Unit Cognitive Assessment Tool (NUCOG) to assess cognitive differences between individuals with SCI and age-matched able-bodied (AB) controls. We then use an N-back working memory task and functional near-infrared spectroscopy (fNIRS) to elucidate the neurovascular correlates of cognitive function in individuals with SCI. We observed significant differences between the SCI and AB groups on measures of executive function on the NUCOG test. On the N-back task, across the three levels of difficulty: 0-back, 2-back, and 3-back, no significant differences were observed between the SCI and AB group; however, both groups performed worse as the level of difficulty increased. Although there were no significant differences in N-back performance scores between the two groups, functional brain hemodynamic activity differences were observed between the SCI and AB groups, with the SCI group exhibiting higher maximum oxygenated hemoglobin concentration in the right inferior parietal lobe. These findings support the use of fNIRS to study cognitive function in individuals with SCI and may provide a useful tool during rehabilitation to obtain quantitative functional brain activity metrics.

Switchable deep eutectic solvent as green and efficient media for liquid-phase microextraction of phenoxyacetic acid herbicides in water and food matrices.

In this work, a switchable deep eutectic solvent (SDES) based on fatty acid and polyetheramine ion pair was prepared for liquid-phase microextraction (LPME) of phenoxyacetic acid herbicides in drinking water, beverage and honey matrices. The as-synthesized SDES equipped with an interesting characteristic of fast and reversible polarity switching, achieving homogeneous extraction and rapid bi-phase separation simultaneously. Several key parameters affecting the extraction performance were investigated comprehensively by Box-Behnken design. Under the optimal conditions, the method exhibited excellent linearity (15-4000 µg L-1), low detection limits (3-5 µg L-1), desirable precision (RSD < 8.1 %), and satisfactory recovery (72.6-98.7 %). More importantly, the introduction of SDES can simplify the pre-treatment procedure, shorten extraction time (4 min), and avoid the usage of traditional organic solvent during the whole extraction process. In addition, the switching mechanism of SDES was characterized by FT-IR and 1H NMR, and the forming mechanism of SDES was investigated using density-functional theory. The green of the method was estimated using the analytical ecological scale, the analytical green calculator, and the green analytical procedure index. The cytotoxicity of SDES was investigated and the result displayed that toxicity of the SDES was very low with the EC50 > 500 mg/L. Therefore, the proposed method was green and efficient and revealed considerable application prospects for the extraction of trace analytes from complex materials.

The significance and limited influence of cerebrovascular reactivity on age and sex effects in task- and resting-state brain activity.

Functional MRI measures the blood-oxygen-level dependent signals, which provide an indirect measure of neural activity mediated by neurovascular responses. Cerebrovascular reactivity affects both task-induced and resting-state blood-oxygen-level dependent activity and may confound inter-individual effects, such as those related to aging and biological sex. We examined a large dataset containing breath-holding, checkerboard, and resting-state tasks. We used the breath-holding task to measure cerebrovascular reactivity, used the checkerboard task to obtain task-based activations, and quantified resting-state activity with amplitude of low-frequency fluctuations and regional homogeneity. We hypothesized that cerebrovascular reactivity would be correlated with blood-oxygen-level dependent measures and that accounting for these correlations would result in better estimates of age and sex effects. We found that cerebrovascular reactivity was correlated with checkerboard task activations in the visual cortex and with amplitude of low-frequency fluctuations and regional homogeneity in widespread fronto-parietal regions, as well as regions with large vessels. We also found significant age and sex effects in cerebrovascular reactivity, some of which overlapped with those observed in amplitude of low-frequency fluctuations and regional homogeneity. However, correcting for the effects of cerebrovascular reactivity had very limited influence on the estimates of age and sex. Our results highlight the limitations of accounting for cerebrovascular reactivity with the current breath-holding task.

Cerebrovascular reactivity increases across development in multiple networks as revealed by a breath-holding task: A longitudinal fMRI study.

Functional magnetic resonance imaging (fMRI) has been widely used to understand the neurodevelopmental changes that occur in cognition and behavior across childhood. The blood-oxygen-level-dependent (BOLD) signal obtained from fMRI is understood to be comprised of both neuronal and vascular information. However, it is unclear whether the vascular response is altered across age in studies investigating development in children. Since the breath-hold (BH) task is commonly used to understand cerebrovascular reactivity (CVR) in fMRI studies, it can be used to account for developmental differences in vascular response. This study examines how the cerebrovascular response changes over age in a longitudinal children's BH data set from the Nathan Kline Institute (NKI) Rockland Sample (aged 6-18 years old at enrollment). A general linear model approach was applied to derive CVR from BH data. To model both the longitudinal and cross-sectional effects of age on BH response, we used mixed-effects modeling with the following terms: linear, quadratic, logarithmic, and quadratic-logarithmic, to find the best-fitting model. We observed increased BH BOLD signals in multiple networks across age, in which linear and logarithmic mixed-effects models provided the best fit with the lowest Akaike information criterion scores. This shows that the cerebrovascular response increases across development in a brain network-specific manner. Therefore, fMRI studies investigating the developmental period should account for cerebrovascular changes that occur with age.

A systematic review of the role of chemotherapy in retroperitoneal sarcoma by the Australia and New Zealand sarcoma association clinical practice guidelines working party.

BACKGROUND: In primary localised resectable retroperitoneal sarcoma (RPS), loco-regional and distant relapse occur frequently despite optimal surgical management. The role of chemotherapy in improving outcomes is unclear. METHODS: A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether neoadjuvant or adjuvant chemotherapy improve outcomes in adults with primary localised resectable RPS. Medline, Embase and Cochrane Central were queried for publications from 1946 to June 2022 that evaluated recurrence free survival, overall survival, and post operative complications. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed. RESULTS: Twenty three studies were identified; one meta-analysis of retrospective studies and 22 retrospective studies including three with propensity matched cohorts. Most studies did not analyse outcomes by histology, detail treatment regimens, provide baseline characteristics or selection criteria for those receiving chemotherapy. Evidence of selection bias was illustrated in several studies. Newcastle-Ottawa quality of retrospective cohort studies was good for 12 studies and poor for 10 studies. All studies were assessed as Level III-2 evidence by the Australian NHMRC hierarchy. Overall, the addition of neoadjuvant or adjuvant chemotherapy to surgery was not associated with improvement in local recurrence, metastasis free survival, disease free survival or overall survival in primary localised resectable RPS. There is some evidence of an association of chemotherapy with worse overall survival. One single centre study showed that neoadjuvant chemotherapy was not associated with increased post operative complications compared to surgery alone in primary localised resectable RPS. CONCLUSIONS: There is currently no evidence that demonstrates the addition of chemotherapy to surgery improves outcomes in adult patients with primary localised resectable RPS. Available evidence is limited by its retrospective nature and high likelihood of selection bias with chemotherapy generally administered to patients at higher risk of recurrence and many patients not receiving care in high volume sarcoma centres. Randomised trials are required to conclusively determine the role of chemotherapy in primary localised resectable RPS.

Systematic screening of hepatoprotective components from traditional Chinese medicine: Zuojin Pill as an example.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP), composed of Coptis chinensis Franch. and Euodia ruticarpa (A. Juss.) Benth. in a mass ratio of 6:1, is a famous traditional Chinese medicine (TCM) formula recorded in "Danxi's Experiential Therapy", an ancient medical book from the Ming Dynasty of China. It is used to treat liver fire invading the stomach, which is caused by liver stagnation transforming into fire and disharmony between the liver and stomach. AIM OF THE STUDY: To develop a systematic strategy to screen hepatoprotective components from TCM using ZJP as a model sample. MATERIALS AND METHODS: A CCl4-induced mouse model of acute liver injury was used for the verification of the hepatoprotective effects of ZJP. UPLC-Q-Exactive Plus Orbitrap MS/MS was used for the identification of the components in mouse serum after intragastric administration of ZJP. The hepatoprotective activities of the components found in mouse serum were tested in primary cultured mouse hepatocytes induced by CCl4. RESULTS: Nine components with significant hepatoprotective activity including berberine, epiberberine, coptisine, palmatine, jatrorrhizine, rutaecarpin, dehydroevodiamine, evocarpine and chlorogenic acid were successfully screened out. CONCLUSIONS: Our developed strategy has the advantages of high efficiency and low cost, and would provide a powerful tool for screening potential hepatoprotective components from TCM.

Comprehensive Stereoselectivity Assessment of Toxicokinetics, Tissue Distribution, Cytotoxicity, and Environmental Fate of Chiral Pesticide Propiconazole.

Propiconazole (PRO) has been widely used in the treatment of fungal infection in fruits, vegetables, cereals, and seeds. In this study, a newly established chiral liquid chromatography tandem mass spectrometry method was applied to the systemic stereoselectivity evaluation of PRO enantiomers, including toxicokinetics, tissue distributions, cytotoxicity, accumulation, and degradation. Our results showed that both trans (+)-2S,4S-PRO and cis (-)-2S,4R-PRO had lower Cmax and AUC0-∞ and higher CLz/F values in plasma and lower accumulation concentrations in the liver, heart, and brain. In cytotoxic assays, cis (-)-2S,4R-PRO exhibited the lowest cytotoxicity in PC12 neuronal, N9 microglia, SH-SY5Y neuroblastoma, and MRC5 lung fibroblast cell lines. Moreover, the Eisenia fetida incubation experiment revealed that the accumulations of both trans (+)-2S,4S-PRO and cis (-)-2S,4R-PRO were higher than those of their antipodes in E. fetida. In summary, our findings first suggested that the application of cis (-)-2S,4R-PRO for agriculture would hugely reduce the environmental risk.